Makris, M.

Spahn, D. R.

Tucci, M. A.

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‘‘I would have everie man write what he knowes and no more.’’—MontaigneBRITISH JOURNAL OF ANAESTHESIAVolume 94, Number 5, May 2005EditorialIs recombinant FVIIa the magic bullet in the treatment of major bleeding?Recombinant activated factor VII (rFVIIa) (NovoSeven1,Novo Nordisk, Bagsvaerd, Denmark) was originally devel-oped to treat bleeding in haemophiliacs with antibodies tofactor VIII and IX.1 2 At present, rFVIIa is approved in theEuropean Union for this indication and also for the treatmentof bleeding in FVII deficiency and Glanzmann throm-basthenia refractory to platelet transfusions.FVIIa normally circulates in minute quantities and bindsto tissue factor (TF) expressed by the damaged vascular bed.The TF-FVIIa complex on TF-bearing cells activates FIXand FX. FXa remains in close proximity to TF-bearing cellsand activates FV. The FXa–FVa complex on TF-bearingcells rapidly converts small amounts of prothrombin intothrombin.1 3 This initial small amount of thrombin activatesplatelets, FVIII, FV and FXI. On the surface of activatedplatelets, FVIIIa and FIXa gather to activate large quantitiesof FX which finally (in conjunction with FVa) will resultin the large thrombin burst which enables the conversionof fibrinogen to fibrin with initial clot formation. Theadministration of exogenous rFVIIa accelerates the abovemechanism and in haemophiliacs with antibodies to factorVIII and IX, rFVIIa may loosely bind to platelets and acti-vate significant quantities of FX resulting in the thrombinburst necessary for the transformation of fibrinogen to fibrinwith local clot formation.It is tempting to speculate that exogenous rFVIIa,by activating blood coagulation in the close vicinity ofTF-bearing cells, may help stop major bleeding in traumaand surgery with absence of general thrombosis. Since theinitial spectacular case report in a young Israeli solder,4a large number of case reports of successful use of rFVIIain patients with uncontrolled bleeding including trauma,surgery, warfarin therapy and pregnancy have been pub-lished.2 5–8 The problem with these reports is potential pub-lication bias of positive cases, which, understandably,editors are more likely to publish. Registries of similarpatient groups9 are also susceptible to submission andpublication bias of successful cases. Only recently, ‘non-responders’7 and complications10 11 of rFVIIa treatmenthave been described in bleeding patients. Faced with apatient with uncontrolled bleeding the clinician is thusleft with significant uncertainty as to whether he or she isobliged to use rFVIIa in an ‘off-label’ or ‘out-of-license’indication or whether this could be withheld as there is littlepublished high level scientific evidence nor approval by anyhealth authority in Europe or the US. This dilemma is ampli-fied by the fact that any decision in this scenario is oftenassociated with mortality, morbidity and high cost.Bleeding is a major cause of mortality and morbidityduring the peri- and post-partum period. Several case reportshave described dramatic effects in patients suffering frommassive bleeding.2 4 5 7 8 In this issue of the Journal, Ahonenand Jokela describe another series of life-threatening post-partum bleeding in 12 patients treated with rFVIIa.12 Theauthors report a partial or good response in 11 of their12 patients to rFVIIa after a blood loss of between 5 and15 litres. Despite such partial or good responses, 4 patientshad to undergo subsequent arterial embolization.12 Arterialembolization, however, is not generally available on a 24 hbasis in all centres and its efficacy depends on the inter-vential radiologist’s skill. Ideally, a randomized placebo-controlled trial should be performed in patients with massiveblood loss associated with delivery. This is unlikely tohappen, owing to the rarity of the complication, the difficultyin obtaining informed consent and the highly positive resultsin already published cases and case series. In the report byAhonen and Kjokela, rFVIIa was used relatively late and42% of patients had already had a hysterectomy. A numberof centres are