European Journal of Vascular & Endovascular Surgery
Volume 35, Issue 2 , Pages 145-152, February 2008

Recombinant Activated Factor VII: A Solution to Refractory Haemorrhage in Vascular Surgery?

  • O.J. Warren

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • Corresponding Author InformationCorresponding author. Mr. O. Warren BSc (Hons) MRCS, Department of BioSurgery and Surgical Technology, Imperial College, London, 10th Floor QEQM Building, St. Mary's Hospital, London, W2 1NY, United Kingdom.
    • ,
  • E.M.H. Alcock

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • ,
  • A.M.T.L. Choong

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • Regional Vascular Unit, St. Mary's Hospital, London, United Kingdom
    • ,
  • D.R. Leff

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • ,
  • I. Van Herzeele

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • Regional Vascular Unit, St. Mary's Hospital, London, United Kingdom
    • ,
  • A.W. Darzi

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • ,
  • T. Athanasiou

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • ,
  • N.J.W. Cheshire

      Affiliations

    • Department of BioSurgery and Surgical Technology, Imperial College, London, United Kingdom
    • Regional Vascular Unit, St. Mary's Hospital, London, United Kingdom

Accepted 27 August 2007. published online 26 October 2007.

Article Outline

Objectives

Post-operative haemorrhage is a recognised complication and independent predictor of outcome in complex vascular surgery. The off-license administration of activated Recombinant Factor VII (rFVIIa) to treat haemorrhage in other surgical settings has been investigated, but concerns over potential adverse events have limited its use in vascular surgery. This article reports rFVIIa's method of action and systematically reviews rFVIIa's role in complex vascular surgery.

Methods

A systematic literature search identified articles reporting on rFVIIa administration within vascular surgery patients. Patient-specific data regarding transfusion requirements was extracted and pooled statistical analysis performed.

Results

15 articles reporting 43 patients were identified. RFVIIa has been administered in open and endovascular procedures and in both elective and emergency settings. Major aortic surgery accounted for 75% of cases. The range of rFVIIa administered as a cumulative dose was large, as was the variation in initial dose. Transfusion data from 9 patients was pooled and analysed. Significant differences were found between pre- and post- rFVIIa for packed red cell transfusions (mean 29.2 vs. 8.2, p=0.015). Intra-arterial thrombosis was reported in 3 cases.

Conclusions

RFVIIa may reduce haemorrhage in selected vascular surgical patients. Randomized controlled trials are justified to definitively investigate its role within this setting.

Keywords: Haemorrhage, Recombinant FVIIa, Vascular Diseases, Surgery, Aneurysm

 

Back to Article Outline

Introduction 

Complex vascular surgery, with or without extracorporeal circulatory support, is associated with altered haemostasis and increased post-operative bleeding, even in patients with normal preoperative coagulation parameters.1, 2 Excessive blood loss, and blood product transfusion requirements, are two key independent predictors of outcome in major vascular surgery patients.3, 4 Research into haemorrhage reduction in this setting includes the use of antifibrinolytics (e.g. aprotinin) and intra-operative autologous transfusion devices.5, 6, 7 However these have met with limited results. The need for novel haemostatic solutions to refractory haemorrhage in vascular surgical patients therefore persists.

Recombinant factor VIIa (rFVIIa) (NovoSeven; NovoNordisk®, Bagsvaerd, Denmark) was first licensed for the treatment of haemorrhage in patients with hemophilia A or B with neutralizing auto-antibodies (coagulation inhibitors) to factor VIII or IX.8, 9 In 2005 the United States Food and Drug Administration increased rFVIIa's license to include surgical procedures in the same patient group, and patients with congenital factor VII (FVII) deficiency.10 The surgical literature increasingly reports the off-license administration of rFVIIa to arrest haemorrhage refractory to other interventions.11, 12, 13

Whilst off-label use of rFVIIa within vascular surgical practice has been reported, this has been predominantly within case reports or series 14, 15, 16, 17, 18 or as part of larger cohort studies of mixed patient groups,19, 20, 21 and thus the role of rFVIIa in vascular surgery is currently unclear. In this paper we describe the mechanism of action of rFVIIa, systematically review the available evidence on the efficacy, dosage, safety and cost implications of rFVIIa use in vascular surgery, and formulate proposals for future research.

Back to Article Outline

Mechanism of Action of rFVIIa 

The molecular mechanisms by which rFVIIa induces the formation of a stable haemostatic plug remain unclear. Whilst it is generally agreed that rFVIIa enhances thrombin generation at sites of tissue injury, controversy exists regarding the mechanisms by which this comes about, particularly the source and role of the protein, Tissue Factor (TF).

