Article

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: 6.09). 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.

0 0
 · 
0 Bookmarks
 · 
82 Views
  • Source
    [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. · 3.40 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Malaria is a disease that causes enormous human morbidity and mortality. One feature of mature Plasmodium falciparum-infected erythrocytes leading to the development of severe malaria is thought to be cytoadherence and blockage of the microvasculature. Therefore, an understanding of mechanisms that mediate parasite adhesion leading to malaria pathology is needed to yield new treatments for malaria. However, to date, cytoadherence-associated pathology is still under debate. Is cytoadherence needed to develop severe malaria? This review will discuss the available information on associations of cytoadherence with the development of severe malaria.
    The Malaysian journal of medical sciences : MJMS. 04/2012; 19(2):5-18.
  • [show abstract] [hide abstract]
    ABSTRACT: Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in pro- and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13 and disease outcome. We analysed plasma of 50 patients taken on the day of admission for ALI/ALF. Plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared to healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared to control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications. Conclusion: highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet-induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ADAMTS13 ratio. (HEPATOLOGY 2013.).
    Hepatology 03/2013; · 12.00 Impact Factor