Competitive Binding, and Accounting for Procoagulant Platelets, Significantly Change Thrombin Profiles in in vitro Coagulation

Susree, Modepalli and Panteleev, Mikhail A and Mohan, Anand (2019) Competitive Binding, and Accounting for Procoagulant Platelets, Significantly Change Thrombin Profiles in in vitro Coagulation. In: 27th Biennial Congress of the International Society on Thrombosis and Haemostasis (ISTH), 2019, Melbourne, Australia.

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Abstract

Background: The 'cascade' model is the accepted view for in vitro coagulation. In the cascade model, most of the coagulation reactions take place in plasma while platelets supply only amino-phospholipids for assembly of procoagulant complexes. However, the role and interaction mechanism of platelets in coagulation have been continually redefined since. Aims: Only a fraction of the activated platelets is now thought to contribute to assembly of procoagulant complexes. Further, instead of each zymogen binding to a specific number of binding sites, it is now believed that all zymogens and enzymes (except IIa) bind competitively to the shared phosphatidylserine-dependent sites on procoagulant platelets. These new findings need to be incorporated in a mechanistic model of coagulation, and their effect on thrombin profiles studied. Methods: The mechanistic model for in vitro coagulation in Susree et al (2018) incorporates a thrombin dose-dependent fraction of procoagulant platelets and competitive binding of procoagulant enzymes (except IIa) and zymogens to these platelets. Simulations of the model are compared with those from an earlier model (in Susree & Anand (2017)) with the same reactions but without these additional features. Results: Competitive binding alone (δ = 1 in Fig 1) reduces the time for peak thrombin concentration by 78.9%. Procoagulant fraction of activated platelets (δ = 0.12 in Fig 1) leads to 35.2% higher peak thrombin concentration when comparing new and old models. In the new model, peak thrombin concentration is significantly overestimated- by 299.4% and 24.7%, respectively: see Fig 2- when procoagulant fraction or thrombin dose-dependence are not included. Conclusions: Competitive binding of enzymes and zymogens, combined with thrombin dose-dependence of procoagulant platelets, causes significant qualitative and quantitative changes in the predicted thrombin profiles for in vitro coagulation. This makes a case for new hypotheses concerning role of platelets to be incorporated in mechanistic models of coagulation.

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