Coagulation factor IX concentrate: historical perspective

Abstract

Several historical findings have led to the development of a plasma-derived virus inactivated concentrate largely composed of factor IX with only traces of the other vitamin K dependent clotting factors and used exclusively for treating factor IX deficient patients (haemophilia B). The observations that have led to the identification of haemophilia B as a different entity from haemophilia A will be reviewed first. The development of a plasma-derived product for replacement therapy in haemophilia B patients, the specific complications associated with its use, and the approaches taken to try to understand and prevent these complications, will be considered next. The development of techniques that allowed the separation of factor IX from the other vitamin K dependent clotting factors will be reviewed, as will the characteristics of Coagulation Factor IX apart from the other vitamin K dependent clotting factors. The characteristics of Coagulation Factor IX for therapeutic use and the results obtained using animal models will also be analysed. The advances that have resulted in the decreased risk of virus transmission due to more detailed screening of blood donors and submitting the concentrate to a virus inactivation treatment will not be considered here.

Continuous infusion of FVIII and FIX concentrates:in vitroanalysis of clinically relevant parameters

“…The generation of thrombogenic components following the reconstitution and administration of some FIX‐containing concentrates obtained from several manufacturers has raised serious concern [39, 40]. Thrombogenicity, although rare, was evident following the use of the prothrombin complex concentrates, which contained a high degree of impurities that probably accounted for the life‐threatening events, especially in patients who received large bolus doses postoperatively or those with liver disease [40, 41]. Although the newer concentrates appear to be largely devoid of these complications, even when applied as a bolus injection [42–45], proof of absence of potentially thrombogenic components is required.…”

“…This is governed by concerns regarding the sterility during home‐care use as well as by the experience with earlier factor concentrates that had lower specific activities and proved unstable upon prolonged incubation. The high or ultra‐high purity factor concentrates available at present have high specific activity [40, 43, 45, 49], are stable and sterile for several days in reconstituted form [50] and have low potential to generate activated (thrombogenic) components.…”

Prothrombin Complex Concentrate, a General Antidote for Oral Anticoagulation

“…Factor IX belongs to the group of vitamin Kdependent proteins, including, among others, the procoagulant factors II (prothrombin), VII, IX, and X. Due to the presence of the other vitamin K-dependent coagulation factors in partly purified factor IX concentrates, its use was also recognized for the treatment of congenital factor VII and factor X deficiencies, as well as for acquired deficiencies in vitamin K-dependent coagulation factors due to liver disease [14]. And last but not least, partly purified factor IX concentrates appeared extremely useful in rapid reversal of anticoagulation by vitamin K antagonists like warfarin [15,16].…”