Factor VIII-bypassing activity of bovine tissue factor using the canine hemophilic model.

Abstract

The bleeding disorder of hemophilia A currently treated by replacement therapy of the missing coagulation factor, factor VIII, is frequently complicated by the development of neutralizing antibodies. The therapeutic potential of attenuated forms of the lipid-associated glycoprotein tissue factor, a known initiator of coagulation, was investigated as a factor VIII-bypassing activity. The protein moiety of tissue factor (Apo-TF) was partially purified and exhibited minimal procoagulant activity before relipidation in vitro. In pilot studies, Apo-TF injection into rabbits previously anticoagulated with an antibody to factor VIII was found to have a procoagulant effect. The efficacy of the material was further demonstrated when injection of Apo-TF in hemophilic dogs resulted in a normalization of the cuticle bleeding time. Little or no change in the blood parameters associated with disseminated intravascular coagulation was observed at lower doses, although mild to moderate effects were seen at higher doses. These data suggest a novel role for Apo-TF preparations as a potential therapeutic agent for hemophiliacs with antibodies to factor VIII once the potential thrombogenicity of such materials is evaluated.

In vivo models of haemophilia – status on current knowledge of clinical phenotypes and therapeutic interventions

“…O’Brien et al. [44] demonstrated a bypassing effect of the delipidated protein moiety of tissue factor (Apo‐TF) in haemophilic rabbits and dogs. In a group of haemophilia B dogs, recombinant human FIX was evaluated for therapeutic effect [41] and concluded to be highly effective both for replacement therapy and prophylaxis.…”

“…The deficiency has been induced by administration of anti‐factor antibodies or other inhibitors [42]. Such models have been reported in rabbits [43–45], mice [46] and cynomolgous monkeys [42]. Table 2 provides an overview of these models.…”

“…O’Brien et al. [44] developed a model of transient haemophilia A in rabbits by infusing normal animals with a cross‐reacting human anti‐FVIII antibody. This method led to a decrease in FVIII plasma activity from ∼5 U mL −1 to below detection limit in 30 min.…”

Coagulation factor VIII

“…This treatment is only successful for 25-50% of the cases (108) and the activated concentrates may be thrombogenic (109,110,111). However, a preparation containing only FVIIa (recombinant) has successfully been used in an inhibitor patient during synovectomy (112), and it has been possible to stop bleedings in haemophilia A dogs with FVIIa (113) or TF (114). This shows that the amplification loop ( Fig.…”

Normalization of the Haemostatic Plugs of Dogs with Haemophilia A (Factor VIII Deficiency) Following the Infusion of a Combination of Factor Xa and Phosphatidylcholine/Phosphatidylserine Vesicles

“…In previous studies, wo developed the methodology for.studyirg the forming haemostatic plug in the vascular bed of the injured dog nail cuticle (10). This was based on a reproducible model of cuticle bleeding in haemophilic dogs (11) that we have used to evaluate this and other potential FVIII bypassing therapies such as tissue factor (12) and FVIIa (13). In particular, we emphasized the need to develop and use methods for objectively quantifying the morphological changes noted over time.…”