Sensitivity and Robustness of Spatially Dependent Thrombin Generation and Fibrin Clot Propagation

Abstract

Blood coagulation is a delicately regulated space-and time-dependent process that leads to the formation of fibrin clots preventing blood loss upon vascular injury. The sensitivity of the coagulation network was previously investigated without accounting for transport processes. To investigate its sensitivity to coagulation factor deficiencies in a spatial reactiondiffusion system, we combined an in vitro experimental design with a computational systems biology model. Clot formation in platelet-free plasma supplemented with phospholipids was activated with identical amounts of tissue factor (TF) either homogeneously distributed (concentration 5 pM, homogeneous model) or immobilized on the surface (surface density 100 pmole/m 2 , spatially heterogeneous model). Fibrin clot growth and thrombin concentration dynamic in space were observed using video microscopy in plasma of healthy donors or patients with deficiencies in factors (F) II, FV, FVII, FVIII, FIX, FX, or FXI. In the spatially heterogeneous model, near-activator thrombin generation was decreased in FV-, FVII-, and FX-deficient plasma. In the homogeneous model, clotting was not registered in these samples. The simulation and experiment data showed that the coagulation threshold depended on the TF concentration. Our data indicate that the velocity of spatial clot propagation correlates linearly with the concentration of thrombin at the clot wave front but not with the overall thrombin wave amplitude. Spatial clot growth in normal plasma at early stages was neither reaction nor diffusion limited but became diffusion limited later. In contrast, clot growth was always diffusion limited in FV-, FVII-, and FX-deficient plasma and reaction limited in FVIII-, FIX-, and FXI-deficient plasma. We conclude that robustness of the spatially heterogeneous coagulation system was achieved because of the combination of 1) a local high TF surface density that overcomes activation thresholds, 2) diffusion control being shared between different active factors, and 3) an early saturated stimulus-response dependence of fibrin clot formation by thrombin.

Tissue Factor-Independent Coagulation Correlates with Clinical Phenotype in Factor XI Deficiency and Replacement Therapy

“…45,46 The phenotype observed in normal plasma spiked with C7P (►Fig. 2A-D) is in line with the model of FXI-deficient coagulation described by Kuprash et al 38 2. TF-independent TG and fibrin formation are reduced in FXI-deficient bleeders…”

“…For details on TG threedimensional plots see legend of ►Fig. 2 and studies of Dashkevich et al 31 and Kuprash et al 38…”

In Silico Hemostasis Modeling and Prediction

“…Recently, a detailed model of spatial thrombin generation and clot formation consisting of 21 partial differential equations and three ODEs was used to investigate blood coagulation sensitivity to coagulation factor deficiencies. 88 The authors concluded that the spatially heterogeneous coagulation system was robust to factor concentration variation due to combination of local high TF surface, diffusion control being shared between different active factors, and early saturated dependence of fibrin clot formation by thrombin. These studies ultimately led to the proposal of a modular concept of blood coagulation network (►Fig.…”

Damped White Noise Diffusion with Memory for Diffusing Microprobes in Ageing Fibrin Gels

“…Fibrin is a protein polymer network that plays a crucial role in blood clotting, wound healing, and other biological processes, such as blood vessel formation and cell growth (1)(2)(3)(4)(5)(6). Aside from its importance in clinical applications, fibrin also finds an increasing role in tissue regeneration and engineering (5,7,8).…”