The aim of the proposed research is to study the biochemistry and pathophysiology of the early stages plasma coagulation and kinin forming systems in man. Previous biochemical accomplishments of this laboratory have been focused on the pathways of activation of this system including the biochemistry of the interactions between prekallikrein activators (activated factor XII), prekallikrein and kallikrein, and high molecular weight kininogen. During the next grant period we will extend these observations to include exploration of the domains of prekallikrein and factor XI responsible for complex formation with high molecular weight kininogen. We will also elucidate the effect of high molecular weight kininogen in protecting kallikrein and factor XIa against inhibition by plasma protease inhibitors including Cl--inhibitor, Alpha1-antitrypsin, antithrombin III, and Alpha2-macroglobulin. Kinetic, molecular and immunochemical approaches will be used. Clinical investigation will attempt to improve existing functional assay for components of the contact system and to development of radioimmunoassay for kallikrein inhibitor complexes. These improved assays will be applied to study hypotensive endotoxemia, myocardial ischemia, nephrotic syndrome, rocky mountain spotted fever and transient ischemic attacks in man. We will also seek to determine what contact factors or protease inhibitors are present in platelets as well as subcellular localization and mechanism of release. We will explore whether plasma kallikrein or XIa can stimulate platelets and whether these components bind to platelets. This combined biochemical, immunological and clinical approach should further our understanding of this important system in host defenses as well as in the pathogenesis of disease states.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL024365-07
Application #
3337648
Study Section
(EH)
Project Start
1978-12-01
Project End
1986-11-30
Budget Start
1984-12-01
Budget End
1985-11-30
Support Year
7
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Kaufman, N; Page, J D; Pixley, R A et al. (1991) Alpha 2-macroglobulin-kallikrein complexes detect contact system activation in hereditary angioedema and human sepsis. Blood 77:2660-7
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Bradford, H N; Schmaier, A H; Colman, R W (1990) Kinetics of inhibition of platelet calpain II by human kininogens. Biochem J 270:83-90
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Clarke, B J; Cote, H C; Cool, D E et al. (1989) Mapping of a putative surface-binding site of human coagulation factor XII. J Biol Chem 264:11497-502
Scott, C F; Colman, R W (1989) Factors influencing the acceleration of human factor XIa inactivation by antithrombin III. Blood 73:1873-9
Gustafson, E J; Schmaier, A H; Wachtfogel, Y T et al. (1989) Human neutrophils contain and bind high molecular weight kininogen. J Clin Invest 84:28-35

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