In physiological conditions, TF is absent from vascular cells that come into contact with flowing blood and is present as an inactive pool on sub-endothelial cells. Vessel injury exposes this TF to the blood, where it binds and activates FVII. The resulting TF-FVIIa complex catalyzes the conversion of factor X into its active form (Xa), induces thrombin generation, and leads to fibrin formation and platelet activation.

The situation differs in pathological conditions. Within atherosclerotic plaques, vascular smooth muscles cells, monocytes and endothelial cells have all been reported to aberrantly express and expose TF to the circulation.22 Not only has this been shown to be a critical event in atherothrombosis, but this expression and exposition has been shown to occur at higher levels in patients with symptomatic coronary and carotid disease, suggesting a role for TF in plaque instability.23, 24 Elsewhere, pro-inflammatory cytokines released during the acute phase response, have been shown to induce the production and expression of TF on circulating neutrophils and monocytes.25, 26 Recently, controversy has arisen over the presence, concentration and function of ‘micro-particles’ of TF within circulating blood27; some authors have reported the presence of physiologically active blood-borne TF28, 29, 30 whilst others have refuted it's existence.31, 32

Regardless of location, the exact role that TF plays in Recombinant FVIIa's mechanism of action requires further clarification. Knowledge of the normal haemostatic process, plus the fact that rFVIIa appears to induce thrombosis at sites of tissue injury, led to the hypothesis that rFVIIa acts via a TF-dependent mechanism.33, 34, 35 Whilst supported by various studies using different models,36 the high plasma concentrations of rFVIIa required to induce haemostasis suggest that TF-dependent activation cannot be the sole mechanism. RFVIIa has been shown to directly activate Factor X on phospholipid vesicles, activated platelets or monocytes independently of TF,37, 38, 39 although this process is much less efficient and has not been replicated by all groups.40

It is likely that rFVIIA probably functions via a combination of TF-dependent and TF-independent pathways. The level and location of TF expression in patients undergoing vascular surgery are likely to be significantly higher and more widespread than in normal subjects, due to their pre-existing atherosclerotic disease as well as the acute physiological disruption caused by major vessel surgery. Therefore the appropriateness of administering rFVIIa to these patients requires careful review.

Back to Article Outline

Methods 

Literature search 

A Medline, Google Scholar, Embase, Ovid and Cochrane database search was performed to identify all studies concerned with the use of rFVIIa in vascular surgery. The following MeSH headings were used: “recombinant FVIIa”, and “vascular diseases”, “aorta”, “haemorrhage”, “aneurysm” and “surgery”. The “related articles” function was utilised to broaden the search, and all abstracts, studies, and citations scanned and reviewed. Based on the title and abstract of the publication, we retrieved articles containing clinical data on the use of rFVIIa. References of the articles acquired were also searched manually. No language restrictions were made. Laboratory and animal studies were excluded. The latest date for this search was 1st May 2007.

Inclusion and exclusion criteria 

We included any article that reported on the administration of rFVIIa to stop haemorrhage in patients who had undergone vascular surgery. For the purpose of this review, we defined ‘vascular surgery’ to include intervention upon the descending thoracic aorta (distal to the left subclavian artery), the remainder of the aorta distally and peripheral arteries. Aortic arch, valvular or coronary artery surgery was deemed to be the domain of the cardiothoracic surgeon. This area has been recently reviewed 11 and thus these patients or studies were excluded. In one instance, peripheral vascular intervention was required as a complication of cardiothoracic surgery and this patient was included as haemorrhage pertained to this portion of the procedure. Articles that studied the effect of rFVIIa on a mixed cohort of patients, e.g. those in Intensive Care Units, were studied and data for vascular patients involved in those studies was extracted as far as possible. Publications or patients were excluded if they involved complex multiple trauma or the prophylactic impact of rFVIIa. Articles were classified as case reports or series, retrospective database (or chart) reviews, and clinical studies.

Data extraction and validation of studies 

Three reviewers (EA, IVH, and DL) independently extracted the following data from each study: first author, year of publication, study population characteristics, study type, number of subjects, pathology and procedure type. Data was retrieved on the following outcomes of interest: Dosage (initial and cumulative), pre- and post-intervention transfusion requirements, adverse events (stroke, myocardial infarction and other thromboembolic effects) and mortality.

