The same heterozygous T -> C transition at nt 8567 of the von Willebrand factor (vWF)

Summary.  Inherited defects of platelet function are a heterogeneous group of disorders that can result in bleeding symptoms ranging from mild bruising to severe mucocutaneous haemorrhage. These defects may be classified according to their effect on the various steps of platelet microthrombi formation including initiation, extension and cohesion, or based on their particular structural or functional deficiency. Platelet membrane receptor deficiencies result in the rare, but well‐characterized syndromes of defective clot initiation, such as Bernard–Soulier Syndrome. Platelet storage pool defects are the most common disorders affecting the extension phase of clot formation. Glanzmann thrombasthenia, with absent or dysfunctional αIIbβ3 receptor is the prototypical defect of the cohesion/aggregation phase of microthrombi formation. Many of these disorders share common treatments although some therapies will have greater efficacy for one patient than another and should be individualized so as to provide optimal control of symptoms. Currently much effort is being put into methods to more rapidly and accurately diagnose patients with platelet disorders and to initiate appropriate therapy and prevent life threatening bleeding.

The genes encoding the coagulation factor proteins were among the first human genes to be characterized over 25 years ago. Since then, significant progress has been made in the translational application of this information for the 2 commonest severe inherited bleeding disorders, hemophilia A and B. For these X-linked disorders, genetic characterization of the disease-causing mutations is now incorporated into the standard of care and genetic information is used for risk stratification of treatment complications. With electronic databases detailing >2100 unique mutations for hemophilia A and >1100 mutations for hemophilia B, these diseases are among the most extensively characterized inherited diseases in humans. Experience with the genetics of the rare bleeding disorders is, as expected, less well advanced. However, here again, electronic mutation databases have been developed and provide excellent guidance for the application of genetic analysis as a confirmatory approach to diagnosis. Most recently, progress has also been made in identifying the mutant loci in a variety of inherited platelet disorders, and these findings are beginning to be applied to the genetic diagnosis of these conditions. Investigation of patients with bleeding phenotypes without a diagnosis, using genome-wide strategies, may identify novel genes not previously recognized as playing a role in hemostasis.

Summary. We have tested the DNA of a large series of Glanzmann thrombasthenia patients for polymorphisms in platelet membrane glycoproteins. To our surprise, we noted a high prevalence of the HPA-1b allele of b3, the minority allele in a normal population. This proved to be due to the presence of nine patients homozygous for the so-called French gypsy mutationSeven of these patients were homozygous for the HPA-1b alloantigen and the other two heterozygous HPA-1a/1b. As the aIIb and b3 genes are both on chromosome 17, it is highly probable that the French gypsy mutation first arose on a chromosome encoding HPA-1b. For other adhesion receptors, no major differences were seen in the distribution of the A1, A2 and A3 alleles in the a2 gene, or in the Kozak or HPA-2 polymorphisms of GPIba, suggesting that none of these alleles result in increased survival in Glanzmann thrombasthenia.

Summary. We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P ¼ 0.012) or when genderspecific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit a 2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.