[Genetic polymorphism of von Willebrand factor (VWF)-cleaving protease, ADAMTS13].

Platelet aggregation plays a key role in hemostasis and thrombosis, and it is partly regulated by a plasma glycoprotein known as von Willebrand factor (VWF). VWF is primarily synthesized in vascular endothelial cells and secreted into the plasma as unusually large multimers. Normally, these VWF multimers are quickly degraded into smaller forms by a plasma metalloproteinase, namely, VWF-cleaving protease. In 2001, the protease was identified as ADAMTS13, a member of the ADAMTS metalloprotease family. Functional deficiency of ADAMTS13 caused by genetic mutation and inhibitory autoantibodies leads to the accumulation of unusually large VWF multimers in the plasma and results in a thrombotic disease known as thrombotic thrombocytopenic purpura (TTP). TTP caused by congenital ADAMTS13 deficiency is called Upshaw-Schulman syndrome (USS). Thus far, more than 80 causative mutations have been identified in the ADAMTS13 gene of the patients with USS. Almost all patients are compound heterozygotes or homozygotes of mutated ADAMTS13. In addition, 11 missense polymorphisms in ADAMTS13 were identified in the general population: some of them are found in populations throughout the world and some in specific ethnic groups. Among these polymorphisms, P475S is the only one that reduces the plasma ADAMTS13 activity. At present, there is no evidence of a relationship between ADAMTS13 polymorphisms and thrombotic diseases such as acute ischemic stroke and acute myocardial infarction; further research is required to clarify whether any relationship exists between them.