The Evaluation of a Prothrombotic Risk in a Human Fibrinogen Concentrate

Fibrinogen is a circulating coagulant protein which is converted to polymerizable fibrin by thrombin. The human fibrinogen concentrate (FC) (CSL Behring) has been used for the treatment of bleeding in fibrinogen deficiency. In this investigation we investigated the prothrombotic potential of FC using the in-vivo, Wessler venous stasis assay in rabbits Thrombogenicity in clinical use was assessed in a postmarketing drug surveillance review. Forty-five rabbits were randomized to receive either placebo or 40 mg/kg of one of four different lots of FC, injected into a marginal ear vein. Thirty seconds thereafter, a segment of the right jugular vein (1.5 – 2.0 cm) was ligated. After 15 minutes the segment was removed and evaluated for thrombus formation according to a score system from 0 –3. Thrombogenic materials, such as activated prothrombin complexes, have consistently shown high scores of thrombus formation in this assay. The mean score in the FC treated rabbits (0.85 ± 1.04) was not different from that in the placebo-treated rabbits (0.8 ± 0.84). Postmarketing data was comprised of spontaneous reports to a postmarketing surveillance system for Adverse Drug Reports (ADR). The number of ADR reports was expressed relative to the number of estimated single standard doses. The estimated dose per patient was adjusted to the degree of bleeding (between one to eight gram). Between January 01, 1986 and April 30, 2008 in total 983,195 g of Haemocomplettan^® P had been distributed. Very few reports (n=9) of thromboembolic events have been reported throughout postmarketing surveillance, corresponding to one case report for every 13,655 treatments of 8 grams FC. The reported thromboembolic events occurred in patients with congenital afibrinogenemia or acquired hypofibrinogenemia. In most cases, patients had additional risk factors (e.g. concomitant administration of blood products prothrombin complex concentrate, platelet concentrates, activated factor VII, etc.). Although a causal relationship to administration of FC could not be definitely excluded, the occurrence of thromboembolic events is very rare. From congruent results of both a classical preclinical model of thrombogenicity and analysis of postmarketing data, FC appears to have a very low risk of thrombogenicity.