Data analysis 

Outcome data was heterogeneous, and in some cases unavailable, and this prevented a formal meta-analysis being performed. However, where articles reported individual patient-specific data regarding blood product requirements prior to and after RFVIIa infusion this was extracted and a pooled analysis performed. Data are expressed either as raw count and percentages or as mean value plus or minus standard deviation. Kolmogorov-Smirnov test was performed to test normality of distributions and revealed the data to be normally distributed. Thus Paired Samples T-Test was performed. All statistical analysis was performed using SPSS 14.0 (SPSS Inc., Chicago, IL).

Back to Article Outline

Results 

Study identification 

Fig. 1 outlines the systematic search strategy and results. 377 publications were identified of which 357 were excluded following title and abstract review. 21 publications were investigated in full. Of these, 6 further articles failed to meet our inclusion criteria and 1 study was excluded due to duplication in a report published by the same group one year earlier.41 1 further study was identified from a detailed reference check. 15 articles were therefore included in our study, 5 purely on vascular patients 14, 15, 16, 17, 18 and the remaining 10 regarding mixed populations containing some vascular patients.19, 20, 21, 42, 43, 44, 45, 46, 47, 48 Of the 15 articles, 5 were case reports or series,15, 16, 17, 18, 42 and 10 were retrospective database or chart reviews.14, 19, 20, 21, 43, 44, 45, 46, 47, 48

Case mix and patient demographics 

The 15 articles reported on the administration of rFVIIa to a total of 273 patients, of whom 43 had undergone vascular surgery as previously defined. The patients ranged from 39 to 83 years of age, 51% were male, 26% female and in 23% the gender of the patient was not declared.

The variety of procedures performed upon rFVIIa-treated patients is outlined in Table 1. One patient received rFVIIa after two different operations separated by a 34 day period on the Intensive Care Unit,16 and thus 44 procedural episodes are described in 43 patients. Unsurprisingly major thoracoabdominal or abdominal aortic (both supra- and infrarenal) surgery accounts for the vast majority of cases (75%). RFVIIa has been administered in both elective18, 48 and emergency43 settings, to assist in the management of perioperative complications, such as evacuation of post-operative haematoma14 and repair of leak,42 and in both open and endovascular procedures. One major venous injury has been treated with rFVIIa,19 and one patient had rFVIIa administered via a standard catheter directly into a false aneurysm of the descending thoracic aorta which had developed following thoracoabdominal aortic replacement.17

Table 1. Case Mix
ProcedureNumber (%)
Thoracoabdominal Aortic Surgery7 (15.9)

Descending thoracic reconstruction

4

Descending thoracic, aorto-femoral and aorto-iliac reconstruction

1

Thoracoabdominal aneurysm repair

1

Allograft replacement of infected descending thoracic prosthesis

1

Abdominal Aortic Surgery26 (59.1)

Suprarenal aneurysm repair

9

Open infrarenal aneurysm repair

Post-operative leak

2

Ruptured

2

Elective

2

Unspecified

6

Endovascular infrarenal aneurysm repair

2

Re-do Aorto-bifemoral bypass grafting

2

Aorto-iliac pseudoaneurysm ligation & axillo-femoral bypass grafting

1

Non-Aortic or Non-specified Vascular Surgery11 (25)

‘Major vascular procedure’

4

Evacuation of post-operative haematoma and repair of leak

3

Femoro-femoral crossover graft (following type a aortic dissection)

1

‘Perioperative haemorrhage’

1

Inferior vena caval thrombus removal and repair

1

Local infusion into false aneurysm

1

Total44 (100)

It was not possible to ascertain any accurate data on the proportion of patients who had a declared degree of pre-operative coagulopathy e.g. secondary to hepatic disease, or anticoagulant or antiplatelet therapy, predominantly because this was not stated in the paper. However, three patients who received major thoracic surgery underwent intra-operative cardiopulmonary bypass, a recognised contributor to peri-operative coagulopathy.49

Studies were searched to find any potential conflicts of interest. None of the authors of the fifteen articles had a financial arrangement with NovoNordisk.®

