title: Flow and delta-P dictate where thrombin, fibrin, and von Willebrand Factor will be found.
abstract: Hemostasis occurs in two different topological scenarios: complete severing of a vessel or disruption of the vessel wall. Either to meet the daily rigors of active life or during an acute trauma, hemostasis involves the regulated and self-limiting production of thrombin to stop bleeding. In contrast, arterial and venous thrombosis typically involves the unregulated, intraluminal growth of a clot, in the absence of bleeding. For either hemostasis or thrombosis, the presence of flow and pressure gradients (delta-P, ΔP) dictates when and where thrombin and fibrin are located and in what quantity. For hemostatic clots, fibrin formation helped limit clot growth. We found that γ'-fibrinogen had a role in limiting clot growth via anti-thrombin activity at venous, but not arterial conditions. For hemophilic blood, severe factor deficiency (<1% healthy) led to a defect in both platelet and fibrin deposition under flow. However, moderate deficiency, which is associated with a less severe bleeding phenotype, had normalized platelet function but still lacked fibrin production. We conclude signaling levels of thrombin can be generated during moderate hemophilia to sufficiently activate platelets to achieve primary hemostasis, even if fibrin formation remains defective. Finally, as a clot grows, shear stresses can become sufficiently extreme in diseased arteries to drive von Willebrand Factor self-association into massive fibers, potentially the final burst of clot growth towards full thrombotic occlusion.
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: sld@seas.upenn.edu.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D005337:Fibrin / Q000378:metabolism*; D006467:Hemophilia A / Q000097:blood / Q000378:metabolism / Q000473:pathology; D006487:Hemostasis; D006801:Humans; D015539:Platelet Activation; D013314:Stress, Mechanical; D013917:Thrombin / Q000378:metabolism*; D013927:Thrombosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D014841:von Willebrand Factor; D005337:Fibrin; D013917:Thrombin
keywords: Hemodynamics; Platelet; Thrombin; fibrin; shear stress; stenosis