Expert Review of Hematology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Drug Profile
NovoSeven (recombinant factor VIIa) for the treatment of bleeding episodes and perioperative management in patients with Glanzmann’s thrombasthenia Expert Rev. Hematol. 7(6), 733–740 (2014)
Massimo Franchini*1 and Giuseppe Lippi2 1 Department of Hematology and Transfusion Medicine, C. Poma Hospital, Mantova, Italy 2 Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy *Author for correspondence: [email protected].
Glanzmann’s thrombasthenia is a rare inherited autosomal recessive bleeding disorder caused by qualitative or quantitative defects of the platelet membrane glycoprotein IIb/IIIa. The ensuing lack of platelet aggregation is frequently associated with mucocutaneous bleeding that may be variable in both frequency and intensity, ranging from minimal bruising to severe and life-threatening hemorrhages. A number of treatment modalities have been proposed to manage the bleeding episodes, which include local measures, antifibrinolytic agents, platelet transfusions and recombinant activated factor VII. The role of this bypassing hemostatic agent for treatment or prevention of bleeding episodes in Glanzmann’s thrombasthenia patients is critically analyzed in this review. KEYWORDS: bleeding • Glanzmann’s thrombasthenia • NovoSeven • recombinant activated factor VII • surgery
Glanzmann’s thrombasthenia was first described in 1918 by a Swiss pediatrician, Dr Edwards Glanzmann, who identified a group of patients with hemorrhagic symptoms, normal platelet count but prolonged bleeding time and abnormal clot retraction. Glanzmann’s thrombasthenia is a rare autosomal recessive inherited platelet disorder characterized by impaired platelet aggregation. It is mainly caused by defects in the platelet GPIIb-IIIa membrane complex, which is involved in platelet aggregation by mediating the binding of fibrinogen to this glycoprotein complex on activated platelets [1–3]. The GPIIb/IIIa or aIIbb3 complex represents a member of the ubiquitous integrin family of cell surface receptors, and usually Glanzmann’s thrombasthenia is considered the most frequent inherited integrin disorder [4]. The integrin aIIbb3 is encoded by ITGA2B and ITGB3 genes located on chromosome 17, and more than 100 different mutations have been described so far, including point mutations, informahealthcare.com
10.1586/17474086.2014.980811
insertions and deletions [5]. Bleeding manifestations in this autosomal recessive disorder occur in patients who are homozygous or compound heterozygous for GP IIb/IIIa mutations. Glanzmann’s thrombasthenia is usually characterized by a platelet count within the normal reference range and normal platelet morphology, a prolonged bleeding time and defective platelet aggregation. Testing with platelet function analyzer (e.g., using PFA-100, Dade/Behring, Marburg, Germany) is usually consistent with prolonged closure times. This is mainly due to the fact that thrombasthenic platelets are refractory to aggregation in response to agonists such as ADP, collagen, thrombin and adrenaline, but do agglutinate in the presence of ristocetin. However, definitive diagnosis can only be made by flow cytometry using antibodies to GPIIb (CD41) and GPIIIa (CD61) [6,7]. The bleeding manifestations, which usually appear in early childhood, include easy bruising, purpura, epistaxis, gingival bleeding and
2014 Informa UK Ltd
ISSN 1747-4086
733
Expert Review of Hematology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Drug Profile
Franchini & Lippi
menorrhagia. Gastrointestinal bleeding, hematuria, hemarthrosis, muscle hematoma and central nervous system hemorrhages are less frequently observed [7]. Although the bleeding tendency varies in frequency and severity, Glanzmann’s thrombasthenia is conventionally considered a severe hemorrhagic disorder, because most patients have a significant history of red blood cell and/or platelet transfusions. This is particularly evident for women who frequently suffer from severe menorrhagia, especially at menarche, and who are at increased risk of serious bleeding during pregnancy and delivery. Spontaneous, unprovoked bleeding is uncommon in Glanzmann’s thrombasthenia and, in general, the severity is reduced with ageing [1]. In contrast, bleeding after trauma or invasive procedures, including minor procedures such as circumcision and dental interventions, is common and may be severe [1]. Overview of the market