Dosage and frequency of administration 

To allow data synthesis, we arbitrarily chose three dosing levels of rFVIIa (see Table 2). The frequency of rFVIIa administration was variable. Whilst some groups prescribed only a single bolus 17, 18, 19 others administered further doses if bleeding failed to stop.42, 48 Therefore if patients received multiple doses, their cumulative dose per kilogram body weight was recorded. The range of rFVIIa administered as a cumulative dose was large (24μg/kg – 360μg/kg, mean=87.6μg/kg) as was the variation in initial dose (24μg/kg – 120μg/kg), and the total number of doses (1 - 4). 59.1% of the patients within the series had documented cumulative doses ≤ 90μg/kg. The mode dose was 90μg/kg, the recommended dose in haemophiliacs. The timing of administration, and the criteria upon which the decision to do so was made are frequently unclear. Some groups rely on surgeon and haemaologist ‘discretion’,14, 21whilst others specify the receipt of specific quantities of blood products by the patient.19 RFVIIa is manufactured in vials of 1.2, 2.4 and 4.8mg and is expensive (approaching US$1/μg),50 and this appears to have led some centres to utilise a ‘best-fit’ dosing regimen to avoid opening more vials than necessary.44, 48

Table 2. Variations in Dosing
Dosing (n=44)Frequency (%)
Low Dose (< 60μg/kg)15 (34.1)
Mid–Dose (60–90μg/kg)11 (25)
High Dose (> 90μg/kg)6 (13.6)
Undisclosed12 (27.2)

Total44 (100)

Effect on haemorrhage 

Whilst the majority of articles reported some reduction in blood loss, either as witnessed by the clinician 18, 47 or a reduction in the need for further blood products,46 this was not a uniform finding.48 Furthermore, this was frequently a subjective assessment. 5 articles presented patient-specific transfusion data, both pre- and post-rFVIIa administration, on 9 different patients.15, 16, 42, 43, 48 This data, along with mean and standard deviation is presented in Table 3. A statistically and clinically significant reduction in packed red cell transfusions following rFVIIa administration was demonstrated (p=0.015), as was a reduction of borderline statistical significance in platelet transfusions (p=0.057). No significant effect on fresh frozen plasma or cryoprecipitate administration was found. To ensure the findings were not related to the papers studied, regression analysis was performed, taking into account the article from which the data was extracted. A group effect (using rFVIIa=yes as an independent group variable and blood product loss as dependent variable) was detected.

Table 3. Blood Product Requirements Pre- and Post-RFVIIa administration
PatientsPre-rFVIIa PRCPost-rFVIIa PRCPre-rFVIIa PltsPost-rFVIIa PltsPre-rFVIIa FFPPost-rFVIIa FFPPre-rFVIIa CryoPost-rFVIIa Cryo
1. Pugh et al.4229402418221040
2. Pugh et al.421442358010
3. Cheng et al.1517032019000
4. Clark et al.482761184100
5. Clark et al.48281422871010
6. Clark et al.4825611441010
7. Raux et al.1666251064000
8. Raux et al.161802009000
9. Aggarwal et al.43392376324500

Mean Units (± S.D)29.2±15.78.2±12.616.4±19.31.9±2.118.6±19.25.4±6.910±15.87.8±13

PRC=Packed Red Cells, Plts=Platelets, FFP=Fresh Frozen Plasma, Cryo=Cryoprecipate, S.D=Standard Deviation.

Adverse events and mortality 

Patient specific thromboembolic adverse event data was not available for 62% of the cohort, and thus calculation of an estimated adverse event rate would be inappropriate. Intra-arterial thrombosis was reported in 3 patients, the risk of which may be increased in vascular patients due to rFVIIa's proposed mechanism of action. It is worth noting however that these cases were all reported by the same group, who administered rFVIIa alongside human factor VIII-von Willebrand factor concentrate and/or human fibrinogen, both of which increase the risk of coagulation and make it unclear as to how much these events are attributable to rFVIIa.45 16.3% of patients in the cohort were reported to have died as a result of refractory haemorrhage, due predominantly to two studies, one of which reported a 22% mortality rate 14 and the other 100%.48

Back to Article Outline

Discussion 

We have synthesised all of the available data within the surgical literature on the administration of rFVIIa to vascular patients suffering from haemorrhage refractory to other conditions. By combining data originally reported in case reports or series, we have demonstrated a clinically significant reduction in blood and platelet transfusion requirements following the administration of rFVIIa, a finding supported by work in other surgical settings.12, 13 Whilst our findings must be interpreted cautiously, as these cases are highly heterogeneous and there is an inherent publication bias in non-comparative reports, we feel they justify more research being performed in this setting. This may help to eradicate the significant variation in practice we have demonstrated.

