Platelet genomics: the role of platelet size and number in health and disease.

Taken together, there is ample evidence of the association of cardiovascular disease, cerebrovascular, and inflammatory disease with single nucleotide variants (SNV) due to their impact on platelet size, number, and function. With the use of electronic medical record (EMR) or other phenotypic-linked bioinformatics sources, the more important "functional" variants are emerging and provide valuable information on their specific role in promoting early onset of disease or poor response to therapeutic measures. This review will focus upon the recognized common polymorphisms or gene variants with small, but functional effects, as it is becoming clear that these contribute to hyper- or hypo-responsive platelet phenotypes.

α2β1 integrin, GPVI receptor, and common FcRγ chain on mouse platelets mediate distinct responses to collagen in models of thrombosis.

Objective: Platelets express the α2β1 integrin and the glycoprotein VI (GPVI)/FcRγ complex, both collagen receptors. Understanding platelet-collagen receptor function has been enhanced through use of genetically modified mouse models. Previous studies of GPVI/FcRγ-mediated collagen-induced platelet activation were perfomed with mice in which the FcRγ subunit was genetically deleted (FcRγ-/-) or the complex was depleted.

Tissue factor inflammatory response regulated by promoter genotype and p38 MAPK in neonatal vs. adult microvascular endothelial cells.

Objective And Design: Variable tissue factor (TF) expression by human microvascular endothelial cells (HMVEC) may be regulated by two promoter haplotypes, distinguished by an 18-basepair deletion (D) or insertion (I) at -1,208. We sought to determine the relationship between these haplotypes and interleukin-1α (IL-1α)-induced TF expression in neonatal versus adult HMVEC.

Results: IL-1-stimulated TF mRNA, protein, and activity were significantly higher in neonatal compared to adult D/D donors.

Genetic sequence analysis of inherited bleeding diseases.

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.

Conditional knockout of integrin α2β1 in murine megakaryocytes leads to reduced mean platelet volume.

We have engineered a transgenic mouse on a C57BL/6 background that bears a floxed Itga2 gene. The crossing of this mouse strain to transgenic mice expressing Cre recombinase driven by the megakaryocyte (MK)-specific Pf4 promoter permits the conditional knockout of Itga2 in the MK/platelet lineage. Mice lacking MK α2β1 develop normally, are fertile, and like their systemic α2β1 knockout counterparts, exhibit defective adhesion to and aggregation induced by soluble type I collagen and a delayed onset to low dose fibrillar collagen-induced aggregation, results consistent with blockade or loss of platelet α2β1.