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Editor's Choice – European Society for Vascular Surgery (ESVS) 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis

  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    ,
    Author Footnotes
    † These authors contributed equally.
    Stavros K. Kakkos
    Correspondence
    Corresponding author.
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    † These authors contributed equally.
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    ,
    Author Footnotes
    † These authors contributed equally.
    Manjit Gohel
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    † These authors contributed equally.
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Niels Baekgaard
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Rupert Bauersachs
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Sergi Bellmunt-Montoya
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Stephen A. Black
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Arina J. ten Cate-Hoek
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Ismail Elalamy
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Florian K. Enzmann
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    George Geroulakos
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Anders Gottsäter
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Beverley J. Hunt
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Armando Mansilha
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Andrew N. Nicolaides
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Per Morten Sandset
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    Gerard Stansby
    Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
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  • Author Footnotes
    b ESVS Guidelines Committee: Gert J. de Borst (chair; Utrecht, The Netherlands), Frederico Bastos Gonçalves (Lisbon, Portugal), Nabil Chakfé (Strasbourg, France), Robert Hinchliffe (Bristol, UK), Philippe Kolh (Liege, Belgium), Igor Koncar (Belgrade, Serbia), Jes S. Lindholt (Odense, Denmark), Riikka Tulamo (Helsinki, Finland), Christopher P. Twine (Bristol, UK), Frank Vermassen (Ghent, Belgium), and Anders Wanhainen (Uppsala, Sweden).
    ESVS Guidelines Committee
    Footnotes
    b ESVS Guidelines Committee: Gert J. de Borst (chair; Utrecht, The Netherlands), Frederico Bastos Gonçalves (Lisbon, Portugal), Nabil Chakfé (Strasbourg, France), Robert Hinchliffe (Bristol, UK), Philippe Kolh (Liege, Belgium), Igor Koncar (Belgrade, Serbia), Jes S. Lindholt (Odense, Denmark), Riikka Tulamo (Helsinki, Finland), Christopher P. Twine (Bristol, UK), Frank Vermassen (Ghent, Belgium), and Anders Wanhainen (Uppsala, Sweden).
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  • Gert J. de Borst
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  • Frederico Bastos Gonçalves
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  • Nabil Chakfé
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  • Robert Hinchliffe
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  • Philippe Kolh
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  • Igor Koncar
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  • Jes S. Lindholt
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  • Riikka Tulamo
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  • Christopher P. Twine
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  • Author Footnotes
    c Document reviewers: Marianne G. De Maeseneer (Rotterdam, The Netherlands), Anthony J. Comerota (Alexandria, VA, USA), Peter Gloviczki (Rochester, MN, USA); Marieke J.H.A. Kruip (Rotterdam, The Netherlands); Manuel Monreal (Badalona and Murcia, Spain); Paolo Prandoni (Bologna, Italy), Melina Vega de Ceniga (Galdakao and Barakaldo, Spain).
    Document reviewers
    Footnotes
    c Document reviewers: Marianne G. De Maeseneer (Rotterdam, The Netherlands), Anthony J. Comerota (Alexandria, VA, USA), Peter Gloviczki (Rochester, MN, USA); Marieke J.H.A. Kruip (Rotterdam, The Netherlands); Manuel Monreal (Badalona and Murcia, Spain); Paolo Prandoni (Bologna, Italy), Melina Vega de Ceniga (Galdakao and Barakaldo, Spain).
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  • Author Footnotes
    a Writing Committee: Stavros K. Kakkos (chair; Patras, Greece), Manjit Gohel (co-chair; Cambridge and London, UK), Niels Baekgaard (Copenhagen, Denmark), Rupert Bauersachs (Darmstadt, Germany), Sergi Bellmunt-Montoya (Barcelona, Spain), Stephen A. Black (London, UK), Arina J. ten Cate-Hoek (Maastricht, The Netherlands), Ismail Elalamy (Paris, France, and Moscow, Russia), Florian K. Enzmann (Salzburg, Austria), George Geroulakos (Athens, Greece), Anders Gottsäter (Malmö, Sweden), Beverley J. Hunt (London, UK), Armando Mansilha (Porto, Portugal), Andrew N. Nicolaides (London, UK, and Nicosia, Cyprus), Per M. Sandset (Oslo, Norway), and Gerard Stansby (Newcastle upon Tyne, UK).
    b ESVS Guidelines Committee: Gert J. de Borst (chair; Utrecht, The Netherlands), Frederico Bastos Gonçalves (Lisbon, Portugal), Nabil Chakfé (Strasbourg, France), Robert Hinchliffe (Bristol, UK), Philippe Kolh (Liege, Belgium), Igor Koncar (Belgrade, Serbia), Jes S. Lindholt (Odense, Denmark), Riikka Tulamo (Helsinki, Finland), Christopher P. Twine (Bristol, UK), Frank Vermassen (Ghent, Belgium), and Anders Wanhainen (Uppsala, Sweden).
    c Document reviewers: Marianne G. De Maeseneer (Rotterdam, The Netherlands), Anthony J. Comerota (Alexandria, VA, USA), Peter Gloviczki (Rochester, MN, USA); Marieke J.H.A. Kruip (Rotterdam, The Netherlands); Manuel Monreal (Badalona and Murcia, Spain); Paolo Prandoni (Bologna, Italy), Melina Vega de Ceniga (Galdakao and Barakaldo, Spain).
    † These authors contributed equally.
Open ArchivePublished:December 14, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.09.023

      List of abbreviations

      ACCP
      American College of Chest Physicians
      aHR
      adjusted hazard ratio
      APC
      activated protein C
      aPL
      antiphospholipid
      APS
      antiphospholipid syndrome
      APTT
      activated partial thromboplastin time
      AT
      antithrombin
      ATTRACT
      Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis
      AVF
      arteriovenous fistula
      BMI
      body mass index
      CAVA
      CAtheter Versus Anticoagulation Alone for Acute Primary Iliofemoral DVT
      CAVENT
      Catheter-Directed Venous Thrombolysis in Acute Iliofemoral Vein Thrombosis
      CAVT
      cancer associated venous thrombosis
      CDT
      catheter directed thrombolysis
      CI
      confidence interval
      CKD
      chronic kidney disease
      CT
      computed tomography
      CrCl
      creatinine clearance
      CRT
      catheter related thrombosis
      CTV
      computed tomography venography
      CUS
      compression ultrasound scanning
      CVC
      central venous catheter
      CXR
      chest X ray
      DACUS
      Duration of Anticoagulation based on Compression UltraSonography
      DASH
      Disabilities of the Arm, Shoulder and Hand
      DOAC
      direct oral anticoagulant
      DVT
      deep vein thrombosis
      ECG
      electrocardiogram
      ECS
      elastic compression stockings
      ESVS
      European Society for Vascular Surgery
      EU
      European Union
      GC
      Guidelines Committee
      GSV
      great saphenous vein
      GWC
      Guideline Writing Committee
      HIT
      heparin induced thrombocytopenia
      HR
      hazard ratio
      INR
      international normalised ratio
      IVC
      inferior vena cava
      IU
      international unit
      IV
      intravenous
      LMWH
      low molecular weight heparin
      MLB
      multilayer bandaging
      MRI
      magnetic resonance imaging
      MRV
      magnetic resonance venography
      NNT
      number needed to treat
      OR
      odds ratio
      PCC
      prothrombin complex concentrate
      PE
      pulmonary embolism
      PCDT
      pharmacomechanical catheter directed thrombolysis
      PF4
      platelet factor 4
      PNH
      paroxysmal nocturnal haemoglobinuria
      POST
      Prospective Observational Superficial Thrombophlebitis
      PTS
      post-thrombotic syndrome
      QoL
      quality of life
      RCT
      randomised controlled trial
      RR
      relative risk
      rtPA
      recombinant tissue plasminogen activator
      RVO
      residual venous obstruction
      SPC
      summary of product characteristics
      SSV
      small saphenous vein
      SVT
      superficial vein thrombosis
      TORPEDO
      Thrombus Obliteration by Rapid Percutaneous Endovenous Intervention in Deep Venous Occlusion
      UEDVT
      upper extremity deep vein thrombosis
      UFH
      unfractionated heparin
      VKA
      vitamin K antagonist
      VTE
      venous thromboembolism
      WLUS
      whole leg ultrasound
      Dedication
      These guidelines are dedicated to the memory of Dr Clive Kearon of McMaster University in Hamilton, Ontario, Canada. Dr Kearon extensively reviewed the first and second versions of the manuscript and he was always very punctual. In the first review round he submitted a review of 16 pages with many detailed and helpful comments. Unaware of his illness, we invited him to review the final version of the guidelines on June 2, 2020, but sadly he passed away one day later, on June 3, 2020. We will always remember Dr Kearon for his many contributions to the field of Thrombosis and Antithrombotic Treatment, including these guidelines.
      (picture reproduced with permission from Weitz JI & Bates SM. Obituary for Dr. Clive Kearon. J Thromb Haemost. 2020;18:2783–2784).

      1. General aspects

      1.1 Purpose and methods of these guidelines

      The European Society for Vascular Surgery (ESVS) has developed a series of clinical practice guidelines for the care of patients with vascular diseases. Their aim is to assist clinicians in selecting the best management strategies to achieve optimal patient outcomes.
      These are the first ESVS guidelines on venous thrombosis. In 2017, the ESVS Guidelines Committee (GC), initiated a process to develop these guidelines. The present guideline document addresses acute deep vein thrombosis (DVT) of the lower extremity (unless otherwise stated), upper extremity DVT (UEDVT), superficial vein thrombosis (SVT), and thrombosis in unusual sites. The guideline document also covers topics in addition to treatments, including investigations and health economics, and includes special patient populations. The topic of venous thrombosis is large and therefore the remit of the guideline has been limited to conditions and situations likely to be commonly encountered by clinical teams/end users managing patients with venous thrombosis and others exposed to this condition. Furtheremore, all recent ESVS guidelines have considered the patient’s perspective.
      • Björck M.
      • Earnshaw J.J.
      • Acosta S.
      • Bastos Gonçalves F.
      • Cochennec F.
      • Debus E.S.
      • et al.
      Editor's Choice – European Society for Vascular Surgery (ESVS) 2020 Clinical Practice Guidelines on the Management of Acute Limb Ischaemia.
      ,
      • Wanhainen A.
      • Verzini F.
      • Van Herzeele I.
      • Allaire E.
      • Bown M.
      • Cohnert T.
      • et al.
      Editor's Choice – European Society for Vascular Surgery (ESVS) 2019 Clinical Practice Guidelines on the Management of Abdominal Aorto-iliac Artery Aneurysms.
      This guideline document was written and approved by the 16 members of the Guideline Writing Committee (GWC). The GWC consisted mainly of ESVS members, and also eminent thrombosis experts from other societies with relevant clinical experience, strong publication records, and academic profiles. The recommendations in this guideline have been formulated by evaluation of the available scientific evidence, with expert opinion to create pragmatic guidance for patient management.
      The recommendations represent the best available knowledge at the time of publication. However, as technology, available evidence, and disease knowledge may evolve rapidly, recommendations can become outdated. It is the aim of the ESVS to update the guidelines when important new insights into the evaluation and management of venous thrombosis become available.
      Although guidelines have the purpose of promoting best practice according to specialists in the field, this guideline document should not be seen as the legal standard of care for all patients with venous thrombosis. The document provides guiding principles and pragmatic recommendations to aid clinical decision making. However, the care given to an individual patient may be dependent on many factors, including symptoms, comorbidities, age, level of activity, treatment setting, available techniques, local expertise, and other considerations.

      1.2 Methodology

      Members of this GWC were selected by the two chairs and approved by the ESVS GC to represent physicians involved in the management of patients with venous thrombosis. The members of the GWC have provided disclosure statements stating all relationships that might be perceived as potential conflicts of interest. These disclosure forms are kept on file at the ESVS headquarters. The ESVS GC was responsible for the overall process of endorsing this guideline. All expert members involved in the GWC have contributed to and approved the final document. The guideline document underwent a formal external expert peer review process, and, additionally, was reviewed and approved by the ESVS GC and by the editors of the European Journal of Vascular and Endovascular Surgery. This document was reviewed over three rounds by 18 reviewers, including 11 members of GC (with a review coordinator) and seven external reviewers from Europe and the USA. All reviewers assessed all versions and approved the final version of this document.

      1.3 Strategy for creating guidelines

      The first GWC meeting was held in May 2018, in Brussels. The table of contents and overall structure of the guideline document was discussed and agreed. Tasks and activities required to create the guideline were evaluated and distributed between GWC members. Contributions from GWC members were compiled into a draft guideline by the co-chairs. At a second meeting, held in Frankfurt in February 2019, the wording/grading of each suggested recommendation was reviewed. If unanimous agreement was not present, reasons for disagreement were discussed and the wording, grade, and level of evidence were amended to try and reach a consensus. If this failed, then the wording, grade, and level of evidence was secured via a majority vote of GWC members. The final version of the guideline was accepted on August 2020. In response to changes in the available evidence and knowledge, it is intended that these guidelines will be updated periodically.

      1.4 Literature search and selection

      Members of the committee, supported by clinical librarians if necessary, performed a literature search for this guideline in MEDLINE (through PubMed), Embase, and clinical trial databases, and the Cochrane Library up to 31 March 2018. Reference checking and hand searches by individual GWC members added other relevant evidence and literature. Additional relevant references were considered and included as GWC members became aware of them. A second formal literature search for papers published between April 2018 and August 2019 was performed in August 2019. Members of the GWC performed the literature selection based on the information provided in the title and abstract of the retrieved studies.
      Criteria for search and selection were (1) English language; (2) level of evidence: when considering which published evidence to include, the literature was considered following the accepted hierarchy of evidence, with priority given to aggregated evidence (meta-analyses), followed by randomised controlled trials (RCTs), then observational studies (the level of available evidence for each section was used to guide the class of each recommendation in the guideline); (3) sample size: larger studies were given more weight than smaller studies; and (4) relevant articles published after the final literature search (August 2019) or in another language were included, but only if they were considered to be of paramount importance to this guideline.

