Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells
Richard Starke , Koralia Paschalaki, Dyer CE
C. Dyer, Kimberly Harrison-Lavoie , Thomas A J McKinnon, McKinnon TA , Daniel F Cutler, Michael Laffan, Anna M Randi, Jacqueline A Cutler , Carolyn M Millar
Von Willebrand disease (VWD) is a heterogeneous bleeding disorder caused by decrease or dysfunction of von Willebrand factor (VWF). A wide range of mutations in the VWF gene have been characterized; however, their cellular consequences are still poorly understood. Here we have used a recently developed approach to study the molecular and cellular basis of VWD. We isolated blood outgrowth endothelial cells (BOECs) from peripheral blood of 4 type 1 VWD and 4 type 2 VWD patients and 9 healthy controls. We confirmed the endothelial lineage of BOECs, then measured VWF messenger RNA (mRNA) and protein levels (before and after stimulation) and VWF multimers. Decreased mRNA levels were predictive of plasma VWF levels in type 1 VWD, confirming a defect in VWF synthesis. However, BOECs from this group of patients also showed defects in processing, storage, and/or secretion of VWF. Levels of VWF mRNA and protein were normal in BOECs from 3 type 2 VWD patients, supporting the dysfunctional VWF model. However, 1 type 2M patient showed decreased VWF synthesis and storage, indicating a complex cellular defect. These results demonstrate for the first time that isolation of endothelial cells from VWD patients provides novel insight into cellular mechanisms of the disease.
von Willebrand disease cellular basis, VWD blood outgrowth endothelial cells, von Willebrand factor mutations, bleeding disorder molecular mechanisms, endothelial cell von Willebrand, VWF multimer analysis, menorrhagia von Willebrand, platelet adhesion defects, VWD type classification, hemostasis coagulation
PMID 23355534 23355534 DOI 10.1182/blood-2012-06-435727 10.1182/blood-2012-06-435727
Cite this article
Starke, R., Paschalaki, K., Dyer, C., Harrison-Lavoie, K., Cutler, J. A., McKinnon, T., Millar, C. M., Cutler, D., Laffan, M., & Randi, A. (2013). Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood, 121(14), 2773-2784. https://doi.org/10.1182/blood-2012-06-435727
Starke R, Paschalaki K, Dyer C, Harrison-Lavoie K, Cutler JA, McKinnon T, et al. Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells. Blood. 2013;121(14):2773-2784. doi:10.1182/blood-2012-06-435727
Starke, Richard, et al. "Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells." Blood, vol. 121, no. 14, 2013, pp. 2773-2784.
Keywords
RNA, Messenger, Von Willebrand Factor
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