Does activation of the blood coagulation cascade have a role in malaria pathogenesis?

Abstract

Plasmodium falciparum infection is often associated with a procoagulant state. Recent identification of tissue factor (TF) in the brain endothelium of patients who died from cerebral malaria casts new light in our understanding of the coagulation disorder found in P. falciparum infection. It has also been revealed that parasitized red blood cells (pRBC) support assembly of multimolecular coagulation complexes. In this article, the role of TF expression by the endothelium and amplification of the coagulation cascade by pRBC and/or activated platelets-particularly at sequestration sitesis discussed as crucial events in mounting and sustaining a coagulation-inflammation cycle that contributes to organ dysfunction and coma in P. falciparum malaria. Blood coagulation and malariaMalaria caused by P. falciparum remains a highly endemic disease; it has been estimated that at least one million deaths occur every year. Children are at high risk, and often severe malaria (severe anemia or cerebral malaria [CM]) is the cause of death in this population 1-4. P. falciparum infection is associated with sequestration 5 -8 , endothelial cell (EC) activation 8-10, increase in inflammatory cytokines 3 , 11, and activation of the coagulation cascade 12 -20. Despite several papers devoted to the coagulation disorder in malaria-many of them published during the 1970s and 1980s (reviewed in Ref. 20)-the mechanism that triggers and propagates the coagulation activation in P. falciparum infection has remained elusive. These studies, however, demonstrated that bleeding and/or hemorrhage are typically not present, although laboratory tests indicate a certain degree of in vivo blood coagulation activation 12 -20 . Accordingly, prothrombin time (PT) and partial thromboplastin time (PTT) are close to normal values or prolonged, whereas thrombin-antithrombin complex (TAT) (which indicates in vivo thrombin formation) and D-dimers (which are a marker of in vivo fibrinolysis) are often elevated, and thrombocytopenia is a usual finding 12 -21 . This laboratory profile is compatible with disseminated intravascular coagulation (DIC), which is diagnosed according to a score defined by the International Society of Thrombosis and Haemostasis (ISTH) 22 . The scoring system takes into account i) platelet count, ii) elevated fibrin related markers, iii) prolonged prothrombin time, and iv) fibrinogen level 22 23 . Depending on the score punctuation, levels < 5 are suggestive of non-overt (compensated) DIC while scores > or = 5 are compatible with overt (decompensated) DIC. Bleeding is more common in overt DIC, but it is not needed for the formal diagnosis 22 23. In other words, absence of bleeding in P. falciparum-infected patients does not exclude the presence of DIC in this same population; actually, most of these patients meet the criteria for DIC as defined above 22 . Unfortunately, absence of bleeding is often mistakenly regarded as the reason why DIC is supposedly not present in malaria. Further, some reports do not support the view that coa...

Persistently Elevated Laboratory Markers of Thrombosis and Fibrinolysis After Clinical Recovery in Malaria Points to Residual and Smouldering Cellular Damage

“…Differences in the clothing habits of males and females in India and also the feeding habits of Anopheles vectors in the evening and outdoors would have contributed to this difference in sex incidence. Thrombocytopenia (platelet count \150,000/mm 3 ) was present in almost all (97.5%) patients (78/80; P. vivax 39/40 and P. falciparum 39/40) in this study in accordance with similar high incidence reported by earlier studies [4,6]. In order to find correlation between thrombocytopenia and the presence or absence of hemorrhage, the platelet counts were categorized into five subgroups representing different degrees of thrombocytopenia (Table 8).…”

“…Role of circulating immune complexes and inflammatory mediators (e.g. TNF-a, IL-6 and Interferon) has also been postulated [4,6]. It is now well established that patients with thrombocytopenia due to peripheral destruction of normally functioning platelets and normal bone marrow (e.g.…”

Perioperative considerations of the patient with malaria

“…66 Malaria is also associated with activation of the coagulation and fibrinolytic pathways, with tissue factor activation suggested as the unifying mechanism in the pathology of severe malaria. 67 Disseminated intravascular coagulation can occur but is seen in only 1% of cases. 68 …”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…However, most investigators propose that P. falciparum infection is associated with a procoagulant state (Francischetti 2008). Francischetti et al proved that the coagulation cascade played a crucial role in the pathogenetic processes leading to the cerebral complications (Francischetti 2008).…”

“…However, most investigators propose that P. falciparum infection is associated with a procoagulant state (Francischetti 2008). Francischetti et al proved that the coagulation cascade played a crucial role in the pathogenetic processes leading to the cerebral complications (Francischetti 2008). Tissue factor expression in the endothelium, and the amplification of the coagulation cascade by pRBCs and platelets at sequestration sites, contribute critically in initiating and maintaining a coagulation-inflammation cycle which leads to cerebral involvement in falciparum malaria (Francischetti 2008).…”