Thrombin generation is not increased in the blood of hemophilia B patients after the infusion of a purified factor IX concentrate

Abstract

Prothrombin complex concentrates (PCC), licensed for the treatment of hemophilia B, are known to carry a significant risk of thromboembolic complications. Although the reasons for thrombogenicity are not completely understood, several manufacturers have developed purified factor IX concentrates that contain negligible amounts of the other vitamin K-dependent factors. To evaluate whether or not the infusion of such a factor IX concentrate is followed by lesser activation of the hemostatic system than by the infusion of a PCC, we performed a series of coagulation assays on 11 hemophilia B patients before and after the administration of these two types of concentrate using a randomized cross-over design. The levels of prothrombin fragment F1 + 2, a sensitive measure of the in vivo cleavage of prothrombin by factor Xa, was significantly increased in plasma after PCC, but not after factor IX concentrate. Plasma fibrinopeptide A, a sensitive index of the enzymatic activity of thrombin on fibrinogen, also increased significantly after PCC but not after factor IX concentrate. The fragment B beta 15–42, a sensitive index of the enzymatic action of plasmin on fibrin II, did not change after either concentrate. There were also no differences in less sensitive coagulation measurements, such as plasma fibrinogen, antithrombin III, and fibrin monomers, nor in indices of platelet activation, such as beta-thromboglobulin and platelet factor 4. These findings show that the infusion of a purified factor IX concentrate can result in substantially less activation of the coagulation cascade than may be seen with PCC.

Epidemiology of Coagulation Factors, Inhibitors and Activation Markers: The Third Glasgow Monica Survey I. Illustrative Reference Ranges by Age, Sex and Hormone Use

“…Although these correlations are modest (r < 0·21), this may reflect the short plasma half-lives of F1, 2 (90 min) and TAT (15 min) (Bauer & Rosenberg, 1994) compared to those of coagulation factors or inhibitors, as well as the many other variables which affect both activation markers and coagulation factors or inhibitors . Furthermore, these associations are consistent with each other; with previous reports that factor VII is associated with FpA (Lowe et al, 1991) and with F1, 2 in population samples; with elevations in F1, 2 and TAT following intravenous infusions of prothrombin complex concentrates (Mannucci et al, 1990;Hampton et al, 1993) or recombinant factor VIIa ; with increased generation of thrombin in vitro after elevation of factor VIII by desmopressin infusion (Ibbotson et al, 1992); and by increased levels of F1, 2 and FpA in heterozygous protein C deficiency (Bauer et al, 1988;Mannucci et al, 1992).…”

“…The Northwick Park Heart Study has also associated both high and low antithrombin levels with CHD , and there are anecdotal reports of arterial thrombosis in protein C or protein S deficiency (Allaart & Briet, 1994). Increased plasma levels of coagulation factors, decreased levels of coagulation inhibitors, or standard cardiovascular risk factors may be associated with ongoing activation of blood coagulation, as measured by increased plasma levels of activation markers such as fibrinopeptide A (FpA), prothrombin fragment F1, 2 (F1, 2), or thrombin-antithrombin complexes (TAT) (Bauer et al, 1988;Lowe et al, 1991;Miller et al, 1991;Mannucci et al, 1990Mannucci et al, , 1992Bauer & Rosenberg, 1994).…”

An ultrapure plasma-derived monoclonal antibody-purified factor IX concentrate (Nonafact®), results of phase III and IV clinical studies

“…In case of inhibitor formation additional tests were performed according to CPMP guidelines [5,6]. Thrombogenicity markers were determined by assessment of appropriate activation peptide markers and fragment 1 + 2 [7][8][9]. In the phase III and IV studies, clinical evaluation of thrombosis was undertaken in case of suspicion of a thrombo-embolic event [9].…”

Why Prescribe Highly Purified Factor VIII and IX Concentrates?

“…Thus, there is reason to expect them to be less thrombogenic than PCCs. It has also been shown that puritied concentrates, in contrast to PCCs, do not generate thrombin after infusion in vivo [42]. In fact, there have been no reports of thromboembolic complications after replacement with purified FIX concentrates.…”