Molecular structure and biological function of von Willebrand factor

K.Bykowska

Department of Haemostasis and Thrombosis, Institute of Hematology and Blood Transfusion, Warsaw

In 1926, Eric von Willebrand a medical doctor from Helsinki described for the first time a family with prolonged bleeding time. The predominant symptoms in this family were nose and gum bleeding, bleeding after tooth extraction, menorrhagia and bleeding from trivial wounds. After him this disorder was named called von Willebrand disease and the protein deficient from the blood in this family was called –the von Willebrand factor. This factor plays two major hemostatic roles. It mediates platelet attachment, through Ib/IX/V glikoprotein complex to subendothelial tissue at the site of vascular injury under condition of high shear rate. It is the carrier protein of coagulation factor VIII, an essential cofactor in coagulation, thats protects factor VIII from proteolytic degradation. Von Willebrand factor (vWF) is a large, single chain adhesive glikoprotein synthesized exclusively in endothelial cells and megakariocytes under the control of a gene located on chromosome 12. The translation product contains an 22 amino acid signal peptide, large propeptide sequence (741 amino acids) and mature vWf protein (2050 amino acids) composed of many regions differ in their structure and function. In the endoplasmic reticulum the signal peptide is cleaved, the precursors form dimers by disulfide bonding at the C-terminal ends of monomers. Then dimers multimerize in Golgi apparatus by forming of additional disulfide bonds at the N-terminal ends of dimers. After multimeryzation propeptide is removed by intra-celular proteolysis. Molecules are then subjected to further modification , glycosylation and sulfation. The multimers are constitutively secreted to blood stream after stimulation of respective cells by a variety of stimuli. A portion of them is stored in Weibel-Palade bodies of endothelial cells and also in platelets α granules. The newly synthesized vWF and stored in endothelial cells is ultra large (ultralarge, UvWF) and hyperreactive in hemostasis. Ultralarge vWf forms spontaneously bonds with the platelet GP Ib/IX/V complex resulting in platelet adhesion, aggregation and thrombus formation In healthy persons this is prevented by metalloprotease cleaving ultralarge vWf to less active multimers with lower molecular weight, present in human plasma.

Synthesis reduction , defect in amino acid composition of vWF as well as defects in dimerization or multimerization may lead to bleeding disorder. The increase of vWF concentration in plasma to level above normal as well as presence of ultralarge multimers may lead to thrombosis.

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