Abstract

To explore interrelated functions of hemostatic, kinin-releasing and complement systems in plasma we will examine certain functions of: 1) the serum inhibitor of the activated first component of complement (Cl-Inhibitor), 2) high molecular weight kininogen (HMW-K), 3) Hageman factor and fragments cleaved from Hageman factor (HFf) in the following approaches: 1) The capacity of dysmorphic C1-Inhibitor proteins isolated from plasma of certain persons with hereditary angioneurotic edema to inhibit activated Hageman factor, plasma kallikrein, and plasmin will be tested. Normal C1-Inhibitor blocks these hemostatic enzymes, as well as Cl, but dysmorphic C1-Inhibitors do not inhibit C1. Fragments released from normal and dysmorphic C1-Inhibitors during cyanogen bromide cleavage will be compared as to their inhibitory and binding properties with respect to each enzyme. 2) Monoclonal antibody to light chain of HMW-K will be prepared, fluorescinated and used to locate HMW-K in tissues and cells of blood and endothelial cells. The effect of anti-HMW-K upon platelet functions will be tested, if HMW-K is present on platelet membranes. Anti-HMW-K will be tested for its effect on directed mobility of polymorphonuclear cells in a modified Boyden Chamber. If HMW-K is found on endothelial cells, the possibility that it may affect the morphology of these cells, or play a role in the release of coagulant activity from the cells will be examined. 3) With antibody to Hageman factor fragments (HFf), we will examine plasma from individuals susceptible to thromboembolism, as well as normal persons, to see if HFf in plasma may be associated with a thromboembolic tendency. The possibility that the initial step in the activation of Hageman factor may involve non-enzymatic cleavage of an internal thioester bond in the single-chain Hageman factor molecule will be examined.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL015690-14
Application #
3335018
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1978-09-01
Project End
1988-08-31
Budget Start
1985-09-01
Budget End
1986-08-31
Support Year
14
Fiscal Year
1985
Total Cost
Indirect Cost

  Institution

Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229

  Publications

Donaldson, V H; Wagner, C J; Mitchell, B H et al. (1998) An HMG-I protein from human endothelial cells apparently is secreted and impairs activation of Hageman factor (factor XII). Proc Assoc Am Physicians 110:140-9
Donaldson, V H; Wagner, C J; Davis 3rd, A E (1996) An autoantibody to C1-inhibitor recognizes the reactive center of the inhibitor. J Lab Clin Med 127:229-32
Donaldson, V H; Bissler, J J; Welch, T R et al. (1996) Antibody to C1-inhibitor in a patient receiving C1-inhibitor infusions for treatment of hereditary angioneurotic edema with systemic lupus erythematosus reacts with a normal allotype of residue 458 of C1-inhibitor. J Lab Clin Med 128:438-43
Shoemaker, L R; Schurman, S J; Donaldson, V H et al. (1994) Hereditary angioneurotic oedema: characterization of plasma kinin and vascular permeability-enhancing activities. Clin Exp Immunol 95:22-8
Donaldson, V H; Falconieri, M W (1993) A modification of an affinity procedure for purification of human C1- inhibitor that provides a homogeneous stable preparation. J Immunol Methods 157:101-4
Kleniewski, J; Donaldson, V H (1993) Endothelial cells produce a substance that inhibits contact activation of coagulation by blocking the activation of Hageman factor. Proc Natl Acad Sci U S A 90:198-202
Kleniewski, J; Blankenship, D T; Cardin, A D et al. (1992) Mechanism of enhanced kinin release from high molecular weight kininogen by plasma kallikrein after its exposure to plasmin. J Lab Clin Med 120:129-39
Donaldson, V H; Bissler, J J (1992) C1- inhibitors and their genes: an update. J Lab Clin Med 119:330-3
Donaldson, V H; Bernstein, D I; Wagner, C J et al. (1992) Angioneurotic edema with acquired C1- inhibitor deficiency and autoantibody to C1- inhibitor: response to plasmapheresis and cytotoxic therapy. J Lab Clin Med 119:397-406
Donaldson, V H; Mitchell, B H; Everson, B et al. (1990) Interactions of C1(-)-inhibitors from normal persons and patients with type II hereditary angioneurotic edema with purified activated Hageman factor (factor XIIa). Blood 75:911-21

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