Thrombotic thrombocytopenic purpura: a thrombotic disorder caused by ADAMTS13 deficiency

Abstract

A serious disorder with characteristic microvascular thrombosis involving the brain and other organs, thrombotic thrombocytopenic purpura (TTP) typically presents with thrombocytopenia, hemolysis with schistocytes on blood smears, and mental changes or seizures. It may progress rapidly to a fatal end if the patient is not treated immediately with plasma. Recent advances have shown that TTP is caused by deficiency of a circulating, von Willebrand factor cleaving metalloprotease, ADAMTS13. This new knowledge will provide clues to improve the diagnosis and management of this intriguing disease.

Figure 1

Domain structure of ADAMTS13. The consensus sequence for zinc binding, potential N- and O-glycosylation sites, and the regions sufficient for VWF cleaving activity and for interaction with IgG antibodies of TTP are marked. Truncation upstream of the spacer domain markedly decreases the cleaving activity against either VWF multimers or VWF fragments of the A2 domain, while truncation downstream of the spacer domain decreases the cleaving activity against VWF multimers.

Figure 2

A scheme depicting how ADAMTS13 deficiency may lead to VWF-platelet aggregation and microvascular thrombosis. Some of the VWF molecules secreted from endothelial cells may remain transiently anchored to endothelial surface. After exposure to wall shear stress, VWF is conformationally unfolded and is immediately cleaved ADAMTS13 to smaller forms. In the absence of ADAMTS13, VWF becomes activated, leading to intravascular VWF-platelet binding and microvascular thrombosis.

Figure 3

VWF multimer changes in TTP and HUS. A. VWF multimers and fragments in a representative case of acute TTP. Compared to normal plasma (NP), a gradient of decreased large multimers is noted in TTP. The decrease of large multimers is due to consumption as shear stress induces binding of large VWF multimers to platelets. In the absence of ADAMTS13, the 350kD and 200kD fragments of VWF are decreased. B. Serial changes of VWF multimers in TTP. A typical loss of large multimers is noted on day 1. As the patient improves with plasma exchange, ultra large multimers are present in subsequent days. The multimer pattern shows a gradually shift toward normal as the platelet count and ADAMTS13 activity level increase (bottom). C. VWF multimers and fragments in a representative case of shiga toxin associated HUS. VWF multimer is normal during the stage of colitis but shows a gradient of decreased large multimers at the onset of HUS. The VWF fragments are markedly increased, which are attributable to both increased VWF antigen level and increased proteolysis by ADAMTS13 [74]. VWF multimers are separated by SDS agarose gel electrophoresis and visualized. VWF fragments are separated by SDS agarose PAGE under non-reducing conditions. VWF is visualized with rabbit polyclonal anti-VWF and ¹²⁵I labeled or horseradish peroxidase labeled goat anti-rabbit IgG.