The role of recombinant factor VIIa (FVIIa) in fibrin structure in the absence of FVIII/FIX

Abstract

Summary. Patients with hemophilia have an impaired thrombin generation and therefore form loose fibrin hemostatic plugs that are easily dissolved by fibrinolysis. This prevents maintained hemostasis in these patients, resulting in a severe bleeding disorder. Recombinant (F)VIIa has been shown to enhance thrombin generation on already thrombin-activated platelets in the absence of FVIII and FIX. An efficacy rate of 80-90% has been found in hemophilia patients with inhibitors against FVIII or FIX both in association with major surgery and in the treatment of serious bleedings. In a model measuring fibrin clot permeability in a platelet-containing system described by Blombäck et al. (1994) this was demonstrated to be dependent on the concentration of FVIII and FIX. The addition of rFVIIa in concentrations of 1.9, 4.8 and 9.6 mg mL À1 normalized fibrin clot permeability. The concentration of 1.9 mg mL À1 of rFVIIa normalized clot permeability in this system and the higher concentrations of rFVIIa added only slightly to the effect. No further decrease in clot permeability was found when rFVIIa in a concentration of 1.9 mg mL À1 was added to a sample with a normal concentration (100%) of FVIII or FIX. Higher concentrations of rFVIIa added to the plasma containing 100% of FVIII or FIX induced only a slight further decrease of fibrin permeability constant, arguing against any unwanted effect of extra rFVIIa on clot permeability in the case of a normal hemostasis. Furthermore, the fibrin network was studied with 3D microscopy and the loose network found in the absence of FVIII or FIX increased in density with increasing FVIII or FIX concentrations. The addition of rFVIIa to FVIII-or FIX-deficient systems altered the network structure, making the fibers thinner and more tightly packed.

Redistribution and Hemostatic Action of Recombinant Activated Factor VII Associated with Platelets

“…7,9,35,44 The thrombin generated in the previous situations influences the formation of a fibrin net and improves its structure and stability, which is not achieved at lower doses of rFVIIa. 45 Notably, in our studies using blood samples from patients with FVII deficiency, addition of platelets containing rFVIIa promoted the formation of larger platelet aggregates, but did not result in an increased fibrin deposition. It is likely that the reduced plasma levels of FVIIa in these patients were insufficient to cause the generation of fibrin that occurs in healthy donors.…”

A Variant of Recombinant Factor VIIa With Enhanced Procoagulant and Antifibrinolytic Activities in an In Vitro Model of Hemophilia

“…2,3,5 RFVIIa also shortens the time to onset of fibrin clot formation and normalizes the fibrin structure and porosity of clots formed under hemophilic conditions (absence of factors VIII and/or IX). 5,6 Furthermore, rFVIIa improves fibrin clot formation in a fibrinolytic environment, suggesting that rFVIIa may improve hemostasis by improving formation of the primary clot, as well as formation of subsequent clots if the primary clot fails. 5 After 10 years of clinical experience with rFVIIa in the treatment of hemophilia, it is increasingly evident that the dosing must be individualized to achieve an optimal treatment outcome.…”

The Frequency of Iron Deficiency among Patients with Hemophilia

“…The structure of hemostatic plugs in haemophiliacs are characterized by defective stabilization of initial platelet rich plug in a fibrin meshwork [9][10]. The fibrin formed under these condition are thus abnormal structure with increased permeability and decreased mechanical strength [11] [12]. In addition, haemophilia patients have impaired wound healing as adequacy & stability of initial fibrin clot is an important determinant of wound healing [13].…”