The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the "missing heritability" for other complex genetic traits.genome-wide association study | linkage study | venous thromboembolic disease | von Willebrand disease | quantitative trait loci V on Willebrand factor (VWF) is a multimeric plasma glycoprotein that plays a central role in hemostasis by acting as a molecular bridge tethering platelets to injured endothelium and as a carrier molecule for coagulation factor VIII (1). Quantitative or qualitative deficiencies in VWF lead to von Willebrand Disease (VWD), the most common inherited bleeding disorder, with an estimated prevalence of 0.002-0.01% worldwide (1, 2). Type I VWD is characterized by mild to moderate bleeding and low circulating VWF levels. This form of VWD is generally associated with haploinsufficiency for VWF and is characterized by incomplete penetrance. In contrast, elevated levels of plasma VWF are an independent risk factor for venous thromboembolic disease (3), myocardial infarction (4), stroke (5, 6), and also complicate anticoagulant management (7).Plasma VWF levels vary by approximately fivefold in healthy populations and are influenced by both environmental and inherited factors. Increased levels of VWF occur with advancing age (8), may rise acutely because of inflammation or infection, and may serve as a surrogate marker for endothelial dysfunction and atherosclerosis (9-11). Estimates for the heritability of plasma VWF levels in the general population from previous family-based studies range from 32-75%. A 1985 study in Norwegian twins reported the heritability of VWF at 66%, with 30% of this effect attributable to ABO blood type (12). More recent studies estimated the heritabil...

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Patients with myeloproliferative disorders (MPD) are prone to develop thrombotic complications and thus frequently receive heparin. Surprisingly heparin-induced thrombocytopenia (HIT) has been rarely reported in MPD and is potentially under-diagnosed due to the relatively high platelet count. We report three patients with MPD who developed HIT; all presented with a relative fall of platelet counts (although without an absolute thrombocytopenia), thrombosis or skin necrosis and a positive test for HIT antibodies (particle gel immunoassay). Risk factors for developing HIT in our patients were exposure to unfractionated heparin, a recent surgical procedure and female gender. We review the literature on HIT in MPD and discuss the diagnosis of HIT in the absence of an absolute thrombocytopenia. Am. J. Hematol. 83:420-423, 2008. V

Patients with hepatic sarcoidosis rarely require orthotopic liver transplantation (OLT). Progression of granulomatous activity involving other organs after OLT has rarely been described. We describe a 32-year-old woman who underwent liver transplantation for sarcoidosis-associated end-stage liver disease. She presented 4 years later with shortness of breath, hilar lymphadenopathy, and interstitial lung abnormalities. Liver functions were normal. Open lung biopsy results revealed granulomata compatible with sarcoidosis. The patient made a complete recovery after corticosteroid treatment. To the best of our knowledge, this is a first description of severe exacerbation of pulmonary sarcoidosis in an immunosuppressed patient who underwent liver transplantation for sarcoidosis-associated liver disease.