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

Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, the Netherlands.
Thrombosis and Haemostasis (Impact Factor: 4.98). 01/2010; 103(1):181-7. DOI: 10.1160/TH09-04-0223
Source: PubMed

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.

9 Reads
  • Source
    • "A deficiency in ADAMTS13 (a von Willebrand factor (VWF) cleaving protease ) is associated with accumulation of prothrombogenic unusually large VWF multimers in plasma. It has been reported that symptomatic Plasmodium falciparum infection was associated with a significant increase in VWF and active VWF levels and a decrease in ADAMTS13 activity, resulting in the presence of circulating ultra-large VWF multimers [14]. The presence of reduced ADAMTS13 activity may contribute to the pathophysiological changes observed in severe malaria and particularly to microvascular disorders as observed in other groups of thrombotic microangiopathy. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A 63-year-old Caucasian woman developed severe Plasmodium falciparum malaria when travelling back from Cameroun. No antimalarial chemoprophylaxis had been observed. The patient was immediately admitted to the intensive care unit after evidence of multiple organ failure (coma, shock, acute respiratory distress syndrome, acute renal failure, etc.). However, initial parasitemia was less than 1%. The patient was managed by intravenous quinine and norepinephrine infusion due to refractory shock. The patient developed as an early complication ischemic lesions of both arms and feet. In addition to laboratory changes consistent with disseminated intravascular coagulation, there was also evidence for a low activity of the von Willebrand factor (VWF) cleaving protease ADAMTS13. Later complications included repeated candidemia and bacteraemia despite appropriate therapy; the origin appeared to be diffuse ischemic injury of the gastrointestinal tract. The patient ultimately recovered, but quadriamputation was necessary to treat symmetrical peripheral gangrene (SPG). In severe Plasmodium falciparum malaria, ischemic changes may be due to microvascular obstruction, but, in patients with low parasitemia, other endothelial factors may also be involved as observed in other groups of thrombotic microangiopathies.
    Case Reports in Medicine 04/2014; 2014:696725. DOI:10.1155/2014/696725
  • Source
    • "Moreover, there was abnormal ULVWF, a highly active form of vWF contributing to large platelet adhesion and aggregation to the vessel wall, in SM and CM patients rather than normal control [4,5]. These data correspond with the reduced activity of ADAMTS13 in SM and CM patients [4,6]. Furthermore, most symptoms of CM including fever, renal failure, microangiopathic haemolytic anaemia, neurological deficits and thrombocytopaenia, are commonly found in thrombotic thrombocytopaenic purpura (TTP), a rare life-threatening disease, which is caused by a congenital or acquired deficiency of ADAMTS13. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Severe falciparum malaria (SM) remains a major cause of death in tropical countries. The reduced activity of ADAMTS13, increasing levels of ultra-large von Willebrand factor (ULVWF) in SM patients, are assumed as factors that intensify disease severity. However, the reason why ADAMTS13 activity is reduced in SM remains unclear.Objectives: To investigate whether rs4962153, febrile temperature, and microparticles, contribute to reduced ADAMTS13 activity. Genotypic association of rs4962153 with ADAMTS13 antigen and activity was examined in 362 healthy Thai participants. The collagen binding assay was used to study the effects of febrile temperature and microparticles on ADAMTS13 activity. ADAMTS13 antigen and activity were decreased in participants with AA genotype, compared to AG and GG (antigen: p-value = 0.014, and < 0.001; activity: p-value = 0.036, and < 0.002, respectively). There was significantly reduced ADAMTS13 antigen in AG compared to GG (p-value = 0.013), but not in ADAMTS13 activity (p-value = 0.082). The number of rs4962153 A alleles correlated with the reduced level of antigen and activity (p-value <0.001 and p-value = 0.001, respectively). MPs showed an inhibitory effect on ADAMTS13 activity (p-value = 0.025). Finally, ADAMTS13 activity was decreased in a temperature and time-dependent manner. The interaction between these two factors was also observed (p-value <0.001). These findings suggest that the A allele of rs4962153, MPs, and febrile temperature, contribute to reduce ADAMTS13 activity in plasma. These data are useful in malaria or other diseases with reduced ADAMTS13 activity.
    Malaria Journal 01/2014; 13(1):3. DOI:10.1186/1475-2875-13-3 · 3.11 Impact Factor
  • Source
    • "In the only detailed autopsy study of fatal knowlesi malaria, widespread microvascular parasite accumulation was found, including within the brain, but no features to suggest cytoadherence of parasitized red cells to endothelial cells, a hallmark of the pathophysiology of severe falciparum malaria (31). Additional causes of impaired microvascular flow and organ dysfunction in falciparum malaria include dysregulated immune responses (32), endothelial activation with elevated angiopoietin-2 and von Willebrand factor (33,34), and decreased vascular nitric oxide bioavailability (25) and red cell deformability (35), but their roles in knowlesi malaria remain unknown. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The simian parasite Plasmodium knowlesi causes severe human malaria; the optimal treatment remains unknown. We describe the clinical features, disease spectrum, and response to antimalarial chemotherapy, including artemether-lumefantrine and artesunate, in patients with P. knowlesi malaria diagnosed by PCR during December 2007-November 2009 at a tertiary care hospital in Sabah, Malaysia. Fifty-six patients had PCR-confirmed P. knowlesi monoinfection and clinical records available for review. Twenty-two (39%) had severe malaria; of these, 6 (27%) died. Thirteen (59%) had respiratory distress; 12 (55%), acute renal failure; and 12, shock. None experienced coma. Patients with uncomplicated disease received chloroquine, quinine, or artemether-lumefantrine, and those with severe disease received intravenous quinine or artesunate. Parasite clearance times were 1-2 days shorter with either artemether-lumefantrine or artesunate treatment. P. knowlesi is a major cause of severe and fatal malaria in Sabah. Artemisinin derivatives rapidly clear parasitemia and are efficacious in treating uncomplicated and severe knowlesi malaria.
    Emerging Infectious Diseases 07/2011; 17(7):1248-55. DOI:10.3201/eid1707.101017 · 6.75 Impact Factor
Show more