The original stasis thrombosis model of Wessler has been modified. Numerous thrombogenic agents were evaluated for their pathophysiologic effects and were classified in terms of stasis clot in the jugular vein. Alterations produced in coagulation parameters, such as the PT, APTT, thrombin time, activated recalcification time (Hemachron), and thrombelastographic pattern were recorded. Since the pathophysiologic activation of the hemostatic system varies considerably in different diseases, a proper animal model along with a proper type of thrombogenic trigger should be carefully selected to produce pathogenesis and to study the therapeutic responses of heparin and its derivatives. In the modified stasis thrombosis model, besides monitoring the formation of the jugular vein stasis clot, it is proposed that the following tests may be useful to establish hypercoagulable states: Functional levels of various coagulation factors, platelet counts, fibrinogen levels, and whole blood activated clotting times. The nature of activation processes in each thrombogenic challenge should be carefully analyzed in terms of pathways involved; for example, the administration of heterologous serum (such as human, monkey) to rabbits produces anaphylactoid reactions, including hemolysis, thrombocytopenia, clinical chemistry abnormalities (enzymes), and many problems that may involve the complement and immune systems. All previous data obtained using heterologous sera as a thrombogenic trigger are of questionable value as to the efficacy of some of the antithrombotic agents tested against it. In addition to the species and the thrombogenic challenge, the following factors may contribute significantly to the pathophysiologic response and its alteration by various agents: (1) Composition of the thrombogenic agent; (2) effect of preparatory drugs, such as anesthetics, on the hemostatic parameters; (3) alterations on injection time, volume, osmolarity, and temperature; (4) variations in the circulation time of the thrombogenic agent and stasis time of the ligated jugular vein stasis segment; and (5) blood sample collection and handling. Since the kallikrein-kinin cascade is closely associated with the coagulation and the fibrinolytic network, a systemic monitoring of blood pressure may provide information on the effect of thrombogenic agents on hemodynamics.(ABSTRACT TRUNCATED AT 400 WORDS)

We have extensively studied the hemostatic parameters and the responses to the anticoagulant action of heparin and its fractions in the primate model (M. mulatta) and found these to be identical to those obtained in humans. The functional properties of antithrombin III, alpha 2-antiplasmin, and platelet factor 4 were also identical to humans in amidolytic and coagulant assays. Human antibodies against FPA, B beta 15-42 peptide, platelet factor 4, and thromboxane B2 reacted with the primate antigen, and assays were developed to measure these parameters in primates. Infusion of activated prothrombin complex concentrates (more than 100 U/kg/day) on a continual basis up to 3 days resulted in a hypercoagulable state manifested by an elevation of FPA, thromboxane B2, and changes in the thrombelastographic patterns. Similarly, infusion of homologous primate serum also resulted in a hypercoagulable state, as was evident by a sharp increase in the FPA levels. The antithrombotic effects of intravenous and subcutaneous administration of heparin, its low molecular fraction, and their constituents were studied after intravenous and subcutaneous injections. The low molecular weight fractions showed the most effective antithrombotic effects, whereas somewhat milder protection was observed with the starting material and highly anionic fraction. The prolongation of global tests, such as the APTT, TT, and changes in the thromboelastogram did not correlate with the reduction in the blood markers of hypercoagulable state. A modified simplate bleeding time method was used to study the effect of heparin and its fractions on the bleeding profile of heparin fractions. The components of fibrinolytic systems were also measurable in both the clot-based and amidolytic methods to predict the profibrinolytic actions of heparin fractions in its mode. These studies suggest that plasma markers, such as the platelet release proteins, products of thrombin activation, and prostaglandin metabolites, may provide better indices in the monitoring of the antithrombotic actions of newer heparins and antithrombotic drugs. Studies suggest that the pathophysiologic responses after a thrombogenic trigger in the primate model are close to humans, and drug modulation of these may provide relevant clinical information. This model provides the most similar preclinical model to study the actions of heparin fractions.

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