Collagen Receptors/ eht / Index / itga2 / Cardiovascular / GP6 / Aspirin

Von Willebrand Disease
            
An association of candidate gene haplotypes and bleeding severity in Von Willebrand Disease (VWD) type 1 pedigrees.

Kunicki TJ, Federici AB, Salomon DR, Koziol JA, Head SR, Mondala TS, Chismar JD, Baronciani L, Canciani MT, Peake IR.

Blood. 2004 Jun 29 [Epub ahead of print]

Von Willebrand Disease (VWD) type 1 is difficult to diagnose because of bleeding variability and low heritability of Von Willebrand Factor (VWF) levels. We compared a bleeding severity score and bleeding times to candidate gene haplotypes within pedigrees of fourteen index cases, using a covariance components model for multivariate traits (Mendel: QTL Association). These pedigrees included 13 affected and 40 unaffected relatives, as defined by plasma Ristocetin cofactor (VWF:RCo) levels. The bleeding severity score was derived from a detailed history. Donors were genotyped using a primer extension method, and nine candidate genes were selected for analysis. VWF:RCo levels had the strongest influence on bleeding severity score and bleeding time. ITGA2 haplotype 2 (807C) and ITGA2B haplotype 1 (Ile(843)) were each associated with increased bleeding severity scores (p=0.00009 and p = 0.00496, respectively). GP6 haplotype b (Pro(219)) was also associated with increased scores (p = 0.02912) after adjustment for donor age. No association was observed with six other candidate genes, GP1BA, ITGB3, VWF, FGB, IL6 or TXA2R. Increased plasma VWF:Ag levels were associated with VWF haplotype 1 (-1793G) (p=0.02314). These results establish that genetic differences in the adhesion receptor subunits alpha(2), alpha(IIb) and GPVI can influence the phenotype of VWD type1.

            

            
            

Low platelet a2b1 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system.

Di Paola J, Federici AB, Mannucci PM, Canciani MT, Kritzik M, Kunicki TJ, Nugent D 

Blood. 1999. 93(11):3578-82.

Platelet adhesion to collagen-coated surfaces in whole blood under flow conditions is mediated by both von Willebrand factor (vWF)-dependent recruitment of the platelet glycoprotein Ib-IX receptor complex and collagen interaction with the integrin a2b1. In type 1 von Willebrand disease (vWD), platelet adhesive functions are impaired due to the decrease in vWF levels in plasma and platelets. There are at least three alleles of the human a2 gene, distinguishable by a cluster of silent or noncoding sequence differences within a segment of the gene. Two alleles, associated with low receptor density can be distinguished by nucleotide 807C, while the third allele associated with high receptor density, expresses nucleotide 807T. Gene frequencies of these alleles in a normal population (n = 167) are 0.58 for 807C and 0.42 for 807T. We measured the frequencies of these alleles in symptomatic patients with five types of vWD (type 1, n = 78; type 2A, n = 25, type 2B, n = 14; type 2M, n = 10; and type 3, n = 20). Compared with the normal group, no significant difference in allele frequencies was observed among individuals with types 2A, 2B, 2M, or 3 vWD. However, the frequency of the 807C allele, associated with low collagen receptor density, among type 1 vWD patients (807C =.71; 807T =.29) was significantly higher than that of the normal population (P =.007). Also, in patients with vWD type 1 and borderline to normal ristocetin-cofactor (vWF:RCo) activity values, collagen receptor density correlates inversely with closure time in a high shear stress system (platelet function analyzer [PFA-100]). We propose that low platelet a2b1 density results in less efficient primary platelet adhesion and may result in increased tendency to bleed, as evidenced by the high frequency of this polymorphism in patients with type 1 vWD compared with normal individuals. In addition, this may account for the variability between patients with similar levels of vWF antigen, but strikingly different bleeding histories.

Collagen Receptors : Von Willebrand Disease
created by Thomas J. Kunicki tomk@scripps.edu
Scripps Research Institute

 

Copyright © 2001 Thomas J. Kunicki. All rights reserved. Reproduction in whole or in part in any form or medium without express written permission of author is prohibited.

URL: http://www.scripps.edu/mem/eht/kunicki/vonwd.html

Collagen Receptors/ eht / Index / itga2 / Cardiovascular / GP6 / Aspirin