Hypercoagulability and vascular proinflammatory activation promote cardiac-cerebral fibrinogenesis in a rodent model of Chagas disease.

Abstract

Cardiomyopathy and stroke are major complications of Chagas disease (CD). We investigated if hypercoagulability, endothelial cell (EC) dysfunction, and blood stasis cause cardiac-cerebral fibrinogenesis in CD. C57BL/6 mice infected with() were evaluated at acute (AT), indeterminate (IT), and chronic (CT) stages of CD. Mice were given anti-parasite, bicistronic immunogens (BCV or BCVR) to determine the role ofin fibrinogenesis. We monitored (1) platelet and coagulation cascade activation; (2) cardiac-cerebral blood vessels injury; (3) proinflammatory/prothrombotic phenotypes of microglia, macrophages, and vascular cells; and (4) fibrinogenesis. After a quiescent acute phase, plasma levels of coagulation and other factors of platelet activation/aggregation, hypercoagulability, and clotting capacity were increased in IT-CT mice. Proinflammatory and prothrombotic cytokines/chemokines in cardiac-cerebral blood vessels were also significantly increased in IT-CT mice. Loss of cardiac EC and a marked increase in their proinflammatory/cell-adhesion response were not compensated for by a pro-angiogenic/wound-healing response in cardiac-cerebral tissues of infected mice. Microglial proinflammatory activation preceded the vascular inflammation suggesting a feedback cycle of EC activation in brain of infected mice. Treatment with BCV/BCVR controlled the parasite persistence and hypercoagulability/vascular inflammation in infected mice. Importantly, BCV/BCVR treatment abolished the fibrin clots that otherwise were pronounced in heart and brain of IT-CD mice. We conclude that acuteinfection triggered a subdued hemodynamic disorder, and the persistence of low-grade parasites contributed to a cardiovascular/cerebrovascular proinflammatory and prothrombotic response and fibrin deposition in mice. BCV/BCVR offer potential immunotherapies for reducing the recurrent clot formation and risk of stroke in CD.