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For decades acute lower limb deep venous thrombosis (DVT) has been subdivided into distal DVT (isolated to the calf veins) and proximal DVT (extending above calf vein level). The aim of this study was to analyse the anatomical site and extent of thrombus in a large cohort of patients with acute DVT.
Methods
A retrospective analysis of all patients aged >18 years, presenting with unilateral DVT according to duplex ultrasound investigation was performed at the University Hospital of Antwerp, Belgium (1994–2012). The anatomical site and extent of thrombus was registered and subdivided into five segments: calf veins (segment 1), popliteal vein (segment 2), femoral vein (segment 3), common femoral vein (segment 4), and iliac veins, with or without inferior vena cava (segment 5).
Results
The median age of the 1,338 patients (50% male) included was 62 years (range 18–98 years). Left sided DVT was predominant (57%). DVT was limited to one segment in 443 patients, of whom 370 had DVT isolated to the calf veins (28% of total cohort). In 968 patients with what was previously called “proximal DVT”, the median number of affected segments was three (range 1–5 segments). In this group iliofemoral DVT (at least involving segment four and/or five) was present in 506 patients (38% of total cohort), whereas the remaining patients had femoropopliteal DVT (at least in segment two and/or three but not in four or five). Iliofemoral DVT without thrombus in segments one and two was present in 160 patients (12% of total cohort).
Conclusion
This study illustrates the large diversity of thrombus distribution in patients previously described as having “proximal DVT”. Therefore, this term should be abandoned and replaced with iliofemoral and femoropopliteal DVT. Patients with iliofemoral DVT (38%) could be considered for early clot removal; 12% of all patients with DVT would be ideal candidates for such intervention.
This study reports the detailed duplex ultrasound results of the largest cohort to date of patients with acute unilateral deep venous thrombosis (DVT) of the lower extremity. It underscores the fact that the general term “proximal DVT” should be abandoned and replaced with a more precise description of involved segments, resulting in a further sub-classification into iliofemoral and femoropopliteal DVT with potential differentiation of treatment.
Introduction
According to recent guidelines acute deep venous thrombosis (DVT) frequently results in significant post-thrombotic morbidity despite adequate treatment.
Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence based clinical practice guide lines.
The risk of developing recurrent thrombosis and the severity of post-thrombotic syndrome (PTS) are related to the number and anatomical site of involved venous segments.
The worst PTS occurs when the initial thrombus involves the iliac or iliocaval outflow segment and when multiple segments are involved. Depending on the central extent of the DVT, a different therapeutic approach may be warranted. There is growing evidence that patients with iliocaval or iliofemoral DVT may benefit from early clot removal by catheter directed thrombolysis (CDT), or other means.
A meta-analysis of randomised studies comparing CDT with anticoagulant treatment alone in patients with acute iliofemoral DVT has shown a reduced incidence of PTS, and less reflux and residual obstruction.
In clinical practice and in the majority of studies of acute DVT of the lower limbs, the description of the extent and location of thrombus has been limited to distinguishing between “distal” and “proximal” DVT. Distal DVT is defined as thrombus confined to one or more of the calf veins. A proximal DVT is defined as a thrombus involving one or more of the more central veins including the popliteal (PV), femoral (FV), common femoral (CFV), profunda femoris, external iliac (EIV), internal iliac, and common iliac (CIV) veins, and the inferior vena cava (IVC). In practice, such simple subdivision between proximal and distal is inadequate for two main reasons. First, considering as one large heterogeneous group, all patients with DVT above the level of the calf veins, causes difficulties in comparing aetiology, pathophysiology, clinical impact, and outcome of treatment between different studies. Second, such an imprecise description of the extent and site of an acute DVT does not allow for the selection of patients who might benefit from an alternative therapeutic approach to anticoagulation alone. The iliofemoral venous segment (iliac veins and/or CFV, with or without IVC involvement) has to be differentiated from the femoropopliteal vein segment (femoral or popliteal venous segments or both, without extension to the CFV or iliac veins), as it constitutes the single common venous outflow of the lower limb and is unique in this aspect.
