Administration Of Recombinant Factor VII Research Articles

Uses of recombinant factor VIIa in trauma

Despite advances in the care of the injured, the morbidity and mortality of traumatic hemorrhage remain a significant problem. Traumatologists continue to look for ways to treat bleeding and prevent the sequelae of hemorrhagic shock. Recombinant factor VIIa, developed for the treatment of patients with hemophilia, has been used with some success in acute bleeding associated with injuries. The mechanism of action is via a tissue factor-dependent effect and/or platelet activation. Coagulation occurs at the site of tissue injury, where tissue factor is exposed. Case series have described the beneficial effects of recombinant factor VIIa in the treatment of acute hemorrhage, early treatment of traumatic brain injury, and reversal of premorbid anticoagulation. In addition, there have been numerous reports of recombinant factor VIIa use in acute bleeds secondary to other causes as well as some evidence that recombinant factor VIIa may be efficacious when used prophylactically in high-risk patients and for high-risk procedures. Typical doses range from 50 to 100 microg/kg as a single bolus. Although there has been concern over the risk of inappropriate thrombosis with recombinant factor VIIa administration, this complication has seldom been described in published series. Although case experience is encouraging, no level 1 evidence has been published that demonstrates clinical or economic benefit of the use of recombinant factor VIIa in trauma patients. Many questions remain to be answered, ideally through randomized, prospective clinical trials. In particular, the issues of patient selection, ideal dosing, and factors associated with futile administration need to be elucidated.

Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann's thrombasthenia: results of an international survey

Antibodies to glycoprotein (GP) IIb-IIIa and/or HLA may render platelet transfusions ineffective to stop bleeding or to cover surgery in patients with Glanzmann's thrombasthenia (GT). Anecdotal reports suggest recombinant factor (rF)VIIa might be a therapeutic alternative in these situations. An international survey was conducted to evaluate further the efficacy and safety of rFVIIa in GT patients. We analyzed the use of rFVIIa during 34 surgical/invasive procedures and 108 bleeding episodes in 59 GT patients including 29 with current or previous antiplatelet antibodies, and 23 with a history of refractoriness to platelet transfusion. rFVIIa was effective in 29 of the 31 evaluable procedures, and in 77 of the 103 evaluable bleeding episodes of which eight had a recurrence. A significantly higher success rate was observed in severe bleeding episodes when an arbitrarily defined 'optimal regimen' derived from the Canadian pilot study results (> or = 80 micro g kg(-1) rFVIIa/injection, dosing interval < or = 2.5 h, three or more doses before failure declaration) was used compared with other regimens (77%; 24/31 vs. 48%, 19/40; chi(2), P = 0.010). Patients given maintenance doses had significantly fewer recurrences within 48 h of bleed cessation compared with those not given any (Fisher's exact test, P = 0.022). One thromboembolic event and one blood clot in the ureter occurring in surgical patients following prolonged continuous infusion of high-dose rFVIIa and antifibrinolytic drug use have been previously reported. rFVIIa seems a potential alternative to platelet transfusion in GT patients, particularly in those with antiplatelet antibodies and/or platelet refractoriness.

Successful use of recombinant factor VIIa for management of severe menorrhagia in an adolescent with an acquired inhibitor of human thrombin

Antibodies directed against human thrombin are exceedingly rare, having only been reported in adult patients with underlying diseases. Consensus on the most appropriate management has not yet been reached. A 12-y-old girl presented with intractable menorrhagia several days after an acute infectious episode. Laboratory tests revealed disturbed clotting tests: prothrombin index 17%, activated partial thromboplastin time >150 s, thrombin time >120 s, and failure to achieve correction with a normal pooled plasma. Further studies demonstrated the presence of an antibody directed against human thrombin. Viral serology revealed a 1/128 titre for adenovirus. Massive haemorrhage was unresponsive to standard treatments, but intravenous administration of recombinant factor VIIa resulted in a successful outcome. This is the first report of an anti-human thrombin antibody associated with severe bleeding in a child. Recombinant factor VIIa could represent a novel therapeutic approach for such patients.

