title: Agonist-induced platelet procoagulant activity requires shear and a Rac1-dependent signaling mechanism.
abstract: Activated platelets facilitate blood coagulation by exposing phosphatidylserine (PS) and releasing microvesicles (MVs). However, the potent physiological agonists thrombin and collagen poorly induce PS exposure when a single agonist is used. To obtain a greater procoagulant response, thrombin is commonly used in combination with glycoprotein VI agonists. However, even under these conditions, only a percentage of platelets express procoagulant activity. To date, it remains unclear why platelets poorly expose PS even when stimulated with multiple agonists and what the signaling pathways are of soluble agonist-induced platelet procoagulant activity. Here we show that physiological levels of shear present in blood significantly enhance agonist-induced platelet PS exposure and MV release, enabling low doses of a single agonist to induce full-scale platelet procoagulant activity. PS exposed on the platelet surface was immediately released as MVs, revealing a tight coupling between the 2 processes under shear. Using platelet-specific Rac1(-/-) mice, we discovered that Rac1 plays a common role in mediating the low-dose agonist-induced procoagulant response independent of platelet aggregation, secretion, and the apoptosis pathway. Platelet-specific Rac1 function was not only important for coagulation in vitro but also for fibrin accumulation in vivo following laser-induced arteriolar injury.
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Michael Keegan
authors: MK
authors: Delaney
authors: Institute of Medical Science, Shanghai Jiao Tong University School of Medicine, Shanghai, China; and.
authors: Junling
authors: J
authors: Liu
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Kyungho
authors: K
authors: Kim
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Bo
authors: B
authors: Shen
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Aleksandra
authors: A
authors: Stojanovic-Terpo
authors: Division of Experimental Hematology, Cincinnati Children's Research Foundation, University of Cincinnati, Cincinnati, OH.
authors: Yi
authors: Y
authors: Zheng
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Jaehyung
authors: J
authors: Cho
authors: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL;
authors: Xiaoping
authors: X
authors: Du
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D055252:Cell-Derived Microparticles / Q000502:physiology; D003094:Collagen / Q000008:administration & dosage / Q000502:physiology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000097:blood* / Q000172:deficiency / Q000235:genetics; D010718:Phosphatidylserines / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction; D013917:Thrombin / Q000008:administration & dosage / Q000502:physiology; D020830:rac1 GTP-Binding Protein / Q000097:blood* / Q000172:deficiency / Q000235:genetics
chemical_list: D009479:Neuropeptides; D010718:Phosphatidylserines; C484602:Rac1 protein, mouse; D003094:Collagen; D013917:Thrombin; D020830:rac1 GTP-Binding Protein