Transport physics and biorheology in the setting of hemostasis and thrombosis

Abstract

The biophysics of blood flow can dictate the function of molecules and cells in the vasculature with consequent effects on hemostasis, thrombosis, embolism, and fibrinolysis. Flow and transport dynamics are distinct for (i) hemostasis vs. thrombosis and (ii) venous vs. arterial episodes. Intraclot transport changes dramatically the moment hemostasis is achieved or the moment a thrombus becomes fully occlusive. With platelet concentrations that are 50- to 200-fold greater than platelet-rich plasma, clots formed under flow have a different composition and structure compared with blood clotted statically in a tube. The platelet-rich, core/shell architecture is a prominent feature of self-limiting hemostatic clots formed under flow. Importantly, a critical threshold concentration of surface tissue factor is required for fibrin generation under flow. Once initiated by wall-derived tissue factor, thrombin generation and its spatial propagation within a clot can be modulated by γ'-fibrinogen incorporated into fibrin, engageability of activated factor (FIXa)/activated FVIIIa tenase within the clot, platelet-derived polyphosphate, transclot permeation, and reduction of porosity via platelet retraction. Fibrin imparts tremendous strength to a thrombus to resist embolism up to wall shear stresses of 2400 dyne cm(-2) . Extreme flows, as found in severe vessel stenosis or in mechanical assist devices, can cause von Willebrand factor self-association into massive fibers along with shear-induced platelet activation. Pathological von Willebrand factor fibers are A Disintegrin And Metalloprotease with ThromboSpondin-1 domain 13 resistant but are a substrate for fibrin generation due to FXIIa capture. Recently, microfluidic technologies have enhanced the ability to interrogate blood in the context of stenotic flows, acquired von Willebrand disease, hemophilia, traumatic bleeding, and drug action.

Keywords: fibrin; hemodynamics; platelet; shear stress; thrombin; von Willebrand factor.

Fig. 1. Physical processes in haemostasis

The core/shell architecture of hemostatic clots results in a self-limiting event that sustains a transclot pressure drop (ΔP = P_vessel − P_interstitial) (A). In a mouse arteriole laser injury, the dense core is P-selectin positive and adjacent to the wound site and surrounded by a shell of less tightly bound, P-selectin negative platelets (B). A similar core/shell architecture is seen with human blood perfused over collagen/TF where the labeled P-selectin layer is also rich in thrombin and fibrin (C). The core region is highly contracted, thrombin and fibrin rich, and displays lower protein mobility than the shell, with fibrin playing a role in clot stability and limiting thrombin activity via γ′-fibrinogen (especially at venous shear rates) (D). Panels B, C, D from [30,50] with permission.

Fig. 2. Physical processes in arterial thrombosis

A ruptured atherosclerotic plaque triggers thrombosis under conditions of high wall shear stress and wall shear rate as blood jets through the stenosis (A). VWF factor is required for platelet capture under arterial flow conditions and extreme wall shear stresses can drive VWF fiber formation on an exposed collagen surface (B). Perfusion of whole blood over a 250 μm × 250 μm collagen/TF patch results in rapid platelet accumulation in dense clumps (green) that undergo retraction while fibrin (red) polymerizes under, around, and downstream of the platelets. Extreme wall shear rates (10,000 s⁻¹) produce thick VWF fibers (blue) that grow around a 30-μm wide micropost that can subsequently bind platelets perfused at 1000 s⁻¹ (D) that will activate and present P-selectin at 3000 s⁻¹ (E). Panels B, D, E from [68,70] with permission.