Platelets co-stimulated with collagen and thrombin display a number of unusual features. As initially described, these dual activated platelets, referred to a COAT-platelets (collagen and thrombin stimulated-platelets), express high levels of surface-bound factor V. This sub-population of platelets represents approximately 30 percent of the total and is most prominent among young platelets. COAT-platelets are also observed upon activation with thrombin plus convulxin, an agonist for glycoprotein VI; however, no single agonist examined was able to produce COAT-platelets. The functional significance of FV on COAT-platelets was shown by demonstrating high factor V activity, preferential binding of factor Xa and significant prothrombinase activity. In addition, COAT-platelets were found to have several other alpha-granule proteins including von Willebrand factor, fibrinogen, fibronectin, thrombospondin and alpha2-antiplasmin, bound at high levels. Unexpectedly, COAT-platelet formation is prevented by transglutaminase inhibitors including dansyl cadaverine, putrescine, and acetyl-casein, and a synthetic peptide substrate for transglutaminases is incorporated in COAT- platelets. The platelet component serving as the acyl acceptor for the transglutaminase reaction was found to be serotonin, and multi-valent serotonin-adducts of albumin were effective inhibitors of COAT-platelet formation. Fibrinogen isolated from COAT-platelets was also found to have conjugated serotonin. This proposal will further characterize COAT-platelets by identifying serotonin-adducts of other alpha-granule proteins found on COAT- platelets, by characterizing the serotonin binding sites present on COAT-platelets, and by evaluating the physiological manipulation of COAT-platelets in experimental animals.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068129-02
Application #
6624504
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
2002-04-01
Project End
2006-03-31
Budget Start
2003-04-01
Budget End
2004-03-31
Support Year
2
Fiscal Year
2003
Total Cost
$219,750
Indirect Cost
Name
University of Oklahoma Health Sciences Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
878648294
City
Oklahoma City
State
OK
Country
United States
Zip Code
73117
Valaydon, Zina S; Lee, Petrova; Dale, George L et al. (2009) Increased coated-platelet levels in chronic haemodialysis patients. Nephrology (Carlton) 14:148-54
Prodan, C I; Joseph, P M; Vincent, A S et al. (2007) Coated-platelet levels are influenced by smoking, aspirin, and selective serotonin reuptake inhibitors. J Thromb Haemost 5:2149-51
Prodan, Calin I; Ross, E D; Vincent, A S et al. (2007) Coated-platelets correlate with disease progression in Alzheimer disease. J Neurol 254:548-9
Prodan, Calin I; Ross, Elliott D; Vincent, Andrea S et al. (2007) Coated-platelets are higher in amnestic versus nonamnestic patients with mild cognitive impairment. Alzheimer Dis Assoc Disord 21:259-61
Dale, G L; Friese, P (2006) Bax activators potentiate coated-platelet formation. J Thromb Haemost 4:2664-9
Prodan, Calin I; Szasz, Robert; Vincent, Andrea S et al. (2006) Coated-platelets retain amyloid precursor protein on their surface. Platelets 17:56-60
Remenyi, Gyula; Szasz, Robert; Friese, Paul et al. (2005) Role of mitochondrial permeability transition pore in coated-platelet formation. Arterioscler Thromb Vasc Biol 25:467-71
Dale, G L (2005) Coated-platelets: an emerging component of the procoagulant response. J Thromb Haemost 3:2185-92
Dale, G L; Remenyi, G; Friese, P (2005) Quantitation of microparticles released from coated-platelets. J Thromb Haemost 3:2081-8
Hamilton, Stephen F; Miller, Matt W; Thompson, Cris A et al. (2004) Glycoprotein IIb/IIIa inhibitors increase COAT-platelet production in vitro. J Lab Clin Med 143:320-6

Showing the most recent 10 out of 12 publications