Flow-simulated thrombin generation profiles as a predictor of thrombotic risk among pre-menopausal women

BACKGROUND: A large number of individuals are at risk for deep venous thrombosis (DVT) due to alterations in multiple coagulation factors and inhibitors secondary to malignancy, drug interactions, or other general medical conditions. Traditional metrics of haemostasis such as prothrombin time, partial thromboplastin time, and bleeding time, generally estimate anticoagulation status and bleeding risk rather than thrombosis risk. OBJECTIVE: The objective of this study was to correlate a novel, systems-based metric of clotting potential to risk of DVT from a database derived from the Leiden Thrombophilia Study (LETS). METHODS: We utilized a computational model of blood coagulation, which addresses the interplay between biochemical factors, blood flow, and physiologic surface initiation of coagulation, to calculate an individualized, systems-based metric of clotting potential, termed the flow simulated thrombin generation (FSTG), for 210 pre-menopausal women in LETS. RESULTS: Both DVT and oral contraceptive (OC) use were associated with higher values of FSTG. We demonstrated a nearly 3-fold increased risk of DVT for each standard deviation increase above the mean in FSTG determined under venous flow conditions, which remained highly predictive after adjustment for age and OC status (adjusted OR 2.66; 95% CI 1.69–4.19; P<0.0001). CONCLUSIONS: A systems-based screening approach that integrates biochemical factors and flow haemodynamics identifies small subgroups of patients at risk of thrombosis that may benefit from oral anticoagulants

Simulated Surface-Induced Thrombin Generation in a Flow Field

A computational model of blood coagulation is presented with particular emphasis on the regulatory effects of blood flow, spatial distribution of tissue factor (TF), and the importance of the thrombomodulin-activated protein C inhibitory pathway. We define an effective prothrombotic zone that extends well beyond the dimensions of injury. The size of this zone is dependent on the concentrations of all reactive species, the dimensions of TF expression, the densities of surface molecules, and the characteristics of the flow field. In the case of tandem sites of TF, the relationship between the magnitude of the effective prothrombotic zone and the interval distance between TF sites dictate the net response of the system. Multiple TF sites, which individually failed to activate the coagulation pathway, are shown to interact in an additive manner to yield a prothrombotic system. Furthermore, activation of the thrombomodulin-activated protein C pathway in the regions between sites of TF downregulate the thrombin response at subsequent TF sites. The implications of prothrombotic effects, which extend downstream beyond the discrete site of injury to interact with subsequent lesions are critical given the systemic nature of atherosclerotic disease