Coagulation disturbance in experimental cerebral malaria

Author(s)

Ana Carolina Andrade Vitor Kayano

• Document type: Doctoral Thesis
• Press: Campinas, SP.
• Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Biologia
• Defense date: 2016-04-26

Examining board members

Fabio Trindade Maranhão Costa; Robson de Queiroz Monteiro; Claudio Romero Farias Marinho; Fernanda Loureiro de Andrade Orsi; Selma Giorgio

• Advisor: Fabio Trindade Maranhão Costa

Abstract

Cerebral malaria (CM) is the most severe complication resulting from P. falciparum infection which leads to death thousands of people every year. Despite scientific advances to unveil the factors responsible for CM, its pathogenesis is not well understood. CM is a multifactorial syndrome involving parasite sequestration in the microvasculature and increased expression of proinflammatory cytokines. Although it is not clear how these factors are orchestrated, they result in endothelial dysfunction and coagulopathy that contribute significantly in clinical aggravation. Thus, the understanding of coagulopathy mechanims related to cerebral malaria opens new perspectives for the development of therapeutic strategies. In this work we use the cerebral malaria model: C57BL/6 mice infected by Plasmodium berghei ANKA (PbA). To ensure that experimental cerebral malaria (ECM) was characterized by a dysfunction in the coagulation process, similar to human infections, PbA-infected mice were submitted to surgery for induction of photochemically arterial thrombus and time for thrombus formation was determined. These tests showed that the ECM has a prothrombotic phenotype dependent of immuno-competent cells and strain specific, since animals infected with P. berghei NK65 (non cerebral strain) showed no equivalent dysfunction. Furthermore, the presence of the parasite appears to be critical in the coagulopathy process as well as CD8+ T lymphocytes. The dysfunction of hemostasis was also demonstrated in the brain of these animals through increased expression of icam1, tf and epcr and elevated retention time of platelets in the brain vessels. Furthermore, the increase in thrombin-antithrombin and the euglobulin lysis time, together with high levels of inhibitor of plasminogen activator (PAI-1) indicate a hypercoagulability, with activation of coagulation associated with decreased fibrin degradation. To determine whether this phenotype could be related to the disease development, animals were treated with tranexamic acid (an inhibitor of the fibrinolytic system) and subsequently infected with PbA. The mice showed an early death compared to untreated group, as well as increased expression of tnfa, ifng and prf1. Furthermore, mice deficient in PAI-1 (PAI-1-/-) infected with PbA did not succumbed to ECM and protection was associated with low levels of inflammatory molecules and prevention of endothelial activation. These findings show that ECM, as well as endothelial dysfunction is dependent on the presence of PAI-1. Collectively, these findings open new perspectives for the understanding of the cerebral malaria pathophysiology and the design of new therapeutic approaches (AU)

• FAPESP's process: 10/18570-0 - Coagulation disorder in experimental cerebral malária
• Grantee: Ana Carolina Andrade Vitor Kayano
• Support Opportunities: Scholarships in Brazil - Doctorate