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Blood. 2016 May 12;127(19):2281-8. doi: 10.1182/blood-2015-11-636464. Epub 2016 Feb 5.

Emerging roles for hemostatic dysfunction in malaria pathogenesis.

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Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital, and.
Department of Clinical Medicine, School of Medicine, Trinity College Dublin, Dublin, Ireland; National Children's Research Centre, Our Lady's Children's Hospital, Crumlin, Dublin, Ireland; and.
Haemostasis Research Group, Institute of Molecular Medicine, Trinity Centre for Health Sciences, St. James's Hospital, and National Centre for Hereditary Coagulation Disorders, St. James's Hospital, Dublin, Ireland.


Severe Plasmodium falciparum malaria remains a leading cause of mortality, particularly in sub-Saharan Africa where it accounts for up to 1 million deaths per annum. In spite of the significant mortality and morbidity associated with cerebral malaria (CM), the molecular mechanisms involved in the pathophysiology of severe malaria remain surprisingly poorly understood. Previous studies have demonstrated that sequestration of P falciparum-infected erythrocytes within the microvasculature of the brain plays a key role in the development of CM. In addition, there is convincing evidence that both endothelial cell activation and platelets play critical roles in the modulating the pathogenesis of severe P falciparum malaria. In this review, we provide an overview of recent studies that have identified novel roles through which hemostatic dysfunction may directly influence malaria pathogenesis. In particular, we focus on emerging data suggesting that von Willebrand factor, coagulation cascade activation, and dysfunction of the protein C pathway may be of specific importance in this context. These collective insights underscore a growing appreciation of the important, but poorly understood, role of hemostatic dysfunction in malaria progression and, importantly, illuminate potential approaches for novel therapeutic strategies. Given that the mortality rate associated with CM remains on the order of 20% despite the availability of effective antimalarial therapy, development of adjunctive therapies that can attenuate CM progression clearly represents a major unmet need. These emerging data are thus not only of basic scientific interest, but also of direct clinical significance.

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