now, based on anectodal reports, using rFVIIaimmediately before the decision to perform a hysterectomywhen arterial embolization is not available. Because ofthe rapidity of the rFVIIa action, it is possible to wait andobserve the rFVIIa effect, if any, before proceeding tohysterectomy.There is scientific evidence that rFVIIa may be efficac-ious in experimental trauma. Treatment with rFVIIA(180 mg kg1) after grade V liver injury decreased bloodloss by nearly 50% in pigs.13 Even in pigs with coagulo-pathy, with grade V liver injury, blood loss was reduced by50% in rFVIIa (180 and 720 mg kg1) treated animals.14Interestingly, rFVIIa (180 and 720 mg kg1) treatmentbefore puncturing a 2 mm hole into the aorta did notdecrease the initial blood loss but diminished significantlyre-bleeding during resuscitation, and rFVIIa treated animals# The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions@oupjournals.orgtolerated a higher blood pressure before re-bleeding.15Patients suffering from major trauma may also benefitfrom rFVIIa according to a recently completed prospectiverandomized double-blind placebo-controlled multi-centrestudy. In total, 301 patients with blunt or penetrating traumarequiring transfusion of 8 units of red blood cells wererecruited.16 In this trial, three doses of rFVIIa were given:200 mg kg1 at study entry, 100 mg kg1 at 1 h and another100 mg kg1 at 3 h. In blunt trauma red blood cell trans-fusions and the incidence of acute respiratory distresssyndrome (ARDS) were reduced and the incidence ofmulti-organ failure tended to be reduced in patients withpenetrating trauma.16 Mortality, however, was equal inthe two groups.So far, only two prospective randomized double-blindplacebo-controlled studies evaluating the efficacy of rFVIIain reducing blood loss and red blood cell transfusion needs insurgery have been published.17 18 In 36 patients undergoingopen radical prostatectomy, relatively low doses of20 mg kg1 and 40 mg kg1 of rFVIIa decreased periopera-tive blood loss by more than 50% and allogeneic bloodtransfusions were equally reduced.17 In contrast, in 204 non-cirrhotic patients undergoing partial hepatectomy rFVIIa atdoses of 20 mg kg1 or 80 mg kg1 did not decrease peri-operative blood loss and allogeneic blood transfusions.18The study by Raobaikady and colleagues19 published inthis issue of the Journal is important since it representsonly the third prospective randomized double-blindplacebo-controlled study in this setting. The authors rando-mized 48 patients undergoing major pelvic-acetabularsurgery to rFVIIa (90 mg kg1) or placebo. The primaryoutcome variable was the total volume of perioperativeblood loss. In contrast to the study by Friederich andcolleagues,17 no reduction in perioperative blood loss orallogeneic blood transfusion was observed.19 The onlydifference was a slightly reduced postoperative blood loss(240 ml vs 370 ml) in the rFVIIa-treated patients. Why werethese results so different, despite the fact that pre-definedtransfusion guidelines were used in both studies? First,assessment of perioperative blood loss is notoriouslyfraught with difficulties and imprecision. In addition, andmore importantly, the timing of the rFVIIa dosing wasdifferent. In the study by Friederich and colleagues17 therFVIIa was given during the operation, just prior to the mainblood loss, whereas in the studies by Raobaikady andcolleagues19 and Lodge and colleagues,18 rFVIIa wasadministered at skin incision. Given the rather short halflife of rFVIIa of approximately 2 h in bleeding patients,dosing at skin incision might have been somewhat earlyin operations with an average duration of 3 and 4 h.18 19Alternatively, local blood coagulation could already bemaximally stimulated in patients undergoing orthopaedicsurgery without the addition of exogenous rFVIIa,such that rFVIIa treatment cannot improve local bloodcoagulation any further, at least not in patients withoutcompromised blood coagulation. For now, rFVIIa is notindicated for routine use prior to high bleeding risk electivesurgery.More recently, another ‘off-label’ use of rFVIIa has beenreported in patients with acute intracerebral haemorrhagebut without an