ADAMTS13: The von Willebrand Factor Cleaving Protease and Its Role in Thrombotic Thrombocytopenic Purpura

Since the discovery of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in the twentieth century, significant advancements have been made in understanding its role in hemostasis, molecular structure, genetics and genotype-phenotype relationships. It is a member of the ADAMTS family of matrix proteases and is responsible for the cleavage of ultra-large molecules of von Willebrand factor (VWF), thus regulating the adhesion of platelets to VWF multimers. Structurally, it resembles other members of the ADAMTS family with the exception of the number of thrombospondin-1 repeats and the presence of two CUB domains at the carboxyl terminal. The proteolytic activity of ADAMTS13 is mediated via an adamalysin-like metalloprotease domain. The ADAMTS13 gene was cloned in 2001 and since then a number of disease-causing mutations have been discovered across the entirety of this gene. Additionally, ten different splicing isoforms have been described for ADAMTS13 gene and a significant amount of genetic variations in this gene arises from the 1000 genome project (single nucleotide polymorphisms (SNPs)). Phylogenetic origins of ADAMTS13 are also discussed. Deficiency of this necessary protease activity due to autosomal recessive mutations of the ADAMTS13 gene are implicated in congenital thrombotic thrombocytopenic purpura, also called Upshaw-Schulman syndrome. Ongoing research focuses on the role of ADAMTS13 in other forms of thrombotic microangiopathy and the development of either a plasma-derived or recombinant form of ADAMTS13 for therapeutic purposes.