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Dysregulation of coagulation in cerebral malaria.

Moxon CA, Heyderman RS, Wassmer SC - Mol. Biochem. Parasitol. (2009)

Bottom Line: The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood.This new insight offers important therapeutic potential.This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at possible underlying mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Malawi Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Chichiri, PO Box 30096, Blantyre 3, Malawi. cmoxon@liverpool.ac.uk

ABSTRACT
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection and represents a major cause of morbidity and mortality worldwide. The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood. It has recently emerged that in addition to their conventional role in the regulation of haemostasis, coagulation factors have an inflammatory role that is pivotal in the pathogenesis of a number of acute and chronic conditions, including CM. This new insight offers important therapeutic potential. This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at possible underlying mechanisms. We discuss areas for future research to improve understanding of CM pathogenesis and for the development of new therapeutic approaches.

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Related in: MedlinePlus

Theoretical model for the dysregulation of the coagulation system in cerebral malaria. (a) Early in infection the coagulation system is activated by a combination of the host immune response and parasite-derived protein interactions with host endothelium, and circulating cells. This leads to: (1) the generation of thrombin and intracellular signalling through PAR; (2) the activation and recruitment of platelets and monocytes; (3) the vesiculation of microparticles from the endothelium and platelets; (4) an excessive visibility of TF on the following activated components: endothelium, platelets, monocytes and microparticles. In most patients this system is balanced by the protein C and AT III pathways (latter not pictured here). However, at the most severe end of the spectrum these pathways are impaired by intense sequestration of PfIE within the microvasculature (b). This sets up a potential positive feedback cycle of inflammatory and coagulation events. Thrombin promotes the conversion of fibrinogen to fibrin which adheres to activated platelets to form thrombi and is itself pro-inflammatory. Excessive inflammation at these sites from a combination of inflammatory events and cytokines, unbuffered by anticoagulants, and activation of apoptosis by PfIE contact and TGF-β, leads to endothelial damage and loss of tight junction function. This creates gaps in vessels and, in the context of excessive local consumption of coagulants by the thrombi, leads to microhaemorrhages. L-α: lymphotoxin-α; IL-6: interleukin-6.
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fig1: Theoretical model for the dysregulation of the coagulation system in cerebral malaria. (a) Early in infection the coagulation system is activated by a combination of the host immune response and parasite-derived protein interactions with host endothelium, and circulating cells. This leads to: (1) the generation of thrombin and intracellular signalling through PAR; (2) the activation and recruitment of platelets and monocytes; (3) the vesiculation of microparticles from the endothelium and platelets; (4) an excessive visibility of TF on the following activated components: endothelium, platelets, monocytes and microparticles. In most patients this system is balanced by the protein C and AT III pathways (latter not pictured here). However, at the most severe end of the spectrum these pathways are impaired by intense sequestration of PfIE within the microvasculature (b). This sets up a potential positive feedback cycle of inflammatory and coagulation events. Thrombin promotes the conversion of fibrinogen to fibrin which adheres to activated platelets to form thrombi and is itself pro-inflammatory. Excessive inflammation at these sites from a combination of inflammatory events and cytokines, unbuffered by anticoagulants, and activation of apoptosis by PfIE contact and TGF-β, leads to endothelial damage and loss of tight junction function. This creates gaps in vessels and, in the context of excessive local consumption of coagulants by the thrombi, leads to microhaemorrhages. L-α: lymphotoxin-α; IL-6: interleukin-6.

Mentions: Using available evidence we propose a model for the involvement of dysregulation of coagulation in the pathophysiology of CM in which intense sequestration in microvessels leads to a reinforcing cycle of inflammatory and coagulant events resulting in focal endothelial damage, thrombi and microhaemorrhage (Fig. 1). Inflammatory events are also likely to increase sequestration through upregulation of receptors on the endothelial surface such as ICAM-1.


Dysregulation of coagulation in cerebral malaria.

