title: Platelet surface-associated activation and secretion-mediated inhibition of coagulation factor XII.
abstract: Coagulation factor XII (fXII) is important for arterial thrombosis, but its physiological activation mechanisms are unclear. In this study, we elucidated the role of platelets and platelet-derived material in fXII activation. FXII activation was only observed upon potent platelet stimulation (with thrombin, collagen-related peptide, or calcium ionophore, but not ADP) accompanied by phosphatidylserine exposure and was localised to the platelet surface. Platelets from three patients with grey platelet syndrome did not activate fXII, which suggests that platelet-associated fXII-activating material might be released from α-granules. FXII was preferentially bound by phosphotidylserine-positive platelets and annexin V abrogated platelet-dependent fXII activation; however, artificial phosphotidylserine/phosphatidylcholine microvesicles did not support fXII activation under the conditions herein. Confocal microscopy using DAPI as a poly-phosphate marker did not reveal poly-phosphates associated with an activated platelet surface. Experimental data for fXII activation indicates an auto-inhibition mechanism (ki/ka = 180 molecules/platelet). Unlike surface-associated fXII activation, platelet secretion inhibited activated fXII (fXIIa), particularly due to a released C1-inhibitor. Platelet surface-associated fXIIa formation triggered contact pathway-dependent clotting in recalcified plasma. Computer modelling suggests that fXIIa inactivation was greatly decreased in thrombi under high blood flow due to inhibitor washout. Combined, the surface-associated fXII activation and its inhibition in solution herein may be regarded as a flow-sensitive regulator that can shift the balance between surface-associated clotting and plasma-dependent inhibition, which may explain the role of fXII at high shear and why fXII is important for thrombosis but negligible in haemostasis.
authors: National Research Center for Hematology, Moscow, Russia; Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Natalia V
authors: NV
authors: Zakharova
authors: Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Elena O
authors: EO
authors: Artemenko
authors: National Research Center for Hematology, Moscow, Russia; Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Nadezhda A
authors: NA
authors: Podoplelova
authors: Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia.
authors: Anastasia N
authors: AN
authors: Sveshnikova
authors: Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia.
authors: Irina A
authors: IA
authors: Demina
authors: National Research Center for Hematology, Moscow, Russia; Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia; Faculty of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors: Fazly I
authors: FI
authors: Ataullakhanov
authors: National Research Center for Hematology, Moscow, Russia; Center for Theoretical Problems of Physicochemical Pharmacology, Moscow, Russia; Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia; Faculty of Physics, M.V. Lomonosov Moscow State University, Moscow, Russia; Faculty of Biological and Medical Physics, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
authors: Mikhail A
authors: MA
authors: Panteleev
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001777:Blood Coagulation / Q000187:drug effects; D019774:Blood Coagulation Factor Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D055252:Cell-Derived Microparticles / Q000378:metabolism; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005174:Factor XII / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D005190:Family; D005260:Female; D055652:Gray Platelet Syndrome / Q000097:blood / Q000378:metabolism; D006801:Humans; D008297:Male; D008954:Models, Biological; D011485:Protein Binding; D022142:Secretory Vesicles / Q000378:metabolism
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D003174:Complement C1 Inactivator Proteins; D005174:Factor XII