Ever since Kenet et al. reported the successful use of rFVIIa in military trauma in 1999,51 research has been undertaken in most surgical specialities to identify any potential role for rFVIIa. Vascular surgery lagged behind the other surgical specialities in this regard. One reason for this may be theoretical concern regarding the exacerbation of conditions mediated by TF exposure to the circulation. Atherosclerotic plaques express TF, and both surgical injury and extracorporeal circulation up-regulate systemic TF expression. Thus patients undergoing major vascular surgery who receive rFVIIa may be at increased risk of unwanted systemic thrombosis. These concerns are not unwarranted; A recent review of thromboembolic complications in patients treated with rFVIIa reported to the FDA database from 1999 to end 2004 suggested an increased rate in those treated for unlabelled conditions,10 an alarming result considering the morbidity and mortality from events such as stroke and myocardial infarction is so high. Furthermore, whilst an estimated adverse event rate for the cohort was not possible in our review due to absence of data, three patients were identified who suffered intra-arterial thrombosis following rFVIIa administration. However, similar theoretical concerns also apply to cardiac surgical patients. This group was recently reviewed by Warren et al., who aggregated the available data within cardiac surgical patients treated with rFVIIa for refractory haemorrhage and found a thromboembolic adverse event rate of 5.3% for adult patients.11 This figure tallied with that of Levy et al. who reviewed 13 NovoNordisk®-sponsored clinical trials of rFVIIa in patients with coagulopathy secondary to anti-coagulation, cirrhosis or severe traumatic injury and found an adverse thromboembolic event rate of 6% with no significant difference between treated patients and placebo (p=0.57).52 Similarly a recent randomized controlled trial of rFVIIa in trauma patients did not find an increased risk of thromboembolic events in the treatment group.53

Recommendations for the administration of rFVIIa in major vascular surgery have been made previously by Shander et al. 54 Based on an expert panel's experience and a literature review they deemed the use of rFVIIa as a rescue therapy to be ‘appropriate’ in thoracic aortic surgery if significant clotting factor replacement had been attempted, but suggested that the evidence for its use in abdominal aortic surgery was less certain. They suggested a dose of 41 to 90μg/kg but we have demonstrated a significant range of dosage currently in reported practice. Similar recommendations were made by Goodnough and colleagues, who advised caution in those with a history of vascular disease.55 Whilst it is difficult for us to make clear evidence-based recommendations regarding the appropriate indications for rFVIIa in vascular surgery patient, there seems little evidence to suggest a dose of greater than 90μg/kg is any more efficacious than that recommended by these groups. Furthermore, in all cases where rFVIIa has been reported to be effective adequate clotting replacement therapy has been undertaken prior to administration, a practice supported by physiological knowledge of it's mechanism of action.

The key for vascular surgeons when considering the risk-benefits of rFVIIa administration likely lies in the clinical situation; we would argue that on occasion some vascular patients have life threatening bleeding so severe as to warrant the consideration of any therapy that may potentially prevent mortality. This viewpoint is supported by Roberts who advocated rFVIIa for life-threatening refractory haemorrhage in most scenarios, despite sometimes the absence of controlled clinical trials.56

Limitations and recommendations for further research 

The major limitation of this systematic review and pooled data analysis is the paucity of current evidence; the number of patients within the literature is small and they are derived from 15 different papers, all of which are retrospective and non-comparative. Therefore we are unable to perform meta-analysis. However, the primary value of our systematic review and critique of the available literature is to make the vascular surgical community aware of rFVIIa's proposed method of action, highlights it's potential role in haemorrhage refractory to all other interventions and outline the deficiencies within the literature, thus guiding future research. To this end we have formulated recommendations using the ‘EPICOT’ guidelines.57 Firstly, having reviewed all the data, we believe that well-designed, randomized controlled trials are required to definitively answer questions on the cost effectiveness, appropriate dosing regime, and safety profile of rFVIIa. With the justifiable concerns regarding inappropriate intra-arterial thrombosis, trials must initially focus on patients in extremis, in whom all other efforts to staunch haemorrhage have been exhausted. This will allow rFVIIa to be, at least initially, compared to placebo, and avoid the confusion in results interpretation that may arise if rFVIIa is given in combination with other pro-coagulants, such as Factor VIII.45 Outcomes must include subsequent requirement for transfusion, with strict protocols for triggering blood product administration in place prospectively, thromboembolic adverse event rates and 30-day mortality. Any study should also include a cost-effectiveness analysis.

