Thrombocytopenia in Dengue: Interrelationship between Virus and the Imbalance between Coagulation and Fibrinolysis and Inflammatory Mediators

Abstract

Dengue is an infectious disease caused by dengue virus (DENV). In general, dengue is a self-limiting acute febrile illness followed by a phase of critical defervescence, in which patients may improve or progress to a severe form. Severe illness is characterized by hemodynamic disturbances, increased vascular permeability, hypovolemia, hypotension, and shock. Thrombocytopenia and platelet dysfunction are common in both cases and are related to the clinical outcome. Different mechanisms have been hypothesized to explain DENV-associated thrombocytopenia, including the suppression of bone marrow and the peripheral destruction of platelets. Studies have shown DENV-infected hematopoietic progenitors or bone marrow stromal cells. Moreover, anti-platelet antibodies would be involved in peripheral platelet destruction as platelets interact with endothelial cells, immune cells, and/or DENV. It is not yet clear whether platelets play a role in the viral spread. Here, we focus on the mechanisms of thrombocytopenia and platelet dysfunction in DENV infection. Because platelets participate in the inflammatory and immune response by promoting cytokine, chemokine, and inflammatory mediator secretion, their relevance as "immune-like effector cells" will be discussed. Finally, an implication for platelets in plasma leakage will be also regarded, as thrombocytopenia is associated with clinical outcome and higher mortality.

Figure 1

Coagulation and inflammatory response activation during dengue. DENV infection is often associated with coagulation disorders. The coagulation system is activated by the host immune response. The activation of coagulation system leads to the generation of thrombin and intracellular signaling through PAR; platelet and monocyte activation and recruitment; and increased TF expression on the endothelium and monocytes. The following anticoagulant pathways balance this system: the protein C system, antithrombin (AT), and Tissue Factor Pathway Inhibitor (TFPI). Increased CD62P expression in platelets from dengue patients indicates platelet activation and therefore favors homo- and heterotypic interactions with immune cells and endothelial cells. Additionally, CD40L (CD154) expressing platelets can interact with CD40 on endothelial cells, inducing upregulation of adhesion molecule (e.g., ICAM-1), chemokine secretion (e.g., CCL2), and leukocyte recruitment. Evidence of increased circulating TF levels in dengue patients and increased expression in monocytes from severe patients suggests its importance in disease pathogenesis. The release of inflammatory cytokines leads to activation of the coagulation cascade through the TF pathway. Coagulation factors (e.g., thrombin) activate PAR and amplify proinflammatory cytokine production (e.g., TNF-α, IL-1β, IL-6, and CCL2) and leukocyte migration to the infection site. EPCR: endothelial protein C receptor; TM: thrombomodulin.