Endothelial, Platelet, & Coagulation Factor Abnormalities in Abnormal Hemostasis

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Abstract

Characterization of Platelet Function in Patients with Bleeding Disorders: In FY2015 (the fourth year of this project) we have studied several patients with suspected or documented disorders of platelet function and have identified patients with deficiency of dense granules (storage pool disease), and characterized platelet function in people with congenital or acquired platelet dysfunction. The ability to make a reliable, detailed characterization of platelet function may help investigators who are studying genetics of inherited platelet disorders. One family with abnormal platelet function and other abnormalities has been described and submitted to the journal Blood for consideration to be published (York Platelet Syndrome, T. Markello et al, authors and collaborators). Another patient has been identified who has a novel platelet disorder that may be a variant of Glanzmann's thrombasthenia. He has been referred to the Undiagnosed Diseases Program (NIH/NHGRI) for further analysis and possible genome sequencing to identify the basis of this disorder. Characterization of D-Dimer and Related Coagulation Proteins in HIV-Infected Research Subjects Undergoing IL-2 Therapy: During the fifth year of this project, in support of intramural NIH research protocols, we have measured D-dimer levels and numerous coagulation parameters in research subjects who are infected with HIV or who are normal volunteers. We seek to correlate the D-dimer levels with these various parameters to gain insights into the mechanism for the observed elevations in D-dimer levels in HIV infected patients that correlate with increased morbidity and mortality. Effect of Factor VIII Haplotypes on Inhibitor Development. We have identified a set of 800 DNA samples from patients with severe hemophilia A in an NHLBI repository and have IRB approval to determine their factor VIII protein-coding polymorphisms to determine the effect of factor VIII haplotype on inhibitor development. We expect to complete the DNA sequence determinations in the coming fiscal year, and will see if the effect of protein coding polymorphisms on inhibitor development that was seen in a minority population (African-Americans) can be seen in the population as a whole. We have observed two cases of acquired factor VIII inhibitor in the setting of non-myeloablative stem cell transplantation for sickle cell disease in African-Americans, a report on one of which has now been published.