The Need for Highly Purified Products to Treat Hemophilia B

Abstract

Thromboembolic complications of prothrombin complex concentrate (PCC) therapy were first reported by Kasper in 1973 [N Engl J Med 1973;289:160]. The following contaminants were discussed as possible contributors to the thrombogenicity risk: the presence of other zymogens in PCCs, the presence of activated factor IX or activated factor X, or the presence of phospholipids from platelets resulting from insufficient centrifugation of the donor plasma. Activated factor IX is now accepted as a major causative factor. After numerous additional reports of thromboembolic complications in patients treated with PCCs, the International Society on Thrombosis and Haemostasis (ISTH) Scientific and Standardization Committee (SSC) Thrombogenicity Registry was established in 1988. Lusher collected 72 cases worldwide for the SSC/ ISTH in 1988 and 1989. Thromboembolic complications and myocardial infarctions, however, continue to be serious problems associated with PCC therapy – even in the 1990s – underscoring the urgent need for high-purity factor IX products. Results from several studies by Mannucci, Bauer, and other authors demonstrated that patients treated with high-purity products developed no activation of prothrombin or thrombin, as indicated by appearance of thrombogenicity markers such as fibrinopeptide A and the amino-terminal fragments of prothrombin (F₁₊₂). Other authors demonstrated that in patients at high risk for thrombotic complications, particularly those with liver disease, or postsurgery, or in those requiring repeated treatments, high-purity concentrates appear to be safe, regarding both thrombosis and risk of virus transmission.

The safety and efficacy of recombinant human blood coagulation factor IX in previously untreated patients with severe or moderately severe hemophilia B

“…8 The development of high-purity pdFIX concentrates led to the successful treatment of patients with hemophilia B who previously experienced hypercoagulable events or thromboembolic phenomena (or both) after using intermediate-purity PCCs. 7,37 As expected, there was no evidence that rFIX significantly increased thrombin generation in this study; only one patient had a thrombotic event (a blood clot associated with a port site), which was deemed unrelated to rFIX.…”

“…[4][5][6] In the past decade, the development of high-purity pdFIX preparations has reduced the thrombogenic risks associated with FIX replacement therapy. [7][8][9] In addition, the introduction of improved viral attenuation methods during manufacture has reduced the risk of viral transmission with pdFIX products. 10 Nevertheless, current viral attenuation methods may not eliminate nonenveloped viruses, including hepatitis A (HAV) and parvovirus, or bloodborne prions associated with transmissible spongiform encephalopathies, such as variant Creutzfeldt-Jacob disease.…”

Blood

“…Thromboembolic complications are the major adverse events during the treatment of patients with prothrombin complex concentrates (PCCs) [44][45][46][47]. Prothrombin complex concentrates contain the coagulation factors II, VII, IX and X, protein Z, as well as the coagulation inhibitors protein C and S. These products are indicated for the treatment of patients with decreased levels of factors of the prothrombin complex due to vitamin K deficiencies, overdosing of oral anticoagulants, e.g., vitamin K, or decreased synthesis caused by liver dysfunctions.…”

“…There is a trend to high purity concentrates, since the lacking factor can be substituted in a more controlled fashion, and impurities are kept low. Such impurities could be associated with unwanted effects, such as immunosuppression, or thrombogenicity [65], [44].…”

Nonacog alfa

“…The delayed clearance and accumulation of these extraneous products were implicated in the development of thrombogenic complications, such as venous thrombosis, myocardial infarction and disseminated intravascular coagulation, particularly with extensive use during surgery [1,5,8].…”