A plasma inhibitor of platelet aggregation in patients with Lassa fever

Abstract

Summary Previous studies have shown that haemorrhage in Lassa fever is associated with abnormal in vitro platelet aggregation and a high mortality. In Sierra Leone we studied platelet aggregation in healthy local subjects, patients with laboratory‐confirmed Lassa fever and febrile patients in whom Lassa virus infection was excluded. There were no significant differences in the mean platelet counts of these groups. Patients with fulminant Lassa virus infection showed a gross depression of in‐vitro platelet responsiveness to 1 and 5 μm ADP and 4 μg/ml collagen compared to other groups (P=0·0004–0·0008 when compared to healthy controls, P=0·002–0·0008 when compared to mild Lassa fever patients). When plasma samples from five of these patients were mixed 1:1 with control platelet‐rich plasma, a marked inhibition of ADP‐induced aggregation was observed. No inhibitory activity was detected in plasma obtained from healthy subjects or febrile control patients. The presence of inhibitor was strongly associated with the occurrence of haemorrhage (P=0·03), depression of platelet aggregation (P=0·004) and severity of Lassa fever (P=0·007).

Early Blood Profiles of Virus Infection in a Monkey Model for Lassa Fever

“…Downregulation of COX-2 occurs during overdose of drugs such as rofecoxib (Vioxx), which are known to deplete prostacyclins, destroy clotting, and cause hemorrhage (63). Our findings with COX-2 corroborate studies by Fisher-Hoch and Cummins et al that show a decrease in prostacyclin in monkeys with Lassa fever (18,28). The decrease in PTGS2 expression during virulent disease is not directly attributable to viral gene functions but can provide a mechanism for the coagulation defects (18,55), cardiac dysfunction (61,64), and capillary leakage (55) that are hallmarks of arenavirus hemorrhagic fever.…”

“…Our findings with COX-2 corroborate studies by Fisher-Hoch and Cummins et al that show a decrease in prostacyclin in monkeys with Lassa fever (18,28). The decrease in PTGS2 expression during virulent disease is not directly attributable to viral gene functions but can provide a mechanism for the coagulation defects (18,55), cardiac dysfunction (61,64), and capillary leakage (55) that are hallmarks of arenavirus hemorrhagic fever. In summary, microarray analysis of blood from rhesus monkeys revealed how infection with a virulent arenavirus regulates gene expression in an animal model.…”

“…In the monkey model, viremia is detectable in blood approximately 4 days after the initial exposure (22,48). The blood later exhibits elevated liver enzymes and coagulation defects (18,27). Additional disease signs include petechial rashes, pulmonary edema, cardialgia, renal failure, hemorrhage, and hypoxia, leading to death approximately 2 weeks after virus exposure (46,62).…”

The Role of Platelets in Viral Hemorrhagic Fevers

“…In conclusion, a detailed description of the hemorrhagic fever Hantavirus [166] SFTS [69] Hantavirus [139] Hantavirus [166] DENV [112,167,168] DENV [169] LASV [71] JUNV [74,170] JUNV [72] Ebola [62] a Destruction of platelets by direct interaction: SomeHFV can bind platelets directly causing activation and granules release.…”

“…In West Africa, Lassa fever virus is responsible for about 300,000 cases per year with 5,000 deaths. Interestingly, platelet numbers during Lassa fever disease can be within the normal range, but arenaviral infection appear to induce a soluble factor that inhibits platelet aggregation [71,72]. Soluble P-selectin serum levels increase during arenavirus infection of mice, indicating that platelets can be activated during infection [73].…”