      1.5 Weighing the evidence

      To define the current guidelines, members of the GWC reviewed and summarised the relevant peer reviewed published literature. Conclusions were drawn based on the available scientific evidence. In keeping with other published ESVS guidelines, the clinical practice recommendations in this document are presented using the European Society of Cardiology grading system. For each recommendation, the letter A, B, or C indicates the level of current evidence guiding the recommendation (Table 1).
      Table 1Levels of evidence
      Level of evidence AData derived from multiple randomised clinical trials or meta-analyses
      Level of evidence BData derived from a single randomised clinical trial or large non-randomised studies
      Level of evidence CConsensus of experts opinion and/or small studies, retrospective studies, and registries
      Depending on whether the recommendation is strongly supportive of an intervention, weakly supportive, or strongly against an intervention, each recommendation is categorised as either Class I, IIa/IIb, and III, respectively (Table 2). The lower the class number, the greater the evidence and/or general agreement in favour of an intervention.
      Table 2Classes of recommendations
      Class of recommendationDefinition
      Class IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, and effective
      Class IIConflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure
      Class IIaWeight of evidence/opinion is in favour of usefulness/efficacy
      Class IIbUsefulness/efficacy is less well established by evidence/opinion
      Class IIIEvidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful

      1.6 The patient's perspective

      The importance of patient and public involvement in clinical guideline development is widely recognised and accepted. Patient and public engagement improves validity, increases quality of decisions, and is encouraged by national and international societies.
      In order to improve accessibility and interpretability for patients and the public, a plain English summary was produced for this guideline and subjected to a lay review process. Information for patients was drafted for each subchapter which was read and amended by a vascular nurse specialist and one lay person.
      Lay summaries were evaluated by eight patients with a history of venous thrombosis in the UK National Health Service and four lay members of the public without venous thrombosis. For all patients and members of the public asked to scrutinise the lay summary, the background and rationale for the ESVS venous thrombosis guidelines was explained. Honest feedback was encouraged on any aspect of the summary. The feedback was collated, and several themes were identified. Firstly, both patients and lay members of the public recognised the importance of venous thrombosis and welcomed the engagement. Several respondents commented that other conditions seemed to get much more public attention than venous thrombosis. All respondents acknowledged the importance of anticoagulant medication and appreciated that significant advances had been made with the widespread use of direct oral anticoagulants (DOACs).
      Most feedback related to the use of interventions to reduce long term sequelae of venous thrombosis, particularly compression and early thrombus removal strategies for upper and lower extremity DVT. All respondents offered positive feedback about compression therapy, with the majority of patients with a history of venous thrombosis stating that this was not offered to them at the time of the initial presentation. They appreciated that the recommendations were based on the latest published evidence but expressed that even if the benefit was uncertain or modest, it should be discussed with future patients. Clinical teams managing patients with venous thrombosis should consider this feedback and ensure that potential interventions are discussed with patients and the rationale for offering or not offering early thrombus removal is clearly explained to the patient. Feedback from the focus group was used to amend and improve the clarity of the lay summaries.

      2. Lower extremity venous thrombosis

      2.1 Introduction

      2.1.1 Epidemiology and burden of the disease

      The annual incidence of first episode of symptomatic DVT in the adult population ranges from 50 to 100 per 100 000 population, with the overall incidence of venous thromboembolism (VTE) around 25% higher with the addition of pulmonary embolism (PE) events.
      • Heit J.A.
      • Spencer F.A.
      • White R.H.
      The epidemiology of venous thromboembolism.
      ,
      • Spencer F.A.
      • Emery C.
      • Joffe S.W.
      • Pacifico L.
      • Lessard D.
      • Reed G.
      • et al.
      Incidence rates, clinical profile, and outcomes of patients with venous thromboembolism. The Worcester VTE study.
      Published epidemiology studies are either retrospective, using national or regional patient cohorts studied over several years, or prospective ultrasound based studies performed over 1 – 2 years.
      • Baekgaard N.
      Incidence and location of deep vein thrombosis in the lower extremities: what do we know?.
      The incidence of DVT is slightly greater in women aged 20 – 45 years, but men have a higher incidence between 45 and 60 years of age.
      • Heit J.A.
      • Spencer F.A.
      • White R.H.
      The epidemiology of venous thromboembolism.
      ,
      • Silverstein M.D.
      • Heit J.A.
      • Mohr D.N.
      • Petterson T.M.
      • O'Fallon W.M.
      • Melton III, L.J.
      Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study.
      The incidence is higher for males for all age groups if female specific risk factors (oral contraceptives and pregnancy) are excluded.
      • Roach R.E.
      • Cannegieter S.C.
      • Lijfering W.M.
      Differential risks in men and women for first and recurrent venous thrombosis: the role of genes and environment.
      The incidence increases twofold per 10 year age increase. At least one in 12 middle aged adults will develop either DVT and/or PE in their remaining lifetime and 60% of all VTE events occur in patients aged > 65 years.
      • Heit J.A.
      • Spencer F.A.
      • White R.H.
      The epidemiology of venous thromboembolism.
      ,
      • Bell E.J.
      • Lutsey P.L.
      • Basu S.
      • Cushman M.
      • Heckbert S.R.
      • Lloyd-Jones D.M.
      • et al.
      Lifetime risk of venous thromboembolism in two cohort studies.
      African Americans have a higher incidence of DVT than Caucasians and Native Americans, whereas Asians (China and Korea) have a lower incidence. A seasonal variation occurs, with a higher incidence of VTE in the winter, peaking in February.
      • Dentali F.
      • Ageno W.
      • Rancan E.
      • Donati A.V.
      • Galli L.
      • Squizzato A.
      • et al.
      Seasonal and monthly variability in the incidence of venous thromboembolism. A systematic review and a meta-analysis of the literature.
      The rate of recurrent VTE is around 10% the first year and 30% after 5 – 8 years for patients with unprovoked DVT with an unidentified triggering factor (see also Table 13, Table 14).
      • Khan F.
      • Rahman A.
      • Carrier M.
      • Kearon C.
      • Weitz J.I.
      • Schulman S.
      • et al.
      Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis.
      The annual incidence of VTE has not changed in the last two to three decades, although the prevalence of cancer, major surgery, trauma, and obesity has increased, and the widespread availability of improved diagnostic modalities with computed tomography (CT) and magnetic resonance imaging (MRI) leading to increased detection of incidental VTE in patients with cancer.
      • Heit J.A.
      • Ashrani A.
      • Crusan D.J.
      • McBane R.D.
      • Petterson T.M.
      • Bailey K.R.
      Reasons for the persistent incidence of venous thromboembolism.

      2.1.2 Risk factors

      DVT is considered unprovoked if no clear precipitating risk factor can be identified. Risk factors are either hereditary or more often acquired. For provoked DVT, risk factors include cancer, acute medical illness, surgery, trauma, immobility (often in hospital and lasting at least three days), obesity, inflammatory diseases/infection, hormone therapy (oestrogen containing), pregnancy (particularly the postpartum period), long distance travel, recent hospitalisation, and antiphospholipid syndrome (APS). Primary varicose veins constitute a minor risk factor only. More recently, prolonged computer related “seated immobility syndrome” has also been recognised as a potential risk factor.
      • Braithwaite I.
      • Healy B.
      • Cameron L.
      • Weatherall M.
      • Beasley R.
      Venous thromboembolism risk associated with protracted work- and computer-related seated immobility: a case–control study.
      The most common inherited risk factor is a non-O blood type, which is associated with double the risk of VTE.
      • Franchini M.
      • Mannucci P.M.
      ABO blood group and thrombotic vascular disease.
      Another common thrombophilia is heterozygous factor V Leiden gene polymorphism, which may increase the risk of VTE by a factor of 3 – 8 in selected populations. Severe thrombophilia comprising homozygous factor V Leiden, deficiency of antithrombin, protein C or protein S, and APS increases the risk of DVT by a factor of 20 – 80.
      • Olaf M.
      • Cooney R.
      Deep venous thrombosis.
      Important risk factors for arterial thromboembolism such as hypertension and diabetes are also risk factors for VTE, but their significance is far less prominent.
      • Gaertner S.
      • Cordeanu E.M.
      • Mirea C.
      • Frantz A.S.
      • Auger C.
      • Bilbault P.
      • et al.
      Increased risk and severity of unprovoked venous thromboembolism with clustering cardiovascular risk factors for atherosclerosis: results of the REMOTEV registry.
      For patients with cancer, an externally validated clinical prediction model incorporating D dimer and only one clinical factor (tumour site category) has been shown to predict the risk of VTE.
      • Pabinger I.
      • van Es N.
      • Heinze G.
      • Posch F.
      • Riedl J.
      • Reitter E.M.
      • et al.
      A clinical prediction model for cancer-associated venous thromboembolism: a development and validation study in two independent prospective cohorts.

      2.1.3 Pathophysiology of deep vein thrombosis

      The precise cause of DVT is likely to vary from patient to patient, but the main pathophysiological factors implicated in thrombosis are considered to be increased procoagulant activity in the blood, vein wall damage, and impaired venous flow (Virchow’s triad). Impaired flow, known also as venous stasis, may result from external compression by aneurysms, tumours, or the right common ilac artery, which compresses and causes fibrosis of the underlying left common iliac vein in May–Thurner syndrome (iliac vein compression syndrome). The thrombotic process leads to increased outflow resistance and decreased outflow volume with increased venous pressure, which, together with perivascular inflammation, is responsible for the characteristic symptoms and signs of DVT. Patients suffer swelling, pain, and tenderness, usually in the calf, but symptoms may also involve the thigh in the case of iliofemoral DVT. The symptoms typically diminish as the inflammatory reaction decreases and usually disappear if the veins can recanalise fully without structural damage to the vein wall or damaged valves. The recanalisation rate is around 80% in calf veins but only 20% in the iliac segments. Prolonged venous obstruction may result in chronic venous outflow obstruction and secondary venous valve damage, causing reflux after recanalisation. Venous obstruction, reflux, or a combination may lead to the development of post-thrombotic syndrome (PTS).
      • Lee B.B.
      • Nicolaides A.N.
      • Myers K.
      • Meissner M.
      • Kalodiki E.
      • Allegra C.
      • et al.
      Venous hemodynamic changes in lower limb venous disease: the UIP consensus according to scientific evidence.
      The first signs of PTS usually develop within three months of the onset of DVT, and PTS symptoms and signs may progress and deteriorate for years.
      • Kahn S.R.
      • Comerota A.J.
      • Cushman M.
      • Evans N.S.
      • Ginsberg J.S.
      • Goldenberg N.A.
      • et al.
      The postthrombotic syndrome: evidence-based prevention, diagnosis, and treatment strategies: a scientific statement from the American Heart Association.
      The most extreme clinical presentation of DVT may occur when there is occlusion of the common femoral and external iliac veins, completely obstructing the outflow of all deep and superficial veins of the limb, as well as collaterals, and is termed phlegmasia cerulea dolens (see Chapter 2.10). Anticoagulation therapy is used to reduce the risk of PE and prevent the progression of DVT. However, resolution of thrombus is dependent on the endogenous fibrinolytic activity in the affected veins.

      2.1.4 Clinical manifestations of deep vein thrombosis

      Symptoms and signs are generally more severe as the thrombosis extends more proximally, reflecting the greater degree of outflow obstruction and haemodynamic disturbance. Among the three anatomical types of DVT, i.e., iliofemoral, femoropopliteal, and calf DVT (see Chapter 2.2.2.1), iliofemoral DVT tends to be associated with the most severe symptoms. Symptoms from calf DVT may vary, and even be asymptomatic, depending on the collateral drainage. It should be noted that up to 80% of DVT cases may not be clinically apparent, with pain being the only feature. In DVT cases located at iliofemoral level the leg is usually considerably swollen and painful, with decreased mobility and oedema from the groin and distally due to limited venous collateral drainage in the pelvic region. Prominent superficial veins may be seen. For DVT originating in the iliac veins, back pain may be an early feature. Several lower extremity disorders may mimic DVT. These include lymphoedema, SVT, PTS, cellulitis, ruptured Baker cyst, and trauma.
      • Meissner M.H.
      The clinical presentation and natural history of acute deep venous thrombosis.
      Isolated calf DVT is seen in approximately 30% and thrombosis involving the iliofemoral segment accounts for around 30%.
      • Partsch H.
      Therapy of deep vein thrombosis with low molecular weight heparin, leg compression and immediate ambulation.
      ,
      • De Maeseneer M.G.
      • Bochanen N.
      • van Rooijen G.
      • Neglen P.
      Analysis of 1,338 patients with acute lower limb deep venous thrombosis (DVT) supports the inadequacy of the term "proximal DVT".
      Iliofemoral DVT is more commonly left sided, probably owing to the frequent compression of the left common iliac vein by the overriding right common iliac artery.
      • De Maeseneer M.G.
      • Bochanen N.
      • van Rooijen G.
      • Neglen P.
      Analysis of 1,338 patients with acute lower limb deep venous thrombosis (DVT) supports the inadequacy of the term "proximal DVT".

      2.1.5 Health economics of deep vein thrombosis

      The financial burden of DVT and PE is substantial owing to the treatment costs related to DVT (inpatient or outpatient treatment, re-admission/recurrence) or PE (additional costs for re-admission/recurrence), costs related to complications of treatment, including bleeding and heparin induced thrombocytopenia (HIT), and costs related to long term complications, including PTS and chronic thromboembolic pulmonary hypertension.
      • Barco S.
      • Woersching A.L.
      • Spyropoulos A.C.
      • Piovella F.
      • Mahan C.E.
      European Union-28: an annualised cost-of-illness model for venous thromboembolism.
      A health economic modelling study using 2014 values estimated that annual total costs may range from €1.5 to €13.2 billion for the 28 member states of the European Union (EU).
      • Barco S.
      • Woersching A.L.
      • Spyropoulos A.C.
      • Piovella F.
      • Mahan C.E.
      European Union-28: an annualised cost-of-illness model for venous thromboembolism.
      The same study estimated that preventable costs may range from €0.5 to €7.3 billion, implying that better prophylaxis, optimisation of outpatient treatment, and earlier hospital discharge of patients with PE and DVT may result in cost savings. Another recent review investigated the economic burden of VTE healthcare costs in the USA.
      • Grosse S.D.
      • Nelson R.E.
      • Nyarko K.A.
      • Richardson L.C.
      • Raskob G.E.
      The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs.
      For 375 000 – 425 000 newly diagnosed VTE events per annum in the USA, a conservative cost estimate for medical treatment to the healthcare system was $7 – $10 billion each year, a much higher cost than for the EU.
      • Grosse S.D.
      • Nelson R.E.
      • Nyarko K.A.
      • Richardson L.C.
      • Raskob G.E.
      The economic burden of incident venous thromboembolism in the United States: a review of estimated attributable healthcare costs.