Back to Article Outline

Conclusion 

Recombinant factor VIIa is a potent pro-haemostatic agent, which vascular surgeons should consider as a potential therapeutic agent in patients with severe haemorrhage refractory to conventional treatments. However, administration of rFVIIa is not without risk, and should only occur in line with current literature guidelines. Well-designed randomized controlled trials are required to fully elucidate the cost effectiveness, appropriate dosing regime, and safety profile of rFVIIa within vascular surgery patients.

Back to Article Outline

Acknowledgments 

The authors declare that they have no competing interests. This study was undertaken as part of ongoing research at the Department of BioSurgery and Surgical Technology, Imperial College London, and did not receive separate funding.

Authors' contributions

OW, NC, AC and TA were responsible for the study conception, design, data interpretation, manuscript drafting and for important intellectual content. EA, IVH, and DL were responsible for the collection, extraction and synthesis of data. TA and OW were responsible for statistical analysis. AD, OW and TA were responsible for providing important intellectual content throughout the manuscript's production and for approval of the final version. NC is the guarantor. His involvement was critical to every phase of this work and he had access to the data and controlled the decision to publish. All authors read and approved the final manuscript.

Back to Article Outline

References 

  1. Cohen JR, Angus L, Asher A, Chang JB, Wise L. Disseminated intravascular coagulation as a result of supraceliac clamping: implications for thoracoabdominal aneurysm repair. Ann Vasc Surg. 1987;1(5):552–557
  2. Jelenska MM, Szmidt J, Bojakowski K, Grzela T, Palester-Chlebowczyk M. Compensated activation of coagulation in patients with abdominal aortic aneurysm: effects of heparin treatment prior to elective surgery. Thromb Haemost. 2004;92(5):997–1002
  3. Halpern VJ, Kline RG, D'Angelo AJ, Cohen JR. Factors that affect the survival rate of patients with ruptured abdominal aortic aneurysms. J Vasc Surg. 1997;26(6):939–945[discussion 945–938]
  4. Sultan S, Manecksha R, O'Sullivan J, Hynes N, Quill D, Courtney D. Survival of ruptured abdominal aortic aneurysms in the west of Ireland: do prognostic indicators of outcome exist?. Vasc Endovascular Surg. 2004;38(1):43–49
  5. Sedrakyan A, Wu A, Sedrakyan G, Diener-West M, Tranquilli M, Elefteriades J. Aprotinin use in thoracic aortic surgery: safety and outcomes. J Thorac Cardiovasc Surg. 2006;132(4):909–917
  6. Huber TS, Carlton LC, Irwin PB, Flug RR, Harward TR, Flynn TC, et al. Intraoperative autologous transfusion during elective infrarenal aortic reconstruction. J Surg Res. 1997;67(1):14–20
  7. Milne AA, Drummond GB, Paterson DA, Murphy WG, Ruckley CV. Disseminated intravascular coagulation after aortic aneurysm repair, intraoperative salvage autotransfusion, and aprotinin. Lancet. 1994;344(8920):470–471
  8. Hedner U, Glazer S, Pingel K, Alberts KA, Blomback M, Schulman S, et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet. 1988;2(8621):1193
  9. Hedner U. Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000. Semin Thromb Hemost. 2000;26(4):363–366
  10. O'Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295(3):293–298
  11. Warren O, Mandal K, Hadjianastassiou V, Knowlton L, Panesar S, John K, et al. Recombinant activated factor VII in cardiac surgery: a systematic review. Ann Thorac Surg. 2007;83(2):707–714
  12. Friederich PW, Henny CP, Messelink EJ, Geerdink MG, Keller T, Kurth KH, et al. Effect of recombinant activated factor VII on perioperative blood loss in patients undergoing retropubic prostatectomy: a double-blind placebo-controlled randomised trial. Lancet. 2003;361(9353):201–205
  13. Raobaikady R, Redman J, Ball JA, Maloney G, Grounds RM. Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis or pelvis and acetabulum: a double-blind, randomized, placebo-controlled trial. Br J Anaesth. 2005;94(5):586–591