The treatment measures for mild bleeding in Glanzmann’s thrombasthenia include local pressure through nasal packing with gelatin sponge for epistaxis, local hemostatics (e.g., fibrin glue and topical thrombin), as well as antifibrinolytic agents. The latter, in particular, have been used successfully, alone or as an adjunct to other hemostatic agents, for the treatment of menorrhagia in Glanzmann’s thrombasthenia patients [1]. For patients who scarcely respond to these treatments and those with severe bleeding, platelet transfusion is currently regarded as the standard of treatment. However, repeated transfusion may result in development of antibodies against GPIIb/IIIa and/or human leukocyte antigens, thus causing several degrees of refractoriness to further platelet transfusions [2]. For this reason, there is increasing interest toward the use of recombinant activated coagulation factor VII (rFVIIa, NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Indeed, a number of case reports and case series have documented in the last 15 years the safety and efficacy of this bypassing agent for the prophylaxis and treatment of bleeding in Glanzmann’s thrombasthenia patients [8–10]. Recently, a rFVIIa analog (i.e., vatreptacog alfa) with three amino acid substitutions and 99% identity to native FVIIa has been developed and tested in a large randomized controlled trial for treatment of hemophilic patients with inhibitors [11]. Although both NovoSeven and vatreptacog alfa were found to be equally effective in controlling bleeding at 12 h, the latter agent displayed superior performance with regard to prevention of secondary outcomes such as the dosage need to treat a bleed and control of sustained bleeding up to 48 h after the first dose. In contrast to NovoSeven, however, a remarkable number of patients (8/71; 11%) developed antibodies against vatreptacog alfa, so the company finally decided to discontinue the development of this agent on 28 September 2012. In this review, after a brief overview on hemostasis and on the mechanisms of rFVIIa activity, we will focus on the clinical use of rFVIIa in Glanzmann’s thrombasthenia patients. 734
Introduction of drug rFVIIa development
Recombinant FVIIa is a coagulation protein that, at pharmacologic doses, induces hemostasis through direct activation of factor X (FX), thus enhancing thrombin generation at the surface of activated platelets and providing the necessary amount of thrombin for formation of a stable fibrin hemostatic plug [12]. Recombinant FVIIa, which was originally developed for the treatment of bleeding episodes in patients with congenital hemophilia and inhibitors, has been approved for the treatment of bleeding in patients with hemophilia A and B and inhibitor antibodies, acquired hemophilia, factor VII deficiency or Glanzmann’s thrombasthenia refractory to platelet administration [13–16]. In addition, it has also been used off-label in a number of other acquired hemostatic abnormalities such as hemorrhage associated with severe trauma, oral anticoagulant therapy, thrombocytopenia, liver disease and transplantation, dengue hemorrhagic fever, post-hematopoietic stem cell transplantation, spontaneous and traumatic intracranial hemorrhage, general and cardiac surgery, as well as in life-threatening obstetric postpartum hemorrhages [17–26]. Chemistry
NovoSeven is a recombinant human coagulation FVIIa produced in baby hamster kidney cells that is used for promoting hemostasis by direct activation of the extrinsic pathway of blood coagulation. It belongs to the pharmaceutical category of the so-called ‘by-passing agents’, because its mechanism of action is virtually independent of the so-called thrombin burst. This recombinant protein is structurally similar to human plasma-derived Factor VIIa and consists of 406 amino acid residues with a molecular weight of approximately 50 kDA [27]. Mechanism of action
Hemostasis is conventionally defined as a delicate balance between procoagulant and anticoagulant forces. Under physiological conditions, the anticoagulant forces prevail and prevent the undue clotting of the blood with the blood vessels (i.e., thrombosis). Conversely, when blood vessels are injured, the procoagulant forces usually overwhelm the anticoagulant forces, thus allowing the formation of blood clots that should be effective to prevent excessive bleeding [28]. In general, hemostasis is classified as primary and secondary. The former pathway, also known as blood coagulation, initiates with the release of tissue factor (TF) or other procoagulant substances (i.e., cancer procoagulant), which soon interact with FVII to initiate blood coagulation. Once formed in the blood vessel, the complex TF-FVII auto-catalyze the activation of FVII to FVIIa that, in turn, activates FX to activated FX (FXa) (FIGURE 1) [29]. Interestingly, the efficiency of FVIIa alone is approximately 0.0001 that of the TF-FVIIa complex for activating the coagulation cascade. Once activated, FXa (with its co-factor, FV) then catalyzes the activation of FII (i.e., prothrombin) to FIIa (i.e., thrombin), which in turn promotes the conversion of fibrinogen into fibrin. This first phase of Expert Rev. Hematol. 7(6), (2014)
Expert Review of Hematology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
rFVIIa in Glanzmann’s thrombasthenia
Drug Profile
Sub-endothelial matrix hemostasis activation is only effective to generate a modest amount of thrombin (i.e.,
Drug Profile
NovoSeven (recombinant factor VIIa) for the treatment of bleeding episodes and perioperative management in patients with Glanzmann’s thrombasthenia Expert Rev. Hematol. 7(6), 733–740 (2014)
Massimo Franchini*1 and Giuseppe Lippi2 1 Department of Hematology and Transfusion Medicine, C. Poma Hospital, Mantova, Italy 2 Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy *Author for correspondence: [email protected].