The 2012 guidelines of the Society for Vascular Surgery and the American Venous Forum clearly established the need for precision in the diagnosis of DVT, with guideline 1.1 stating: “We recommend use of precise terminology to characterize the most proximal extent of venous thrombosis as involving the iliofemoral veins, with or without extension into the inferior vena cava; the femoropopliteal veins; or isolated to the calf veins in preference to simple characterization of a thrombus as proximal or distal”.
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
Nowadays, duplex ultrasound (DUS) has become the gold standard for the diagnosis of DVT, but to date no similar cohort study has been reported in which DUS had been used for DVT diagnosis. The aim of the present study was therefore to identify precisely, and retrospectively analyse the anatomical sites and extent of acute DVT in a large consecutive cohort of patients undergoing DUS scanning for acute DVT.
Patients and Methods
Since 1988 all patients presenting to the Department of Thoracic and Vascular Surgery at the University Hospital of Antwerp (UZA), Belgium, with clinical suspicion of DVT have been submitted to venous colour DUS performed by well trained vascular technologists or by vascular surgeons. A complete DUS of both limbs was performed, usually in the supine and prone position.
This consisted of compression ultrasound, where appropriate (CFV, FV, PV), in combination with colour flow interrogation of the remaining veins (calf veins and veins above the inguinal ligament up to the level of the IVC whenever feasible). In very obese patients at least the EIV was visualised above the inguinal ligament. The profunda femoris and the internal iliac veins were not studied in detail. From 1994, the procedure was to draw on a standardised diagram the exact location and extent of the thrombus (Fig. 1). If thrombus had been found in only one of two veins of a duplicated venous system, typically at the level of the FV or PV, this segment was indicated as containing thrombus without differentiating between thrombus in one vein or in both veins. If a concomitant superficial vein thrombosis (SVT) was present, it was indicated on the diagram as well.
Figure 1Diagram used for deep venous thrombosis diagnosis according to duplex ultrasound. The venous vasculature is subdivided into five segments.
In 2012, a retrospective database of patients diagnosed with DVT at UZA was constructed. Initial diagrams of 1,701 consecutive patients presenting with a first episode of acute DVT of the lower limb between January 1994 and July 2012 were available. Patients <18 years of age, patients with bilateral DVT, or files with missing data were excluded from the analysis (Fig. 2). Basic demographic data such as age and sex were directly retrieved from the patient's identification on the diagram. Date of DVT diagnosis, affected side (right or left), presence of a concomitant SVT, and anatomical site and extent of thrombus were registered in the database. Five segments were identified on each diagram (Fig. 1), corresponding with the following veins involved: calf veins (posterior and anterior tibial veins and peroneal veins), including muscular veins (gastrocnemius and soleus veins) (segment one); PV (segment two); FV (segment three); CFV (segment four); and EIV/CIV with or without IVC (segment five). Involvement of the internal iliac vein and the profunda femoris vein was not recorded consistently on the diagram and was excluded from the database.
Figure 2Flow diagram of the study showing selection of patients with a first episode of acute unilateral deep venous thrombosis (DVT) included in the analysis.
The UZA ethics committee approved the study (Ref. EC/PC/avl/2015.016). The database was analysed for demographics, side of acute DVT, location of thrombus (affected vein segments), extent of DVT (number and presentation of affected segments), and presence of concomitant SVT. The left to right lower limb ratio (L:R ratio) was calculated per segment and the global L:R ratio was calculated as the number of left sided versus right sided segments containing thrombus. An additional analysis of the extent of thrombus was performed by examining whether thrombus formation probably started at iliac level (e.g. in case of an underlying compressive lesion
) and extended peripherally (retrogradely), or started in the calf and extended centrally (antegradely).
