The ADAMTS13 (a disintegrin and metalloprotease with thrombospond type 1 motif) gene codes for the plasma metalloprotease enzyme. This enzyme cleaves the platelet-adhesive plasma protein von Willebrand factor (VWF) multimers at its Y1605-M1606 peptidyl bond to smaller, less active form. VWF is normally involved in platelet adhesion at the site of vascular damage, which is essential for blood clotting. ADAMTS13 enzyme is involved in the regulation of the size of the VWF by cleaving the newly released and circulating VWF to smaller and less active form in order to prevent unwanted platelet thrombus formation.
The ADAMTS13 gene is located on the long arm of chromosome 9 at 9q34 and spans approximately 37 kb of genomic DNA and its coding sequence consists of six 29 exons. The ADAMTS13 protein consists of 1,427 amino acids weighing approximately 15 KDa.
The ADAMTS13 protein has a multi-domain structure that is common among proteases of the ADAMTS family, but also contains two unique CUB domains. Alternative splicing of this gene gives rise at least seven variants with differences in tissue expressivity
More than 70 mutations in the ADAMTS13 gene have been reported in patients with the familial form of thrombotic thrombocytopenic purpura. Mutations in the ADAMTS13 gene severely reduce the activity of the ADAMTS13 enzyme, leading to the accumulation of superactive forms of VWF. This would lead to the formation and then the accumulation of the intravascular platelet thrombosis even in the absence of injury, as seen in patients with thrombotic thrombocytopenic purpura (TTP).
Savasan et al. (2003) identified a novel mutation which is a deletion of a dinucleotide (TT) in the exon 15 of the ADAMTS13 gene, resulting in a frameshift after His594 and followed by truncation of the predicted protein product. Savasan et al. (2003) found this mutation in homozygous state in a Yemenite girl with congenital thrombotic thrombocytopenic purpura (TTP) born to heterozygous first-cousin parents of Yemenite background. She developed thrombocytopenia and microangiopathy soon after birth and, thus, she required plasma infusion (10 mL/kg) every 2 weeks. The VWF cleaving protease activity of the ADAMTS13 enzyme was also very low (<0.1 U/ mL) in the patient with partial deficiency in her parents. This result is consistent with the genetic nature of the mutation that was found in this family. However, this patient and her parents were previously reported (by Savasan et al. 2001) to have normal level of the VWF cleaving protease activity of the ADAMTS13 enzyme by using the same techniques, but with differences in the experimental procedures. These contradictory results led Savasan et al. (2003) to highlight the importance of future research to establish a standardized, validated procedure for the measurement of ADAMTS13 enzymatic activity that can be readily adapted to the clinical laboratory.