Use of recombinant factor VIIa (NovoSeven®) in patients with Glanzmann thrombasthenia

Hemophilia is a bleeding disorder caused by mutations in the genes encoding coagulation Factor VIII (FVIII) or FIX. Current treatment is through intravenous infusion of the missing protein. The major complication of treatment is the development of neutralizing Ab’s to the clotting factor. Infusion of recombinant activated human Factor VII (rhFVIIa), driving procoagulant reactions independently of human FVIII (hFVIII) or hFIX, has been successful in such patients and could in theory provide hemostasis in all hemophilia patients. However, its high cost and short half-life have limited its use. Here, we report a novel treatment strategy with a recombinant adeno-associated virus vector delivering a modified FVII transgene that can be intracellularly processed and secreted as activated FVII (FVIIa). We show long-term expression, as well as phenotypic correction of hemophilia B mice following gene transfer of the murine FVIIa homolog, with no evidence of thrombotic complications at these doses. These data hold promise for a potential treatment for hemophilia and other bleeding disorders

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“…Bernard-Soulier syndrome, and Factor VII deficiency, as has already been shown for rhFVIIa protein infusion therapy (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 79%

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

Margaritis¹,

Arruda²,

Aljamali³

et al. 2004

J. Clin. Invest.

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“…3,4 Originally developed for treatment of patients with inhibitor-complicated hemophilia, 5 rFVIIa is thought to enhance thrombin generation at the site of vessel wall damage. In vitro experiments showed that enhancement of thrombin generation by rFVIIa can proceed via tissue factor (TF)-dependent 6-9 or -independent 10-12 pathways, and it has been postulated that both mechanisms are operative in vivo.…”

Section: Introductionmentioning

confidence: 99%

Recombinant factor VIIa restores aggregation of αIIbβ3-deficient platelets via tissue factor–independent fibrin generation

Lisman

Adelmeijer²,

Heijnen³

et al. 2004

Blood

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Recombinant factor VIIa (rFVIIa) is a safe and effective prohemostatic drug for patients with Glanzmann thrombasthenia (GT). However, the mechanism of action of rFVIIa in these patients is still unclear. Although patients with GT are characterized by a complete absence of platelet aggregation to a variety of agonists, it has been shown that GT platelets are able to form aggregates, provided polymerizing fibrin is present. We studied the effect of rFVIIa-mediated fibrin formation on aggregation of ␣IIb␤3-deficient platelets. When washed platelets from GT patients or platelets from healthy volunteers treated with an arginyl-glycyl-aspartylcontaining peptide were activated with collagen in the presence of rFVIIa and purified coagulation factors X, II, and fibrinogen, complete aggregation occurred after a lag phase. Fibrin generation proceeded via rFVIIa-mediated thrombin generation on the activated platelet surface independently of tissue factor. Electron microscopic analysis of ␣IIb␤3-independent platelet aggregates showed a densely packed structure suggestive of a true platelet-fibrin interaction and not via trapping of platelets into a fibrin network. Also, rFVIIa-mediated ␣IIb␤3-independent aggregation was demonstrated under conditions of flow using a collagencoated surface. In conclusion, the efficacy of rFVIIa in GT patients might be explained by induction of ␣IIb␤3-independent platelet aggregation, which compensates the lack of ␣IIb␤3-dependent aggregation. ( IntroductionThe platelet integrin ␣IIb␤3 plays a pivotal role in hemostasis since patients with Glanzmann thrombasthenia (GT), who have a qualitative or quantitative defect in this receptor, suffer from a severe bleeding tendency. 1 A deficiency of ␣IIb␤3 on the platelet membrane results in the absence of platelet aggregation in response to agonists such as collagen, adenosine diphosphate (ADP), and epinephrine. Furthermore, platelet-vessel wall interaction is disturbed as ␣IIb␤3 mediates platelet binding to the subendothelium via collagen-bound von Willebrand factor (VWF), fibrin, vitronectin, and thrombospondin. 2 Prophylaxis or treatment of bleeding episodes in patients with GT consists of infusion of platelet concentrates. However, alloimmunization to human leukocyte antigens or to ␣IIb␤3 might occur, rendering further administration of donor platelets ineffective.Recombinant factor VIIa (rFVIIa; NovoSeven; Novo Nordisk, Bagsvaerd, Denmark) has been shown to be an alternative to platelet transfusion for patients with GT. 3,4 Originally developed for treatment of patients with inhibitor-complicated hemophilia, 5 rFVIIa is thought to enhance thrombin generation at the site of vessel wall damage. In vitro experiments showed that enhancement of thrombin generation by rFVIIa can proceed via tissue factor (TF)-dependent 6-9 or -independent 10-12 pathways, and it has been postulated that both mechanisms are operative in vivo. 13 The consequences of enhanced thrombin generation for the composition and stability of the hemostatic plug may be multifactorial....

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“…3 A novel approach to treat patients with GT during bleeding episodes or surgery is the administration of recombinant factor VIIa (rFVIIa; Novo Nordisk, Bagsvaerd, Denmark). 5,6 rFVIIa was originally developed for the treatment of inhibitor-complicated hemophilia A and B. 7,8 Currently, novel indications for rFVIIa, including its use in patients with liver disease, 9,10 thrombocytopenia, 11 and platelet function defects, 6,12 and in patients without coagulation disorders who are bleeding as a result of extensive surgery or major trauma, 13,14 are explored in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

“…5,6 rFVIIa was originally developed for the treatment of inhibitor-complicated hemophilia A and B. 7,8 Currently, novel indications for rFVIIa, including its use in patients with liver disease, 9,10 thrombocytopenia, 11 and platelet function defects, 6,12 and in patients without coagulation disorders who are bleeding as a result of extensive surgery or major trauma, 13,14 are explored in clinical trials. The use of rFVIIa in patients with GT appears to be safe and effective, although randomized controlled clinical trials have not been performed in this small patient group.…”

Section: Introductionmentioning

confidence: 99%

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

Lisman

Moschatsis

Adelmeijer

et al. 2003

Blood

106

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A novel approach to treat bleeding episodes in patients with Glanzmann thrombasthenia (GT) and perhaps also in patients receiving ␣ IIb ␤ 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 rFVIIamediated thrombin formation on adhesion of ␣ IIb ␤ 3 -deficient platelets under flow conditions. Adhesion of ␣ IIb ␤ 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 ␣ IIb ␤ 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-␣ IIb ␤ 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 ␣ IIb ␤ 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

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Use of recombinant factor VIIa (NovoSeven®) in patients with Glanzmann thrombasthenia

Cited by 65 publications

References 27 publications

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

Novel therapeutic approach for hemophilia using gene delivery of an engineered secreted activated Factor VII

Recombinant factor VIIa restores aggregation of αIIbβ3-deficient platelets via tissue factor–independent fibrin generation

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

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