      2.2 Diagnosis and investigation

      2.2.1 Diagnosis of deep vein thrombosis and imaging strategies

      2.2.1.1 Clinical assessment and pre-test probability score

      Several clinical features are known to be suggestive of DVT. These comprise symptoms, signs, and other clinical risk factors. Although useful to raise the clinical suspicion of DVT, these factors cannot be used individually to confirm or exclude the diagnosis. However, when incorporated in decision tools, an individualised pre-test probability of DVT can be assigned to patients, aiding decision making strategies.
      • Goodacre S.
      • Sampson F.
      • Stevenson M.
      • Wailoo A.
      • Sutton A.
      • Thomas S.
      • et al.
      Measurement of the clinical and cost-effectiveness of non-invasive diagnostic testing strategies for deep vein thrombosis.
      ,
      • Stevens S.M.
      • Ageno W.
      Review: the Wells rule is more useful than individual clinical features for predicting risk of deep venous thrombosis.
      The most thoroughly studied and validated clinical decision score is the Wells DVT score (Table 3), which categorises the pre-test probability scores of DVT into two (DVT likely if score ≥ 2 or unlikely if score < 2) or three groups (high likelihood of DVT if ≥ 3; moderate likelihood if 1 – 2; low likelihood if ≤ 0).
      • Wells P.S.
      • Owen C.
      • Doucette S.
      • Fergusson D.
      • Tran H.
      Does this patient have deep vein thrombosis?.
      The dichotomised Wells score is simpler and more widely used than the Wells three category version and significant advantages to stratification into three groups have not been demonstrated. Although the Wells DVT score is useful, the probability of DVT in the low risk group has been reported to be as high as 5%.
      • Stevens S.M.
      • Ageno W.
      Review: the Wells rule is more useful than individual clinical features for predicting risk of deep venous thrombosis.
      With this risk of a false negative result, the score cannot be used as a standalone test to confirm or exclude DVT. However, when used in conjunction with additional investigations, namely D dimer measurements and/or ultrasound, it is a valuable tool for accurate decision making.
      • Geersing G.J.
      • Zuithoff N.P.
      • Kearon C.
      • Anderson D.R.
      • Ten Cate-Hoek A.J.
      • Elf J.L.
      • et al.
      Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.
      Table 3Wells score for the prediction of lower extremity deep vein thrombosis
      • Wells P.S.
      • Owen C.
      • Doucette S.
      • Fergusson D.
      • Tran H.
      Does this patient have deep vein thrombosis?.
      Clinical characteristicScore
      Active cancer (patient either receiving treatment for cancer within the previous six months or currently receiving palliative treatment)1
      Paralysis, paresis, or recent cast immobilisation of the lower extremities1
      Recently bedridden for ≥3 days, or major surgery within the previous 12 weeks requiring general or regional anaesthesia1
      Localised tenderness along the distribution of the deep venous system1
      Entire leg swelling1
      Calf swelling at least 3 cm larger than on the asymptomatic side (measured 10 cm below tibial tuberosity)1
      Pitting oedema confined to the symptomatic leg1
      Unilateral collateral superficial veins (non-varicose)1
      Previously documented deep vein thrombosis1
      Alternative diagnosis at least as likely as deep vein thrombosis–2
      Total
      Wells scoring system: –2 to 1 = deep vein thrombosis is unlikely; 2 to 8 = deep vein thrombosis likely. Or, probability for deep vein thrombosis: –2 to 0 = low; 1 to 2 = moderate; 3 to 8 = high.
      Wells scoring system: –2 to 1 = deep vein thrombosis is unlikely; 2 to 8 = deep vein thrombosis likely. Or, probability for deep vein thrombosis: –2 to 0 = low; 1 to 2 = moderate; 3 to 8 = high.

      2.2.1.2 D dimer measurement

      D dimers are fibrin degradation products and are increased in any condition with increased fibrin formation, such as venous thrombosis. The sensitivity of the most commonly used quantitative assay is approximately 95%, with a negative predictive value of 99% – 100%.
      • Stein P.D.
      • Hull R.D.
      • Patel K.C.
      • Olson R.E.
      • Ghali W.A.
      • Brant R.
      • et al.
      D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.
      False negatives can still occur, particularly in patients treated with anticoagulants, with calf DVT or with symptoms lasting for longer than two to three weeks.
      • Bernardi E.
      • Camporese G.
      Diagnosis of deep-vein thrombosis.
      D dimer testing is limited by its low specificity (35% – 55%),
      • Stein P.D.
      • Hull R.D.
      • Patel K.C.
      • Olson R.E.
      • Ghali W.A.
      • Brant R.
      • et al.
      D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review.
      and false positives are common as numerous other conditions yield increased D dimer levels, including infection, cancer, and pregnancy. Older age is also associated with higher baseline D dimer concentrations and although age adjusted cutoffs have been introduced, the specificity remains low (51.1%).
      • Parry B.A.
      • Chang A.M.
      • Schellong S.M.
      • House S.L.
      • Fermann G.J.
      • Deadmon E.K.
      International, multicenter evaluation of a new D-dimer assay for the exclusion of venous thromboembolism using standard and age-adjusted cut-offs.

      2.2.1.3 Ultrasound

      Two distinct ultrasound assessment approaches are practised to investigate for DVT in symptomatic patients: two or three point compression ultrasound scanning (CUS) and whole leg ultrasound scanning (WLUS). In CUS, deep vein patency is only assessed in two or three venous territories (usually the common femoral vein, the popliteal vein ± the femoral vein). Although the most proximal segments of the tibial veins can be interrogated during popliteal assessment, isolated calf DVT is not excluded by this technique. However, WLUS provides a more extensive examination, where the entire deep vein network of the leg is scanned from the common femoral vein to the distal veins.
      • Bernardi E.
      • Camporese G.
      Diagnosis of deep-vein thrombosis.
      ,
      • Needleman L.
      • Cronan J.J.
      • Lilly M.P.
      • Merli G.J.
      • Adhikari S.
      • Hertzberg B.S.
      • et al.
      Ultrasound for lower extremity deep venous thrombosis: multidisciplinary recommendations from the Society of Radiologists in Ultrasound Consensus Conference.
      Although both CUS and WLUS are safe to exclude suspected symptomatic DVT,
      • Gibson N.S.
      • Schellong S.M.
      • Kheir D.Y.
      • Beyer-Westendorf J.
      • Gallus A.S.
      • McRae S.
      • et al.
      Safety and sensitivity of two ultrasound strategies in patients with clinically suspected deep venous thrombosis: a prospective management study.
      each approach has different advantages and limitations, and their applicability varies accordingly. CUS is quicker, simpler, has better reproducibility, and is readily available as comprehensive venous ultrasound skills are not needed. However, as it cannot detect distal (calf) DVT, a negative CUS examination alone cannot exclude calf DVT, and rescanning may be required five to seven days later for confirmation.
      • Cogo A.
      • Lensing A.W.
      • Koopman M.M.
      • Piovella F.
      • Siragusa S.
      • Wells P.S.
      • et al.
      Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.
      Conversely, WLUS can be considered conclusive after one assessment, obviating the need for rescanning or additional examinations.
      • Schellong S.M.
      • Schwarz T.
      • Halbritter K.
      • Beyer J.
      • Siegert G.
      • Oettler W.
      • et al.
      Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis.
      Also, detailed investigation of the whole leg may permit prompt identification of other pathological conditions.
      However, WLUS requires a skilled operator, advanced ultrasound machines, and more time, limiting its widespread availability. Also, as WLUS allows for the detection of isolated calf DVT of uncertain clinical significance, overdiagnosis may occur, potentially exposing patients to unnecessary anticoagulation and associated risks,
      • Righini M.
      • Paris S.
      • Le Gal G.
      • Laroche J.P.
      • Perrier A.
      • Bounameaux H.
      Clinical relevance of distal deep vein thrombosis. Review of literature data.
      as well as increased healthcare costs. Therefore, appropriate selection of patients for WLUS assessment is necessary.
      Considering the differences between these techniques, the Palladio study proposed a comprehensive diagnostic algorithm for DVT, in which WLUS and CUS were used, depending on D dimer measurements and the pre-test probability of DVT.
      • Ageno W.
      • Camporese G.
      • Riva N.
      • Iotti M.
      • Bucherini E.
      • Righini M.
      • et al.
      Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): a prospective, multicentre, cohort study.
      In this study, D dimer measurement and pre-test probability assessment were performed on admission in the study population. On the basis of pre-test probability assessment, patients were stratified into three groups:
      • Group 1: pre-test probability unlikely and D dimer negative (DVT excluded)
      • Group 2: either pre-test probability for DVT likely or positive for D dimer (CUS only)
      • Group 3: pre-test probability for DVT likely and positive D dimer (WLUS)
      The results of this study favoured the use of this algorithm, as the incidence of thromboembolic events at three months was negligible in group 1 (< 0.3%), and similar to those reported in other validated algorithms in group 2 (1%). More importantly, by applying such an algorithm, WLUS was performed in only 35% of patients with suspected DVT, of whom half (49%) had DVT. This study demonstrated the potential of this algorithm to safely rule out DVT on the day of referral, while reducing the risk of overdiagnosis of low risk isolated calf DVT.
      • Ageno W.
      • Camporese G.
      • Riva N.
      • Iotti M.
      • Bucherini E.
      • Righini M.
      • et al.
      Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): a prospective, multicentre, cohort study.
      However, this algorithm is not validated, and therefore the GWC is in favour of WLUS whenever there is clinical suspicion of calf DVT and WLUS is available.

      2.2.1.4 Computed tomography venography

      CT venography (CTV) is an effective technique for the diagnosis of proximal DVT in patients with suspected DVT and PE, with sensitivity and specificity comparable to ultrasound. CTV offers definite advantages over ultrasound when evaluating the pelvic veins or the inferior vena cava (IVC) and can detect concurrent medical conditions that cause pain and swelling. Moreover, owing to its excellent spatial resolution, it may facilitate vessel measurement and case planning, when intervention is deemed necessary. However, CTV is expensive, requires the use of iodine contrast, and involves radiation exposure, which constitutes a significant concern, particularly in younger patients.
      • Karande G.Y.
      • Hedgire S.S.
      • Sanchez Y.
      • Baliyan V.
      • Mishra V.
      • Ganguli S.
      • et al.
      Advanced imaging in acute and chronic deep vein thrombosis.

      2.2.1.5 Magnetic resonance venography

      The role of magnetic resonance venography (MRV) for the diagnosis of lower extremity DVT has been poorly described in the literature. Although a systematic review and meta-analysis found MRV to have equivalent sensitivity and specificity to ultrasound assessment, cautious interpretation of these results is needed, as significant heterogeneity between studies was observed. Like CTV, MRV offers definite advantages over ultrasound when evaluating the pelvic veins or the IVC and can detect concurrent medical conditions that cause pain and swelling, such as extrinsic venous compression syndromes or incidental pelvic malignancies. However, as MRI is relatively expensive and intravenous (IV) contrast is usually required, it has clear disadvantages compared with ultrasound. As such, there may be a role for MRV in patients in whom ultrasound is not appropriate, not feasible, or is inconclusive,
      • Sampson F.C.
      • Goodacre S.W.
      • Thomas S.M.
      • van Beek E.J.
      The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis.
      although there is no evidence to suggest it can replace venography in such cases.
      Recent studies have assessed the role of MRV in follow up after DVT, and differentiation between new and recurrent DVT. In fact, although duplex ultrasound cannot reliably determine the age of a thrombus and therefore distinguish acute recurrent DVT from persisting previous thrombus, magnetic resonance direct thrombus imaging may help distinguish between acute recurrent thrombus and a persisting thrombus in the same location, with further implications for treatment regimens.
      • Mendichovszky I.A.
      • Priest A.N.
      • Bowden D.J.
      • Hunter S.
      • Joubert I.
      • Hilborne S.
      • et al.
      Combined MR direct thrombus imaging and non-contrast magnetic resonance venography reveal the evolution of deep vein thrombosis: a feasibility study.
      ,
      • van Dam L.F.
      • Dronkers C.E.A.
      • Gautam G.
      • Eckerbom A.
      • Ghanima W.
      • Gleditsch J.
      • et al.
      Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis.
      In the Theia study, 119 patients with suspected recurrent DVT had magnetic resonance direct thrombus imaging negative for both DVT and SVT and were not treated with any anticoagulant during follow up. The three month incidence of recurrent symptomatic VTE was 1.7% (95% confidence interval [CI] 0.20% – 5.9%), suggesting that whenever recurrent ipsilateral DVT is suspected and a WLUS is inconclusive, magnetic resonance direct thrombus imaging should be considered for therapeutic management decisions.

      2.2.1.6 Venography

      Historically, contrast venography was the first line imaging for the diagnosis of DVT and considered the gold standard. Although effective, this procedure is invasive, requires IV contrast, and involves exposure to radiation. Therefore, venography is now seldom performed, except when other investigations yield inconclusive results or concurrent catheter based intervention is being considered.
      • Karande G.Y.
      • Hedgire S.S.
      • Sanchez Y.
      • Baliyan V.
      • Mishra V.
      • Ganguli S.
      • et al.
      Advanced imaging in acute and chronic deep vein thrombosis.
      Given the variety of diagnostic methods available to healthcare professionals involved in the management of DVT, it is imperative that a validated diagnostic pathway is used. Ultrasound is the initial imaging method of choice in modern day practice.
      Tabled 1
      Recommendation 1
      When deep vein thrombosis is suspected, a clinical assessment of the pre-test probability is recommended as part of the diagnostic process.
      ClassLevelReferences
      ICGeersing et al. (2014),
      • Geersing G.J.
      • Zuithoff N.P.
      • Kearon C.
      • Anderson D.R.
      • Ten Cate-Hoek A.J.
      • Elf J.L.
      • et al.
      Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis.
      Kelly & Hunt (2003)
      • Kelly J.
      • Hunt B.J.
      The utility of pretest probability assessment in patients with clinically suspected venous thromboembolism.
      Tabled 1
      Recommendation 2
      All healthcare professionals involved in the diagnosis of deep vein thrombosis should use a validated diagnostic pathway.
      ClassLevelReference
      ICAgeno et al. (2015)
      • Ageno W.
      • Camporese G.
      • Riva N.
      • Iotti M.
      • Bucherini E.
      • Righini M.
      • et al.
      Analysis of an algorithm incorporating limited and whole-leg assessment of the deep venous system in symptomatic outpatients with suspected deep-vein thrombosis (PALLADIO): a prospective, multicentre, cohort study.
      Tabled 1
      Recommendation 3
      For patients with suspected deep vein thrombosis requiring imaging, ultrasound is recommended as the first modality.
      ClassLevelReferences
      ICConsensus
      Tabled 1
      Recommendation 4
      For patients with suspected deep vein thrombosis with a likely pre-test probability and negative compression ultrasound scanning, repeat ultrasound assessment should be considered after 5–7 days.
      ClassLevelReference
      IIaCCogo et al. (1998)
      • Cogo A.
      • Lensing A.W.
      • Koopman M.M.
      • Piovella F.
      • Siragusa S.
      • Wells P.S.
      • et al.
      Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study.
      Tabled 1
      Recommendation 5
      For patients with suspected proximal deep vein thrombosis where ultrasound assessment is inconclusive or not feasible, computed tomography venography, magnetic resonance venography, or venography should be considered.
      ClassLevelReferences
      IIaCSampson et al. (2007),
      • Sampson F.C.
      • Goodacre S.W.
      • Thomas S.M.
      • van Beek E.J.
      The accuracy of MRI in diagnosis of suspected deep vein thrombosis: systematic review and meta-analysis.
      Karande et al. (2016),
      • Karande G.Y.
      • Hedgire S.S.
      • Sanchez Y.
      • Baliyan V.
      • Mishra V.
      • Ganguli S.
      • et al.
      Advanced imaging in acute and chronic deep vein thrombosis.
      Dronkers, et al. (2016)
      • Dronkers C.E.
      • Klok F.A.
      • Huisman M.V.
      Current and future perspectives in imaging of venous thromboembolism.
      Tabled 1
      Recommendation 6
      When performing ultrasound imaging in patients with suspected calf deep vein thrombosis, whole leg ultrasound is recommended.
      ClassLevelReference
      ICSchellong et al. (2003)
      • Schellong S.M.
      • Schwarz T.
      • Halbritter K.
      • Beyer J.
      • Siegert G.
      • Oettler W.
      • et al.
      Complete compression ultrasonography of the leg veins as a single test for the diagnosis of deep vein thrombosis.

