Download PDF
Thromb Haemost 2010; 103(01): 181-187
DOI: 10.1160/TH09-04-0223
Wound Healing and Inflammation/Infection
Schattauer GmbH

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

Ester C. Löwenberg
1   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
,
Prakaykaew Charunwatthana
2   Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
,
Sophie Cohen
1   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
,
Bert-Jan van den Born
1   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
,
Joost C. M. Meijers
1   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
,
Emran B. Yunus
3   Chittagong Medical College Hospital, Chittagong, Bangladesh
,
Mahtab B. Hassan
3   Chittagong Medical College Hospital, Chittagong, Bangladesh
,
Gofranul Hoque
3   Chittagong Medical College Hospital, Chittagong, Bangladesh
,
Richard J. Maude
2   Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
4   Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
,
Forradee Nuchsongsin
2   Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
,
Marcel Levi
1   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands
,
Arjen M. Dondorp
2   Mahidol-Oxford Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
4   Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK
› Author Affiliations
Further Information

Publication History

Received: 03 April 2009

Accepted after minor revision: 02 August 2009

Publication Date:
22 November 2017 (online)

    Permissions and Reprints

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.

Keywords

ADAMTS13 - falciparum malaria - thrombotic microangiopathy - thrombotic thrombocytopenic purpura - von Willebrand factor cleaving pro-tease
 

  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 6 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347: 589-600.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 26 Skudowitz RB, Katz J, Lurie A. et al. Mechanisms of thrombocytopenia in malignant tertian malaria. Br Med J 1973; 02: 515-518.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 30 Crawley JT, Lam JK, Rance JB. et al. Proteolytic inactivation of ADAMTS13 by thrombin and plasmin. Blood 2005; 105: 1085-1093.
    PubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar