Acta Tropica 89 (2004) 309–317 Reduced microcirculatory flow in severe falciparum malaria: pathophysiology and electron-microscopic pathology Arjen M. Dondorp a,b,* , Emsri Pongponratn a , Nicholas J. White a,b a Faculty of Tropical Medicine, Mahidol University, 420/6 Rajvithi Road, Bangkok 10400, Thailand b Nuffield Department of Clinical Medicine, Centre for Tropical Medicine, John Radcliffe Hospital, Headington, Oxford, UK Abstract The pathophysiology of severe falciparum malaria is complex, but evidence is mounting that its central feature is the old concept of a mechanical microcirculatory obstruction. Autopsy studies, but also in vivo observations of the microcirculation, demonstrate variable obstruction of the microcirculation in severe malaria. The principal cause of this is cytoadherence to the vascular endothelium of erythrocytes containing the mature forms of the parasite, leading to sequestration and obstruction of small vessels. Besides, parasitized red cells become rigid, compromising their flow through capillaries whose lumen has been reduced by sequestered erythrocytes. Adhesive forces between infected red cells (auto-agglutination), between infected and uninfected red cells (rosetting) and between uninfected erythrocytes (aggregation) could further slow down microcirculatory flow. A more recent finding is that uninfected erythrocytes also become rigid in severe malaria. Reduction in the overall red cell deformability has a strong predictive value for a fatal outcome. Rigidity may be caused by oxidative damage to the red blood cell membrane by malaria pigment released at the moment of schizont rupture. Anti-oxidants, such as N-acetylcysteine can reverse this effect and are promising as adjunctive treatment in severe malaria. © 2003 Elsevier B.V. All rights reserved. Keywords: Severe malaria; Microcirculation; Red blood cell deformability; Oxidative stress; Haemozoin 1. Introduction Severe malaria, caused by the parasite Plasmod- ium falciparum, is a potentially fatal disease, with a case mortality rate of 15–20% despite adequate treat- ment and access to facilities for intensive treatment (WHO, 2000). Despite serious scientific efforts, the pathophysiology of severe falciparum malaria is still incompletely understood. A lot of research has been focussed on the immunopathogenesis of the disease, establishing the role of cytokines and other mediators * Corresponding author. E-mail address: AMDondorp@yahoo.com (A.M. Dondorp). like nitric oxide. This short review, however, will fo- cus on the role of a compromised microcirculation in the pathogenesis of severe malaria. The two mecha- nisms are not mutually exclusive: for example coma in cerebral malaria is probably not simply a result of global cerebral hypoxia, but it may result from neuro- transmitter abnormalities secondary to microvascular obstruction and the consequent abnormal metabolic milieu and local release of parasite-derived toxic ma- terial and host derived inflammatory mediators. Clinically severe malaria is characterised by mul- tiple organ failure, with a variable mix of affected organs, which partly depends on the age of the patient. Severe anaemia, hypoglycaemia and convulsions are 0001-706X/$ – see front matter © 2003 Elsevier B.V. All rights reserved. doi:10.1016/j.actatropica.2003.10.004