      2.2.2 Classification of deep vein thrombosis

      2.2.2.1 Anatomical level

      Depending on the venous territory involved, DVT may be classified as proximal or distal. Thrombosis of the iliac, femoral, and/or popliteal veins is classified as proximal DVT, regardless of the presence of concomitant calf (distal) DVT. Further differentiation into iliofemoral and femoropopliteal DVT can be performed and may be useful. Similarly, thrombosis that is confined to calf (distal) deep veins may be termed as calf or distal DVT.
      • Jenkins J.S.
      Endovascular therapies to treat iliofemoral deep venous thrombosis.
      As the risk of PE, risk of developing PTS, and overall prognosis are different depending on the affected venous territory, accurate anatomical classification of DVT is important for diagnostic, therapeutic, and prognostic purposes.

      2.2.2.2 Aetiological classification

      DVT may be categorised as either provoked or unprovoked, depending on the presence or absence of associated risk factors. Unprovoked DVT refers to venous thrombosis in the absence of clearly identifiable environmental or acquired risk factors. Similarly, provoked DVT occurs in the presence of such risk factors, which can be further classified as transient or persistent (depending on whether they persist after the event) and into major or minor (Table 4).
      • Kearon C.
      • Ageno W.
      • Cannegieter S.C.
      • Cosmi B.
      • Geersing G.J.
      • Kyrle P.A.
      • et al.
      Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.
      Understanding the provoked or unprovoked nature of DVT, as well as the chronicity of any provoking risk factors (transient or persistent), has significant prognostic and treatment implications, as recurrence risk and anticoagulation regimens differ accordingly. If a DVT is provoked by a major transient risk factor (such as trauma or surgery, oestrogen therapy, pregnancy, or puerperium), there is a very low risk of recurrence when anticoagulation is stopped, provided the risk factor is no longer present.
      • Avnery O.
      • Martin M.
      • Bura-Riviere A.
      • Barillari G.
      • Mazzolai L.
      • Mahe I.
      • et al.
      D-dimer levels and risk of recurrence following provoked venous thromboembolism: findings from the RIETE registry.
      • Kearon C.
      • Parpia S.
      • Spencer F.A.
      • Schulman S.
      • Stevens S.M.
      • Shah V.
      • et al.
      Long-term risk of recurrence in patients with a first unprovoked venous thromboembolism managed according to d-dimer results: a cohort study.
      • Blanco-Molina A.
      • Trujillo-Santos J.
      • Pesavento R.
      • Rosa V.
      • Falga C.
      • Tolosa C.
      • et al.
      Outcome after discontinuing anticoagulant therapy in women with venous thromboembolism during hormonal use.
      • Baglin T.
      • Luddington R.
      • Brown K.
      • Baglin C.
      Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study.
      Conversely, when DVT is known to be provoked by a persistent and progressive risk factor (such as malignancy), the risk of recurrence is significantly higher in the same conditions. Finally, patients with unprovoked DVT have an intermediate risk of recurrence.
      • Kearon C.
      • Ageno W.
      • Cannegieter S.C.
      • Cosmi B.
      • Geersing G.J.
      • Kyrle P.A.
      • et al.
      Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.
      The definition of risk factors associated with provoked DVT are listed in Table 4.
      Table 4Definition of transient or persistent provoked risk factor for deep vein thrombosis. Modified with permission from Kearon et al., 2016
      • Kearon C.
      • Ageno W.
      • Cannegieter S.C.
      • Cosmi B.
      • Geersing G.J.
      • Kyrle P.A.
      • et al.
      Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.
      Provoked risk factorDefinition
      Transient
       Major
      Example: major transient risk factors: surgery with general anaesthesia for > 30 min; acute illness confined to bed in hospital for at least three days; caesarean section; oestrogen therapy; pregnancy or puerperium.
      Half the risk of recurrent VTE after stopping anticoagulant therapy (vs. if there was no transient risk factor), when the risk factor occurred up to three months before the VTE
      A >10 fold increase in the risk of having a first VTE
       Minor
      Example: minor transient risk factors: surgery with general anaesthesia for < 30 min; admission to hospital for < 3 days with an acute illness; confined to bed out of hospital for at least three days with an acute illness; leg injury associated with reduced mobility for at least three days.
      Half the risk of recurrent VTE after stopping anticoagulant therapy (vs. if there was no transient risk factor), when the risk factor occurred up to two months before the VTE
      A 3–10 fold increase in the risk of having a first VTE
      Persistent
      Example: persistent risk factor: cancer; inflammatory bowel disease.
      Cancer, if:
      • has not received potentially curative treatment
      • there is evidence that treatment has not been curative (e.g., recurrent or progressive disease)
      • treatment is ongoing
      Ongoing non-malignant condition associated with at least a twofold risk of recurrent VTE after stopping anticoagulant therapy
      VTE = venous thromboembolism.
      Example: major transient risk factors: surgery with general anaesthesia for > 30 min; acute illness confined to bed in hospital for at least three days; caesarean section; oestrogen therapy; pregnancy or puerperium.
      Example: minor transient risk factors: surgery with general anaesthesia for < 30 min; admission to hospital for < 3 days with an acute illness; confined to bed out of hospital for at least three days with an acute illness; leg injury associated with reduced mobility for at least three days.
      Example: persistent risk factor: cancer; inflammatory bowel disease.

      2.2.3 Investigation for pulmonary embolism

      Occult PE is known to be prevalent in patients with lower extremity DVT. Several studies have reported that around 30% – 40% of patients with DVT have high probability pulmonary scintigraphy or CT findings suggesting clinically silent PE,
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      ,
      • Tzoran I.
      • Saharov G.
      • Brenner B.
      • Delsart D.
      • Roman P.
      • Visona A.
      • et al.
      Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs.
      but prevalences as high as 66% have been reported.
      • Garcia-Fuster M.J.
      • Fabia M.J.
      • Furio E.
      • Pichler G.
      • Redon J.
      • Forner M.J.
      • et al.
      Should we look for silent pulmonary embolism in patients with deep venous thrombosis?.
      For patients diagnosed with DVT, the prevalence of clinically silent PE increases with age,
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      and is higher in patients with proximal DVT,
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      ,
      • Garcia-Fuster M.J.
      • Fabia M.J.
      • Furio E.
      • Pichler G.
      • Redon J.
      • Forner M.J.
      • et al.
      Should we look for silent pulmonary embolism in patients with deep venous thrombosis?.
      compared with those with calf DVT. In a systematic review of patients with calf DVT, the prevalence of silent PE was 13%.
      • Hughes M.J.
      • Stein P.D.
      • Matta F.
      Silent pulmonary embolism in patients with distal deep venous thrombosis: systematic review.
      The presence of silent and undetected PE in patients with DVT may be clinically relevant as patients with subsequent pulmonary symptoms may be mistakenly diagnosed as PE, despite anticoagulation, which may lead to unneccessary therapeutic measures such as caval filter insertion.
      • Monreal M.
      • Ruiz J.
      • Fraile M.
      • Bonet M.
      • Davant E.
      • Muchart J.
      • et al.
      Prospective study on the usefulness of lung scan in patients with deep vein thrombosis of the lower limbs.
      As silent PE can occur even in central pulmonary arteries,
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      ,
      • Garcia-Fuster M.J.
      • Fabia M.J.
      • Furio E.
      • Pichler G.
      • Redon J.
      • Forner M.J.
      • et al.
      Should we look for silent pulmonary embolism in patients with deep venous thrombosis?.
      pulmonary hypertension may ensue. Patients with DVT and silent PE are also more likely to suffer recurrent PE than patients with DVT without silent PE.
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      For patients with silent PE at the time of proximal lower extremity DVT diagnosis, there is increased risk of symptomatic PE occurring during the initial two weeks of treatment,
      • Tzoran I.
      • Saharov G.
      • Brenner B.
      • Delsart D.
      • Roman P.
      • Visona A.
      • et al.
      Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs.
      ,
      • Girard P.
      • Decousus M.
      • Laporte S.
      • Buchmuller A.
      • Herve P.
      • Lamer C.
      • et al.
      Diagnosis of pulmonary embolism in patients with proximal deep vein thrombosis: specificity of symptoms and perfusion defects at baseline and during anticoagulant therapy.
      whereas no such significant difference remains after three months of treatment.
      • Tzoran I.
      • Saharov G.
      • Brenner B.
      • Delsart D.
      • Roman P.
      • Visona A.
      • et al.
      Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs.
      Routine screening for PE in newly diagnosed DVT patients has therefore been advocated,
      • Stein P.D.
      • Matta F.
      • Musani M.H.
      • Diaczok B.
      Silent pulmonary embolism in patients with deep venous thrombosis: a systematic review.
      ,
      • Hughes M.J.
      • Stein P.D.
      • Matta F.
      Silent pulmonary embolism in patients with distal deep venous thrombosis: systematic review.
      as baseline imaging may be helpful if the patient subsequently develops respiratory symptoms. Moreover, imaging would potentially allow individualisation of anticoagulant treatment to counteract the higher risk of symptomatic PE in those with silent PE, particularly in the first two weeks after diagnosis.
      • Tzoran I.
      • Saharov G.
      • Brenner B.
      • Delsart D.
      • Roman P.
      • Visona A.
      • et al.
      Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs.
      ,
      • Girard P.
      • Decousus M.
      • Laporte S.
      • Buchmuller A.
      • Herve P.
      • Lamer C.
      • et al.
      Diagnosis of pulmonary embolism in patients with proximal deep vein thrombosis: specificity of symptoms and perfusion defects at baseline and during anticoagulant therapy.
      However, such a strategy would incur added costs,
      • Garcia-Fuster M.J.
      • Fabia M.J.
      • Furio E.
      • Pichler G.
      • Redon J.
      • Forner M.J.
      • et al.
      Should we look for silent pulmonary embolism in patients with deep venous thrombosis?.
      and increase exposure to both radiation and contrast media. In the absence of high quality evidence demonstrating clinical and health economic benefits of routine investigation for PE, such an approach cannot currently be recommended. There may be benefits of screening for PE in subgroups of patients with DVT,
      • Tzoran I.
      • Saharov G.
      • Brenner B.
      • Delsart D.
      • Roman P.
      • Visona A.
      • et al.
      Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs.
      such as those with electrocardiogram (ECG) or chest X ray (CXR) abnormalities, free floating thrombus, or cardiac biomarkers, suggesting possible pulmonary involvement, or increased bleeding risk. However, level I evidence for such an approach is lacking.
      Tabled 1
      Recommendation 7
      For patients with deep vein thrombosis, routine investigation for occult pulmonary embolism in the absence of symptoms or signs is not recommended.
      ClassLevelReference
      IIICGarcia-Fuster et al. (2014)
      • Garcia-Fuster M.J.
      • Fabia M.J.
      • Furio E.
      • Pichler G.
      • Redon J.
      • Forner M.J.
      • et al.
      Should we look for silent pulmonary embolism in patients with deep venous thrombosis?.

      2.2.4 Investigation for malignancy

      The association between DVT and occult malignancy has prompted the question of whether unselected patients with DVT should be routinely investigated for cancer.
      • Prandoni P.
      • Lensing A.W.
      • Buller H.R.
      • Cogo A.
      • Prins M.H.
      • Cattelan A.M.
      • et al.
      Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.
      Between 4% and 12% of patients with unprovoked DVT without a history of malignancy at baseline are diagnosed with cancer during treatment of their VTE,
      • Prandoni P.
      • Lensing A.W.
      • Buller H.R.
      • Cogo A.
      • Prins M.H.
      • Cattelan A.M.
      • et al.
      Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      • Delluc A.
      • Ianotto J.C.
      • Tromeur C.
      • De Moreuil C.
      • Couturaud F.
      • Lacut K.
      • et al.
      Real-world incidence of cancer following a first unprovoked venous thrombosis: results from the EPIGETBO study.
      usually during the first months after VTE diagnosis.
      • Prandoni P.
      • Lensing A.W.
      • Buller H.R.
      • Cogo A.
      • Prins M.H.
      • Cattelan A.M.
      • et al.
      Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.
      ,
      • Delluc A.
      • Ianotto J.C.
      • Tromeur C.
      • De Moreuil C.
      • Couturaud F.
      • Lacut K.
      • et al.
      Real-world incidence of cancer following a first unprovoked venous thrombosis: results from the EPIGETBO study.
      In addition to the unprovoked nature of the DVT, several factors have been identified as being independently associated with the diagnosis of malignancy in patients with DVT, including recurrent DVT, advanced patient age, male sex, smoking, low body weight, elevated platelet count, anaemia, chronic lung disease, prior VTE event, and recent surgery.
      • Prandoni P.
      • Lensing A.W.
      • Buller H.R.
      • Cogo A.
      • Prins M.H.
      • Cattelan A.M.
      • et al.
      Deep-vein thrombosis and the incidence of subsequent symptomatic cancer.
      ,
      • Delluc A.
      • Ianotto J.C.
      • Tromeur C.
      • De Moreuil C.
      • Couturaud F.
      • Lacut K.
      • et al.
      Real-world incidence of cancer following a first unprovoked venous thrombosis: results from the EPIGETBO study.
      ,
      • Jara-Palomares L.
      • Otero R.
      • Jimenez D.
      • Carrier M.
      • Tzoran I.
      • Brenner B.
      • et al.
      Development of a risk prediction score for occult cancer in patients with VTE.
      A risk score based on the presence of these factors, followed by more extensive examination for cancer in those with a high score has therefore been proposed,
      • Jara-Palomares L.
      • Otero R.
      • Jimenez D.
      • Carrier M.
      • Tzoran I.
      • Brenner B.
      • et al.
      Development of a risk prediction score for occult cancer in patients with VTE.
      but external validation is awaited.
      Detection of underlying malignancy present at diagnosis of DVT may require extensive investigations, however, and the disease may already be widespread and incurable despite screening and detection.
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      Extensive screening strategies also incur increased costs, are associated with the risks of false positive findings
      • Kleinjan A.
      • van Doormaal F.F.
      • Prins M.H.
      • Buller H.R.
      • Otten J.M.
      Limitations of screening for occult cancer in patients with idiopathic venous thromboembolism.
      and with hazards from radiation exposure and contrast media. The effects of added physical discomfort and emotional distress to patients should also be considered.
      In clinical studies including patients with DVT, limited screening for malignancy has often been defined as a medical history (including asking for red flag cancer symptoms), a full clinical examination and basic blood tests. On occasion, additional investigations such as CXR and sex specific screening tests such as prostate specific antigen in men have also been included.
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      ,
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      Several studies have compared limited screening with more extensive cancer screening protocols including rectal examination, faecal occult blood testing, thoracic CT or positron emission tomography imaging, and mammography and abdominopelvic CT scanning for women.
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      ,
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      Two meta-analyses have amalgamated the published data in patients with unprovoked VTE comparing more extensive investigation strategies with limited screening only.
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      ,
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      Extensive screening diagnosed a higher number of malignancies compared with limited screening (7.5% vs. 6.1%; relative risk [RR] 1.22; 95% CI 0.90 – 1.65)
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      but conferred no significant reduction in all cause mortality (RR 0.86; 95% CI 0.58 – 1.27),
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      ,
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      or cancer related mortality (RR 0.86 [95% CI 0.46 – 1.62] in one study,
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      and 0.93 [95% CI 0.54 – 1.58] in another).
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      Similarly, a recent Cochrane review suggested that there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in people with a first episode of unprovoked VTE (DVT or PE) in reducing cancer or VTE related morbidity and mortality.
      • Robertson L.
      • Yeoh S.E.
      • Broderick C.
      • Stansby G.
      • Agarwal R.
      Effect of testing for cancer on cancer- or venous thromboembolism (VTE)-related mortality and morbidity in people with unprovoked VTE.
      Based on current evidence, limited rather than extensive screening for occult cancer should be undertaken in patients with provoked or unprovoked DVT. A clinical history and physical examination should be performed, although additional sex specific tests may be warranted, based on findings.
      Tabled 1
      Recommendation 8
      For patients with unprovoked deep vein thrombosis, clinical examination and sex specific cancer screening, as opposed to routine extensive screening, for occult malignancy is recommended.
      ClassLevelReferences
      IAZhou et al. (2017),
      • Zhou M.
      • Zhang L.
      • Ding Y.
      • Wang Y.
      • Yan D.
      • Lin C.
      • et al.
      Extensive screening for occult malignancy in unprovoked venous thromboembolism: a meta-analysis.
      Klein et al. (2017),
      • Klein A.
      • Shepshelovich D.
      • Spectre G.
      • Goldvaser H.
      • Raanani P.
      • Gafter-Gvili A.
      Screening for occult cancer in idiopathic venous thromboembolism – systemic review and meta-analysis.
      Kleinjan et al. (2012)
      • Kleinjan A.
      • van Doormaal F.F.
      • Prins M.H.
      • Buller H.R.
      • Otten J.M.
      Limitations of screening for occult cancer in patients with idiopathic venous thromboembolism.