Glanzmann’s thrombasthenia is a rare inherited autosomal recessive bleeding disorder caused by qualitative or quantitative defects of the platelet membrane glycoprotein IIb/IIIa. The ensuing lack of platelet aggregation is frequently associated with mucocutaneous bleeding that may be variable in both frequency and intensity, ranging from minimal bruising to severe and life-threatening hemorrhages. A number of treatment modalities have been proposed to manage the bleeding episodes, which include local measures, antifibrinolytic agents, platelet transfusions and recombinant activated factor VII. The role of this bypassing hemostatic agent for treatment or prevention of bleeding episodes in Glanzmann’s thrombasthenia patients is critically analyzed in this review. KEYWORDS: bleeding • Glanzmann’s thrombasthenia • NovoSeven • recombinant activated factor VII • surgery
Glanzmann’s thrombasthenia was first described in 1918 by a Swiss pediatrician, Dr Edwards Glanzmann, who identified a group of patients with hemorrhagic symptoms, normal platelet count but prolonged bleeding time and abnormal clot retraction. Glanzmann’s thrombasthenia is a rare autosomal recessive inherited platelet disorder characterized by impaired platelet aggregation. It is mainly caused by defects in the platelet GPIIb-IIIa membrane complex, which is involved in platelet aggregation by mediating the binding of fibrinogen to this glycoprotein complex on activated platelets [1–3]. The GPIIb/IIIa or aIIbb3 complex represents a member of the ubiquitous integrin family of cell surface receptors, and usually Glanzmann’s thrombasthenia is considered the most frequent inherited integrin disorder [4]. The integrin aIIbb3 is encoded by ITGA2B and ITGB3 genes located on chromosome 17, and more than 100 different mutations have been described so far, including point mutations, informahealthcare.com
10.1586/17474086.2014.980811
insertions and deletions [5]. Bleeding manifestations in this autosomal recessive disorder occur in patients who are homozygous or compound heterozygous for GP IIb/IIIa mutations. Glanzmann’s thrombasthenia is usually characterized by a platelet count within the normal reference range and normal platelet morphology, a prolonged bleeding time and defective platelet aggregation. Testing with platelet function analyzer (e.g., using PFA-100, Dade/Behring, Marburg, Germany) is usually consistent with prolonged closure times. This is mainly due to the fact that thrombasthenic platelets are refractory to aggregation in response to agonists such as ADP, collagen, thrombin and adrenaline, but do agglutinate in the presence of ristocetin. However, definitive diagnosis can only be made by flow cytometry using antibodies to GPIIb (CD41) and GPIIIa (CD61) [6,7]. The bleeding manifestations, which usually appear in early childhood, include easy bruising, purpura, epistaxis, gingival bleeding and
2014 Informa UK Ltd
ISSN 1747-4086
733
Expert Review of Hematology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
Drug Profile
Franchini & Lippi
menorrhagia. Gastrointestinal bleeding, hematuria, hemarthrosis, muscle hematoma and central nervous system hemorrhages are less frequently observed [7]. Although the bleeding tendency varies in frequency and severity, Glanzmann’s thrombasthenia is conventionally considered a severe hemorrhagic disorder, because most patients have a significant history of red blood cell and/or platelet transfusions. This is particularly evident for women who frequently suffer from severe menorrhagia, especially at menarche, and who are at increased risk of serious bleeding during pregnancy and delivery. Spontaneous, unprovoked bleeding is uncommon in Glanzmann’s thrombasthenia and, in general, the severity is reduced with ageing [1]. In contrast, bleeding after trauma or invasive procedures, including minor procedures such as circumcision and dental interventions, is common and may be severe [1]. Overview of the market
The treatment measures for mild bleeding in Glanzmann’s thrombasthenia include local pressure through nasal packing with gelatin sponge for epistaxis, local hemostatics (e.g., fibrin glue and topical thrombin), as well as antifibrinolytic agents. The latter, in particular, have been used successfully, alone or as an adjunct to other hemostatic agents, for the treatment of menorrhagia in Glanzmann’s thrombasthenia patients [1]. For patients who scarcely respond to these treatments and those with severe bleeding, platelet transfusion is currently regarded as the standard of treatment. However, repeated transfusion may result in development of antibodies against GPIIb/IIIa and/or human leukocyte antigens, thus causing several degrees of refractoriness to further platelet