Platelets are involved in promoting the interactions and activations of coagulation proteins at various stages of the intrinsic system, including contact activation, factor-X activation and prothrombin activation. Recent studies from our laboratory, supported by the present grant favoring this general hypothesis include the following observations: 1) platelets promote the proteolytic activation of factor XI in the presence of HMW kininogen and either factor XIIa of kallikrein; 2) activated platelets bind both factor XI and XIa tightly and specifically in the presence of HMW kininogen and enhance 10- to 40-fold the coagulant activities of both factors XI and XIa 3) the functional and structural integrity of factor XIa is fully retained when it is bound to the platelet surface; 4) the factor-Xa catalyzed activation of factor IX appears to be physiologically significant reaction as judged from kinteic parameters; 5) platelet membranes contain a molecule functionally and antigenically similar to plasma factor XI but different in molecular weight and subunit structure that may substitute for plasma factor XI in coagulation reactions and 6) the prothrombinase complex, consisting of facotr Va, factor Xa and a phospholipid cofactor, is assembled on platelet membrane components that are specifically associated with triton-insoluble cytoskeletons of activated platelets. Several lines of evident suggest the hypothesis, so far not studied directly that platelets may interact specifically with factor IX and factor IXa, thereby promoting factorX activation. Specifically, the objectives of these investigations are: 1) to investigate the binding of factor IX and factor IXa to platelets, including studies of a) time course and requirements for protein cofactors, electrolytes and divalent cations, state of platelet activation and platelet agonists; b) specificity; c) saturability and reversibility; d) derivation of binding constants. 2) To study the platelet contribution to factor-X activation, indcluding a) requirements for protein factors, electrolytes and divalent cations, state of platelet activation and platelet agonists; b) effects of phospholipids cofactor VIII and platelets on kinetics of factor X activation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Hematology Subcommittee 2 (HEM)
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Temple University
Schools of Medicine
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Ho, D H; Baglia, F A; Walsh, P N (2000) Factor XI binding to activated platelets is mediated by residues R(250), K(255), F(260), and Q(263) within the apple 3 domain. Biochemistry 39:316-23
Ahmad, S S; Wong, M Y; Rawala, R et al. (1998) Coagulation factor IX residues G4-Q11 mediate its interaction with a shared factor IX/IXa binding site on activated platelets but not the assembly of the functional factor X activating complex. Biochemistry 37:1671-9
Scandura, J M; Zhang, Y; Van Nostrand, W E et al. (1997) Progress curve analysis of the kinetics with which blood coagulation factor XIa is inhibited by protease nexin-2. Biochemistry 36:412-20
Baglia, F A; Walsh, P N (1996) A binding site for thrombin in the apple 1 domain of factor XI. J Biol Chem 271:3652-8
Scandura, J M; Walsh, P N (1996) Factor X bound to the surface of activated human platelets is preferentially activated by platelet-bound factor IXa. Biochemistry 35:8903-13
London, F; Ahmad, S S; Walsh, P N (1996) Annexin V inhibition of factor IXa-catalyzed factor X activation on human platelets and on negatively-charged phospholipid vesicles. Biochemistry 35:16886-97
Scandura, J M; Ahmad, S S; Walsh, P N (1996) A binding site expressed on the surface of activated human platelets is shared by factor X and prothrombin. Biochemistry 35:8890-902
Baglia, F A; Seaman, F S; Walsh, P N (1995) The Apple 1 and Apple 4 domains of factor XI act synergistically to promote the surface-mediated activation of factor XI by factor XIIa. Blood 85:2078-83
Baglia, F A; Jameson, B A; Walsh, P N (1995) Identification and characterization of a binding site for platelets in the Apple 3 domain of coagulation factor XI. J Biol Chem 270:6734-40
Seaman, F S; Baglia, F A; Gurr, J A et al. (1994) Binding of high-molecular-mass kininogen to the Apple 1 domain of factor XI is mediated in part by Val64 and Ile77. Biochem J 304 ( Pt 3):715-21

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