(72b) An Integrated Engineering Control System Model of Primary and Secondary Hemostasis

Hemostasis, the physiological process that arrests bleeding and keeps blood within an injured blood vessel, consists of a set of reactions and sub-processes that can be divided into various functional components. Normal functioning of the components is necessary to achieve a delicate balance between effective hemostasis and pathological conditions such as thrombosis, one of the major causes of death in the world, or hemophilia. Because the components of the hemostatic process interact in complex ways, how the various components work together to implement fast, effective and stable responses to vascular injury cannot be fully understood using traditional experimental methods alone—quantitative models are required. However, developing a faithful mathematical representation of known mechanistic details of the entire hemostatic process using standard modeling approaches will produce a model containing an inordinately large number of variables and an even larger number of unknown parameters. An alternative conceptual paradigm is required if the important complex details are to be represented adequately, with sufficient fidelity, and in mathematically tractable form.  

From a process engineering perspective, we observe that hemostasis is mediated by an automatic biological control system with clearly identifiable control system components such as sensors, controllers, and actuators.  Our modeling approach uses such an engineering control system representation as the basis for organizing information efficiently into a holistic model, with the control system components as “functional modules,” thereby facilitating development, validation and systematic analysis of the complete hemostatic process as a combination of the component modules.  

In this presentation, we will discuss the development of a comprehensive hemostasis model, and its validation against experimental data from the literature. We will first present a high-level engineering control system block diagram for hemostasis that shows the two major,  distinct sub-processes: primary hemostasis (responsible for platelet aggregation) and secondary hemostasis (responsible for coagulation) and their interconnections. We will then present mathematical models developed and validated for each sub-process separately and subsequently connected via three known interaction mechanisms: (1) Platelet activation and aggregation (via primary hemostasis) provides biologically active surfaces for the enzyme reactions of the coagulation cascade (in secondary hemostasis); (2) thrombin (produced by secondary hemostasis) is a potent agonist for platelet activation (in primary hemostasis); and (3) platelet activation (in primary hemostasis) triggers the release of coagulation factor V stored within platelets, which in turn promotes thrombin production (in secondary hemostasis). We will then show results of the dynamic characteristics of hemostatic response predicted by our comprehensive model, and demonstrate how the interactions between the components in hemostasis contribute to the overall effectiveness of the hemostatic process.

The validated model will subsequently be used for systematic analysis of the overall integrated process of hemostasis and to generate hypotheses for rational diagnosis and treatment of pathological hemostasis conditions.