transfusions [2]. For this reason, there is increasing interest toward the use of recombinant activated coagulation factor VII (rFVIIa, NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Indeed, a number of case reports and case series have documented in the last 15 years the safety and efficacy of this bypassing agent for the prophylaxis and treatment of bleeding in Glanzmann’s thrombasthenia patients [8–10]. Recently, a rFVIIa analog (i.e., vatreptacog alfa) with three amino acid substitutions and 99% identity to native FVIIa has been developed and tested in a large randomized controlled trial for treatment of hemophilic patients with inhibitors [11]. Although both NovoSeven and vatreptacog alfa were found to be equally effective in controlling bleeding at 12 h, the latter agent displayed superior performance with regard to prevention of secondary outcomes such as the dosage need to treat a bleed and control of sustained bleeding up to 48 h after the first dose. In contrast to NovoSeven, however, a remarkable number of patients (8/71; 11%) developed antibodies against vatreptacog alfa, so the company finally decided to discontinue the development of this agent on 28 September 2012. In this review, after a brief overview on hemostasis and on the mechanisms of rFVIIa activity, we will focus on the clinical use of rFVIIa in Glanzmann’s thrombasthenia patients. 734
Introduction of drug rFVIIa development
Recombinant FVIIa is a coagulation protein that, at pharmacologic doses, induces hemostasis through direct activation of factor X (FX), thus enhancing thrombin generation at the surface of activated platelets and providing the necessary amount of thrombin for formation of a stable fibrin hemostatic plug [12]. Recombinant FVIIa, which was originally developed for the treatment of bleeding episodes in patients with congenital hemophilia and inhibitors, has been approved for the treatment of bleeding in patients with hemophilia A and B and inhibitor antibodies, acquired hemophilia, factor VII deficiency or Glanzmann’s thrombasthenia refractory to platelet administration [13–16]. In addition, it has also been used off-label in a number of other acquired hemostatic abnormalities such as hemorrhage associated with severe trauma, oral anticoagulant therapy, thrombocytopenia, liver disease and transplantation, dengue hemorrhagic fever, post-hematopoietic stem cell transplantation, spontaneous and traumatic intracranial hemorrhage, general and cardiac surgery, as well as in life-threatening obstetric postpartum hemorrhages [17–26]. Chemistry
NovoSeven is a recombinant human coagulation FVIIa produced in baby hamster kidney cells that is used for promoting hemostasis by direct activation of the extrinsic pathway of blood coagulation. It belongs to the pharmaceutical category of the so-called ‘by-passing agents’, because its mechanism of action is virtually independent of the so-called thrombin burst. This recombinant protein is structurally similar to human plasma-derived Factor VIIa and consists of 406 amino acid residues with a molecular weight of approximately 50 kDA [27]. Mechanism of action
Hemostasis is conventionally defined as a delicate balance between procoagulant and anticoagulant forces. Under physiological conditions, the anticoagulant forces prevail and prevent the undue clotting of the blood with the blood vessels (i.e., thrombosis). Conversely, when blood vessels are injured, the procoagulant forces usually overwhelm the anticoagulant forces, thus allowing the formation of blood clots that should be effective to prevent excessive bleeding [28]. In general, hemostasis is classified as primary and secondary. The former pathway, also known as blood coagulation, initiates with the release of tissue factor (TF) or other procoagulant substances (i.e., cancer procoagulant), which soon interact with FVII to initiate blood coagulation. Once formed in the blood vessel, the complex TF-FVII auto-catalyze the activation of FVII to FVIIa that, in turn, activates FX to activated FX (FXa) (FIGURE 1) [29]. Interestingly, the efficiency of FVIIa alone is approximately 0.0001 that of the TF-FVIIa complex for activating the coagulation cascade. Once activated, FXa (with its co-factor, FV) then catalyzes the activation of FII (i.e., prothrombin) to FIIa (i.e., thrombin), which in turn promotes the conversion of fibrinogen into fibrin. This first phase of Expert Rev. Hematol. 7(6), (2014)
Expert Review of Hematology Downloaded from informahealthcare.com by Nanyang Technological University on 04/26/15 For personal use only.
rFVIIa in Glanzmann’s thrombasthenia
Drug Profile
Sub-endothelial matrix hemostasis activation is only effective to generate a modest amount of thrombin (i.e.,
