Portal de Periódicos da CAPES

Editorial

2005; Elsevier BV; Volume: 94; Issue: 5 Linguagem: Inglês

10.1093/bja/aei103

1471-6771

D. R. Spahn, M Tucci, Michael Makris,

Platelet Disorders and Treatments

Recombinant activated factor VII (rFVIIa) (NovoSeven®, Novo Nordisk, Bagsvaerd, Denmark) was originally developed to treat bleeding in haemophiliacs with antibodies to factor VIII and IX.1Roberts HR Monroe DM Escobar MA Current concepts of hemostasis: implications for therapy.Anesthesiology. 2004; 100: 722-730Crossref PubMed Scopus (105) Google Scholar2Ghorashian S Hunt BJ ‘Off-license’ use of recombinant activated factor VII.Blood Rev. 2004; 18: 245-259Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar At present, rFVIIa is approved in the European Union for this indication and also for the treatment of bleeding in FVII deficiency and Glanzmann thrombasthenia refractory to platelet transfusions. FVIIa normally circulates in minute quantities and binds to tissue factor (TF) expressed by the damaged vascular bed. The TF-FVIIa complex on TF-bearing cells activates FIX and FX. FXa remains in close proximity to TF-bearing cells and activates FV. The FXa–FVa complex on TF-bearing cells rapidly converts small amounts of prothrombin into thrombin.1Roberts HR Monroe DM Escobar MA Current concepts of hemostasis: implications for therapy.Anesthesiology. 2004; 100: 722-730Crossref PubMed Scopus (105) Google Scholar3Bombeli T Spahn DR Updates in perioperative coagulation: physiology and management of thromboembolism and haemorrhage.Br J Anaesth. 2004; 93: 275-287Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar This initial small amount of thrombin activates platelets, FVIII, FV and FXI. On the surface of activated platelets, FVIIIa and FIXa gather to activate large quantities of FX which finally (in conjunction with FVa) will result in the large thrombin burst which enables the conversion of fibrinogen to fibrin with initial clot formation. The administration of exogenous rFVIIa accelerates the above mechanism and in haemophiliacs with antibodies to factor VIII and IX, rFVIIa may loosely bind to platelets and activate significant quantities of FX resulting in the thrombin burst necessary for the transformation of fibrinogen to fibrin with local clot formation. It is tempting to speculate that exogenous rFVIIa, by activating blood coagulation in the close vicinity of TF-bearing cells, may help stop major bleeding in trauma and surgery with absence of general thrombosis. Since the initial spectacular case report in a young Israeli solder,4Kenet G Walden R Eldad A Martinowitz U Treatment of traumatic bleeding with recombinant factor VIIa.Lancet. 1999; 354: 1879Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar a large number of case reports of successful use of rFVIIa in patients with uncontrolled bleeding including trauma, surgery, warfarin therapy and pregnancy have been published.2Ghorashian S Hunt BJ ‘Off-license’ use of recombinant activated factor VII.Blood Rev. 2004; 18: 245-259Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar5Goodnough LT Lublin DM Zhang L Despotis G Eby C Transfusion medicine service policies for recombinant factor VIIa administration.Transfusion. 2004; 44: 1325-1331Crossref PubMed Scopus (120) Google Scholar, 6Grounds M Recombinant factor VIIa (rFVIIa) and its use in severe bleeding in surgery and trauma: a review.Blood Rev. 2003; 17: S11-S21Abstract Full Text PDF PubMed Scopus (77) Google Scholar, 7Dutton RP McCunn M Hyder M et al.Factor VIIa for correction of traumatic coagulopathy.J Trauma. 2004; 57: 709-719Crossref PubMed Scopus (263) Google Scholar, 8Eikelboom JW Bird R Blythe D et al.Recombinant activated factor VII for the treatment of life-threatening haemorrhage.Blood Coagul Fibrinolysis. 2003; 14: 713-717Crossref PubMed Scopus (80) Google Scholar The problem with these reports is potential publication bias of positive cases, which, understandably, editors are more likely to publish. Registries of similar patient groups9Kessler C Haemostasis.com: clinical experiences in the investigational use of rFVIIa in the management of severe haemorrhage.Br J Haematol. 