      2.2.5 Testing for hereditary and acquired thrombophilias

      2.2.5.1 Details of thrombophilias and thrombophilia testing

      Thrombophilia testing is poorly understood. The intended goal is to detect currently known hereditary or acquired pro-thrombotic states that predispose to VTE. The testing should be used to help assess the risk of recurrent VTE in patients after their first unprovoked event. The term “thrombophilia testing” refers to testing for antithrombin, protein C and protein S deficiencies, activated protein C (APC) resistance and/or factor V Leiden, prothrombin G20210A mutation, and antiphospholipid antibodies (lupus anticoagulant, anti-beta-2 glycoprotein I, and anticardiolipin IgG and IgM antibodies).
      • Baglin T.
      • Gray E.
      • Greaves M.
      • Hunt B.J.
      • Keeling D.
      • Machin S.
      • et al.
      Clinical guidelines for testing for heritable thrombophilia.
      Previously, homocysteine and C677T methylenetetrahydrofolate reductase mutation were included, but these are now excluded from testing in most centres as the associated risk with VTE is weak.
      Thrombophilia testing became popular after the detection of the single gene mutations in the antithrombin, protein C, and protein S genes in the 1980s. It was initially thought that these thrombophilias would explain the majority of VTE. However, thrombophilia testing has fallen out of favour as these investigations usually add little to the clinical management of the patients for the following reasons.
      Firstly, the absence of a hereditary thrombophilia in a patient with a strong family history does not exclude a hereditary defect, as only about 50% of families with a strong history of VTE will be diagnosed with a currently recognised thrombophilia. There are probably other inherited defects that remain unrecognised. It is now recognised that clinical factors are more important determinants of the risk of recurrent VTE (National Institute of Health and Care Excellence Clinical Guideline 144).

      National Institute for Health and Care Excellence. Venous thromboembolic diseases: diagnosis, management and thrombophilia testing (clinical guideline 144). Available at: www.nice.org.uk/guidance/cg144.

      • Kearon C.
      • Akl E.A.
      • Comerota A.J.
      • Prandoni P.
      • Bounameaux H.
      • Goldhaber S.Z.
      • et al.
      Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Secondly, being diagnosed and labelled with a thrombophilia may add unnecessary anxiety and medicalisation, particularly as most people with a low risk hereditary thrombophilia such as heterozygous factor V Leiden will never have a VTE event and are not at increased risk of recurrent VTE.
      Thirdly, it should be recognised that hereditary thrombophilia has been studied mainly in the white population. For example, factor V Leiden mutation is the most common hereditary thrombophilia, with a prevalence of 5% – 10%, although it is rarely seen in non-white populations.
      • Heit J.A.
      • Armasu S.M.
      • McCauley B.M.
      • Kullo I.J.
      • Sicotte H.
      • Pathak J.
      • et al.
      Identification of unique venous thromboembolism-susceptibility variants in African-Americans.
      ,
      • Jiang J.
      • Jiao Y.
      • Ding X.
      • Zhang B.
      Association between genetic polymorphisms and deep vein thrombosis in a Chinese population.
      Different types of recognised thrombophilia are presented in Table 5. The prevalence and relative risk of development of VTE of the most common hereditary and acquired haematological alterations related to clinical thrombophilia is shown in Table 20 in Chapter 4.4.1.
      Table 5Core hereditary and acquired thrombophilias
      Thrombophilia
      Hereditary
       Antithrombin deficiency
       Protein C deficiency
       Protein S deficiency
       Factor V Leiden
       Activated protein C resistance
      Not everyone has factor V Leiden.
       Prothrombin G20210A variants
       Dysfibrinogenaemia
       Factor XIII 34val
       Fibrinogen (G) 10034T
       A and/or B alleles of the ABO blood group
       Prothrombin Yukuhashi (II R596L)
      Acquired
       Antiphospholipid antibodies on two occasions more than 12 weeks apart. Three assays are performed:
      • lupus anticoagulant
      • anticardiolipin antibodies
      • anti-beta-2 glycoprotein I antibodies
       Paroxysmal nocturnal haemoglobinuria
       Myeloproliferative syndromes with JAK2V617F mutation
      Other causes
       Haemolytic states, e.g., sickle cell crises
       Any inflammatory disease such as infections, e.g., pneumonia, rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, Adamantiades-Behçet disease.
       Nephrotic syndrome (loss of antithrombin in the urine)
      Not everyone has factor V Leiden.

      2.2.5.1.1 Hereditary antithrombin, protein C, and protein S deficiency

      Deficiencies of these natural anticoagulants are inherited as an autosomal dominant trait and account for 10 – 15% of familial thrombophilias. However, such deficiencies are rare in the general population, with an estimated prevalence of about one in 5 000 individuals. Because of their genetic heterogeneity, they are diagnosed by antigenic or functional assays. Deficiencies can be either type 1, where there is a parallel reduction in biochemical activity and antigen concentration, or type 2, a functional defect where biochemical activity is reduced, despite normal antigen concentration.
      Antithrombin is the main inhibitor of thrombin. Binding to heparin or heparan sulphate dramatically enhances this inhibitory activity. With the exception of mutations affecting the heparin binding site, homozygous antithrombin deficiency is considered incompatible with life. Heterozygous antithrombin deficiency results in a 5 – 20 fold increased risk of VTE, with affected individuals typically presenting with thrombosis at an early age.
      Protein C is a vitamin K dependent protease, synthesised in the liver, which, when activated by thrombin, has an anticoagulant effect by proteolytic degradation of activated factors V and VIII. Homozygotes or compound heterozygotes are just compatible with life (protein C < 0.01 U/mL), presenting with spontaneous skin necrosis in neonatal life (neonatal purpura fulminans), or if less severely affected (protein C 0.4 – 0.6 U/mL) with a 7 – 10 fold increased risk of VTE in later life. Patients with purpura fulminans require protein C replacement with either fresh frozen plasma or protein C concentrates. Individuals with protein C deficiency are at increased risk of skin necrosis during the initiation of vitamin K antagonist (VKA) therapy (known also as warfarin induced skin necrosis) because the half life of protein C is shorter than that of the other vitamin K dependent coagulation factors, resulting in a temporary hypercoagulable state.
      Protein S is a vitamin K dependent protease that serves as a co-factor for the anticoagulant function of APC. Protein S circulates in two forms, approximately 40% as free protein S and the remainder reversibly bound to complement 4b binding protein. Only free protein S has cofactor activity for APC. The proportion of free and bound protein S depends on the functional protein integrity and levels of complement 4b binding protein. Reduced concentration of free protein S is associated with an approximately 2 – 10 fold increased risk of VTE and an increased risk of skin necrosis during the initiation of a VKA.

      2.2.5.1.2 Factor V Leiden

      The factor V Leiden variant is a single point mutation at nucleotide position 1691 in the factor V gene that causes a substitution of arginine by glutamine. This amino acid substitution prevents APC from recognising a cleavage site on factor V, leading to resistance to the anticoagulant action of APC. Factor V Leiden mutation is the most common cause of APC resistance. The variant is more often present in the white population than in other ethnic groups, such as Asians or Africans. Heterozygosity results in a fivefold increase in VTE risk, whereas homozygotes have an 80 fold increase in VTE risk.

      2.2.5.1.3 Prothrombin G20210A variant

      The prothrombin G20210A variant is a single nucleotide substitution from glutamine to arginine at position 20210 of the prothrombin gene, which results in an approximately 30% increase in prothrombin antigen or activity assays. Carriers have an increased risk of DVT.

      2.2.5.1.4 Other hereditary associations

      Dysfibrinogenaemias may cause bleeding and thrombotic episodes, sometimes in the same individual. They are extremely rare and best managed by thrombophilia experts. Other hereditary thrombophilias are being described in non-white populations; for example, there is a protein C variant that has a prevalence of 2% in the Chinese population that predisposes to VTE.

      2.2.5.1.5 Antiphospholipid syndrome

      APS is the association between antiphospholipid (aPL) antibodies and thrombosis and/or certain problems in pregnancy. The key difference between APS and the other thrombophilias is that the former can cause thrombosis in any vascular bed, not only DVT, and therefore APS is an important cause of stroke at young age, thrombotic myocardial infarction, and placental dysfunction.
      • Corban M.T.
      • Duarte-Garcia A.
      • McBane R.D.
      • Matteson E.L.
      • Lerman L.O.
      • Lerman A.
      Antiphospholipid syndrome: role of vascular endothelial cells and implications for risk stratification and targeted therapeutics.
      Antiphospholipid antibodies are a family of antibodies reactive with proteins that are themselves complexed with negatively charged phospholipids such as beta-2 glycoprotein I. To detect an aPL antibody there are three laboratory tests required (it is important to do all three as many are only positive for one): these are the lupus anticoagulant; anticardiolipin antibodies; and anti-beta-2 glycoprotein I antibodies.
      • Tektonidou M.G.
      • Andreoli L.
      • Limper M.
      • Amoura Z.
      • Cervera R.
      • Costedoat-Chalumeau N.
      • et al.
      EULAR recommendations for the management of antiphospholipid syndrome in adults.
      Because transient antibodies can occur, the test must be performed again 12 weeks later. The lupus anticoagulant is an in vitro phenomenon in which the aPL antibody slows down clot formation, thereby prolonging the clotting time. The lupus anticoagulant assay is a double misnomer: it is neither a test of lupus nor an in vivo anticoagulant.
      The catastrophic APS is an aggressive variant of APS with multi-organ system involvement that includes small vessel thrombosis and can develop rapidly.
      • Legault K.
      • Schunemann H.
      • Hillis C.
      • Yeung C.
      • Akl E.A.
      • Carrier M.
      • et al.
      McMaster RARE – Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome.
      It is a life threatening medical condition with a 50% mortality rate. Disseminated intravascular coagulation is present in 25% of cases.

      2.2.5.1.6 Paroxysmal nocturnal haemoglobinuria

      Paroxysmal nocturnal haemoglobinuria (PNH) is a rare haematological disease caused by somatic mutations in the phosphatidylinositol glycan A gene (PIGA) in haematopoietic stem cells.
      • Hill A.
      • Kelly R.J.
      • Hillmen P.
      Thrombosis in paroxysmal nocturnal hemoglobinuria.
      Complement action at the surface of haematopoietic cells, including platelets and leucocytes, induces an increased risk of thromboembolic events.
      • Hill A.
      • Kelly R.J.
      • Hillmen P.
      Thrombosis in paroxysmal nocturnal hemoglobinuria.
      Traditionally, PNH was managed by supportive care (e.g., transfusions and anticoagulation) and allogeneic stem cell transplant. Use of eculizumab, an anti-C5 monoclonal antibody, has significantly changed PNH management and clinical outcomes.
      • Patriquin C.J.
      • Kiss T.
      • Caplan S.
      • Chin-Yee I.
      • Grewal K.
      • Grossman J.
      • et al.
      How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry.
      However, for patients with PNH with a history of VTE, anticoagulation should be maintained indefinitely.
      • Patriquin C.J.
      • Kiss T.
      • Caplan S.
      • Chin-Yee I.
      • Grewal K.
      • Grossman J.
      • et al.
      How we treat paroxysmal nocturnal hemoglobinuria: a consensus statement of the Canadian PNH Network and review of the national registry.

      2.2.5.2 Whether to test for thrombophilias

      Rather than focusing on thrombophilias, identifying whether a DVT is provoked or unprovoked, patient sex and age are considered much more useful in determining which patients are at high risk of recurrent DVT and therefore who may need long term anticoagulation. It should be recognised that hospital acquired VTEs (defined as a VTE event during hospital admission and up to 90 days after hospital discharge) account for up to two thirds of all VTE events.

      National Institute for Health and Care Excellence. Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep vein thrombosis or pulmonary embolism (clinical guideline 89). Available at: www.nice.org.uk/guidance/cg89.