Statistical analysis
In order to test if the proportion of thrombus location in the left and right leg differed from 50%, a Z-test for a single proportion was used for each segment. The p-values were multiplied by 5, because five segments were tested (Bonferroni correction). The Z-test for two proportions was used to test if the L:R ratio differed between segments one and five. One-sample Z-tests were programmed using Excel 2010 (Microsoft, Redmond, WA, USA). Statistical significance was accepted at p < .05.
Results
In total, data from 1,338 patients with acute unilateral DVT of the lower limb were available for analysis (Fig. 2). The median age of the patients was 62 years (range 18–98 years), 50% were male, and in 57% of patients the left leg was affected.
Anatomical site of the thrombus
The segments involved in the DVTs are shown in Table 1. Thrombosis isolated to the calf veins (so called “distal DVT”) was diagnosed in 370 patients (28%). In 325 (24%) patients the DVT involved veins above the inguinal ligament (segment five). There was a left sided predominance at each of the five segments involved in DVT (Bonferroni-corrected p < .05 for all segments). The global L:R ratio was 1.4/1 and the L:R ratio was larger in segment five than in segment one, but this difference did not reach statistical significance (p = .20). Concomitant SVT was present in 179 patients (13%).
Table 1Thrombus location in segments 1–5 in left and right lower limbs given as the total number of limbs, percentage of all lower limbs (n = 1,338) and left to right side ratio (L:R ratio).
In 443 patients (33%), of whom 370 had thrombosis isolated to the calf veins, DVT was limited to one segment. DVT involved two segments in 208 patients (16%), three segments in 345 patients (26%), four segments in 149 patients (11%), and all five segments in 193 patients (14%). Fig. 3 shows the subdivision according to the number of segments involved in the DVT in 968 patients with iliofemoral or femoropopliteal DVT. The median number of affected segments was three (range 1–5 segments). Fig. 4 presents a more detailed analysis of the extent of thrombus in these patients. Twenty-three patients were not included in this sub-analysis as they had DVT in non-adjacent segments. Of the remaining 945 patients with a DVT previously described as “proximal”, according to the new definition,
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
iliofemoral DVT was present in 506 (54% [38% of the total cohort]), whereas femoropopliteal DVT was seen in the remaining 439 patients. The most commonly found DVT was the combination “1 + 2 + 3” (femoropopliteal DVT involving the calf veins, PV, and FV) in 267 patients (20% of total cohort). Of the 506 patients with iliofemoral DVT, 189 had no involvement of segment one, the calf veins, and 160 (12% of the total cohort) had no involvement of segments one or two, meaning the thrombus did not extend more distally than the FV.
Figure 3Number of segments involved in 968 patients with acute unilateral “proximal deep venous thrombosis”.
Figure 4Distribution of the extent of thrombus in 945 patients with “proximal deep venous thrombosis” in one segment, or two and more adjacent segments. Data of 23 patients are excluded from this analysis because they had deep venous thrombosis in two or more non-adjacent segments.
The extent of thrombus in relation to the underlying pathophysiology
If thrombus is limited to only one segment, it must have been initiated in that segment, unless part of the thrombus embolised. DVT isolated to the calf veins (segment one) was far more common (n = 370) than DVT isolated to one of the other segments: in three patients segment two alone was involved, in 37 patients segment three, in 25 patients segment four, and in eight patients segment five.
Thrombus probably started at the level of the calf in 872 patients (65% of total cohort): this group included those with the extent of thrombus limited to the calf, segment 1 (n = 370), thrombus located in segments 1 + 2 (n = 111), in segments 1 + 2 + 3 (n = 267), and in segments 1 + 2 + 3 + 4 (n = 124). Thrombus was most probably formed at the iliac or iliocaval level in 126 patients (9% of total cohort), consisting of those with thrombus in segment 5 (n = 8), in segments 4 + 5 (n = 31), in segments 3 + 4 + 5 (n = 67), and in segments 2 + 3 + 4 + 5 (n = 20). None of these had calf vein (segment one) involvement. In the remaining patients with all five segments involved, it was uncertain where the thrombus was formed initially (but most likely in the calf).
