Platelet function alterations in dengue are associated with plasma leakage

Abstract

Severe dengue is characterised by thrombocytopenia, plasma leakage and bleeding. Platelets are important for preservation of endothelial integrity. We hypothesised that platelet activation with secondary platelet dysfunction contribute to plasma leakage. In adult Indonesian patients with acute dengue, we measured platelet activation status and the response to the platelet agonist TRAP using flow cytometer-based assays. Patients were monitored daily for plasma leakage by ultrasonography. Acute dengue was associated with platelet activation with an increased expression of the activated fibrinogen receptor (αIIbβ3), the lysosomal marker CD63 and the alpha-granule marker CD62P (P-selectin). Upon maximal platelet activation by TRAP, platelet function defects were observed with a significantly reduced maximal activated αIIbβ3 and CD63 expression and reduced platelet-monocyte and platelet-neutrophil complexes. Patients in the lowest tertile of activated αIIbβ3 and CD63 expression had an odds ratio for plasma leakage of 5.2 (95% confidence interval [CI] 1.3-22.7) and 3.9 (95% CI 1.1-13.7), respectively, compared to the highest tertile. Platelet-derived serotonin has previously been related to plasma leakage and we found increased intra-platelet serotonin concentrations in our patients. In conclusion, platelet activation with platelet function alterations can be found in patients with acute dengue and this may contribute to dengue-associated plasma leakage.

Platelet proteome reveals novel pathways of platelet activation and platelet-mediated immunoregulation in dengue

“…Activation of circulating platelets in patients with dengue has been previously reported [18,20,31]. In our proteome analysis, proteins related to platelet activating signaling including PAR4 (F2RL3), G protein subunits (GNA12 and GNA14) and p38 MAPK (MAPK14) were increased in platelets from patients with dengue (blue dots in Fig 2B and S2D Table ), potentially contributing to increased platelet activation during dengue infection.…”

“…It is the main adhesion molecule responsible for platelet interaction with monocytes [9,13,20,32], and circulating platelet-monocyte aggregates have been detected in dengue-infected patients [20,33]. Despite platelets from patients with dengue have increased P-selectin expression at baseline, it was recently shown that P-selectin trafficking to surface in response to thrombin receptor activating peptide stimulation ex vivo was lower in platelets from dengue patients compared to control [31], which is consistent with platelet exhaustion of α-granules proteins. Beyond P-selectin, platelet α-granules store numerous cytokines, chemokines and growth factors [9].…”

“…Although increased P-selectin surface expression has been shown in platelets from dengue patients [18,31], the mechanisms underlying platelet activation in dengue are not completely understood. As shown here and in previous publications [18,36], platelets can be directly activated by DENV infection in vitro ( Fig 3G ).…”

“…DENV activation of platelets requires infective DENV binding to DC-SIGN [18], a surface receptor involved in DENV binding and replication by platelets [17]. However, platelet activation in patients with dengue peaks at the critical phase of infection, when DENV particles are no longer circulating [18,31]. This indicates that other mechanisms are involved in platelet activation during nonviremic phases of dengue illness.…”

Efficacy & safety of Carica papaya leaf extract (CPLE) in severe thrombocytopenia (≤30,000/μl) in adult dengue – Results of a pilot study

“…Another possibility is the bone marrow hypoplasia and attenuation of megakaryocyte development during the acute phase of DENV infection, causing suppression of platelet production [8]. DENV infection can also lead to apoptosis of bone marrow progenitor cells, destruction of stromal cells or dysregulation of thrombopoiesis [9]. Haemorrhagic manifestations in dengue are usually the result of a complex interplay of peripheral platelet dysfunction and loss and/or disseminated intravascular coagulation.…”