  14. Tawfick WA, Tawfik S, Hynes N, Mahendran B, Sultan S. Critical bleeding in vascular surgery: expanding the indication of recombinant activated factor VII. Vascular. 2006;14(1):32–37
  15. Cheng CA, Ho AM. Use of recombinant activated factor VII after axillofemoral bypass grafting. Anaesth Intensive Care. 2006;34(3):375–378
  16. Raux M, Chiche L, Vanhille E, Riou B. Recombinant activated factor vii to control massive post operative bleeding after septic aortobifemoral grafting. Eur J Anaesthesiol. 2005;22(10):805–807
  17. Liem AK, Biesma DH, Ernst SM, Schepens AA. Recombinant activated factor VII for false aneurysms in patients with normal haemostatic mechanisms. Thromb Haemost. 1999;82(1):150–151
  18. Wahlgren CM, Swedenborg J. The use of recombinant activated factor VII to control bleeding during repair of a suprarenal abdominal aortic aneurysm. Eur J Vasc Endovasc Surg. 2003;26(2):221–222
  19. Benharash P, Bongard F, Putnam B. Use of recombinant factor VIIa for adjunctive hemorrhage control in trauma and surgical patients. Am Surg. 2005;71(9):776–780
  20. Laffan M, O'Connell NM, Perry DJ, Hodgson AJ, O'Shaughnessy D, Smith OP. Analysis and results of the recombinant factor VIIa extended-use registry. Blood Coagul Fibrinolysis. 2003;14(1):S35–S38
  21. O'Connell NM, Perry DJ, Hodgson AJ, O'Shaughnessy DF, Laffan MA, Smith OP. Recombinant FVIIa in the management of uncontrolled hemorrhage. Transfusion. 2003;43(12):1711–1716
  22. Kato H. Regulation of functions of vascular wall cells by tissue factor pathway inhibitor: basic and clinical aspects. Arterioscler Thromb Vasc Biol. 2002;22(4):539–548
  23. Jude B, Zawadzki C, Susen S, Corseaux D. Relevance of tissue factor in cardiovascular disease. Arch Mal Coeur Vaiss. 2005;98(6):667–671
  24. Ardissino D, Merlini PA, Ariens R, Coppola R, Bramucci E, Mannucci PM. Tissue-factor antigen and activity in human coronary atherosclerotic plaques. Lancet. 1997;349(9054):769–771
  25. Nijziel M, van Oerle R, van 't Veer C, van Pampus E, Lindhout T, Hamulyak K. Tissue factor activity in human monocytes is regulated by plasma: implications for the high and low responder phenomenon. Br J Haematol. 2001;112(1):98–104
  26. Maugeri N, Brambilla M, Camera M, Carbone A, Tremoli E, Donati MB, et al. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J Thromb Haemost. 2006;4(6):1323–1330
  27. Osterud B, Bjorklid E. Sources of tissue factor. Semin Thromb Hemost. 2006;32(1):11–23
  28. Khan MM, Hattori T, Niewiarowski S, Edmunds LH, Colman RW. Truncated and microparticle-free soluble tissue factor bound to peripheral monocytes preferentially activate factor VII. Thromb Haemost. 2006;95(3):462–468
  29. Diamant M, Nieuwland R, Pablo RF, Sturk A, Smit JW, Radder JK. Elevated numbers of tissue-factor exposing microparticles correlate with components of the metabolic syndrome in uncomplicated type 2 diabetes mellitus. Circulation. 2002;106(19):2442–2447
  30. Giesen PL, Rauch U, Bohrmann B, Kling D, Roque M, Fallon JT, et al. Blood-borne tissue factor: another view of thrombosis. Proc Natl Acad Sci USA. 1999;96(5):2311–2315
  31. Santucci RA, Erlich J, Labriola J, Wilson M, Kao KJ, Kickler TS, et al. Measurement of tissue factor activity in whole blood. Thromb Haemost. 2000;83(3):445–454
  32. Butenas S, Mann KG. Active tissue factor in blood?. Nat Med. 2004;10(11):1155–1156[author reply 1156]
  33. Hedner U, Erhardtsen E. Potential role of recombinant factor VIIa as a hemostatic agent. Clin Adv Hematol Oncol. 2003;1(2):112–119
  34. Butenas S, Brummel KE, Paradis SG, Mann KG. Influence of factor VIIa and phospholipids on coagulation in “acquired” hemophilia. Arterioscler Thromb Vasc Biol. 2003;23(1):123–129
  35. ten Cate H, Bauer KA, Levi M, Edgington TS, Sublett RD, Barzegar S, et al. The activation of factor X and prothrombin by recombinant factor VIIa in vivo is mediated by tissue factor. J Clin Invest. 1993;92(3):1207–1212
