Serotonin, key to thrombocytopenia in dengue?

In this issue of Blood, Masri et al¹  report a newly identified mechanism of dengue virus (DENV)–induced thrombocytopenia. Specifically, they demonstrate that peripheral serotonin derived from mast cells (MCs) increases the activation and clearance of platelets in response to DENV.

Dengue is the most common arboviral disease globally. The rising dengue incidence puts a heavy disease and socioeconomic burden on large parts of the tropics and subtropics. Of the estimated 400 million annual dengue infections worldwide, only ∼25% result in a clinical apparent infection, usually characterized by a nonspecific febrile illness. A small proportion of DENV infections results in complications, which usually develop several days into the illness, frequently around the time of defervescence. These complications typically involve a transient vascular leakage syndrome, hemorrhagic manifestations, and organ dysfunction. Thrombocytopenia, often combined with leukopenia, is an early and consistent feature of dengue. Complications are frequently preceded by a rapid drop in platelet count, often to very low numbers, and daily monitoring of platelet counts may help identify patients at high risk of severe complications.²  Hemorrhagic manifestations usually consist of skin and mucosal bleeding and may lead to hemorrhagic shock. In addition, platelets are important in preservation of vascular integrity, especially during inflammation.³ 

Platelets in dengue patients are activated, and the degree of platelet activation determines the severity of thrombocytopenia.⁴  Different mechanisms of platelet activation have been proposed, including direct activation of platelets by DENV via binding of the dendritic cell–specific intracellular adhesion molecule-3–grabbing nonintegrin,⁵  and the binding of cell-free histone H2A to platelets.⁶  In this context, the novel data presented by Masri et al are of particular relevance. The authors used mouse models of DENV infections, complemented by in vitro experiments with human blood, to study the role of MCs and serotonin in DENV-induced thrombocytopenia. Mice deficient in MCs did not develop thrombocytopenia. Serotonin was subsequently identified as the MC-derived mediator responsible for platelet activation via platelet 5HT_2A receptors. Mice lacking MC-serotonin were protected from thrombocytopenia, whereas administration of exogenous serotonin resulted in thrombocytopenia in these mice. Serotonin is a weak platelet agonist, and both DENV and serotonin were essential for induction of thrombocytopenia in vivo. Platelets store large quantities of serotonin, and serotonin released from MC can initiate a positive feedback loop whereby platelet-derived serotonin amplifies platelet activation.

These findings have several possible implications and raise a number of clinical questions. First, a new role in inducing thrombocytopenia is identified for a molecule best known for its role as a neurotransmitter. Thrombocytopenia is a feature of several, often tropical, infections, and future studies will need to define whether release of MC-derived serotonin mediates thrombocytopenia in other infections as well. Second, serotonin is involved in numerous other nonhemostatic processes, and it is conceivable that MC- and platelet-derived serotonin play a role in dengue pathogenesis beyond hemostasis. Close to 95% of serotonin is produced by the enterochromaffin cells in the gut, and the majority of serotonin in the circulation is stored inside platelets in dense bodies and released upon their activation. In the mouse models used in this report, MCs were the primary source of the serotonin initiating platelet activation, even though MCs are not the major fountainhead of serotonin in humans. Whether MCs are essential as serotonin source in human DENV infection is unknown. Moreover, how DENV activates MCs to release serotonin is awaiting to be elucidated. Over the years, there is also increased appreciation for the role of serotonin in modulation of the inflammatory response and host defense. For example, serotonin was recently identified as a potent therapeutic target of neutrophil-dependent thromboinflammation.⁷  In addition, serotonin released from platelets was found to mediate systemic shock in conditions with circulating immune complexes, a process that requires expression of platelet Fcγ receptor IIA.⁸  Whether serotonin is involved in additional clinical manifestations in dengue beyond thrombocytopenia needs further studies.

Virus-antibody immune complexes that bind FcγRIIA are common in secondary dengue infections, and it is important to note that murine platelets are completely devoid of any FcγRs, emphasizing the importance of considering possible limitations of animal models to fully recapitalize human disease. Developing a relevant murine model for dengue pathogenesis has indeed been challenging.⁹ 

The present findings may open new therapeutic avenues. Prophylactic platelet transfusions are frequently given to dengue patients with severe thrombocytopenia, even though a recent multicenter trial failed to demonstrate a preventive effect of prophylactic platelet transfusion on bleeding complications.¹⁰  Other interventions such as IV immunoglobulins or corticosteroids are ineffective in treating thrombocytopenia. As suggested by Masri et al, use of MC-stabilizing drugs or serotonin receptor blockers such as ketanserin might be attractive options to prevent dengue complications, even though other properties of these drugs, for example, the vasodilatory effects of ketanserin, should be considered. In addition, the therapeutic time window may be limited, because most DENV-infected patients present relatively late in the disease when levels of viremia are already declining. Another interesting question is whether use of selective serotonin reuptake inhibitors, a group of commonly used antidepressants, reduces the risk for DENV-related thrombocytopenia.

Notwithstanding these open questions, this paper not only opens a new avenue in our understanding of the basic pathology of dengue infections but also paves a way for adjunctive treatments. It is clear that both viral and host factors together are responsible for the decrease in platelet number. There are now different options to find out whether treatment with already available drugs can help to prevent or treat dengue-related thrombocytopenia.