Emerging roles for hemostatic dysfunction in malaria pathogenesis

Abstract

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.

Experimental cerebral malaria is associated with profound loss of both glycan and protein components of the endothelial glycocalyx

“…However, other tissues likely contribute to circulating syndecans and glycosaminoglycans. We are aware that CM has a complex pathogenesis that includes dysregulated inflammatory pathways and a poorly regulated coagulation system (63)(64)(65). Thus, even though several inhibitors for various pathways potentially affecting glycocalyx shedding have been explored in this paper, we may have missed important mechanisms.…”

Cerebral malaria is associated with differential cytoadherence to brain endothelial cells

“…The increased binding (at standardised assay conditions of 2% parasitaemia and 5% haematocrit) to EC correlated with increased parasitaemia, but with decreased platelet numbers. Activation of platelets and platelet consumption leads to a pro-coagulant state characterised by an increase in thrombin and von Willebrand factor, which are demonstrated in SM (Dorovini-Zis et al, 2011;O'Sullivan et al, 2016;Thachil, 2017). A recent study in children recruited from the same hospital in 2015-2016 showed that low platelet levels were also associated with retinopathy-positive CM cases and brain swelling (Kessler et al, 2017).…”

“…The negative correlation between peripheral platelets and binding intensity is interesting as thrombocytopenia has been used as a predictor for malaria (Lampah et al, 2015;Thachil, 2017) and specifically for P. falciparum SM (Gerardin et al, 2002;Cserti-Gazdewich et al, 2012). In addition, anti-coagulation and endothelial protective pathways are affected in CM through a decrease in EPCR and thrombomodulin and thus dysfunction of the activated protein C pathway (Moxon et al, 2013(Moxon et al, , 2015O'Sullivan et al, 2016). Some studies have shown that CM cases have more platelets localised in the brain microvasculature Dorovini-Zis et al, 2011) and show increased platelet-mediated clumping of IE (Pain et al, 2001;Wassmer et al, 2008) and platelet involvement in the adhesion of IE to human microvascular EC lacking CD36 (Wassmer et al, 2004).…”

How I treat disseminated intravascular coagulation

“…19 For example, high parasitemia primarily of Falciparum malaria, may be associated with DIC, and high mortality. 20 Factors involved in the development of DIC complicating infections are microbial membrane constituents, such as lipopolysaccharide or lipoteichoic acid, or exotoxins (e.g. Staphylococcaltoxin), evoking a strong immune response and release of cytokines.…”