VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP

Abstract

Absent or severely diminished activity of ADAMTS13 (A Disintegrin And Metalloprotease with a ThromboSpondin type 1 motif, member 13) resulting in the intravascular persistence and accumulation of highly thrombogenic ultra large von Willebrand factor (UL-VWF) multimers is the pathophysiological mechanism underlying thrombotic thrombocytopenic purpura. Reduced VWF-cleaving protease levels, however, are not uniquely restricted to primary thrombotic microangiopathy (TMA), e. g. thrombotic thrombocytopenic purpura, but also occur in other life-threatening thrombocytopenic conditions: severely decreased ADAMTS13 activity is seen in severe sepsis, disseminated intravascular coagulation (DIC) and complicated malarial infection. The clinical relevance of these secondary thrombotic microangiopathies is increasingly recognised, but its therapeutic implications have not yet been determined. The presence of a secondary TMA in certain diseases may define patient groups which possibly could benefit from ADAMTS13 replacement or a VWF-targeting therapy. This short-review focuses on the role of UL-VWF multimers in secondary TMA and discusses the potential of investigational therapies as candidates for the treatment of TTP. In conclusion, prospective clinical trials on the effectiveness of protease replacementin vivo seem reasonable. Carefully selected patients with secondary TMA may benefit from therapies primarily intended for the use in patients with TTP.

Keywords: ADAMTS13; DIC; TTP; VWF; malaria; sepsis.

Figure1. Entrapment of platelets and erythrocytes by uncleaved von Willebrand factor multimers under shear flow causing microvessel occlusion in (A) malarial infection and (B) TTP

(A) Microvessel obstruction by infected red cells is a crucial event in malarial coagulopathy and determines disease severity. Acutely exocytosed ultra large VWF strings attached to the endothelium thereby play a critical role by spontaneously binding large numbers of platelets, which finally facilitate endothelial adhesion and sequestration of red blood cells infected with plasmodia by providing the essential CD36-expressing surfaces. (B) In TTP, strand-shaped hyper-reactive VWF-multimers with a length exceeding 0,2mm spontaneously bind, activate and aggregate platelets leading to widespread depositions of microvessel-occlusive platelet-rich clots. Red blood cells passing through this UL-VWF-platelet meshwork get fragmented into schistocytes and helmet cells. Detaching and cleaving of UL-VWF strings through ADAMTS13 replenishment may interrupt microthrombus formation, re-establish vessel patency and improve organ function. Freely adapted from José A. López (101).