Thrombin-mediated feedback activation of factor XI on the activated platelet surface is preferred over contact activation by factor XIIa or factor XIa.
To study the pathways for initiation of intrinsic blood coagulation, activated human platelets were compared with dextran sulfate as surfaces for factor XI activation by factor XIIa, factor XIa, or thrombin. Activated gel-filtered platelets promoted the activation of factor XI (60 nm) by thrombin (0.02-10 nm, EC(50) approximately 100 pm, threshold concentration approximately 10 pm) at initial rates 2- to 3-fold greater than those obtained with dextran sulfate in the presence of either high molecular weight kininogen (45 nm) and ZnCl(2) (25 micrometer) or prothrombin (1.2 micrometer) and CaCl(2) (2 mm). The maximum rates of factor XI activation achieved in the presence of activated gel-filtered platelets were 30 nm.min(-1) with thrombin, 6 nm.min(-1) with factor XIIa and 2 nm.min(-1) with factor XIa. Values of turnover number calculated at various enzyme concentrations (0.05-1 nm) were 24-167 (mean = 86) min(-1) for thrombin, 4.6-50 (mean = 21) min(-1) for factor XIIa, and 1.3-14 (mean = 8) min(-1) for factor XIa. A physiological concentration of fibrinogen (9.0 micrometer) inhibited factor XI activation by thrombin (but not by factor XIIa) in the presence of dextran sulfate but not in the presence of gel-filtered platelets. Compared with factors XIIa and XIa, thrombin is the preferred factor XI activator, and activated platelets are a relevant physiological surface for thrombin-mediated initiation of intrinsic coagulation in vivo.
Baglia
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FA
Sol Sherry Thrombosis Research Center, Departments of Medicine and Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Walsh
P N
PN
D001792:Blood Platelets / Q000201:enzymology / Q000378:metabolism*; D016264:Dextran Sulfate / Q000494:pharmacology; D005172:Factor XI / Q000378:metabolism*; D015956:Factor XIIa / Q000494:pharmacology*; D015945:Factor XIa / Q000494:pharmacology*; D005340:Fibrinogen / Q000494:pharmacology; D006801:Humans; D015539:Platelet Activation; D013499:Surface Properties; D013917:Thrombin / Q000494:pharmacology*
D005340:Fibrinogen; D005172:Factor XI; D016264:Dextran Sulfate; D015945:Factor XIa; D015956:Factor XIIa; D013917:Thrombin