Volume 49, Issue 1, Pages 39-48 (January 2003)

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ABSTRACT

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Recombinant factor VIIa (NovoSeven®) as a hemostatic agent

Abstract

Recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Denmark) induces hemostasis in life- and limb-threatening bleeds and in major surgery of hemophilia A and B patients, regardless of inhibitor titer. A total of more than 6,500 patients have been treated, and NovoSeven has been administered in more than 180,000 standard doses. Experience gained from these clinical situations suggests that NovoSeven should be administered as a 90- to 110-μg/kg bolus dose every second hour. Hemophilia patients with mild to moderate bleeding episodes require two to three doses to achieve complete hemostasis, whereas patients with severe bleeding episodes may require more doses. For major surgery and in cases of life-threatening bleeding, dosing every second hour for the first 24 hours may be required. Thereafter, the same dose, but with longer intervals between doses, is recommended. Recent in vitro experiments indicate that even higher doses of NovoSeven may be needed to achieve full thrombin generation in the absence of factor VIII (FVIII), factor IX (FIX), and factor XI (FXI).

Article Outline

• Abstract

• NovoSeven (rFVIIa) in nonhemophilic patients with impaired thrombin generation

• NovoSeven in bleeding due to massive tissue trauma as a result of extensive surgery or major trauma

• NovoSeven (rFVIIa) in congenital or acquired FVII deficiency

• Conclusion

• References

• Copyright

Recombinant activated factor VII (rFVIIa; NovoSeven®, Novo Nordisk, Denmark) induces hemostasis in life-and limb-threatening bleeds and in major surgery in hemophilia A and B patients, regardless of inhibitor titer. By January 2001 more than 180,000 standard doses of rFVIIa had been administered.20, 22, 31 Experience gained from these clinical situations suggests that rFVIIa should be given as a 90- to 110-μg/kg bolus dose every second hour. Hemophilia patients with mild to moderate bleeding episodes require two to three doses to achieve complete hemostasis, whereas patients with severe bleeding episodes may require more doses. For major surgery and in cases of life-threatening bleedings, dosing every second hour for the first 24 hours may be required. Thereafter, the same dose, but with longer intervals between doses, is recommended. Recent in vitro experiments indicate that even higher doses of rFVIIa may be required to achieve full thrombin generation.28

Hemostasis is initiated by the formation of a complex between tissue factor (TF) and FVII (FVIIa), normally present in circulating blood.35, 40 TF is not normally exposed to circulating blood, but is found on various types of cells in the deeper layers of the vessel wall, in atherosclerotic plaques, and in some types of tumor cells. Following injury to the vessel wall, TF is exposed to blood and TF-FVIIa complexes are formed on the TF-bearing cells, where they activate FX (FXa), leading to the conversion of prothrombin to thrombin. The limited amount of thrombin formed through this pathway activates FVIII, FV, and FXI, as well as platelets. As a result of thrombin activity, platelets change shape and expose negatively charged phospholipids, such as phosphatidylserine, which are normally not exposed to the blood. The negatively charged phospholipids provide the template for further FX activation and full thrombin generation. This process seems to be compartmentalized and confined to the surface of the thrombin-activated platelets and the TF-bearing cells.35

Full thrombin generation is essential for the formation of a stable fibrin hemostatic plug, resistant to premature fibrinolysis, and thus provides reliable and maintained hemostasis. This process requires not only the presence of the coagulation proteins, including fibrinogen, but also the fibrin-stabilizing factor, FXIII, the thrombin-activatable fibrinolytic inhibitor (TAFI), and possibly other factors of importance in the regulation of fibrinolysis. While FXIII is activated by fairly low concentrations of thrombin, TAFI activation requires higher thrombin concentrations.2 Because TAFI downregulates fibrinolysis, low thrombin generation may result in a defective resistance to fibrinolysis. An increased rate of clot lysis has, in fact, been demonstrated in hemophilia patients.10 Also, the fibrin structure is dependent on the rate as well as the total amount of thrombin formed.9 A fibrin clot formed at lower thrombin concentrations is more porous with a higher permeability and is more easily lysed.9, 44