underlying coagulopathy.20 The furtherincrease in the volume of the intracranial bleeding wasdiminished by rFVIIa (40, 80 and 160 mg kg1) treatmentby 50% and the neurological outcome at 3 months wasimproved. Mortality tended to be lower in rFVIIa-treatedpatients. However, thromboembolic events tended to bemore frequent in rFVIIa-treated patients. This is not asurprise as these are patients with a normal coagulationsystem who may have artherosclerotic plaques exposingTF-bearing cells to the blood.21 This may well be the basisfor rFVIIa-activated local blood coagulation and eventualthrombosis.Recombinant VIIa is a drug that is easy and quick tomix and administer. It is generally well tolerated withthrombosis being the primary adverse effect of concern toclinicians. Although initially thromboses were rare sincethe drug was used in patients with severe coagulopathies,more recently more thromboses have been reported asthe drug was used prophylactically in surgery or in patientswithout a coagulopathy such as in cerebral bleedingreferred to above. Aledort calculated that the risk ofrFVIIa-related thrombosis is 25 per 105 infusions.11 In pub-lished placebo-controlled studies, however, the risk ofthrombosis was not statistically different between patientand control groups.So, where do we stand in May 2005? Are we obliged togive rFVIIa to patients with major bleeding to avoid accusa-tion of substandard treatment or is rFVIIa treatment notindicated, owing to the lack of high level scientific evidence,lack of approval by any health authority, the potential ofserious side-effects and its high cost? No definitive answerscan be given at present. However, the following issuesshould be on the research agenda in the near future forthis interesting drug. First, the clinical scenario, outsidecongenital bleeding disorders, where rFVIIa is beneficialneeds to be defined. In terms of trauma, the trauma trialdiscussed above,16 once published in a peer-reviewed jour-nal, may provide further information. Second, the optimaltiming and dose, which are largely unknown, need to beascertained. Third, the most appropriate co-treatment withconventional blood products,22 the minimum levels of coa-gulation factors and platelets required and also the minimumpH and temperature for the optimal efficacy of rFVIIa needto be determined. Fourth, laboratory monitoring of the effi-cacy of rFVIIa treatment will be helpful. The effect onprothrombin time is particularly marked but this does notalways translate to clinically improved blood coagulation.Similarly measurement of the level of factor VII in plasmadoes not correlate with clinical efficacy. Two promisingmonitoring techniques are thrombelastography13 and theendogenous thrombin potential measured in platelet richplasma.23Editorial554Last but not least, we should keep in mind that the currenttreatment guidelines for the severely bleeding patient of theCommittee on Trauma of the American College of Surgeonsin their ATLS1 program (www.facs.org) simply aim at ‘stopthe bleeding’.24 This may be achieved using differentstrategies, be it a proper surgical source control, emboliza-tion, the use of coagulation enhancing drugs or any combi-nation thereof.In conclusion, rFVIIa is certainly a highly potent sub-stance capable of locally promoting blood coagulationunder certain circumstances. However, its clinical efficacyoutside the setting of congenital coagulation disordersremains to be defined. Whilst nobody should be accusedof providing substandard care when opting not to giverFVIIa for major bleeding, a trial of rFVIIa when conven-tional surgical, interventional and blood product supportmeasures have failed is certainly worth a try.Declaration of interestDonat R. Spahn has served on an Executive Advisory Boardfor Novo Nordisk and is currently on the NovoSeven1European Trauma Advisory Board. Dr Michael Makrishas attended meetings sponsored by Novo Nordisk andis a recipient of a British Society for Haemostasis andThrombosis Novo Nordisk grant.D. R. Spahn*M. A. TucciDepartment of AnaesthesiologyUniversity Hospital Lausanne (CHUV)CH-1011 LausanneSwitzerlandM. MakrisSheffield Haemophilia and Thrombosis CentreRoyal