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INTRODUCTION

SUMMARY

von Willebrand factor (vWF) is a central component of hemostasis, serving both as a carrier for factor VIII (FVIII) and as an adhesive link between platelets and the injured blood vessel wall. Abnormalities in vWF function result in von Willebrand disease (vWD), the most common inherited bleeding disorder in humans. The overall prevalence of vWD has been estimated to be as high as 1% of the general population, although the prevalence of clinically significant disease is probably closer to 1 in 1000. vWD is associated with either quantitative deficiency (type 1 and type 3) or qualitative abnormalities of vWF (type 2). The uncommon type 3 variant is the most severe form of vWD and is characterized by clinically undetectable levels of vWF, a severe bleeding diathesis, and usually an autosomal recessive pattern of inheritance. Partial quantitative deficiency of vWF that is otherwise normal in structure and function is the most common variant. Whereas more severe vWF quantitative deficiencies (vWF levels <30 IU/dL) characterize type 1 vWD, intermediate deficiencies (levels of 30–to 50 IU/dL) are termed “low vWF.” In type 2 vWD, the vWF is abnormal in structure, function, or both. Type 2A vWD is associated with selective loss of the largest and most functionally active vWF multimers. Type 2A results from variants that interfere with vWF biosynthesis and secretion or variants that produce a form of vWF that exhibits an increased sensitivity to proteolysis in plasma. Type 2B vWD is caused by variants clustered within the vWF A1 domain in a segment critical for binding to the platelet glycoprotein Ib receptor. These variants produce a “gain of function,” resulting in spontaneous vWF binding to platelets and clearance of the resulting platelet complexes, leading to thrombocytopenia and loss of the most active (large) vWF multimers. Type 2N vWD is characterized by variants within the FVIII binding domain of vWF, leading to disproportionately decreased blood levels of FVIII and a disorder resembling mild to moderate hemophilia A but with autosomal rather than X-linked inheritance. Type 1 vWD and symptomatic low vWF can often be effectively managed by treatment with DDAVP (deamino D-arginine vasopressin), which produces a two- to threefold increase in plasma vWF level. Response to DDAVP is generally poor in type 3 and some type 2 vWD variants. These disorders often require treatment with vWF replacement.

Acronyms and Abbreviations

ADAMTS 13, a disintegrin and metalloprotease with thrombospondin type 1 motifs; aPTT, activated partial thromboplastin time; BAT, bleeding assessment tool; DDAVP, 1-desamino-8-D-arginine vasopressin, or desmopressin; ER, endoplasmic reticulum; GPIb, glycoprotein Ib; HHT, hereditary hemorrhagic telangiectasia; ISTH, International Society of Thrombosis and Hemostasis; MCMDM, Molecular and Clinical Markers for the Diagnosis and Management; PCR, polymerase chain reaction; RIPA, ristocetin-induced platelet aggregation; t-PA, tissue plasminogen activator; VWD, von Willebrand disease, VWF, von Willebrand factor.

DEFINITION AND HISTORY

In 1926, Eric von Willebrand described a bleeding disorder in 24 of 66 members of a ...

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