The contact activation system consists of several plasma proteins, including factors XII and XI, high molecular weight kininogen, and prekallikrein, which interact in the presence of an activating surface and initiate the reactions of the intrinsic coagulation pathway, the fibrinolytic pathway and the kinin-forming pathway. The clinical observation that patients lacking factor XI have a significant hemorrhagic diathesis whereas those lacking any of the other contact factors do not bleed abnormally suggests the possibility that, physiologically, factor XI may be activated through an alternative mechanism in vivo which can bypass the factor XII-dependent reactions. The fact that, in vitro, factor XI must react in the presence of a negatively charged surface for optimal activation suggests that one possible alternative mechanism might involve activation of factor XI on physiologic surfaces. In this project, we plan to investigate whether the endothelial cell, a surface available in vivo is involved in the activation of factor XI. Initially we will determine whether factor XI binds to cells. Endothelial cells, either normal or damaged, will be incubated with purified factor XI/125I-XI or purified activated factor XI (XIa)/125I-XIa. In addition, cells will be incubated with normal plasma or plasmas deficient in the other contact phase factors containing tracer 125I-factor XI. If binding is observed, the bound factor XI will be examined for cleavage by SDS-polyacrylamide gel electrophoresis and for potential coagulant activity by either clotting or amidolytic assays. Further, the specific characteristics of the binding reaction and the biochemical properties of the cleaving agent will be investigated.
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