Von Willebrand Disease (vWD) is characterized by mucosal bleeding. The collagen receptor (integrin alpha2beta1) density in the platelet membrane varies as much as an order of magnitude between individuals and this may influence the risk for thrombosis or bleeding in vivo. This variation is associated with differential inheritance of three alleles of the human alpha2 gene. The allele 2, which is associated with low alpha2beta1 receptor density, is over represented in patients diagnosed with von Willebrand disease type 1. It has also been shown that a single nucleotide dimorphism (T/C) within the Kozak sequence of the 5' untranslated region of the glycoprotein Ibalpha (GPIba) gene regulates GPIb-IX-V density. Differences in alpha2beta1 or GPIb-IX-V density may not compromise platelet function in otherwise healthy individuals, but it can become an important factor in individuals who are predisposed toward thrombosis or bleeding by an unrelated genetic or acquired condition.
The specific aims of this proposal are: 1. To determine the influence of alpha2 and GPIb genotype on platelet membrane collagen receptor alpha2beta1 and GPIb-IX-V complex density and bleeding phenotype in von Williebrand disease 2. To evaluate the influence of alpha2 and GPIb genotype on platelet adhesion in siblings with von Willebrand disease 3. To determine the influence of alpha2 and GPIb genotype on platelet membrane collagen receptor integrin alpha2beta1 and glycoprotein Ib-IX-V complex and bleeding phenotype in patients with normal von Willebrand factor levels, normal platelet aggregation but evident bleeding tendency. The long-term goal is to identify risk factors that predispose vWD patients to excessive bleeding and increase our understanding of the mechanism of bleeding in patients with normal laboratory values for platelet function. The variability of expression of alpha2beta1 represents one among many factors that may influence the likelihood of bleeding in these patients. This collaborative study will allow us to store DNA from patients with different bleeding diatheses and perform further testing for newly discovered risk factors that may affect clinical presentation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23HL004460-03
Application #
6619767
Study Section
Special Emphasis Panel (ZHL1-CSR-F (M1))
Program Officer
Mondoro, Traci
Project Start
2001-09-20
Project End
2006-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
3
Fiscal Year
2003
Total Cost
$125,010
Indirect Cost
Name
University of Iowa
Department
Pediatrics
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
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