title: Minimum wound size for clotting: flowing blood coagulates on a single collagen fiber presenting tissue factor and von Willebrand factor.
abstract: It is unknown if a lower size limit exists for human blood coagulation under flow over physiological vessel wall triggers as small as a single collagen fiber. Prior determinations of the smallest sized surface stimuli necessary for clotting of human blood, defined as the patch size threshold, have not deployed whole blood, hemodynamic flow, and platelet adhesive stimuli. For whole blood perfused in microfluidic devices, we report that steady venous flow (wall shear rate, 100 s(-1)) was sufficient to drive platelet deposition on 20 micron long zones of collagen fibers or on a single fiber. With tissue factor (TF)-coated collagen, flowing blood generated robust platelet deposits, platelet-localized thrombin, and fibrin on a single collagen fiber, thus demonstrating the absence of a physiological patch size threshold under venous flow. In contrast, at arterial wall shear rate (1000 s(-1)) with TF present, essentially no platelet or fibrin deposition occurred on 20 micron collagen zones or on a single collagen fiber, demonstrating a patch threshold, which was overcome by pre-coating the collagen with von Willebrand factor (vWF). For venous flows, human blood can clot on one of the smallest biological units of a single collagen fiber presenting TF. For arterial flows, vWF together with TF allows human blood to generate thrombin and fibrin on a patch stimulus as limited as a single collagen fiber. vWF-dependent platelet adhesion represents a particle-based sensing mechanism of micron-scale stimuli that then allows amplification of the molecular components of TF-driven thrombin and fibrin production under arterial flow.
authors.affiliation: Institute for Medicine and Engineering, University of Pennsylvania, 1024 Vagelos Research Laboratories, Philadelphia, PA 19104, USA. sld@seas.upenn.edu.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.forename: Maurizio
authors.initials: M
authors.lastname: Tomaiuolo
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
mesh_terms: D001158:Arteries / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology*; D001792:Blood Platelets; D003094:Collagen / Q000737:chemistry*; D004129:Dimethylpolysiloxanes / Q000737:chemistry; D005337:Fibrin / Q000737:chemistry; D006801:Humans; D044085:Microfluidics; D009757:Nylons / Q000737:chemistry; D010973:Platelet Adhesiveness; D011108:Polymers / Q000737:chemistry; D033081:Shear Strength; D013917:Thrombin / Q000737:chemistry; D013925:Thromboplastin / Q000737:chemistry*; D013927:Thrombosis / Q000378:metabolism; D014945:Wound Healing; D014841:von Willebrand Factor / Q000737:chemistry*
chemical_list: D004129:Dimethylpolysiloxanes; D009757:Nylons; D011108:Polymers; C085707:poly(dimethylsiloxane)-polyamide copolymer; D014841:von Willebrand Factor; D005337:Fibrin; D003094:Collagen; D013925:Thromboplastin; D013917:Thrombin