DENGUE FEVER ACTIVATES THE l‐ARGININE–NITRIC OXIDE PATHWAY: AN EXPLANATION FOR REDUCED AGGREGATION OF HUMAN PLATELETS

Abstract

In patients with Dengue fever, a viral inflammatory syndrome, haemorrhage is a significant pathological feature, yet the underlying mechanisms remain unclear. Nitric oxide (NO) is an important regulator of platelet function, inhibiting aggregation, recruitment and adhesion to the vascular endothelium. We have investigated whether changes in the activity of the L-arginine-NO pathway in human platelets may account for increased bleeding in patients with Dengue fever. A total of 16 patients with Dengue fever and 18 age-matched healthy volunteers participated in the study. Collagen induced platelet aggregation in a dose-dependent manner in both Dengue patients and controls, but the degree of platelet aggregation was significantly reduced in the patient group. Elevated rates of L-arginine transport in Dengue fever patients were associated with enhanced NO synthase activity and elevated plasma fibrinogen levels. The present study provides the first evidence that Dengue fever is associated with increased L-arginine transport and NO generation and reduced platelet aggregation.

Hyperthermia induces platelet apoptosis and glycoprotein Ibα ectodomain shedding

“…Previous reports have shown that agonist-induced platelet aggregations are reduced in platelets pre-treated with heat in vitro or in platelets from patients with fever and heatstroke [5,22]. To explore the effect of hyperthermia on platelet function, PRP was isolated and incubated at hypothermia (22 C), normothermia (37 C) or hyperthermia (40 or 42 C) for 1 or 2 h, and then induced to aggregation by ADP.…”

“…Platelet count obviously reduces in most patients with dengue fever [4] or heatstroke [1]. And reduced platelet aggregations have been found in patients with hemorrhage fever [5], raising the possibility that fever or hyperthermia incurs reduction of platelet count or function leading to hemorrhage. Fever or hyperthermia induces a series of physiological responses including cell apoptosis in human body [1,7].…”

“…Postmortem findings in patients that died from heatstroke include diffuse bleeding, hemorrhagic necrosis and widespread microthrombi in most organs of the body [3]. Fever and hemorrhage have emerged as typical symptoms for many viral-related diseases [4][5][6][7] such as dengue fever, endemic in many parts of Asia and America with an estimated 100 million cases each year [4,5], hantavirus pulmonary syndrome [6] and a viral hemorrhagic syndrome induced by an African swine fever (ASF) virus [7]. In addition, thrombocytopenia and hemorrhagic risk also occur in patients with malignant diseases, particularly in patients undergoing hyperthermia therapy [8].…”

THE l‐ARGININE–NITRIC OXIDE PATHWAY: A POTENTIAL THERAPEUTIC TARGET IN DENGUE HAEMORHAGIC FEVER

“…Normal platelet homeostasis involves anti‐aggregatory NO and pro‐aggregatory thromboxane (TX) A 2 13 . Mendes‐Ribiero et al 2 . observed increased NO activity, consistent with the anti‐aggregatory and haemorrhagic tendency in DHF/DSS.…”

“…In this issue of the journal, Mendes Ribeiro et al . have implicated the l ‐arginine–NO pathway in the pathophysiology of dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS) 2 …”