"The U.S. Food and Drug Administration today approved Tretten, Coagulation Factor XIII A-Subunit (Recombinant), the first recombinant product for use in the routine prevention of bleeding in adults and children who have a rare clotting disorder, k"...
Mechanism of Action
Fibrinogen (factor I) is a soluble plasma glycoprotein with a molecular weight of about 340 kDa. The native molecule is a dimer and consists of three pairs of polypeptide chains (Aα, Bβ and γ). Fibrinogen is a physiological substrate of three enzymes: thrombin, factor XIIIa, and plasmin.
During the coagulation process, thrombin cleaves the Aα and Bβ chains releasing fibrinopeptides A and B (FPA and FPB, respectively).2 FPA is separated rapidly and the remaining molecule is a soluble fibrin monomer (fibrin I). The slower removal of FPB results in formation of fibrin II that is capable of polymerization that occurs by aggregation of fibrin monomers.2 The resulting fbrin is stabilized in the presence of calcium ions and by activated factor XIII, which acts as a transglutaminase. Factor XIIIa-induced cross-linking of fibrin polymers renders the fibrin clot more elastic and more resistant to fibrinolysis.3 Cross-linked fibrin is the end result of the coagulation cascade, and provides tensile strength to a primary hemostatic platelet plug and structure to the vessel wall.
Administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) to patients with congenital fibrinogen deficiency replaces the missing, or low coagulation factor. Normal levels are in the range of 200 to 450 mg/dL.4
A prospective, open label, uncontrolled, multicenter pharmacokinetic study was conducted in 5 females and 9 males with congenital fibrinogen deficiency (afibrinogenemia), ranging in age from 8 to 61 years (2 children, 3 adolescents, 9 adults). Each subject received a single intravenous dose of 70 mg/kg RiaSTAP (fibrinogen concentrate (human) for intravenous use) . Blood samples were drawn from the patients to determine the fibrinogen activity at baseline and up to 14 days after the infusion. The pharmacokinetic parameters of RiaSTAP (fibrinogen concentrate (human) for intravenous use) are summarized in Table 2.
No statistically relevant difference was observed between males and females for fibrinogen activity. Subjects less than 16 years of age (n=4) had shorter half-life (69.9 ± 8.5) and faster clearance (0.73 ± 0.14) compared to subjects > 16 years of age. The number of subjects less than 16 years of age in this study limits statistical interpretations.
The incremental in vivo recovery (IVR) was determined from levels obtained up to 4 hours post-infusion. The median incremental IVR was 1.7 mg/dL (range 1.30 – 2.73 mg/dL) ncrease per mg/kg. The median in vivo recovery indicates that a dose of 70 mg/kg will ncrease patients' fibrinogen plasma concentration by approximately 120 mg/dL.
The pharmacokinetic analysis using fibrinogen antigen data (ELISA) was concordant with the fibrinogen activity (Clauss assay).
Table 2: Pharmacokinetic Parameters (n=14) for Fibrinogen
|Parameters||Mean ± SD (range)|
|Half-life [hours]||78.7 ± 18.13 (55.73-117.26)|
|Cmax [mg/dL]||140 ± 27 (100-210)|
|AUC for dose of 70 mg/kg [mg*hr/mL]||124.3 ± 24.16 (81.73-156.40)|
|Clearance [mL/h/kg]||0.59 ± 0.13 (0.45-0.86)|
|Mean residence time [hours]||92.8 ± 20.11 (66.14-126.44)|
|Volume of distribution at steady state [mL/kg]||52.7 ± 7.48 (36.22-67.67)|
The pharmacokinetic study evaluated the single-dose PK (see Pharmacokinetics) and maximum clot firmness (MCF) in subjects with afibrinogenemia. MCF was determined by thromboelastometry (ROTEM) testing. MCF was measured to demonstrate functional activity of replacement fibrinogen when a fxed dose of RiaSTAP (fibrinogen concentrate (human) for intravenous use) was administered. Clot firmness is a functional parameter that depends on: activation of coagulation, fibrinogen content of the sample and polymerization/crosslinking of the fibrin network. Thromboelastometry has been shown to be a functional marker for the assessment of fibrinogen content and for the effects of fibrinogen supplementation on clinical effcacy.5
For each subject, the MCF was determined before (baseline) and one hour after the single dose administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) . RiaSTAP (fibrinogen concentrate (human) for intravenous use) was found to be effective in increasing clot firmness in patients with congenital fibrinogen deficiency (afibrinogenemia) as measured by thromboelastometry. The study results demonstrated that the MCF values were signifcantly higher after administration of RiaSTAP (fibrinogen concentrate (human) for intravenous use) than at baseline (see Table 3). The mean change from pre-infusion to 1 hour post-infusion was 8.9 mm in the primary analysis (9.9 mm for subjects < 16 years old and 8.5 mm for subjects ≥ 16 to < 65 years old). The mean change in MCF values closely approximated the levels expected from adding known amounts of fibrinogen to plasma in vitro6. Hemostatic effcacy in acute bleeding episodes, and its correlation with MCF, are being verifed in a postmarketing study.
Table 3: MCF [mm] (ITT population)
|Time point||n||Mean ± SD||Median (range)|
|Pre-infusion||13||0 ± 0||0 (0-0)|
|1 hour post-infusion||13||10.3 ± 2.7||10.0 (6.5-16.5)|
|Mean change (primary analysis)a||15b||8.9 ± 4.4||9.5 (0-16.5)|
|MCF = maximum clot frmness; mm = millimeter; ITT = intention-to-treat
a p-value was < 0.0001.
b The mean change was set to 0 for 2 subjects with missing MCF data.
1. Peyvandi F, Haertal S, KnaubS, etal. Incidence of bleeding symptoms in 100 patients with nherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost 2006; 4:1634-7.
2. Kreuz W, Meili E, Peter-Salonen K, et al. Pharmacokinetic properties of a pasteurized fibrinogen concentrate. Transfusion and Apheresis Science 2005;32:239-46.
3. Colman R, Clowes A, George J, et al. Overview of Hemostasis. In: Hemostasis and Thrombosis: Basic Principles and Clinical Practice (5th ed.). Colman R, Clowes A, George J, Goldhaber S, MarderVJ (eds.). LippincottWilliams & Wilkins, Philadelphia 2006:11-14.
4. KreuzW, Meili E, Peter-Salonen K, et al. Effcacy and tolerability of a pasteurized human fibrinogen concentrate in patients with congenital fibrinogen deficiency. Transfusion and Apheresis Science 2005;32:247-253.
5. Fries D, Innerhofer P, Reif C, et al. The Effect of Fibrinogen Substitution on Reversal of Dilutional Coagulopathy: An In Vitro Model. Anesth Analg 2006; 102:347-351.
6. Kalina U, Stöhr HA, Bickhard H, et. al. Rotational thromboelastographyfor monitoring of fibrinogen concentrate therapy in fibrinogen deficiency. Blood Coagulation and Fibrinolysis. 2008; 19:777-783.
Last reviewed on RxList: 10/5/2009
This monograph has been modified to include the generic and brand name in many instances.
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