Onset of force development as a marker of thrombin generation in whole blood: the thrombin generation time (TGT)

Prothrombin activation requires the direct interplay of activated platelets and plasma clotting factors. Once formed, thrombin causes profound, irreversible activation of platelets and reinforces the platelet plug via fibrin formation. Delayed or deficient thrombin production increases bleeding risk. Commonly employed coagulation assays, the prothrombin and partial thromboplastin times, use clot formation as a surrogate marker of thrombin generation. These assays routinely utilize platelet-poor plasma and completely miss the effects of platelets. Other markers of thrombin generation, prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex, are typically measured after the fact. We report a simple assay, which employs the onset of platelet contractile force (PCF) as a surrogate marker of thrombin generation. PCF generation occurs concomitant with the burst of F1 + 2 release. The time between assay start and PCF onset is termed the thrombin generation time (TGT). TGT is prolonged in clotting factor deficiencies and in the presence of direct and indirect thrombin inhibitors. TGT shortens to normal with clotting factor replacement and shortens with administration of recombinant factor VIIa. TGT is short in thrombophilic states such as coronary artery disease, diabetes and thromboangiitis obliterans and prolongs toward normal with oral and intravenous anticoagulants.

Activation of coagulation by administration of recombinant factor VIIa elicits interleukin 6 (IL-6) and IL-8 release in healthy human subjects.

The activation of coagulation has been shown to contribute to proinflammatory responses in animal and in vitro experiments. Here we report that the activation of coagulation in healthy human subjects by the administration of recombinant factor VIIa also elicits a small but significant increase in the concentrations of interleukin 6 (IL-6) and IL-8 in plasma. This increase was absent when the subjects were pretreated with recombinant nematode anticoagulant protein c2, the inhibitor of tissue factor-factor VIIa.

Recombinant factor VIIa enhances deposition of platelets with congenital or acquired αIIbβ3 deficiency to endothelial cell matrix and collagen under conditions of flow via tissue factor–independent thrombin generation

A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving alpha IIb beta 3 inhibitors is the administration of recombinant factor VIIa (rFVIIa). The mechanism of action of rFVIIa in these patients is, however, still unclear. We studied the effect of rFVIIa-mediated thrombin formation on adhesion of alpha IIb beta 3-deficient platelets under flow conditions. Adhesion of alpha IIb beta 3-deficient platelets to the extracellular matrix (ECM) of stimulated human umbilical vein endothelial cells or to collagen type III was studied using a model system with washed platelets and red cells. When alpha IIb beta 3-deficient platelets were perfused over the surface at arterial shear rate for 5 minutes, a low surface coverage was observed (GT platelets, mean +/- SEM, 37.5% +/- 5.0%; normal platelets preincubated with an RGD-containing peptide, 7.4% +/- 2.1%). When rFVIIa, together with factors X and II, was added to the perfusate, platelet deposition significantly increased (GT platelets, mean +/- SEM, 67.0% +/- 4.3%; normal platelets preincubated with an RGD-containing peptide, 48.2% +/- 2.9%). The same effect was observed when normal platelets were pretreated with the commercially available anti-alpha IIb beta 3 drugs abciximab, eptifibatide, or tirofiban. It was shown that tissue factor-independent thrombin generation (presumably induced by binding of rFVIIa to adhered platelets) was responsible for the increase in platelet deposition. In conclusion, defective adhesion of alpha IIb beta 3-deficient platelets to ECM can be restored by tissue factor-independent rFVIIa-mediated thrombin formation. The enhanced generation of platelet procoagulant surface facilitates fibrin formation, so that lack of platelet aggregate formation might be compensated for.

