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DOI: 10.1160/TH09-04-0223
Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13
Publikationsverlauf
Received:
03. April 2009
Accepted after minor revision:
02. August 2009
Publikationsdatum:
22. November 2017 (online)
Summary
Severe falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the micro-circulation 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.
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References
- 1 Lopez AD, Mathers CD, Ezzati M. et al. Global and regional burden of disease and risk factors, 2001: systematic analysis of population health data. Lancet 2006; 367: 1747-1757.
- 2 Dondorp AM, Lee SJ, Faiz MA. et al. The relationship between age and the manifestations of and mortality associated with severe malaria. Clin Infect Dis 2008; 47: 151-157.
- 3 Dondorp AM, Pongponratn E, White NJ. Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology. Acta Trop 2004; 89: 309-317.
- 4 Turner GD, Ly VC, Nguyen TH. et al. Systemic endothelial activation occurs in both mild and severe malaria. Correlating dermal microvascular endothelial cell phenotype and soluble cell adhesion molecules with disease severity. Am J Pathol 1998; 152: 1477-1487.
- 5 de Mast Q, Groot E, Lenting PJ. et al. Thrombocytopenia and release of activated von Willebrand Factor during early Plasmodium falciparum malaria. J Infect Dis 2007; 196: 622-628.
- 6 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
- 7 Reiter RA, Knobl P, Varadi K. et al. Changes in von Willebrand factor-cleaving pro-tease (ADAMTS13) activity after infusion of desmopressin. Blood 2003; 101: 946-948.
- 8 Reiter RA, Varadi K, Turecek PL. et al. Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation. Thromb Haemost 2005; 93: 554-558.
- 9 Ono T, Mimuro J, Madoiwa S. et al. Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood 2006; 107: 528-534.
- 10 Franchini M, Montagnana M, Targher G. et al. Reduced von Willebrand factor-cleaving protease levels in secondary thrombotic microangiopathies and other diseases. Semin Thromb Hemost 2007; 33: 787-797.
- 11 Martin K, Borgel D, Lerolle N. et al. Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 2007; 35: 2375-2382.
- 12 Tran TH, Day NP, Nguyen HP. et al. A controlled trial of artemether or quinine in Vietnamese adults with severe falciparum malaria. N Engl J Med 1996; 335: 76-83.
- 13 Kokame K, Nobe Y, Kokubo Y. et al. FRETS-VWF73, a first fluorogenic substrate for ADAMTS13 assay. Br J Haematol 2005; 129: 93-100.
- 14 Raines G, Aumann H, Sykes S. et al. Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel. Thromb Res 1990; 60: 201-212.
- 15 de Mast Q, Groot E, Asih PB. et al. ADAMTS13 deficiency with elevated levels of ultra-large and active von Willebrand factor in P. falciparum and P. vivax malaria. Am J Trop Med Hyg 2009; 80: 492-498.
- 16 Larkin D, de Laat B, Jenkins PV. et al. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. PLoS Pathog 2009; 05: e1000349.
- 17 Mohanty D, Ghosh K, Nandwani SK. et al. Fibrinolysis, inhibitors of blood coagulation, and monocyte derived coagulant activity in acute malaria. Am J Hematol 1997; 54: 23-29.
- 18 Hollestelle MJ, Donkor C, Mantey EA. et al. von Willebrand factor propeptide in malaria: evidence of acute endothelial cell activation. Br J Haematol 2006; 133: 562-569.
- 19 Martin K, Borgel D, Lerolle N. et al. Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med 2007; 35: 2375-2382.
- 20 Kremer Hovinga JA, Zeerleder S, Kessler P. et al. ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock. J Thromb Haemost 2007; 05: 2284-2290.
- 21 Claus RA, Bockmeyer CL, Budde U. et al. Variations in the ratio between von Willebrand factor and its cleaving protease during systemic inflammation and association with severity and prognosis of organ failure. Thromb Haemost 2009; 101: 239-247.
- 22 Grau GE, Mackenzie CD, Carr RA. et al. Platelet accumulation in brain microvessels in fatal pediatric cerebral malaria. J Infect Dis 2003; 187: 461-466.
- 23 Wassmer SC, Lepolard C, Traore B. et al. Platelets reorient Plasmodium falciparum-infected erythrocyte cytoadhesion to activated endothelial cells. J Infect Dis 2004; 189: 180-189.
- 24 Silamut K, Phu NH, Whitty C. et al. A quantitative analysis of the microvascular sequestration of malaria parasites in the human brain. Am J Pathol 1999; 155: 395-410.
- 25 Taylor TE, Fu WJ, Carr RA. et al. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 2004; 10: 143-145.
- 26 Skudowitz RB, Katz J, Lurie A. et al. Mechanisms of thrombocytopenia in malignant tertian malaria. Br Med J 1973; 02: 515-518.
- 27 Butthep P, Bunyaratvej A. An unusual adhesion between red-cells and platelets in falciparum malaria. J Med Assoc Thai 1992; 75 (Suppl. 01) 195-202.
- 28 Studt JD, Hovinga JA, Antoine G. et al. Fatal congenital thrombotic thrombocytopenic purpura with apparent ADAMTS13 inhibitor: in vitro inhibition of ADAMTS13 activity by hemoglobin. Blood 2005; 105: 542-544.
- 29 Bernardo A, Ball C, Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow. Blood 2004; 104: 100-106.
- 30 Crawley JT, Lam JK, Rance JB. et al. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 2005; 105: 1085-1093.
- 31 Zhou Z, Han H, Cruz MA. et al. Haemoglobin blocks von Willebrand factor proteolysis by ADAMTS-13: A mechanism associated with sickle cell disease. Thromb Haemost 2009; 101: 1070-1077.
- 32 Feys HB, Liu F, Dong N. et al. ADAMTS-13 plasma level determination uncovers antigen absence in acquired thrombotic thrombocytopenic purpura and ethnic differences. J Thromb Haemost 2006; 04: 955-962.