      For this population, unless there are other risk factors for DVT, the risk of recurrence is low and therefore only three months of anticoagulation is usually required.
      The patients and situations that require thrombophilia testing remain controversial. Current opinion is that thrombophilia testing should only be performed when patient management will be affected. The first consideration is whether the DVT is provoked or unprovoked. The risk of recurrent events after a provoked event (the most common provoking factor being hospital admission) is small and therefore there is no merit in routinely testing for thrombophilia.
      • Stevens S.M.
      • Woller S.C.
      • Bauer K.A.
      • Kasthuri R.
      • Cushman M.
      • Streiff M.
      • et al.
      Guidance for the evaluation and treatment of hereditary and acquired thrombophilia.
      ,
      • Connors J.M.
      Thrombophilia testing and venous thrombosis.
      In the following circumstances, thrombophilia testing may be potentially useful.
      Firstly, in patients with their first unprovoked DVT to identify whether a patient has a high risk of recurrence and therefore long term anticoagulation may be required. Although this is particularly true for younger patients (e.g., age up to 40 – 45 years) where the frequency of thrombophilia is much higher than in the elderly, a negative thrombophilia test should not be an indication to suggest stopping anticoagulation after three to six months of treatment.
      • Garcia-Horton A.
      • Kovacs M.J.
      • Abdulrehman J.
      • Taylor J.E.
      • Sharma S.
      • Lazo-Langner A.
      Impact of thrombophilia screening on venous thromboembolism management practices.
      However, the presence of a severe thrombophilia may encourage extended treatment.
      • Moll S.
      Thrombophilia: clinical-practical aspects.
      Therefore, testing for the most frequent type of acquired thrombophilia that is the APS should be considered if a decision to stop anticoagulation is contemplated.
      • Connors J.M.
      Thrombophilia testing and venous thrombosis.
      Secondly, consideration of thrombophilia testing is also important in patients with DVT at an unusual site (e.g., cerebral vein), and particularly in those where the event was unprovoked and who have a strong first degree family history of VTE, particularly those under 45 years of age.
      Thirdly, for females with DVT, aPL antibody testing may be especially useful in those with a history of recurrent miscarriages, intra-uterine foetal death, and other late obstetric morbidities due to placental ischaemia, particularly intra-uterine foetal growth restriction and pre-eclampsia. Detection of aPL antibodies is relevant in all of these situations, as these will have an impact on the type and duration of anticoagulation, as well as on thromboprophylaxis to prevent obstetric morbidity.
      • Schreiber K.
      • Sciascia S.
      • de Groot P.G.
      • Devreese K.
      • Jacobsen S.
      • Ruiz-Irastorza G.
      • et al.
      Antiphospholipid syndrome.
      Fourthly, during future medical or surgical treatment, patients with thrombophilia may be prescribed more intensive thromboprophylaxis measures (in terms of dose and/or duration) in view of their probable higher risk of VTE. In a patient with a proven thrombophilia the risk of recurrent VTE varies depending on the type of thrombophilia, and risk is greater with combined defects.

      2.2.5.3 Timing and details of thrombophilia tests

      Thrombophilia testing should not be performed in the acute period after a recent VTE, and especially if the patient is receiving heparin, warfarin, or DOAC. Plasma level assays should better be performed at least two weeks after stopping VKAs or at least three days after stopping a DOAC, although some thrombophilia testing (i.e., antithrombin activity) can be performed while taking DOACs or VKAs. Genetic testing can be performed at any time. Abnormal (phenotypic) plasma thrombophilia tests should always be repeated on a second set of blood samples on a different day for confirmation. Patients studied while receiving anticoagulants should be retested at a later date, as levels of proteins C and S, and routine lupus anticoagulant testing are affected by VKAs and DOACs.
      The laboratory performing the testing should follow international laboratory standards, such as the International Society on Thrombosis and Haemostasis guidelines for lupus anticoagulant.
      • Devreese K.M.J.
      • Ortel T.L.
      • Pengo V.
      • de Laat B.
      Subcommittee on Lupus Anticoagulant/Antiphospholipid A. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH.
      As the detection of combined hereditary thrombophilic defects may significantly influence decisions on type and duration of anticoagulation, patients with high risk thrombophilias (see Chapter 4.4.2. on specific considerations) should be referred to an expert in thrombophilia, who can provide appropriate patient counselling and long term follow up. This is particularly important as there have been rapid advances in the modern management of these conditions. For example, those with antithrombin deficiency may need plasma or recombinant antithrombin concentrates at times of haemostatic stress when they cannot receive anticoagulation. See Fig. 1 for a flowchart for diagnosis and investigations for DVT.
      Tabled 1
      Recommendation 9
      For patients with provoked deep vein thrombosis, thrombophilia testing is not recommended.
      ClassLevelReference
      IIICStevens et al. (2016)
      • Stevens S.M.
      • Woller S.C.
      • Bauer K.A.
      • Kasthuri R.
      • Cushman M.
      • Streiff M.
      • et al.
      Guidance for the evaluation and treatment of hereditary and acquired thrombophilia.
      Tabled 1
      Recommendation 10
      For patients with unprovoked deep vein thrombosis, routine testing for inherited thrombophilias is not recommended.
      ClassLevelReferences
      IIICStevens et al. (2016),
      • Stevens S.M.
      • Woller S.C.
      • Bauer K.A.
      • Kasthuri R.
      • Cushman M.
      • Streiff M.
      • et al.
      Guidance for the evaluation and treatment of hereditary and acquired thrombophilia.
      Connors (2017),
      • Connors J.M.
      Thrombophilia testing and venous thrombosis.
      Garcia-Horton et al. (2017)
      • Garcia-Horton A.
      • Kovacs M.J.
      • Abdulrehman J.
      • Taylor J.E.
      • Sharma S.
      • Lazo-Langner A.
      Impact of thrombophilia screening on venous thromboembolism management practices.
      Tabled 1
      Recommendation 11
      For patients with unprovoked deep vein thrombosis and a family history of venous thromboembolism in a first degree relative, testing for hereditary thrombophilia should be considered.
      ClassLevelReference
      IIaCMoll (2015)
      • Moll S.
      Thrombophilia: clinical-practical aspects.
      Tabled 1
      Recommendation 12
      For patients with unprovoked deep vein thrombosis, testing for antiphospholipid antibodies should be considered if a decision to stop anticoagulation is contemplated.
      ClassLevelReference
      IIaCMoll (2015)
      • Moll S.
      Thrombophilia: clinical-practical aspects.
      Figure 1
      Figure 1Flowchart of recommendations for the diagnosis and investigation of deep vein thrombosis (DVT), including computed tomography venography (CTV) and magnetic resonance venography (MRV). VTE = venous thromboembolism. ∗Using a validated tool such as Wells Criteria; If calf DVT is suspected, whole leg ultrasound is suggested. DVT management should be outpatient based for all but exceptional cases. §Clinical examination and sex specific screening is recommended rather than routine extensive screening for malignancy.

      2.3 Treatment of deep vein thrombosis: anticoagulation

      2.3.1 Phases of anticoagulation for deep vein thrombosis

      Anticoagulation treatment for DVT may be divided into three distinct phases:
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Mazzolai L.
      • Aboyans V.
      • Ageno W.
      • Agnelli G.
      • Alatri A.
      • Bauersachs R.
      • et al.
      Diagnosis and management of acute deep vein thrombosis: a joint consensus document from the European Society of Cardiology working groups of aorta and peripheral vascular diseases and pulmonary circulation and right ventricular function.
      (1) an initial treatment phase (up to 10 days) with the aim of rapidly instigating anticoagulation therapy to prevent propagation of DVT and PE; (2) a principal treatment phase (first three months) to maintain therapeutic levels of anticoagulation to prevent propagation of DVT and PE, and reduce the risk of early recurrent VTE; and (3) an extended treatment phase (beyond three months, with no scheduled stop date) with the specific aim of reducing the long term risk of recurrent VTE.
      After the principal treatment period (three months), the recurrence risk varies depending on the underlying risk factors. Extended anticoagulation treatment may be required for specific patient groups at high risk of recurrent VTE.

      2.3.2 Anticoagulation mechanisms of action

      Indirect anticoagulants, including the heparins, fondaparinux, or danaparoid, require the presence of antithrombin for inhibiting factor IIa (thrombin) and factor Xa, while direct anticoagulants act without the requirement of any co-factor (Fig. 2). Unfractionated heparin (UFH) inhibits both factor IIa and factor Xa with a Xa/IIa inhibition ratio of 1:1, while in low molecular weight heparins (LMWH) the Xa/IIa inhibition ratio varies between 2:1 and 4:1 and depends on the molecular weight of the LMWH.
      • Hirsh J.
      • Bauer K.A.
      • Donati M.B.
      • Gould M.
      • Samama M.M.
      • Weitz J.I.
      Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      LMWHs with a smaller mean molecular weight are excreted predominantly via the kidney and may therefore accumulate in patients with renal insufficiency.
      Figure 2
      Figure 2The three phases of the coagulation cascade (initiation, propagation, and fibrin formation) and targets for anticoagulants. Indirect anticoagulants, which require the presence of antithrombin (AT), are shown on the left. Direct anticoagulants, which do not require the presence of antithrombin, are shown on the right. These agents directly inhibit factor Xa or factor IIa (thrombin) and include hirudin, argatroban, and the direct oral anticoagulant dabigatran. Apixaban, edoxaban, and rivaroxaban are direct oral anticoagulants that directly inhibit factor Xa. VKA = vitamin K antagonist; TF = tissue factor; LMWH = low molecular weight heparin; UFH = unfractionated heparin. Modified with permission from Bauersachs, 2008.
      • Bauersachs R.M.
      Neue antikoaguanzien [New anticoagulants].
      VKAs, such as warfarin, acenocoumarol, and phenprocoumon, are administered orally and inhibit the gamma carboxylation of coagulation factors II, VII, IX, and X, a modification that is necessary for their functional activity. Of note, functional activity of the coagulation inibitors protein C and protein S also requires such gamma carboxylation and are therefore also decreased by VKA. As the half life of protein C is relatively short compared with the clotting factors, there is a transient hypercoagulable shift during the initiation of VKA. Consequently, it is essential that effective overlapping anticoagulation is ensured with heparins or fondaparinux during the initiation of VKA therapy. Parenteral anticoagulation should only be discontinued when it has been given for a minimum of five days and a therapeutic international normalised ratio (INR) > 2.0 is achieved with VKA and maintained over two consecutive days.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      Direct anticoagulants do not require the presence of antithrombin and include the thrombin (IIa) inhibitors hirudin and argatroban, and the DOAC dabigatran, which inhibits factor IIa. DOACs that inhibit factor Xa are also called oral factor Xa inhibitors, and include apixaban, edoxaban, and rivaroxaban.

      2.3.3 Anticoagulant properties and dosing for the treatment of venous thrombosis

      Details are provided in Table 6, Table 7, Table 8.
      Table 6Recommended initial unfractionated heparin dosing for the treatment of deep vein thrombosis. Reproduced from Smythe, 2016
      • Smythe M.A.
      • Priziola J.
      • Dobesh P.P.
      • Wirth D.
      • Cuker A.
      • Wittkowsky A.K.
      Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.
      AdministrationBolusMaintenance dose
      Infusion
       Non-body weight adjusted5 000 IU1 250–1 280 IU/h
       Body weight adjusted80 IU/kg18 IU/kg/h
      Subcutaneous
       Fixed dose333 IU/kg250 IU/kg every 12 h
       Adjusted dose5 000 IU17 500 IU every 12 h; APTT adjusted
      IU = international units; APTT = activated prothrombin time.
      Table 7Nomogram for dose adjustment of the infusion of unfractionated heparin, in relation to the measured activated partial thromboplastin time (APTT), as an alternative to the ratio of measured APTT/normal value. Target APTT is 46–70 s, corresponding to an APTT/normal value ratio of 1.5–2.5. Modified with permission from Hirsh et al., 2008
      • Hirsh J.
      • Bauer K.A.
      • Donati M.B.
      • Gould M.
      • Samama M.M.
      • Weitz J.I.
      Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      APTTRatio APTT/normal valueDose adjustment
      <35 s<1.280 IU/kg bolus, then increase 4 IU/kg/h
      35–45 s1.2–1.540 IU/kg bolus, then increase 2 IU/kg/h
      46–70 s1.5–2.5No change
      71–90 s2.5–3.0Decrease 2 IU/kg/h
      >90 s>3.02 h pause infusion, then decrease 3 IU/kg/h
      IU = international units.
      Table 8Pharmacological properties of oral anticoagulants. Modified with permission from Bauersachs, 2014.
      • Bauersachs R.M.
      Managing venous thromboembolism with novel oral anticoagulants in the elderly and other high-risk patient groups.
      For reversal agents see Table 10
      VKADabigatran etexilateApixabanEdoxabanRivaroxaban
      TargetVitamin K dependent clotting factors (II, VII, IX, X)Thrombin (IIa)Factor XaFactor XaFactor Xa
      ProdrugNoYesNoNoNo
      Dosingo.d. (INR adjusted)b.d.10 mg b.d. for first 7 d followed by 5 mg b.d.60 mg o.d.15 mg b.d. for inital three w, followed by 20 mg o.d.
      Reduced dosing for extended therapyNANA2.5 mg b.d. after six moNA10 mg o.d. after six mo
      Bioavailability – %100≈6506080–100
      Bioavailability of rivaroxaban calculated for 10 mg dose.
      Time to peak – h1.51.5–3.01.5–3.51–22–4
      Half life – h36–4212–1712–1510–145–13
      Renal elimination – %Negligible80≈ 27≈50≈ 35
      Plasma protein binding – %9935875595
      Drug–drug interactionsMultipleP-gp inhibitorsCYP3A4 and P-gp inhibitorsP-gp inhibitorsCYP3A4 and P-gp inhibitors
      Routine coagulation monitoringYesNoNoNoNo
      VKA = vitamin K antagonist; INR = international normalised ratio; NA = not applicable; P-gp = P-glycoprotein; CYP = cytochrome P450; o.d. = once daily; b.d. = twice daily
      Bioavailability of rivaroxaban calculated for 10 mg dose.

      2.3.3.1 Unfractionated heparin

      Unfractionated heparin is currently only used in special clinical situations, such as severe renal insufficiency, haemodialysis, pending interventions, or for critically ill patients. Body weight should be assessed and activated partial thromboplastin time (APTT) evaluation is necessary for accurate and safe administration. Dosing information is summarised in Table 6, Table 7.
      • Hirsh J.
      • Bauer K.A.
      • Donati M.B.
      • Gould M.
      • Samama M.M.
      • Weitz J.I.
      Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      ,
      • Smythe M.A.
      • Priziola J.
      • Dobesh P.P.
      • Wirth D.
      • Cuker A.
      • Wittkowsky A.K.
      Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.
      An APTT ratio of 1.5 – 2.5 should be reached within 24 hours of starting treatment. A lower APTT in the first 24 hours is associated with a higher incidence of recurrent DVT.
      • Hull R.D.
      • Raskob G.E.
      • Hirsh J.
      • Jay R.M.
      • Leclerc J.R.
      • Geerts W.H.
      • et al.
      Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis.
      As numerous variables can affect APTT results, including sample collection, processing, reagents, laboratory instrument, and, importantly, biological factors such as acute phase reaction, monitoring of antifactor Xa activity (target 0.3 – 0.7 IU/mL) can produce more reliable results than APTT monitoring.
      • Smythe M.A.
      • Priziola J.
      • Dobesh P.P.
      • Wirth D.
      • Cuker A.
      • Wittkowsky A.K.
      Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism.