Hallamshire HospitalSheffieldUK*Corresponding author. E-mail: donat.spahn@chuv.hospvd.chReferences1 Roberts HR, Monroe DM, Escobar MA. Current concepts ofhemostasis: implications for therapy. Anesthesiology 2004; 100:722–302 Ghorashian S, Hunt BJ. ‘Off-license’ use of recombinant activatedfactor VII. Blood Rev 2004; 18: 245–593 Bombeli T, Spahn DR. Updates in perioperative coagulation:physiology and management of thromboembolism andhaemorrhage. Br J Anaesth 2004; 93: 275–874 Kenet G, Walden R, Eldad A, Martinowitz U. Treatment oftraumatic bleeding with recombinant factor VIIa. Lancet 1999;354: 18795 Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfu-sion medicine service policies for recombinant factor VIIa admin-istration. Transfusion 2004; 44: 1325–316 Grounds M. Recombinant factor VIIa (rFVIIa) and its use insevere bleeding in surgery and trauma: a review. Blood Rev2003; 17: S11–217 Dutton RP, McCunn M, Hyder M, et al. Factor VIIa for correctionof traumatic coagulopathy. J Trauma 2004; 57: 709–198 Eikelboom JW, Bird R, Blythe D, et al. Recombinant activatedfactor VII for the treatment of life-threatening haemorrhage.Blood Coagul Fibrinolysis 2003; 14: 713–179 Kessler C. Haemostasis.com: clinical experiences in the investiga-tional use of rFVIIa in the management of severe haemorrhage. Br JHaematol 2004; 127: 23010 Siegel LJ, Gerigk L, Tuettenberg J, Dempfle CE, Scharf J, Fiedler F.Cerebral sinus thrombosis in a trauma patient after recombinantactivated factor VII infusion. Anesthesiology 2004; 100: 441–311 Aledort LM. Comparative thrombotic event incidence afterinfusion of recombinant factor VIIa versus factor VIII inhibitorbypass activity. J Thromb Haemost 2004; 2: 1700–812 Ahonen J, Jokela R. Recombinant factor VIIa for life-threateningpost-partum haemorrhage. Br J Anaesth 2005; 94: 592–513 Martinowitz U, Holcomb JB, Pusateri AE, et al. IntravenousrFVIIa administered for hemorrhage control in hypothermiccoagulopathic swine with grade V liver injuries. J Trauma 2001;50: 721–914 Schreiber MA, Holcomb JB, Hedner U, Brundage SI, Macaitis JM,Hoots K. The effect of recombinant factor VIIa on coagulopathicpigs with grade V liver injuries. J Trauma 2002; 53: 252–7; discus-sion 257–915 Sondeen JL, Pusateri AE, Hedner U, Yantis LD, Holcomb JB.Recombinant factor VIIa increases the pressure at which rebleed-ing occurs in porcine uncontrolled aortic hemorrhage model.Shock 2004; 22: 163–816 Rossaint R, Boffard KD, Warren BL, et al. Decreased transfusionutilization using recombinant factor VIIa as an adjunct in trauma.Intensive Care Med 2004; 30 (Suppl. 1): S19917 Friederich PW, Henny CP, Messelink EJ, et al. Effect ofrecombinant activated factor VII on perioperative blood loss inpatients undergoing retropubic prostatectomy: a double-blindplacebo-controlled randomised trial. Lancet 2003; 361: 201–518 Lodge JP, Jonas S, Oussoultzoglou E, et al. Recombinant coagula-tion factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial. Anesthesiology 2005; 102:269–7519 Raobaikady R, Redman J, Ball JAS, Maloney G, Grounds RM.Use of activated recombinant coagulation factor VII in patientsundergoing reconstruction surgery for traumatic fracture ofpelvis and acetabulum: a double blind, randomized, placebo-controlled trial. Br J Anaesth 2005; 94: 586–9120 Mayer SA, Brun NC, Begtrup K, et al. Recombinant activatedfactor VIIa for acute intracerebral hemorrhage. N Engl J Med2005; 352: 777–8521 Charo IF, Taubman MB. Chemokines in the pathogenesis ofvascular disease. Circ Res 2004; 95: 858–6622 Hardy JF, De Moerloose P, Samama M. Massive transfusionand coagulopathy: pathophysiology and implications for clinicalmanagement. Can J Anaesth 2004; 51: 293–31023 Gerotziafas GT, Chakroun T, Depasse F, Arzoglou P, SamamaMM, Elalamy I. The role of platelets and recombinant factor VIIaon thrombin generation, platelet activation and clot formation.Thromb Haemost 2004; 91: 977–8524 American College of Surgeons Committee on Trauma: AdvancedTrauma Life Support1 for Doctors, 2004doi:10.1093/bja/aei103Editorial555

Editorial: Is recombinant FVIIa the magic bullet in the treatment of major bleeding?

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