In hemophilia, only an initial, limited amount of thrombin dependent on the TF-FVIIa is generated, which is insufficient to consolidate and sustain the fibrin plug.8, 11, 28 In a cell-based in vitro model it has been shown that rFVIIa at concentrations between 5 and 50 nm binds to the activated platelet surface with a low affinity and mediates the conversion of FX into FXa independent of TF.35 In the same model, thrombin generation at levels found in the presence of normal plasma concentrations of coagulation proteins was achieved in the absence of FVIII/FIX and FXI after the addition of rFVIIa at concentrations of 50 nm or higher. Full thrombin generation occurred after the addition of up to 150 nm of rFVIIa.28 This indicates that rFVIIa, in concentrations of 50 nm or higher, may be able to compensate for a lack of FVIII/FIX. This is in accordance with clinical experience using rFVIIa in hemophilia patients with inhibitors against FVIII /FIX. In these patients, a dose of approximately 100 μg/kg rFVIIa (roughly corresponding to a concentration of 50 nm and a FVII:C of 70 to 90 U/mL) has provided satisfactory hemostasis in most cases.22, 31 However, although a hemostatic effect is achieved at rFVIIa concentrations of 50 nm in most hemophilia patients, full thrombin generation may require higher doses of rFVIIa in some situations, and in some individuals, to ensure the formation of a fully stabilized hemostatic plug. Recently, it has been demonstrated that the addition of rFVIIa in vitro to platelet-rich FVIII- or FIX-deficient plasma normalizes the porosity and permeability of the fibrin clot formed in the presence of calcium. A fully normalized permeability coefficient (Darcy constant) was achieved at a concentration of 4.6 μg rFVIIa/mL plasma, corresponding to approximately twice the clinical dose currently recommended.19

Factor XI is also activated by thrombin and has been shown to enhance thrombin generation on the activated platelet surface by activating more FIX into FIXa.37 Patients with FXI deficiency often suffer from mucocutaneous bleeds and bleeding in association with surgery. This bleeding pattern may indicate that the hemostatic plugs formed in the absence of full FXI activity are more sensitive to lysis, which may be at least partly due to an impaired TAFI activation. The administration of additional exogenous rFVIIa to patients with FXI deficiency may help to generate the extra thrombin required to achieve full activation of TAFI, and thereby facilitate the formation of hemostatic plugs that are resistant to fibrinolysis. A single dose of rFVIIa may be sufficient to establish an antifibrinolytic effect, through the full activation of TAFI, ensuring hemostasis in patients with FXI deficiency and normal FVIII/FIX levels.

In summary, according to current opinion, rFVIIa induces hemostasis by enhancing thrombin generation on the thrombin-activated platelet surface, thereby providing the formation of a fully stabilized, tight fibrin hemostatic plug, which is resistant to premature fibrinolysis.

NovoSeven (rFVIIa) in nonhemophilic patients with impaired thrombin generation

Patients with platelet defects have impaired thrombin generation and pathological prothrombin consumption. The availability of platelet procoagulant phospholipids is rate-limiting for the production of thrombin.5

In the cell-based hemostasis model, previously described, thrombin generation was shown to be dependent on the number of platelets present.27 In the same model, the addition of rFVIIa at concentrations of 50 to 500 nm caused a dose-dependent increase in the initial rate of thrombin generation and a reduction in the length of the lag phase of platelet activation.27

By 1985 it had been demonstrated that the addition of plasma-derived FVIIa shortened the mesenteric total hemostatic time in a thrombocytopenic rabbit model.21 A pilot study including 74 thrombocytopenic patients with a prolonged bleeding time showed that 52% (55 of the 105 injections of rFVIIa given in total) receiving rFVIIa (50 or 100 μg/kg given as a single bolus dose) had a reduction in bleeding time. Eight patients with overt bleeding (nose bleeds, vaginal bleeds, oozing from catheters, etc) received a single dose of rFVIIa. Bleeding stopped or slowed in all cases (six of eight stopped and two slowed). Even in patients with a platelet count below 10,000/μL, the bleeding stopped following administration of 100 μg/kg of rFVIIa.29