      2.3.3.2 Low molecular weight heparins

      LMWHs are given subcutaneously, with the dose adjusted for patient body weight. LMWHs may be administered once or twice daily according to the specific summary of product characteristics (SPC), which also recommend specific dose adjustments according to renal function. Monitoring is only recommended in special situations; target peak values of antifactor Xa activity four hours after the last injection of 0.6 – 1.0 international units (IU)/mL for twice daily administration (b.d.), and 1.0 – 2.0 IU/mL for once daily (o.d.) administration have been suggested without firm evidence.
      • Samama M.M.
      • Poller L.
      Contemporary laboratory monitoring of low molecular weight heparins.
      To assess potential accumulation, measurement of trough levels is more informative.

      2.3.3.3 Fondaparinux

      Fondaparinux is given subcutaneously at a standard treatment dose of 7.5 mg o.d., while patients weighing < 50 kg receive 5 mg and those weighing > 100 kg receive 10 mg. Because of its low molecular weight, fondaparinux may accumulate in renal insufficiency and should thus not be used in patients with a creatinine clearance (CrCl) < 30 mL/minute.

      2.3.3.4 Dabigatran

      Dabigatran is administered at a dose of 150 mg b.d., which is started after at least five days of initial parenteral anticoagulation. However, patients aged ≥ 80 years, or with concomitant verapamil, should receive 110 mg b.d., while patients aged between 75 and 80 years, those at increased risk of bleeding, or those with a CrCl of 30 – 50 mL/minute may use either dosing regimens, depending on the thromboembolic risk. As dabigatran is primarily excreted by the kidney it is contraindicated in patients with a CrCl < 30 mL/minute and renal function should be monitored.

      2.3.3.5 Edoxaban

      Edoxaban, like dabigatran, requires at least five days of parenteral anticoagulation before starting oral dosing at 60 mg o.d., reduced to 30 mg o.d. if CrCl is < 30 – 50 mL/minute or with concomitant potent P-glycoprotein inhibitors, e.g., ciclosporin, dronedarone, erythromycin, or ketoconazole.

      2.3.3.6 Apixaban

      Apixaban is started without initial parenteral therapy but requires a higher dose (10 mg b.d.) for seven days, followed by the standard treatment dose of 5 mg b.d. In contrast to treatment for atrial fibrillation, no dose adjustment is performed in DVT treatment in the presence of renal insufficiency. However, in patients with a CrCl of 15 – 29 mL/minute, apixaban should be used with caution, and is not recommended with a CrCl < 15 mL/minute. A lower dose of 2.5 mg b.d. is used for extended therapy.

      2.3.3.7 Rivaroxaban

      Rivaroxaban is started without initial parenteral therapy but requires a higher dose (15 mg b.d.) for three weeks, followed by the standard treatment dose of 20 mg o.d. In contrast to atrial fibrillation, no fixed dose adjustment is required for patients with a CrCl of 15 – 49 mL/minute and a dose of either 20 or 15 mg o.d. can be selected, respectively, depending on the risk of bleeding or thromboembolism. A rivaroxaban dose of 20 or 15 mg should be taken with food, which improves its bioavailability. A lower dose of 10 mg o.d. is used for extended therapy.

      2.3.4 Bleeding and other adverse events

      2.3.4.1 Risk assessment

      At present, any anticoagulation therapy is associated with an increased risk of bleeding. Therefore, it is important to assess both the general and individualised bleeding risk. Several risk scores have been proposed. For DVT treatment, the American College of Chest Physicians (ACCP) consensus categorisation of bleeding risk is frequently advocated but has not been validated. It considers risk factors such as age, previous bleeding, cancer, renal or liver failure, thrombocytopenia, diabetes, antiplatelet treatment, poor INR control, comorbidities, recent surgery, frequent falls, and alcohol abuse.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      The problem with this categorisation and other bleeding risk scores is their poor positive predictive value.
      • Palareti G.
      • Antonucci E.
      • Mastroiacovo D.
      • Ageno W.
      • Pengo V.
      • Poli D.
      • et al.
      The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism.
      Nevertheless, clinical consideration of the risk factors should influence the decision on the duration of anticoagulant treatment. The risk of bleeding is frontloaded, with a higher risk during the first three months and gradual reduction in bleeding risk over time.
      For patients with acute VTE treated with UFH, the bleeding risk is < 3% in the initial phase.
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      Risk factors for bleeding include a higher heparin dose and age > 70 years. LMWH use is associated with a lower risk of major bleeding than UFH in patients treated for DVT.
      • Schulman S.
      • Beyth R.J.
      • Kearon C.
      • Levine M.N.
      Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
      Impaired renal function and increased age are risk factors for bleeding with LMWH. DOACs have a statistically significantly lower risk of major bleeding compared with LMWH/VKA (RR 0.61, 95% CI 0.45 – 0.83) and a lower risk of intracranial haemorrhage (RR 0.37, 95% CI 0.21 – 0.68), or fatal bleeding (RR 0.36, 95% CI 0.15 – 0.84).
      • van Es N.
      • Coppens M.
      • Schulman S.
      • Middeldorp S.
      • Buller H.R.
      Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.
      Gastrointestinal bleeding may be higher with dabigatran, rivaroxaban, and edoxaban than with VKA therapy.
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • van Es N.
      • Coppens M.
      • Schulman S.
      • Middeldorp S.
      • Buller H.R.
      Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials.
      • Holster I.L.
      • Valkhoff V.E.
      • Kuipers E.J.
      • Tjwa E.T.
      New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis.
      • Chai-Adisaksopha C.
      • Crowther M.
      • Isayama T.
      • Lim W.
      The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis.

      2.3.4.2 Management of bleeding in patients on anticoagulation

      Warfarin is the drug most strongly associated with drug induced emergency hospitalisations,
      • Budnitz D.S.
      • Lovegrove M.C.
      • Shehab N.
      • Richards C.L.
      Emergency hospitalizations for adverse drug events in older Americans.
      primarily resulting from gastrointestinal bleeding complications, which require inpatient treatment in > 80% of cases. Around 6% of hospital admissions due to warfarin are because of intracranial haemorrhage. Even though vitamin K is a specific and direct antidote to VKA, it may take up to 24 hours or longer for the INR to normalise.
      • Holbrook A.
      • Schulman S.
      • Witt D.M.
      • Vandvik P.O.
      • Fish J.
      • Kovacs M.J.
      • et al.
      Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      • Crowther M.A.
      • Ageno W.
      • Garcia D.
      • Wang L.
      • Witt D.M.
      • Clark N.P.
      • et al.
      Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial.
      • Keeling D.
      • Baglin T.
      • Tait C.
      • Watson H.
      • Perry D.
      • Baglin C.
      • et al.
      Guidelines on oral anticoagulation with warfarin – fourth edition.
      Therefore, in cases of severe bleeding that require immediate reversal of VKA, clotting factors should be administered. Three factor prothrombin complex concentrate (PCC) contains factors II, IX, and X; the four factor PCC also contains factor VII. Fresh frozen plasma was found to be inferior to PCC.
      • Majeed A.
      • Meijer K.
      • Larrazabal R.
      • Arnberg F.
      • Luijckx G.J.
      • Roberts R.S.
      • et al.
      Mortality in vitamin K antagonist-related intracerebral bleeding treated with plasma or 4-factor prothrombin complex concentrate.
      The British Committee for Standards in Haematology issued some guideline recommendations concerning the reversal of VKA for clinical scenarios with major bleeding or a high INR without bleeding.
      • Keeling D.
      • Baglin T.
      • Tait C.
      • Watson H.
      • Perry D.
      • Baglin C.
      • et al.
      Guidelines on oral anticoagulation with warfarin – fourth edition.
      Their recommendations are summarised in Table 9.
      Table 9Recommendations for the reversal of warfarin, adapted from the Guidelines of the British Committee for Standards in Haematology
      • Keeling D.
      • Baglin T.
      • Tait C.
      • Watson H.
      • Perry D.
      • Baglin C.
      • et al.
      Guidelines on oral anticoagulation with warfarin – fourth edition.
      All hospitals managing patients on warfarin should stock a licensed four factor PCC
      Emergency anticoagulation reversal in patients with major bleeding should be with 25–50 IU/kg four factor PCC and 5 mg IV vitamin K
      Recombinant factor VIIa is not recommended for emergency anticoagulation reversal
      FFP produces suboptimal anticoagulation reversal and should only be used if PCC is not available
      Non-major bleeding anticoagulation reversal should be with 1–3 mg IV vitamin K
      Patients with an INR >5.0 but who are not bleeding should have 1–2 doses of warfarin withheld, and their maintenance dose should be reduced. The cause of the elevated INR should be investigated
      Patients with an INR >8.0 should receive 1–5 mg of oral vitamin K
      PCC = prothrombin complex concentrate; IV = intravenous; FFP = fresh frozen plasma; INR = international normalised ratio.

      2.3.4.2.1 Unfractionated heparin reversal

      Protamine sulphate completely reverses the action of UFH, with 1 000 IU (10 mg) of protamine sulphate able to neutralise around 1 000 units of heparin. Dosage varies depending on the duration since the last dose and route of administration of heparin. However, high doses of protamine sulphate may increase the risk of bleeding.
      • Boer C.
      • Meesters M.I.
      • Veerhoek D.
      • Vonk A.B.A.
      Anticoagulant and side-effects of protamine in cardiac surgery: a narrative review.

      2.3.4.2.2 Low molecular weight heparin reversal

      Depending on the specific LMWH, the ratio of anti-Xa to anti-IIa activity varies. Protamine can only neutralise anti-IIa activity, and therefore LMWH is only partially (30% – 40%) neutralised by protamine.
      • Dhakal P.
      • Rayamajhi S.
      • Verma V.
      • Gundabolu K.
      • Bhatt V.R.
      Reversal of anticoagulation and management of bleeding in patients on anticoagulants.
      Around 0.5 – 1 mg of protamine is given per 1 mg of enoxaparin (depending on whether the last dose was more or less than eight hours previously, respectively).
      • Garcia D.A.
      • Baglin T.P.
      • Weitz J.I.
      • Samama M.M.
      Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Therefore, 1 mg or 100 IU protamine neutralises the anti-IIa activity of 0.01 mL or 1 mg enoxaparin. For the residual smaller molecules in LMWH with anti-FXa activity and for the very small molecule fondaparinux, no antidote is currently licensed.
      • Greinacher A.
      • Thiele T.
      • Selleng K.
      Reversal of anticoagulants: an overview of current developments.

      2.3.4.2.3 Dabigatran reversal with idarucizumab

      Idarucizumab has been developed as a direct antidote to dabigatran. This is a humanised monoclonal antibody fragment, which binds dabigatran with high affinity and specificity, and rapidly reverses its anticoagulant activity. Idarucizumab has been tested in > 500 patients taking dabigatran who had uncontrolled bleeding or patients who were about to undergo an urgent procedure.
      • Pollack Jr., C.V.
      • Reilly P.A.
      • van Ryn J.
      • Eikelboom J.W.
      • Glund S.
      • Bernstein R.A.
      • et al.
      Idarucizumab for dabigatran reversal – full cohort analysis.
      Median maximum percentage reversal of dabigatran was 100%. Median time to the cessation of bleeding was 2.5 hours and peri-procedural haemostasis was assessed as normal in 93%, mildly abnormal in 5%, and moderately abnormal in 1.5%. There were no serious adverse safety signals.
      • Pollack Jr., C.V.
      • Reilly P.A.
      • van Ryn J.
      • Eikelboom J.W.
      • Glund S.
      • Bernstein R.A.
      • et al.
      Idarucizumab for dabigatran reversal – full cohort analysis.
      Idarucizumab has been licensed and is available in many countries as a specific antidote for dabigatran in an IV dose of 2 × 2.5 g/50 mL, for emergency operations, urgent interventions, and for life threatening or uncontrolled bleeding.

      2.3.4.2.4 Factor Xa inhibitor reversal with andexanet alpha

      Andexanet alpha is a modified rFXa peptide that has no intrinsic procoagulatory activity but still allows the molecule to bind FXa inhibitors, heparin–antithrombin (AT), and fondaparinux–AT, and thus reduce their anticoagulant activity. Andexanet alpha is given as an IV bolus, followed by a two hour IV infusion. In the ANNEXA-4 study (Prospective Open-Label Study of Andexanet Alfa in Patients Receiving a Factor Xa Inhibitor who Have Acute Major Bleeding), 352 patients who had acute major bleeding within 18 hours after the administration of a factor Xa inhibitor were included. Bleeding was predominantly intracranial in 64% or gastrointestinal in 26%. The bolus dose of andexanet alpha was 400 mg, and the infusion dose was 480 mg, for apixaban or rivaroxaban taken > 7 hours before. For patients who had taken enoxaparin, edoxaban, or rivaroxaban ≤ 7 hours earlier or at an unknown time, the bolus dose was 800 mg and the infusion dose was 960 mg.
      • Connolly S.J.
      • Crowther M.
      • Eikelboom J.W.
      • Gibson C.M.
      • Curnutte J.T.
      • Lawrence J.H.
      • et al.
      Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.
      After bolus administration, the median antifactor Xa activity decreased by 92% from baseline in patients receiving rivaroxaban or apixaban. These levels remained similar during the two hour infusion. Four hours after the infusion, there was a median decrease from baseline Xa activity of 42% in the patients on rivaroxaban and of 32% in those receiving apixaban. Twelve hours after the andexanet alpha infusion, clinical haemostasis was adjudicated as excellent or good in 82% (95% CI 77 – 87). Within 30 days, death occurred in 14% and a thrombotic event in 10%.
      Andexanet alpha is currently available only in the USA and Europe. It is indicated for patients taking rivaroxaban and apixaban, when reversal of anticoagulation is needed owing to life threatening or uncontrolled bleeding. In the low dose regimen (after eight hours or with ≤ 5 mg of apixaban or ≤ 10 mg rivaroxaban) the initial IV bolus is 400 mg at a target rate of 30 mg/minute followed by IV infusion 4 mg/minute for up to 120 minutes; for the high dose regimen (therapeutic doses and < 8 hours or unknow time interval) 800 mg at a target rate of 30 mg/minute followed 8 mg/min for up to 120 minutes. A PCC would represent a general reversal agent for the factor Xa inhibitors, if andexanet alpha is not available.
      • Schulman S.
      • Gross P.L.
      • Ritchie B.
      • Nahirniak S.
      • Lin Y.
      • Lieberman L.
      • et al.
      Prothrombin complex concentrate for major bleeding on factor Xa inhibitors: a prospective cohort study.
      It should not be administered prophylactically in the case of emergency or urgent procedures, but it is recommended to have PCC available in case of uncontrolled bleeding.