Discussion
The present study reports detailed DUS findings of the largest cohort to date of patients presenting with a first episode of acute unilateral symptomatic DVT. It illustrates the great diversity of thrombus location and extent in patients with acute DVT. It shows that 38% of patients with DVT present with iliofemoral DVT. Moreover, the study shows that in the majority of cases the thrombus was initiated in the calf veins. It appears that approximately 9% of all DVTs may be formed at iliac or iliocaval level and then propagate peripherally down the lower limb.
The previous term “proximal DVT” includes a large variety of different presentations of anatomical locations and extent of thrombi, as reported in previous venographic studies.
The present DUS study provides further insight into the wide heterogeneity of the anatomical presentation of “proximal DVT” (Fig. 4). Four different segments may be distinguished at the time of diagnosis, as was registered on the diagrams used in the present study. Equally, during follow up, the evolution of the thrombosis (recanalisation, collateralisation, valvular function) at each of these segments can be represented on a similar diagram for detailed follow up, study, and audit. However, from a practical point of view, it is sufficient to combine these four segments 2 by 2. This allows clear differentiation between thrombus in segments two and three, described as femoropopliteal DVT, and thrombus involving at least segment four and/or five, described as iliofemoral DVT.
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
In the present study, iliofemoral DVT was diagnosed in 506 (38%) patients. In a large cohort of 1,289 consecutive patients with DVT, Partsch also found iliofemoral DVT in 28% of patients.
Thus, involvement of the iliac veins and CFV is a frequent observation. This is an important finding, as nowadays patients with iliofemoral DVT, with or without involvement of the IVC, may benefit from CDT, and pharmaco-mechanical or aspiration thrombectomy, and hence adequate patient selection at the time of diagnosis is mandatory.
Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
Potentially all patients with iliofemoral DVT are candidates for early clot removal. Of these, patients with no calf vein thrombosis have better outcome following invasive treatment of acute iliofemoral DVT and the majority of them (in the present study, 160 patients, 12% of the total cohort) would have been considered “ideal” candidates, as there was no involvement of the PV or calf veins.
The global L:R ratio (1.35) was similar to the findings in a cohort of 885 patients with DVT examined by venography, where a L:R ratio of 1.32 was found.
This anatomical situation not only induces left iliac or iliofemoral DVT more frequently than the right, but also appears to increase the global incidence of left sided DVT, even at the level of the calf veins (Table 1). The latter may be explained by an enhanced venous stasis on the left side, secondary to the compression at iliac level. The L:R ratio was highest in segment five, the segment above the inguinal ligament. In a large series of selected patients with acute iliofemoral DVT, treated with catheter directed thrombolysis, the L:R ratio was much more pronounced (79/24, or L:R 3.29).
In a systematic review of published data from patients with DVT during pregnancy, left sided DVT was reported in 88% of women in which the side of DVT was known.
DVT affected a median of three segments, and in a considerable number of patients four or even five segments were involved. Residual thrombus burden has been shown to influence clinical outcome after treatment.
Patients with DVT involving more vein segments, may have more vein segments with incomplete recanalisation, and are therefore more likely to develop recurrent DVT.
A detailed description of all the segments involved in the DVT at the time of the acute event may allow prediction of the longer term clinical prognosis.
Although the aetiology of DVT has been studied extensively, the pathophysiology of DVT is not always clear in an individual patient. While the three elements of Virchow's triad are variably expressed, one question is where the initial thrombus is formed. In acute iliofemoral DVT there are two main possible scenarios: either thrombus is initiated in the calf and progressed centrally, or it formed at iliac level and extended peripherally. The findings in the present study suggest that in the majority of cases the thrombus was formed in the calf, which is in accordance with previous reports.