Impaired thrombin generation has been demonstrated in patients with functional platelet disorders such as Glanzmann's thrombasthenia (lack of the glycoprotein [GP]IIb/GPIIIa receptor on the platelet membrane) and Bernard-Soulier's syndrome (lack of the GPIb receptor on the platelet membrane).4, 41 The presence of fibrin has been shown to be important for full platelet activation, indicating that platelets adhering to the fibrin surface may enhance thrombin generation in a process independent of the presence of the receptors.4

A hemostatic effect of rFVIIa has been demonstrated in a limited number of patients with Glanzmann's thrombasthenia, as well as in a few patients with Bernard-Soulier's thrombasthenia.12, 38, 39 As in thrombocytopenic patients, rFVIIa may initiate hemostasis by enhancing thrombin generation to the extent that full thrombin generation occurs, independently of any interaction between fibrin and platelets, through GPIb and von Willebrand factor. A significant role of such an interaction in the generation of thrombin has previously been suggested.4 A similar mechanism may be the basis for the hemostatic effect of rFVIIa observed in patients with von Willebrand disease type 3, who lack von Willebrand factor.13, 17

NovoSeven in bleeding due to massive tissue trauma as a result of extensive surgery or major trauma

Patients with profuse bleeding often develop hemodilution coagulopathy characterized by a decreased number of platelets, lowered plasma levels of fibrinogen, FVIII, FV, and vitamin K–dependent coagulation proteins, as well as an increase in fibrinolysis.18 Decreased fibrinogen results in both a loose fibrin structure and porous fibrin plugs and decreased activation of FXIII.9, 34 Following transfusion of more than 10 units of blood, the FVIII plasma level may be below that required for sustaining hemostasis. Furthermore, both FVIII and FV are degraded by plasmin and other proteolytic enzymes. All of these factors, together with the decreased platelet count often found in these patients, may contribute to impaired thrombin generation. This impairment is transient, provided the patient has no basic underlying condition such as liver disease or any type of hematologic disorder, which may result in a coagulation defect. As soon as the bleeding tapers or ceases, the patient is capable of synthesizing coagulation proteins and will soon regulate his or her own coagulopathy. A single injection of rFVIIa may, however, improve this process by giving the patient a burst of thrombin, thereby ensuring the formation of stable, solid fibrin plugs capable of initiating and maintaining hemostasis.

Furthermore, it is important to note that most of the plasma substitutes used in hypovolemic patients contribute to the coagulopathy seen in patients subjected to trauma and excessive bleeding. High molecular starch solutions induce lowering of the plasma levels of FVIII and von Willebrand factor.42 Dextran has also been shown to induce a reduction in FVIII and alter the structure of the thrombus formed, making it more vulnerable to fibrinolysis. The thrombus structure induced by dextran is similar to that seen in von Willebrand patients.1

In summary, a number of hemostatic changes following extensive trauma, surgery, and bleeding occur, all of which contribute to impaired thrombin generation. Full thrombin generation requires normal plasma concentrations of coagulation proteins such as FVIII, FIX, FXI, and fibrinogen, as well as a normal platelet count. These are necessary for the formation of a solid, cross-linked fibrin plug that is resistant to premature fibrinolysis. Activation of TAFI is also required for the formation of a tight fibrin structure, as previously described.9, 36 A decreased fibrinogen concentration may result in impaired FXIII activation (necessary for full fibrin stabilization) and defective thrombin generation.4, 34

A hemostatic effect has been demonstrated following the administration of rFVIIa in a limited number of patients after trauma and bleeding, as well as in patients with heavy bleeding from other causes, such as profuse upper gastrointestinal bleeds.16, 26, 30, 43, 45

