Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13

Abstract

Severe falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the microcirculation caused by cytoadherence and sequestration of parasitized erythrocytes. However, the pathogenesis of many features complicating severe malaria, including coma, renal failure and thrombocytopenia, remains incompletely understood. These disease manifestations are also key features of thrombotic thrombocytopenic purpura, a life-threatening disease strongly associated with a deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13. We measured plasma ADAMTS13 activity, VWF antigen and VWF propeptide levels in 30 patients with severe falciparum malaria, 12 patients with uncomplicated falciparum malaria and 14 healthy Bangladeshi controls. In patients with severe malaria ADAMTS13 activity levels were markedly decreased in comparison to normal controls (mean [95%CI]: 23% [20-26] vs. 64% [55-72]) and VWF antigen and propeptide concentrations were significantly elevated (VWF antigen: 439% [396-481] vs. 64% [46-83]; VWF propeptide: 576% [481-671] vs. 69% [59-78]). In uncomplicated malaria VWF levels were also increased compared to healthy controls but ADAMTS13 activity was normal. The results suggest that decreased ADAMTS13 activity in combination with increased VWF concentrations may contribute to the complications in severe malaria.

Development of a Hyperactive Primary Hemostatic System During Off-Pump Lung Transplantation Resulting From an Unbalance Between von Willebrand Factor and Its Cleaving Protease ADAMTS13

“…This process may ultimately result in organ dysfunction as described previously in several other pathologies and invasive procedures including TTP and liver transplantation (4,5,(20)(21)(22)(23)(24). We speculate that the development of a VWF/ADAMTS13 unbalance during lung transplantation also facilitates thrombus formation within the allograft.…”

A novel role for von Willebrand factor in the pathogenesis of experimental cerebral malaria

“…48 Previous studies have reported modest reductions in plasma ADAMTS13 activity levels in children with P falciparum infection. 17,21,22 In contrast, we observed no significant change in murine plasma ADAMTS13 activity following P berghei infection ( Figure 3B). In addition, despite the presence of circulating UL-VWF, peripheral blood film examination demonstrated no significant features of microangiopathic hemolytic anemia ( Figure 3C).…”

“…In contrast, previous studies did report a mild reduction in plasma ADAMTS13 activity (using both FRETS-VWF75 and fulllength VWF cleavage assays) in children and adult patients with severe malaria compared with healthy controls. 17,21,22 Importantly, however, residual plasma ADAMTS13 levels in African children with CM still remained higher than 60%, which should be sufficient to prevent the accumulation of hyperreactive UL-VWF multimers. …”

Letter by Hugenholtz and Lisman Regarding Article, “Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy”

“…Indeed, after an analysis of the literature on changes in VWF/ADAMTS13 in these pathologies, we found that a proportion of the studies had either no or only partial evidence of ultralarge VWF appearance in the systemic circulation. [3][4][5] Activation of the fibrinolytic system may thus prevent the formation of platelet thrombi in these disorders. Consequently, thrombolytic therapy may slow down the progression to multiorgan failure by preventing or reducing thrombus formation within solid organs.…”