2004; 127: 230Crossref PubMed Scopus (13) Google Scholar are also susceptible to submission and publication bias of successful cases. Only recently, ‘non-responders’7Dutton RP McCunn M Hyder M et al.Factor VIIa for correction of traumatic coagulopathy.J Trauma. 2004; 57: 709-719Crossref PubMed Scopus (263) Google Scholar and complications10Siegel LJ Gerigk L Tuettenberg J Dempfle CE Scharf J Fiedler F Cerebral sinus thrombosis in a trauma patient after recombinant activated factor VII infusion.Anesthesiology. 2004; 100: 441-443Crossref PubMed Scopus (36) Google Scholar11Aledort LM Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity.J Thromb Haemost. 2004; 2: 1700-1708Crossref PubMed Scopus (233) Google Scholar of rFVIIa treatment have been described in bleeding patients. Faced with a patient with uncontrolled bleeding the clinician is thus left with significant uncertainty as to whether he or she is obliged to use rFVIIa in an ‘off-label’ or ‘out-of-license’ indication or whether this could be withheld as there is little published high level scientific evidence nor approval by any health authority in Europe or the US. This dilemma is amplified by the fact that any decision in this scenario is often associated with mortality, morbidity and high cost. Bleeding is a major cause of mortality and morbidity during the peri- and post-partum period. Several case reports have described dramatic effects in patients suffering from massive bleeding.2Ghorashian S Hunt BJ ‘Off-license’ use of recombinant activated factor VII.Blood Rev. 2004; 18: 245-259Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar4Kenet G Walden R Eldad A Martinowitz U Treatment of traumatic bleeding with recombinant factor VIIa.Lancet. 1999; 354: 1879Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar5Goodnough LT Lublin DM Zhang L Despotis G Eby C Transfusion medicine service policies for recombinant factor VIIa administration.Transfusion. 2004; 44: 1325-1331Crossref PubMed Scopus (120) Google Scholar7Dutton RP McCunn M Hyder M et al.Factor VIIa for correction of traumatic coagulopathy.J Trauma. 2004; 57: 709-719Crossref PubMed Scopus (263) Google Scholar8Eikelboom JW Bird R Blythe D et al.Recombinant activated factor VII for the treatment of life-threatening haemorrhage.Blood Coagul Fibrinolysis. 2003; 14: 713-717Crossref PubMed Scopus (80) Google Scholar In this issue of the Journal, Ahonen and Jokela describe another series of life-threatening post-partum bleeding in 12 patients treated with rFVIIa.12Ahonen J Jokela R Recombinant factor VIIa for life-threatening post-partum haemorrhage.Br J Anaesth. 2005; 94: 592-595Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar The authors report a partial or good response in 11 of their 12 patients to rFVIIa after a blood loss of between 5 and 15 litres. Despite such partial or good responses, 4 patients had to undergo subsequent arterial embolization.12Ahonen J Jokela R Recombinant factor VIIa for life-threatening post-partum haemorrhage.Br J Anaesth. 2005; 94: 592-595Abstract Full Text Full Text PDF PubMed Scopus (139) Google Scholar Arterial embolization, however, is not generally available on a 24 h basis in all centres and its efficacy depends on the intervential radiologist’s skill. Ideally, a randomized placebo-controlled trial should be performed in patients with massive blood loss associated with delivery. This is unlikely to happen, owing to the rarity of the complication, the difficulty in obtaining informed consent and the highly positive results in already published cases and case series. In the report by Ahonen and Kjokela, rFVIIa was used relatively late and 42% of patients had already had a hysterectomy. A number of centres are now, based on anectodal reports, using rFVIIa immediately before the decision to perform a hysterectomy when arterial embolization is not available. Because of the rapidity of the rFVIIa action, it is possible to wait and observe the rFVIIa effect, if any, before proceeding to hysterectomy. There is scientific evidence that rFVIIa may be efficacious in experimental trauma. Treatment with rFVIIA (180 μg kg−1) after grade V liver injury decreased blood loss by nearly 50% in pigs.13Martinowitz U Holcomb JB Pusateri AE et al.Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries.J Trauma. 2001; 50: 721-729Crossref PubMed Scopus (160) Google Scholar Even in pigs with coagulopathy, with grade V liver injury, blood loss was reduced by ∼50% in rFVIIa (180 and 720 μg kg−1) treated animals.14Schreiber MA Holcomb JB Hedner U Brundage SI Macaitis JM Hoots K The effect of recombinant factor VIIa on coagulopathic pigs with grade V liver injuries.J Trauma. 2002; 53 (discussion 257–9): 252-257Crossref PubMed Scopus (112) Google Scholar Interestingly, rFVIIa (180 and 720 μg kg−1) treatment before puncturing a 2 mm hole into the aorta did not decrease the initial blood loss but diminished significantly re-bleeding during resuscitation, and rFVIIa treated animals tolerated a higher blood pressure before re-bleeding.15Sondeen JL Pusateri AE Hedner U Yantis LD Holcomb JB Recombinant factor VIIa increases the pressure at which rebleeding occurs in porcine uncontrolled aortic hemorrhage model.Shock. 2004; 22: 163-168Crossref PubMed Scopus (33) Google Scholar Patients suffering from major trauma may also benefit from rFVIIa according to a recently completed prospective randomized double-blind placebo-controlled multi-centre study. In total, 301 patients with blunt or penetrating trauma requiring transfusion of 8 units of red blood cells were recruited.16Rossaint R Boffard KD Warren BL et al.Decreased transfusion utilization using recombinant factor VIIa as an adjunct in trauma.Intensive Care Med. 2004; 30: S199Google Scholar In this trial, three doses of rFVIIa were given: 200 μg kg−1 at study entry, 100 μg kg−1 at 1 h and another 100 μg kg−1 at 3 h. In blunt trauma red blood cell transfusions and the incidence of acute respiratory distress syndrome (ARDS) were reduced and the incidence of multi-organ failure tended to be reduced in patients with penetrating trauma.16Rossaint R Boffard KD Warren BL et al.Decreased transfusion utilization using recombinant factor VIIa as an adjunct in trauma.Intensive Care Med. 2004; 30: S199Google Scholar Mortality, however, was equal in the two groups. So far, only two prospective randomized double-blind placebo-controlled studies evaluating the efficacy of rFVIIa in reducing blood loss and red blood cell transfusion needs in surgery have been published.17Friederich PW Henny CP Messelink EJ 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: 201-205Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar18Lodge JP Jonas S Oussoultzoglou E et al.Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.Anesthesiology. 2005; 102: 269-275Crossref PubMed Scopus (184) Google Scholar In 36 patients undergoing open radical prostatectomy, relatively low doses of 20 μg kg−1 and 40 μg kg−1 of rFVIIa decreased perioperative blood loss by more than 50% and allogeneic blood transfusions were equally reduced.17Friederich PW Henny CP Messelink EJ 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: 201-205Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar In contrast, in 204 noncirrhotic patients undergoing partial hepatectomy rFVIIa at doses of 20 μg kg−1 or 80 μg kg−1 did not decrease perioperative blood loss and allogeneic blood transfusions.18Lodge JP Jonas S Oussoultzoglou E et al.Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.Anesthesiology. 2005; 102: 269-275Crossref PubMed Scopus (184) Google Scholar The study by Raobaikady and colleagues19Raobaikady R Redman R Ball JAS Maloney G Grounds RM Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis and acetabulum: a double blind, randomized, placebo-controlled trial.Br J Anaesth. 2005; 94: 586-591Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar published in this issue of the Journal is important since it represents only the third prospective randomized double-blind placebo-controlled study in this setting. The authors randomized 48 patients undergoing major pelvic-acetabular surgery to rFVIIa (90 μg kg−1) or placebo. The primary outcome variable was the total volume of perioperative blood loss. In contrast to the study by Friederich and colleagues,17Friederich PW Henny CP Messelink EJ 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: 201-205Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar no reduction in perioperative blood loss or allogeneic blood transfusion was observed.19Raobaikady R Redman R Ball JAS Maloney G Grounds RM Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis and acetabulum: a double blind, randomized, placebo-controlled trial.Br J Anaesth. 