  36. Lisman T, De Groot PG. Mechanism of action of recombinant factor VIIa. J Thromb Haemost. 2003;1(6):1138–1139
  37. Bom VJ, Bertina RM. The contributions of Ca2+, phospholipids and tissue-factor apoprotein to the activation of human blood-coagulation factor X by activated factor VII. Biochem J. 1990;265(2):327–336
  38. Monroe DM, Hoffman M, Oliver JA, Roberts HR. Platelet activity of high-dose factor VIIa is independent of tissue factor. Br J Haematol. 1997;99(3):542–547
  39. Hoffman M, Monroe DM, Roberts HR. Human monocytes support factor X activation by factor VIIa, independent of tissue factor: implications for the therapeutic mechanism of high-dose factor VIIa in hemophilia. Blood. 1994;83(1):38–42
  40. Gerotziafas GT, Chakroun T, Depasse F, Arzoglou P, Samama MM, Elalamy I. The role of platelets and recombinant factor VIIa on thrombin generation, platelet activation and clot formation. Thromb Haemost. 2004;91(5):977–985
  41. Manning BJ, Hynes N, Courtney DF, Sultan S. Recombinant factor VIIa in the treatment of intractable bleeding in vascular surgery. Eur J Vasc Endovasc Surg. 2005;30(5):525–527
  42. Pugh RJ, Wenstone R, Martlew VJ, Marx G. Use of recombinant factor VIIa for major haemorrhage. Eur J Anaesthesiol. 2005;22(7):548–550
  43. Aggarwal A, Malkovska V, Catlett JP, Alcorn K. Recombinant activated factor VII (rFVIIa) as salvage treatment for intractable hemorrhage. Thromb J. 2004;2(1):9
  44. Eikelboom JW, Bird R, Blythe D, Coyle L, Gan E, Harvey M, et al. Recombinant activated factor VII for the treatment of life-threatening haemorrhage. Blood Coagul Fibrinolysis. 2003;14(8):713–717
  45. Raivio P, Suojaranta-Ylinen R, Kuitunen AH. Recombinant factor VIIa in the treatment of postoperative hemorrhage after cardiac surgery. Ann Thorac Surg. 2005;80(1):66–71
  46. Khan AZ, Parry JM, Crowley WF, McAllen K, Davis AT, Bonnell BW, et al. Recombinant factor VIIa for the treatment of severe postoperative and traumatic hemorrhage. Am J Surg. 2005;189(3):331–334
  47. Bishop CV, Renwick WE, Hogan C, Haeusler M, Tuckfield A, Tatoulis J. Recombinant activated factor VII: treating postoperative hemorrhage in cardiac surgery. Ann Thorac Surg. 2006;81(3):875–879
  48. Clark AD, Gordon WC, Walker ID, Tait RC. ‘Last-ditch’ use of recombinant factor VIIa in patients with massive haemorrhage is ineffective. Vox Sang. 2004;86(2):120–124
  49. Edmunds LH, Colman RW. Thrombin during cardiopulmonary bypass. Ann Thorac Surg. 2006;82(6):2315–2322
  50. Naik VN, Mazer CD, Latter DA, Teitel JM, Hare GM. Successful treatment using recombinant factor VIIa for severe bleeding post cardiopulmonary bypass. Can J Anaesth. 2003;50(6):599–602
  51. Kenet G, Walden R, Eldad A, Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet. 1999;354(9193):1879
  52. Levy JH, Fingerhut A, Brott T, Langbakke IH, Erhardtsen E, Porte RJ. Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion. 2006;46(6):919–933
  53. Boffard KD, Riou B, Warren B, Choong PI, Rizoli S, Rossaint R, et al. Recombinant factor VIIa as adjunctive therapy for bleeding control in severely injured trauma patients: two parallel randomized, placebo-controlled, double-blind clinical trials. J Trauma. 2005;59(1):8–15[discussion 15–18]
  54. Shander A, Goodnough LT, Ratko T, Matuszewski KA, Cohn S, Diringer M, et al. Consensus recommendations for the off-label use of recombinant human factor VIIa (NovoSeven) therapy. Pharma Ther. 2005;30:644–658
  55. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion. 2004;44(9):1325–1331
  56. Roberts HR. Recombinant factor VIIa: a general hemostatic agent?. Yes. J Thromb Haemost. 2004;2(10):1691–1694
  57. Brown P, Brunnhuber K, Chalkidou K, Chalmers I, Clarke M, Fenton M, et al. How to formulate research recommendations. BMJ. 2006;333(7572):804–806

PII: S1078-5884(07)00557-6

doi:10.1016/j.ejvs.2007.08.018

European Journal of Vascular & Endovascular Surgery
Volume 35, Issue 2 , Pages 145-152, February 2008

Article Tools

* Image Usage & Resolution