In vivo Models of Thrombogenic Potential: Usefulness and Limitations

Abstract

The thrombogenicity of prothrombin complex concentrates (PCCs) has been known as a risk factor since their first clinical use about 30 years ago. The development of in vivo models to define the thrombogenic components in PCCs was instrumental in providing a logical basis for selecting in vitro assays to screen for the distribution of such components during the manufacture of PCCs, and to minimize their appearance in the final product. Even so, these thrombogenic components are not completely removed, as shown in our canine nonstasis model of thrombogenicity: PCCs were still found to elicit a thrombogenic response, shown by increased fibrinopeptide A, fibrin(ogen) degradation products, activated partial thromboplastin time, and decreased fibrinogen and platelet counts when clinically relevant doses were used. The new generation of high-purity factor IX (HP-FIX) concentrates differs from PCCs because these products contain only negligible amounts of clotting factors other than factor IX, lower amounts of activated clotting factors, and, in products we have assayed, no coagulant-active phospholipids. When we infused a number of HP-FIX products in the canine nonstasis model, no thrombogenic response was observed at doses considerably greater than PCC doses that did elicit a response. Likewise, HP-FIX products were much less thrombogenic than PCCs when tested in small-animal stasis and nonstasis thrombogenicity models. Small-animal models are also useful for evaluating the role of factor IXa as a potential thrombogenic contaminant of concentrates and ensuring minimal amounts in the final product. The limitations associated with extrapolating in vivo model data will be shown to be minimal if ongoing clinical studies continue to demonstrate the low thrombogenic potential of HP-FIX concentrates in humans.

Clotting factor product administration and same‐day occurrence of thrombotic events, as recorded in a large healthcare database during 2008–2013

“…Overall, in support of the literature [8,12,[14][15][16]18,19,21,[28][29][30]33,35], our study suggests an increased risk of TEs with FIX complex and FVIIa products, and a potentially lower risk with FIX and FVIII high-purity products. In addition to underlying recipient factors, the identified differences in TE risk by product may be due to variations in the products' mechanism of action, dose and rate of administration.…”

“…advanced age, underlying health conditions and cardiovascular surgeries) and product factors (e.g. dosage and thrombogenic impurity content) [14][15][16][20][21][22][25][26][27][28][29][30][31][32][33][34][35][36]. Although the thrombogenic potential of CF products has been mitigated, procoagulant impurities may still be present in CF products administered to patients and as such may increase the risk of TE, especially in persons with underlying risk factors (e.g.…”

“…Although the thrombogenic potential of CF products has been mitigated, procoagulant impurities may still be present in CF products administered to patients and as such may increase the risk of TE, especially in persons with underlying risk factors (e.g. health conditions or surgeries) [26][27][28][29][30][31][32][33][34][35][36].…”

“…demographic characteristics, underlying health conditions and thrombogenicity), using a large commercial administrative database for 2008-2013 and a laboratory investigation. Due to well-characterized potentially thrombogenic impurities of factor IX (FIX)-containing products, CBER laboratory analysis evaluated and compared the procoagulant activity of different US-licensed FIX-containing products [26][27][28][29][30][31][32][33][34][35][36].…”

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.…”