2005; 94: 586-591Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar The only difference was a slightly reduced postoperative blood loss (240 ml vs 370 ml) in the rFVIIa-treated patients. Why were these results so different, despite the fact that pre-defined transfusion guidelines were used in both studies? First, assessment of perioperative blood loss is notoriously fraught with difficulties and imprecision. In addition, and more importantly, the timing of the rFVIIa dosing was different. In the study by Friederich and colleagues17Friederich PW Henny CP Messelink EJ 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: 201-205Abstract Full Text Full Text PDF PubMed Scopus (398) Google Scholar the rFVIIa was given during the operation, just prior to the main blood loss, whereas in the studies by Raobaikady and colleagues19Raobaikady R Redman R Ball JAS Maloney G Grounds RM Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis and acetabulum: a double blind, randomized, placebo-controlled trial.Br J Anaesth. 2005; 94: 586-591Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar and Lodge and colleagues,18Lodge JP Jonas S Oussoultzoglou E et al.Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.Anesthesiology. 2005; 102: 269-275Crossref PubMed Scopus (184) Google Scholar rFVIIa was administered at skin incision. Given the rather short half life of rFVIIa of approximately 2 h in bleeding patients, dosing at skin incision might have been somewhat early in operations with an average duration of 3 and 4 h.18Lodge JP Jonas S Oussoultzoglou E et al.Recombinant coagulation factor VIIa in major liver resection: a randomized, placebo-controlled, double-blind clinical trial.Anesthesiology. 2005; 102: 269-275Crossref PubMed Scopus (184) Google Scholar19Raobaikady R Redman R Ball JAS Maloney G Grounds RM Use of activated recombinant coagulation factor VII in patients undergoing reconstruction surgery for traumatic fracture of pelvis and acetabulum: a double blind, randomized, placebo-controlled trial.Br J Anaesth. 2005; 94: 586-591Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Alternatively, local blood coagulation could already be maximally stimulated in patients undergoing orthopaedic surgery without the addition of exogenous rFVIIa, such that rFVIIa treatment cannot improve local blood coagulation any further, at least not in patients without compromised blood coagulation. For now, rFVIIa is not indicated for routine use prior to high bleeding risk elective surgery. More recently, another ‘off-label’ use of rFVIIa has been reported in patients with acute intracerebral haemorrhage but without an underlying coagulopathy.20Mayer SA Brun NC Begtrup K et al.Recombinant activated factor VIIa for acute intracerebral hemorrhage.N Engl J Med. 2005; 352: 777-785Crossref PubMed Scopus (1152) Google Scholar The further increase in the volume of the intracranial bleeding was diminished by rFVIIa (40, 80 and 160 μg kg−1) treatment by ∼50% and the neurological outcome at 3 months was improved. Mortality tended to be lower in rFVIIa-treated patients. However, thromboembolic events tended to be more frequent in rFVIIa-treated patients. This is not a surprise as these are patients with a normal coagulation system who may have artherosclerotic plaques exposing TF-bearing cells to the blood.21Charo IF Taubman MB Chemokines in the pathogenesis of vascular disease.Circ Res. 2004; 95: 858-866Crossref PubMed Scopus (645) Google Scholar This may well be the basis for rFVIIa-activated local blood coagulation and eventual thrombosis. Recombinant VIIa is a drug that is easy and quick to mix and administer. It is generally well tolerated with thrombosis being the primary adverse effect of concern to clinicians. Although initially thromboses were rare since the drug was used in patients with severe coagulopathies, more recently more thromboses have been reported as the drug was used prophylactically in surgery or in patients without a coagulopathy such as in cerebral bleeding referred to above. Aledort calculated that the risk of rFVIIa-related thrombosis is 25 per 105 infusions.11Aledort LM Comparative thrombotic event incidence after infusion of recombinant factor VIIa versus factor VIII inhibitor bypass activity.J Thromb Haemost. 