Correction of a coagulopathy using recombinant factor VII before removal of an intra-aortic balloon pump

IN PATIENTS with refractory cardiogenic shock, cardiovascular support with intra-aortic balloon counterpulsation can be life-saving. Specific morbidity may occur, however, related to the placement, use, and removal of these devices. Low levels of anticoagulation are frequently instituted during use of the intra-aortic balloon pump (IABP) to prevent thromboembolic complications. Before removal, however, normalization of coagulation parameters may decrease the potential for bleeding complications. Correction of coagulation may require only discontinuation of heparin administration. In critically ill patients, other factors, such as multisystem organ failure with hepatic dysfunction and associated disseminated intravascular coagulation (DIC), may be present. In this setting, it is generally feasible to correct the coagulation defect with blood products, including platelets, fresh frozen plasma (FFP), and cryoprecipitate. The authors present the case of a 19-year-old woman who suffered cardiogenic shock after an intraoperative cardiac arrest, who was supported with an IABP. Ongoing hepatic dysfunction and DIC resulted in a coagulopathy that was not responsive to the administration of FFP. The administration of recombinant factor VIIa (NovoSeven; Novo Nordisk, Princeton, NJ) normalized coagulation function.

Recombinant factor VIIa improves clot formation but not fibrolytic potential in patients with cirrhosis and during liver transplantation

Cirrhosis is associated with a bleeding tendency, which is particularly pronounced during orthotopic liver transplantation (OLT). A novel approach to treating the bleeding diathesis of patients with cirrhosis is administration of recombinant factor VIIa (rFVIIa). This study examined whether the efficacy of rFVIIa in cirrhosis might be explained in part by enhanced down-regulation of fibrinolysis by thrombin-activatable fibrinolysis inhibitor (TAFI). Addition of therapeutic or supratherapeutic doses of rFVIIa to plasma of 12 patients with stable cirrhosis did not result in a prolongation of clot lysis time, though clotting times were significantly reduced. Also, clot lysis assays of plasma samples taken during and after OLT, which was performed with or without a single bolus dose of rFVIIa, did not show any effect of rFVIIa on plasma fibrinolytic potential. In conclusion, this study shows no evidence for an antifibrinolytic effect of rFVIIa in cirrhotic patients or in patients undergoing OLT. (HEPATOLOGY 2002;35:616-621.)

In vivo bypass of hemophilia A coagulation defect by factor XIIa implant.

Hemophilia A and B coagulation defects, which are caused by deficiencies of Factor VIII and Factor IX, respectively, can be bypassed by administration of recombinant Factor VIIa. However, the short half-life of recombinant Factor VIIa in vivo negates its routine clinical use. We report here an in vivo method for the continuous generation of Factor VIIa. The method depends on the implantation of a porous chamber that contains Factor Xa or XIIa, and continuously generates Factor VIIa bypass activity from the subject's own Factor VII, which enters the chamber by diffusion. Once inside, the Factor VII is cleaved to Factor VIIa by the immobilized Factor Xa or XIIa. The newly created Factor VIIa diffuses out of the chamber and back into the circulation, where it can bypass the deficient Factors VIII or IX, and enable coagulation to occur. In vitro, this method generates sufficient Factor VIIa to substantially correct Factor VIII-deficient plasma when assessed by the classical aPTT coagulation assay. In vivo, a Factor XIIa peritoneal implant generates bypass activity for up to one month when tested in rhesus monkeys. Implantation of such a chamber in a patient with hemophilia A or B could eventually provide a viable alternative to replacement therapies using exogenous coagulation factors.

Treatment of traumatic bleeding with recombinant factor VIIa

Surgical intervention failed to stop life-threatening bleeding caused by injury complicated by severe coagulopathy. Administration of recombinant factor VIIa immediately corrected the coagulopathy and bleeding stopped.