However, 9% of all patients with DVT had thrombus at the iliac or iliocaval level without thrombus in the calf veins. This finding suggests that in these patients thrombus initiated above the inguinal ligament, at iliac or IVC level, and subsequently extended peripherally but did not reach the calf. As mentioned above, in these patients it is particularly beneficial to perform early clot removal.
The initial thrombus formation is probably related to central outflow obstruction of varying types, such as an underlying compression lesion, which may play a role in unprovoked and provoked DVTs. A typical scenario is left sided pregnancy related DVT. Chan et al. found DVT involving all four proximal segments without calf vein involvement in 71% of women with DVT during pregnancy, and 64% of the latter had iliofemoral DVT.
Unilateral or bilateral iliofemoral DVT is also very common in patients with congenital absence of the IVC or post-thrombotic obstruction of the IVC following a DVT in the neonatal period. In a survey including 35 patients with this condition, the acute DVT was situated at the iliac or iliofemoral level in 81% of lower limbs.
The pathophysiology of DVT in patients with isolated DVT either in segments two, three, or four is probably related to local causes. These could be an extension from an ascending SVT through the saphenofemoral junction, through the saphenopopliteal junction, or a perforating vein “per continuitatem” into the deep venous system, or local trauma due to repeated access (intravenous drug users) or other local processes. Thrombus confined to a single segment at the time of diagnosis can also be the result of an initially more extensive DVT, which has resolved owing to spontaneous fibrinolysis in adjacent segments or, more frequently, has undergone partial embolisation into the pulmonary circulation, resulting in subclinical or clinical pulmonary embolism.
This study has some limitations. First, it was only possible to analyse thrombus location and extent in general, without distinguishing between unprovoked and provoked DVT. To achieve this, an additional study of all patient files would have been necessary, which was not feasible. Second, the profunda femoris vein was not studied separately, although this vein may play an important role as part of the collateral circulation. Inflow from the profunda may prevent thrombus extension from the femoral vein centrally or, if not involved, establish a compensatory outflow channel in the future.
Third, no distinction was made between calf vein thrombosis of the peroneal, posterior and anterior tibial veins and muscular calf vein thrombosis, or between DVT in a single calf vein and in multiple deep calf veins. This could have provided interesting data about their frequency of occurrence in this large cohort. It should also be acknowledged that the accuracy of DUS in delineating the central extent of the thrombus in the CIV and IVC may have been limited in certain patients. The involvement of the EIV, that is, extension above the inguinal ligament, was always evaluated, which is sufficient for the present analysis.
In conclusion, patients with an acute lower limb DVT should have a thorough mapping of the thrombus localisation by DUS rather than a simple subdivision into “distal” and “proximal” DVT. The results of detailed mapping illustrated the large diversity of thrombus distribution in patients previously described as having a “proximal DVT”. Therefore this entity should be abandoned and replaced by iliofemoral and femoropopliteal DVT. The study also confirms that a substantial number of patients with DVT (38% in the present cohort) present with iliofemoral DVT. This finding allows differentiation of treatment as per guidelines.
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
In practice, as many as 12% of patients with DVT would be ideal candidates for early clot removal, based on DUS findings.
Conflict of Interest
None.
Funding
None.
Acknowledgements
We would like to thank the vascular technologists and vascular surgeon colleagues, active in the Department of Thoracic and Vascular Surgery of the Antwerp University Hospital between 1994 and 2012, for having carefully registered the extent of DVT on a diagram for every patient.
This study was presented at the 14th annual meeting of the European Venous Forum (EVF) in Belgrade (Serbia) in June 2013 by Niels Bochanen (winner of 3rd EVF prize).
References
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 guide lines.
Early thrombus removal strategies for acute deep venous thrombosis: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum.
Long-term outcome after additional catheter-directed thrombolysis versus standard treatment for acute iliofemoral deep vein thrombosis (the CaVenT study): a randomised controlled trial.
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