NovoSeven (rFVIIa) in congenital or acquired FVII deficiency

Patients with severe congenital FVII deficiency may bleed spontaneously and mildly affected patients usually bleed after surgical challenge or trauma. Recombinant FVIIa has been satisfactorily used in the treatment of severe FVII deficiency.3, 24, 33 Twenty-seven spontaneous bleeding episodes have been treated in 17 FVII-deficient patients (19 in the joints and eight in other sites) and seven major and 13 minor surgical interventions have been performed while the patient was undergoing treatment with rFVIIa. Doses ranged from 21 to 27 μg/kg. The treatment effect was excellent in all hemarthorosis treated. In five of the joint bleeds more than one dose was necessary to stop the bleeding. For all major surgery performed (four synovectomies, one colonectomy, one craniotomy, one inguinal herniotomy) and for nine cases of minor surgery more than one dose was necessary to stop bleeding or prevent rebleeding. Two patients developed antibodies to FVII. One had received an accidental dose of 800 μg/kg and the other developed a low-titer, transient antibody. Both patients had also received plasma. No thrombotic events were reported, even though rFVIIa was used repeatedly in several cases and also in association with tranexamic acid.32

Defective synthesis of FVII occurs in patients with impaired liver function and also in patients receiving oral anticoagulant therapy. In a randomized, double-blind, placebo-controlled study, 28 healthy volunteers received acenocoumarol twice daily in order to obtain international normalized ratio (INR) values within the range used in oral anticoagulant therapy. At INR values greater than 2, plasma levels of FVII were 4% to 17%. Subsequently, rFVIIa was administered in single doses of 2 to 320 μg/kg. The INR normalized in all individuals and the period of normalization was dose-dependent. No signs of systemic activation of the coagulation system were seen.15 One spontaneous nosebleed was reported in a patient on warfarin with an INR of 2.9, which was successfully treated with two doses of 80 μg/kg rFVIIa.7 Positive outcomes have been reported in patients with critically prolonged INRs (range, 3.2 to 13.9).14

The most frequently encountered hematological abnormalities in patients with impaired liver function (cirrhotic) include thrombocytopenia, decreased levels of coagulation proteins synthesized in the liver such as the vitamin K–dependent proteins (FIX, FX, FVII, prothrombin, protein C) and fibrinogen, as well as increased fibrinolysis. In 10 cirrhotic patients with prolonged prothrombin time (PT) FVII level were found to be the lowest compared with all of the other vitamin K–dependent proteins (4% to 17%). Following the administration of rFVIIa in single doses of 5, 20, or 80 μg/kg in a randomized study, PT was normalized and the timing was dose-dependent.6

A blind randomized study including 65 cirrhotic patients undergoing laparoscopic biopsy under the cover of rFVIIa in a dose range of 5 to 120 μg/kg has been reported.25 The authors concluded that laparoscopic liver biopsy can be performed safely and reliably using rFVIIa in patients in whom the standard procedure might be contraindicated due to coagulopathy. In a single-center, open-label pilot study, six patients have successfully received 80 μg/kg rFVIIa prior to liver transplantation.23

Conclusion

rFVIIa may be an effective and safe method to induce hemostasis in patients with a defective thrombin generation resulting in profuse and severe bleeding following various stimuli. Such patients may include those with serious bleeding disorders (hemophilia, platelet defects, etc), as well as patients who following extensive trauma/surgery develop profuse bleeds difficult to stop by mechanical hemostatic procedures or those who develop profuse internal bleeds. By enhancing thrombin generation, a fully stabilized hemostatic fibrin plug with a tight structure decreasing its permeability may be formed. This fibrin plug is less prone to dissolve and therefore provides a reliable and maintained hemostasis.

References

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PII: S0011-5029(03)90013-7

doi:10.1016/S0011-5029(03)90013-7

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