A Comparison of the in Vitro and in Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis (Wessler) and Non-Stasis Rabbit Models

Prowse, Christopher V.; Williams, Anna E.

doi:10.1055/s-0038-1650089

Cited by 16 publications

(12 citation statements)

References 15 publications

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“…Citrated plasma was used to assess fibrinogen (Ellis & Stransky, 1961). factor V. factor IX and the activated partial thromboplastin time (Prowse & Williams. 1980).…”

Section: Methodsmentioning

confidence: 99%

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Studies on the effect of heat treatment on the thrombogenicity of factor IX concentrates in dogs

et al. 1987

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This study examines the effects of heat treatment for 72 h at 80 degrees C on the potential thrombogenicity of lyophilized human coagulation factor IX concentrates. Since heating generated minor amounts of thrombin, concentrate was prepared with antithrombin III addition prior to heat treatment. Changes in coagulation parameters were followed prior to and after infusion of 100 iu/kg of heated and unheated concentrates to dogs. All batches produced a transient fall in platelet count during infusion and a delayed rise in plasma fibrinopeptide A, accompanied by a minor prolongation of the activated partial thromboplastin time. Such changes were less marked for heated batches. Control infusion of a 'failed' factor IX concentrate showed an additional fall in fibrinogen, rise in fibrin degradation products and a more rapid rise in fibrinopeptide A, while thrombin infusion caused an even more dramatic intravascular coagulation. These studies indicated no increase in the potential thrombogenicity of freeze dried factor IX concentrates as a result of heat treatment.

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“…Citrated plasma was used to assess fibrinogen (Ellis & Stransky, 1961). factor V. factor IX and the activated partial thromboplastin time (Prowse & Williams. 1980).…”

Section: Methodsmentioning

confidence: 99%

“…1972: Middletonetal. 1973: Kingdonetal, 1975: Saset al 1975Prowse et al 1979), tests in animal models suggest that such assays are not entirely satisfactory (Kingdon et al, 1975;Hedner et al, 1976;Cash et al, 1978;Hedner et al 1979: Prowse& Williams, 1980: Gilesetal. 1980Harrisonet al, 1985).…”

mentioning

confidence: 99%

Studies on the effect of heat treatment on the thrombogenicity of factor IX concentrates in dogs

et al. 1987

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“…A number of in vivo studies were performed to vali date the basis for in vitro assays of thrombogenicity [9][10][11], These studies indicated that the PCCs that were most active in the in vivo models correlated with those that were active in two in vitro assays -the nonactivated par tial thromboplastin time and the thrombin generation time. The studies also aided in defining the limits of these assays that should be met by in-process materials or final products.…”

Section: Improvement In Product Safetymentioning

confidence: 99%

In vivo Models of Thrombogenic Potential: Usefulness and Limitations

et al. 1995

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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.

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“…3), 7-11 DORIS MBNACHf! animal models, such as a rabbit non-stasis model [28,31], a dog model [32] and a porcine model [33].…”

Section: Detection Of Thrombogenicity In Factor IX Complex Con Centratesmentioning

confidence: 99%

“…Evidence that thrombotic complications are the result of the administration of Factor IX Complex comes from experiments conducted in animals. Administration of Factor IX Complex, at doses used to treat patients, induced thrombosis [25, 28,291 in the rabbit stasis model [30] or DIC (as shown by a decrease in the circulating levels of platelets, fibrinogen, factor V and factor VIII) in several other Q Blackwell Science Ltd lfaemophilia (1995), 1, (Suppl. 3), 7-11 DORIS MBNACHf!…”

Section: Detection Of Thrombogenicity In Factor IX Complex Con Centratesmentioning

confidence: 99%

Coagulation factor IX concentrate: historical perspective

Ménaché

1995

Haemophilia

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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.

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A Comparison of the in Vitro and in Vivo Thrombogenic Activity of Factor IX Concentrates Using Stasis (Wessler) and Non-Stasis Rabbit Models

Cited by 16 publications

References 15 publications

Studies on the effect of heat treatment on the thrombogenicity of factor IX concentrates in dogs

Studies on the effect of heat treatment on the thrombogenicity of factor IX concentrates in dogs

In vivo Models of Thrombogenic Potential: Usefulness and Limitations

Coagulation factor IX concentrate: historical perspective

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