2004; 2: 1700-1708Crossref PubMed Scopus (233) Google Scholar In published placebo-controlled studies, however, the risk of thrombosis was not statistically different between patient and control groups. So, where do we stand in May 2005? Are we obliged to give rFVIIa to patients with major bleeding to avoid accusation of substandard treatment or is rFVIIa treatment not indicated, owing to the lack of high level scientific evidence, lack of approval by any health authority, the potential of serious side-effects and its high cost? No definitive answers can be given at present. However, the following issues should be on the research agenda in the near future for this interesting drug. First, the clinical scenario, outside congenital bleeding disorders, where rFVIIa is beneficial needs to be defined. In terms of trauma, the trauma trial discussed above,16Rossaint R Boffard KD Warren BL et al.Decreased transfusion utilization using recombinant factor VIIa as an adjunct in trauma.Intensive Care Med. 2004; 30: S199Google Scholar once published in a peer-reviewed journal, may provide further information. Second, the optimal timing and dose, which are largely unknown, need to be ascertained. Third, the most appropriate co-treatment with conventional blood products,22Hardy JF De Moerloose P Samama M Massive transfusion and coagulopathy: pathophysiology and implications for clinical management.Can J Anaesth. 2004; 51: 293-310Crossref PubMed Scopus (201) Google Scholar the minimum levels of coagulation factors and platelets required and also the minimum pH and temperature for the optimal efficacy of rFVIIa need to be determined. Fourth, laboratory monitoring of the efficacy of rFVIIa treatment will be helpful. The effect on prothrombin time is particularly marked but this does not always translate to clinically improved blood coagulation. Similarly measurement of the level of factor VII in plasma does not correlate with clinical efficacy. Two promising monitoring techniques are thrombelastography13Martinowitz U Holcomb JB Pusateri AE et al.Intravenous rFVIIa administered for hemorrhage control in hypothermic coagulopathic swine with grade V liver injuries.J Trauma. 2001; 50: 721-729Crossref PubMed Scopus (160) Google Scholar and the endogenous thrombin potential measured in platelet rich plasma.23Gerotziafas 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: 977-985Crossref PubMed Google Scholar Last but not least, we should keep in mind that the current treatment guidelines for the severely bleeding patient of the Committee on Trauma of the American College of Surgeons in their ATLS® program (www.facs.org) simply aim at ‘stop the bleeding’.24American College of Surgeons Committee on Trauma: Advanced Trauma Life Support® for Doctors, 2004Google Scholar This may be achieved using different strategies, be it a proper surgical source control, embolization, the use of coagulation enhancing drugs or any combination thereof. In conclusion, rFVIIa is certainly a highly potent substance capable of locally promoting blood coagulation under certain circumstances. However, its clinical efficacy outside the setting of congenital coagulation disorders remains to be defined. Whilst nobody should be accused of providing substandard care when opting not to give rFVIIa for major bleeding, a trial of rFVIIa when conventional surgical, interventional and blood product support measures have failed is certainly worth a try. Donat R. Spahn has served on an Executive Advisory Board for Novo Nordisk and is currently on the NovoSeven® European Trauma Advisory Board. Dr Michael Makris has attended meetings sponsored by Novo Nordisk and is a recipient of a British Society for Haemostasis and Thrombosis Novo Nordisk grant.