title: Low platelet alpha2beta1 levels in type I von Willebrand disease correlate with impaired platelet function in a high shear stress system.
abstract: 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 alpha2beta1. 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 alpha2 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 alpha2beta1 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.
authors.affiliation: Children's Hospital of Orange County, Orange, CA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Di Paola
authors.forename: A B
authors.initials: AB
authors.lastname: Federici
authors.forename: P M
authors.initials: PM
authors.lastname: Mannucci
authors.forename: M T
authors.initials: MT
authors.lastname: Canciani
authors.forename: M
authors.initials: M
authors.lastname: Kritzik
authors.forename: T J
authors.initials: TJ
authors.lastname: Kunicki
authors.forename: D
authors.initials: D
authors.lastname: Nugent
mesh_terms: D000483:Alleles; D001792:Blood Platelets / Q000473:pathology / Q000502:physiology*; D002478:Cells, Cultured; D006801:Humans; D016023:Integrins / Q000235:genetics* / Q000378:metabolism; D010973:Platelet Adhesiveness / Q000235:genetics; D038981:Receptors, Collagen; D013314:Stress, Mechanical; D014842:von Willebrand Diseases / Q000097:blood* / Q000235:genetics / Q000503:physiopathology*
chemical_list: D016023:Integrins; D038981:Receptors, Collagen