Recombinant Factor VIIa

Recombinant factor VIIa is a preparation of activated coagulation factor VII (factor VIIa) that is produced by recombinant DNA technology. The drug expedites blood coagulation without the need for factors VIII and IX in patients with haemophilia. Indicators of activation of systemic coagulation of blood were unchanged and mean prothrombin times and activated partial thromboplastin times were decreased substantially after administration of recombinant factor VIIa at doses of up to 90 microg/kg in pharmacodynamic studies. Recombinant factor VIIa has been shown to be effective at doses ranging from 17.5 to 120 microg/kg in the control of joint, muscle and mucocutaneous bleeding in patients with haemophilia A or B with inhibitors of factor VIII or IX. Satisfactory postoperative haemostasis was achieved in all patients with haemophilia and inhibitors of factors VIII and IX who received multiple doses of recombinant factor VIIa 90 microg/kg during and after surgery. The drug has also demonstrated some efficacy in the control of internal or CNS bleeding in small numbers of patients. Self-administration of recombinant factor VIIa or administration by caregivers has been used successfully to control bleeding episodes in patients with haemophilia without the need for hospital or clinic admission in home treatment programmes in 3 countries. Recombinant factor VIIa is well tolerated. No thrombotic complications have been reported, and there is no evidence to date of the formation of antibodies to the drug in patients with haemophilia A or B or acquired inhibitors of factor VIII or IX.

Determinants of plasma factor VIIa levels in humans

Several enzymes can activate factor VII in vitro, but the protease responsible for generating factor VIIa in vivo has not been determined. Using recombinant tissue factor that has undergone a COOH-terminal truncation, a sensitive functional assay has been established for measuring plasma factor VIIa levels. To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified concentrates of factor IX and factor VIII to patients with severe deficiencies of these clotting factors. In patients with hemophilia B, factor VIIa levels were initially reduced to 0.5 +/- 0.1 ng/mL and gradually increased to normal after infusing 100 U/kg of body weight (BW) of factor IX. Despite these increases, there were no significant changes in the generation of factor Xa or thrombin. In patients with hemophilia A, only a slight reduction in factor VIIa levels (2.5 +/- 1.3 ng/mL) was observed as compared with controls (3.3 +/- 1.1 ng/mL) and no significant changes were observed after factor VIII levels were normalized. The administration of recombinant factor VIIa (10 micrograms/kg BW) to patients with factor VII deficiency increased the mean circulating level of the enzyme to 118 ng/mL, but this only resulted in normalization of the levels of the activation peptides of factor IX and factor X. The above data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa generated in vivo (ie, in the absence of thrombosis or provocative stimuli) and that changes in the plasma concentrations of free factor VIIa in the blood do not necessarily lead to alterations in the extent of factor X activation.

Determinants of Plasma Factor VIIa Levels in Humans

Several enzymes can activate factor VII in vitro, but the protease responsible for generating factor VIIa in vivo has not been determined. Using recombinant tissue factor that has undergone a COOH-terminal truncation, a sensitive functional assay has been established for measuring plasma factor VIIa levels. To evaluate the mechanism responsible for the generation of factor VIIa in vivo, we measured the levels of this enzyme after administering purified concentrates of factor IX and factor VIII to patients with severe deficiencies of these clotting factors. In patients with hemophilia B, factor VIIa levels were initially reduced to 0.5 +/- 0.1 ng/mL and gradually increased to normal after infusing 100 U/kg of body weight (BW) of factor IX. Despite these increases, there were no significant changes in the generation of factor Xa or thrombin. In patients with hemophilia A, only a slight reduction in factor VIIa levels (2.5 +/- 1.3 ng/mL) was observed as compared with controls (3.3 +/- 1.1 ng/mL) and no significant changes were observed after factor VIII levels were normalized. The administration of recombinant factor VIIa (10 micrograms/kg BW) to patients with factor VII deficiency increased the mean circulating level of the enzyme to 118 ng/mL, but this only resulted in normalization of the levels of the activation peptides of factor IX and factor X. The above data indicate that factor IXa is primarily responsible for the basal levels of free factor VIIa generated in vivo (ie, in the absence of thrombosis or provocative stimuli) and that changes in the plasma concentrations of free factor VIIa in the blood do not necessarily lead to alterations in the extent of factor X activation.