      2.3.4.2.5 Practical considerations for reversal of direct oral anticoagulants

      As DOACs have a short half life (see Table 8), unless the patient has renal impairment, DOACs usually merely need to be discontinued to facilitate elective surgical procedures (see Table 16).
      For bleeding, including life threatening bleeding in patients treated with a DOAC, the therapeutic management is summarised in Table 10.
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • Albaladejo P.
      • Antz M.
      • Desteghe L.
      • et al.
      The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      Table 10Management of bleeding in patients taking direct oral anticoagulants (DOACs). Modified with permission from Steffel et al., 2018
      • Steffel J.
      • Verhamme P.
      • Potpara T.S.
      • Albaladejo P.
      • Antz M.
      • Desteghe L.
      • et al.
      The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.
      Major bleedingDirect thrombin inhibitors (dabigatran)FXa inhibitors (apixaban, edoxaban, rivaroxaban)
      Non-life threateningAssess type and dose of DOAC and last intake
      Local haemostatic measures
      Fluid replacement
      Red blood cell substitution, if necessary
      Platelet substitution (in case of thrombocytopenia or thrombopathy)
      FFP as plasma expander, if necessary (not as reversal agent)
      Tranexamic acid can be considered as adjuvant (1 g IV, repeat every 6 h, if necessary)
      Desmopressin can be considered in special cases
      Estimate normalisation of plasma levels:
      • Normal renal function: 12–24 h
      • CrCl 50–80 mL/min: 24–36 h
      • CrCl 30–50 mL/min: 36–48 h
      • CrCl < 30 mL/min: > 48 h
      Estimate normalisation of plasma levels: 12–24 h
      Maintain diuresisMaintain diuresis
      Consider idarucizumab (see below)
      Life threateningAll of the above measuresAll of the above measures
      IdarucizumabAndexanet alpha
      Alternatively, PCC 50 U/kg (with additional 25 U/kg if clinically needed)
      FFP = fresh frozen plasma; IV = intravenous; CrCl = creatinine clearance; PCC = prothrombin complex concentrate.

      2.3.4.3 Heparin induced thrombocytopenia

      HIT is a significant cause of morbidity and death due to life and limb threatening thrombosis. This extremely prothrombotic disorder is caused by an immune reaction against platelet factor 4 (PF4) complexes with heparin or other polyanions, ultimately initiating a vicious cycle with further platelet activation, aggregation, potential arterial and/or venous thrombosis, and thrombocytopenia, which may also lead to bleeding.
      • Bakchoul T.
      • Greinacher A.
      • Warkentin T.E.
      Heparin-induced thrombocytopenia in 2017 and beyond.
      Risk factors for HIT include duration and type of heparin exposure, patient population, trauma, and other clinical factors. The incidence of HIT varies from < 0.1% in obstetric patients, around 0.6% in medical patients receiving LMWH in prophylactic or therapeutic doses (including VTE treatment), 1% – 3% in cardiac surgery patients, and 1% – 5% in post-operative patients receiving UFH.
      • Linkins L.A.
      • Dans A.L.
      • Moores L.K.
      • Bona R.
      • Davidson B.L.
      • Schulman S.
      • et al.
      Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      There is a 10 fold higher likelihood of HIT in patients receiving UFH vs. LMWH. Fondaparinux does not appear to cause HIT.
      • Warkentin T.E.
      Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia.
      The initial suspicion of HIT is based on clinical features, most practically summarised in the 4T test (Table 11),
      • Warkentin T.E.
      Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia.
      a clinical scoring system for evaluating the clinical probability of HIT.
      • Cuker A.
      • Gimotty P.A.
      • Crowther M.A.
      • Warkentin T.E.
      Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis.
      A low score has a negative predictive value of 99.8% (95% CI 97 – 100), and intermediate and high probability scores have positive predictive values of 14% (95% CI 9 – 22) and 64% (95% CI 40 – 82), respectively.
      • Cuker A.
      Management of the multiple phases of heparin-induced thrombocytopenia.
      Table 11The “4Ts” scoring system for heparin induced thrombocytopenia. Modified from Cuker et al., 2012.
      • Cuker A.
      • Gimotty P.A.
      • Crowther M.A.
      • Warkentin T.E.
      Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis.
      The 4Ts score is the sum of the values for each of the four categories. Scores of 1–3, 4–5, and 6–8 are considered to correspond to a low, intermediate, and high probability of heparin induced thrombocytopenia, respectively
      4Ts2 points1 point0 points
      ThrombocytopeniaPlatelet drop >50% and platelet nadir >20 000/μLPlatelet drop 30%–50% or platelet nadir 10–19 000/μLPlatelet count drop <30% or platelet nadir <10 000/μL
      Timing of platelet count fallClear onset days 5–10 or platelet drop <1 day with prior heparin exposure within 30 dConsistent with days 5–10 fall but not clear (e.g., missing platelet counts) onset after day 10; or drop <1 d (prior heparin exposure 30–100 days ago<4 d without recent heparin exposure
      Thrombosis or other sequelaeNew thrombosis (confirmed); skin necrosis; acute systemic reaction after IV UFH bolusProgressive or recurrent thrombosis; non-necrotising (erythematous) skin lesions; suspected thrombosis (not proven)None
      Other causes of thrombocytopeniaNone apparentPossibleDefinite
      IV = intravenous; UFH = unfractionated heparin.
      The scores from the 4T test help determine subsequent management, which has been summarised in published algorithms.
      • Nagler M.
      • Bakchoul T.
      Clinical and laboratory tests for the diagnosis of heparin-induced thrombocytopenia.
      With an intermediate or high probability of HIT, heparin should be immediately replaced by an alternative anticoagulant (see Chapter 2.3.4.3.1), and a PF4/heparin immunoassay should be obtained. As the sensitivity is high, a negative test result generally rules out HIT. If positive, this should be confirmed with a functional test, e.g., heparin induced platelet activation assay test or serotonin release assay. With a high probability and/or positive tests, diagnostic screening for asymptomatic thrombosis should be conducted. With a low probability 4T test, HIT is reliably excluded.

      2.3.4.3.1 Alternative anticoagulants in suspected or confirmed heparin induced thrombocytopenia

      Non-heparin anticoagulants that have been used in HIT include argatroban, bivalirudin, desirudin, danaparoid, and fondaparinux. However, only argatroban and danaparoid are currently available and licensed for acute HIT. Argatroban has a short half life (40 – 50 minutes) and can be used in patients with renal insufficiency. It is administered as an IV continuous infusion with monitoring and dose adjustment targeted to an APTT of 1.5 – 3.0 times baseline.
      • Cuker A.
      Management of the multiple phases of heparin-induced thrombocytopenia.
      Danaparoid has a renal mode of excretion and is initiated with an IV bolus followed by a dose adjusted to an anti-Xa activity of 0.5 – 0.8 units/mL (danaparoid specific).
      • Cuker A.
      Management of the multiple phases of heparin-induced thrombocytopenia.
      After discontinuation of heparin and initiation of alternative anticoagulation, the platelet count should recover if the patient truly had HIT. Early overlapping with VKA during this phase could cause hypercoagulabilty owing to the rapid reduction in protein C levels, and INR monitoring may be complex as argatroban also affects the INR. Therefore, after the acute phase of HIT, bridging with fondaparinux to VKA has been suggested.
      • Lobo B.
      • Finch C.
      • Howard A.
      • Minhas S.
      Fondaparinux for the treatment of patients with acute heparin-induced thrombocytopenia.
      ,
      • Warkentin T.E.
      Fondaparinux versus direct thrombin inhibitor therapy for the management of heparin-induced thrombocytopenia (HIT) – bridging the River Coumarin.

      2.3.5 Pathways of care for deep vein thrombosis

      The introduction of LMWH led to increasing outpatient treatment of DVT. The safety and efficacy of such an approach was established in randomised studies in the 1990s,
      • Levine M.
      • Gent M.
      • Hirsh J.
      • Leclerc J.
      • Anderson D.
      • Weitz J.
      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
      ,
      • Koopman M.M.
      • Prandoni P.
      • Piovella F.
      • Ockelford P.A.
      • Brandjes D.P.
      • van der Meer J.
      • et al.
      Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group.
      and confirmed by a Cochrane Review published in 2018.
      • Othieno R.
      • Okpo E.
      • Forster R.
      Home versus in-patient treatment for deep vein thrombosis.
      The introduction of DOACs as recommended first line treatment for DVT,
      • Kearon C.
      • Akl E.A.
      • Ornelas J.
      • Blaivas A.
      • Jimenez D.
      • Bounameaux H.
      • et al.
      Antithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report.
      ,
      • Nicolaides A.N.
      • Fareed J.
      • Kakkar A.K.
      • Comerota A.J.
      • Goldhaber S.Z.
      • Hull R.
      • et al.
      Prevention and treatment of venous thromboembolism – International Consensus Statement.
      has further facilitated outpatient treatment, which is now well established as the standard of care for most patients with uncomplicated DVT. Conditions excluded in the original RCTs on home treatment included “massive” or recurrent DVT, PE or a high probability of developing PE, pregnancy, the presence of a contraindication for anticoagulation, comorbidity requiring hospitalisation, living far from a healthcare facility, and the presence of social circumstances not supporting home treatment, such as the possibility of non-compliance, lack of family support, living alone, and difficulty returning if complications develop. Although these conditions only affect a minority of patients in daily practice, they may be potential obstacles for outpatient management.
      Tabled 1
      Recommendation 13
      For most patients with deep vein thrombosis, outpatient management is recommended.
      ClassLevelReferences
      IALevine et al. (1996),
      • Levine M.
      • Gent M.
      • Hirsh J.
      • Leclerc J.
      • Anderson D.
      • Weitz J.
      • et al.
      A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis.
      Koopman et al. (1996),
      • Koopman M.M.
      • Prandoni P.
      • Piovella F.
      • Ockelford P.A.
      • Brandjes D.P.
      • van der Meer J.
      • et al.
      Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. The Tasman Study Group.
      Othieno et al. (2018)
      • Othieno R.
      • Okpo E.
      • Forster R.
      Home versus in-patient treatment for deep vein thrombosis.

      2.3.6 Anticoagulation therapy for the treatment of provoked deep vein thrombosis

      Provoking factors for DVT can be transient (such as surgery or hospital admission with bed rest [strict or with bathroom privileges] lasting at least three days) or persistent (such as thrombophilia) and may be associated with varying risks of DVT recurrence (see Table 4).
      • Kearon C.
      • Ageno W.
      • Cannegieter S.C.
      • Cosmi B.
      • Geersing G.J.
      • Kyrle P.A.
      • et al.
      Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH.
      Treatment options for cancer associated venous thrombosis (CAVT) are presented in Chapter 4.3. The duration of treatment for lower extremity DVT depends on the balance of bleeding risk due to anticoagulation and the risk of recurrence with and without anticoagulation. One published expert consensus suggested that a risk of VTE recurrence > 5% per year or >15% at five years would justify extended anticoagulant therapy as the benefits outweigh the risks.
      • Kearon C.
      • Iorio A.
      • Palareti G.
      Subcommittee on Control of Anticoagulation of the SSC of the ISTH. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting.
      In view of the reduced bleeding risks of DOACs, these recurrence rates should be lowered to < 3% per year, or even further when prophylactic doses of rivaroxaban or apixaban are to be used. The presence or absence of a recognisable risk factor when diagnosing VTE allows more accurate estimation of the potential risk of recurrence. Risk stratification for extended treatment is discussed in Chapter 2.3.7.4.

      2.3.6.1 Risk of recurrence after provoked deep vein thrombosis

      The risk of recurrent venous thrombosis after unprovoked and provoked VTE was evaluated in a meta-analysis.
      • Iorio A.
      • Kearon C.
      • Filippucci E.
      • Marcucci M.
      • Macura A.
      • Pengo V.
      • et al.
      Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review.
      The risk of recurrent VTE after provoked DVT (due to a transient risk factor) after stopping anticoagulation was 3.3% per patient year up to 24 months. Specifically, the risk of recurrent VTE was much lower when the provoking factor was surgery (0.7% per patient year) compared with patients with a non-surgical transient provoking factor (such as immobilisation, hormone therapy, long distance travel, fractures, major trauma, pregnancy, or non-surgical illness; 4.2% per patient year). In a more recent study that was a pooled analysis of the EINSTEIN-Extension
      The Einstein Investigators
      Oral rivaroxaban for symptomatic venous thromboembolism.
      and EINSTEIN CHOICE
      • Weitz J.I.
      • Bauersachs R.
      • Beyer-Westendorf J.
      • Bounameaux H.
      • Brighton T.A.
      • Cohen A.T.
      • et al.
      Two doses of rivaroxaban versus aspirin for prevention of recurrent venous thromboembolism. Rationale for and design of the EINSTEIN CHOICE study.
      RCTs comparing rivaroxaban with aspirin or placebo in patients with VTE, one year VTE recurrence rates were provided in relation to baseline risk factor profiles.
      • Prins M.H.
      • Lensing A.W.A.
      • Prandoni P.
      • Wells P.S.
      • Verhamme P.
      • Beyer-Westendorf J.
      • et al.
      Risk of recurrent venous thromboembolism according to baseline risk factor profiles.
      In this analysis, index VTE events were classified as unprovoked or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at one year were calculated. After unprovoked VTE, or VTE provoked by minor persistent or transient risk factor, rates of recurrence with placebo were 10.0%, 10.7%, and 7.1%, respectively. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR] 0.81, 95% CI 0.56 – 1.16). For patients with unprovoked VTE, provoked VTE by a minor persistent risk factor and provoked VTE by a minor transient provoking risk factor, anticoagulation with rivaroxaban reduced recurrence rates to 2%, 2.4%, and 0.4%, respectively, at 12 months. Therefore, these findings suggest that patients with provoked DVT and minor risk factors may benefit from extended anticoagulation therapy, similarly to patients with unprovoked DVT (see Chapter 2.3.7).

      2.3.6.2 Duration of anticoagulation therapy after provoked deep vein thrombosis

      The risk of recurrent events after discontinuation of anticoagulation for DVT has been studied extensively. In one patient level analysis including seven trials,
      • Boutitie F.
      • Pinede L.
      • Schulman S.
      • Agnelli G.
      • Raskob G.
      • Julian J.
      • et al.
      Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials.
      nearly 3 000 patients were included with > 4 000 patient years of follow up, with 40% of patients with provoked DVT. Groups were stratified on the basis of initial anticoagulation duration: 1 – 1.5 months, three months, and six months. The study included comparative studies comparing anticoagulation treatment durations between 1 – 1.5 months and 3 months,
      • Kearon C.
      • Ginsberg J.S.
      • Anderson D.R.
      • Kovacs M.J.
      • Wells P.
      • Julian J.A.
      • et al.
      Comparison of 1 month with 3 months of anticoagulation for a first episode of venous thromboembolism associated with a transient risk factor.
      • Levine M.N.
      • Hirsh J.
      • Gent M.
      • Turpie A.G.
      • Weitz J.
      • Ginsberg J.
      • et al.
      Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis.
      • Pinede L.
      • Ninet J.
      • Duhaut P.
      • Chabaud S.
      • Demolombe-Rague S.
      • Durieu I.
      • et al.
      Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis.
      1 – 1.5 months and six months,
      • Schulman S.
      • Rhedin A.S.
      • Lindmarker P.
      • Carlsson A.
      • Larfars G.
      • Nicol P.
      • et al.
      A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group.