Moxon CA, Heyderman RS, Wassmer SC - Mol. Biochem. Parasitol. (2009)

Theoretical model for the dysregulation of the coagulation system in cerebral malaria. (a) Early in infection the coagulation system is activated by a combination of the host immune response and parasite-derived protein interactions with host endothelium, and circulating cells. This leads to: (1) the generation of thrombin and intracellular signalling through PAR; (2) the activation and recruitment of platelets and monocytes; (3) the vesiculation of microparticles from the endothelium and platelets; (4) an excessive visibility of TF on the following activated components: endothelium, platelets, monocytes and microparticles. In most patients this system is balanced by the protein C and AT III pathways (latter not pictured here). However, at the most severe end of the spectrum these pathways are impaired by intense sequestration of PfIE within the microvasculature (b). This sets up a potential positive feedback cycle of inflammatory and coagulation events. Thrombin promotes the conversion of fibrinogen to fibrin which adheres to activated platelets to form thrombi and is itself pro-inflammatory. Excessive inflammation at these sites from a combination of inflammatory events and cytokines, unbuffered by anticoagulants, and activation of apoptosis by PfIE contact and TGF-β, leads to endothelial damage and loss of tight junction function. This creates gaps in vessels and, in the context of excessive local consumption of coagulants by the thrombi, leads to microhaemorrhages. L-α: lymphotoxin-α; IL-6: interleukin-6.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2724037&req=5

fig1: Theoretical model for the dysregulation of the coagulation system in cerebral malaria. (a) Early in infection the coagulation system is activated by a combination of the host immune response and parasite-derived protein interactions with host endothelium, and circulating cells. This leads to: (1) the generation of thrombin and intracellular signalling through PAR; (2) the activation and recruitment of platelets and monocytes; (3) the vesiculation of microparticles from the endothelium and platelets; (4) an excessive visibility of TF on the following activated components: endothelium, platelets, monocytes and microparticles. In most patients this system is balanced by the protein C and AT III pathways (latter not pictured here). However, at the most severe end of the spectrum these pathways are impaired by intense sequestration of PfIE within the microvasculature (b). This sets up a potential positive feedback cycle of inflammatory and coagulation events. Thrombin promotes the conversion of fibrinogen to fibrin which adheres to activated platelets to form thrombi and is itself pro-inflammatory. Excessive inflammation at these sites from a combination of inflammatory events and cytokines, unbuffered by anticoagulants, and activation of apoptosis by PfIE contact and TGF-β, leads to endothelial damage and loss of tight junction function. This creates gaps in vessels and, in the context of excessive local consumption of coagulants by the thrombi, leads to microhaemorrhages. L-α: lymphotoxin-α; IL-6: interleukin-6.
Mentions: Using available evidence we propose a model for the involvement of dysregulation of coagulation in the pathophysiology of CM in which intense sequestration in microvessels leads to a reinforcing cycle of inflammatory and coagulant events resulting in focal endothelial damage, thrombi and microhaemorrhage (Fig. 1). Inflammatory events are also likely to increase sequestration through upregulation of receptors on the endothelial surface such as ICAM-1.

Bottom Line: The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood.This new insight offers important therapeutic potential.This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at possible underlying mechanisms.

View Article: PubMed Central - PubMed

Affiliation: Malawi Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, Chichiri, PO Box 30096, Blantyre 3, Malawi. cmoxon@liverpool.ac.uk

ABSTRACT
Cerebral malaria (CM) is a life-threatening complication of Plasmodium falciparum infection and represents a major cause of morbidity and mortality worldwide. The nature of the pathogenetic processes leading to the cerebral complications remains poorly understood. It has recently emerged that in addition to their conventional role in the regulation of haemostasis, coagulation factors have an inflammatory role that is pivotal in the pathogenesis of a number of acute and chronic conditions, including CM. This new insight offers important therapeutic potential. This review explores the clinical, histological and molecular evidence for the dysregulation of the coagulation system in CM, looking at possible underlying mechanisms. We discuss areas for future research to improve understanding of CM pathogenesis and for the development of new therapeutic approaches.

Show MeSH
Related in: MedlinePlus