Leptospira Infection Interferes with the Prothrombinase Complex Assembly during Experimental Leptospirosis

Abstract

Leptospirosis is a worldwide zoonotic and neglected infectious disease of human and veterinary concern, caused by pathogenic Leptospira species. Although bleeding is a common symptom of severe leptospirosis, the cause of hemorrhage is not completely understood. In severe infections, modulation of hemostasis by pathogens is an important virulence mechanism, and hemostatic impairments such as coagulation/fibrinolysis dysfunction are frequently observed. Here, we analyze the coagulation status of experimentally infected hamsters in an attempt to determine coagulation interferences and the origin of leptospirosis hemorrhagic symptomatology. Hamsters were experimentally infected with L. interrogans. The lungs, kidneys, and livers were collected for culture, histopathology, and coagulation assays. L. interrogans infection disturbs normal coagulation in the organs of animals. Our results suggest the presence of a thrombin-like factor or FX activator, which is able to activate FII in the leptospirosis organ extracts. The activity of those factors is accelerated in the prothrombinase complex. Additionally, we show for the first time that live leptospires act as a surface for the prothrombinase complex assembly. Our results contribute to the understanding of leptospirosis pathophysiological mechanisms and may open new routes for the discovery of novel treatments in the severe manifestations of the disease.

Clinical characteristics and outcomes of pulmonary haemorrhage in leptospirosis: A retrospective cohort study from Sri Lanka

“…Furthermore, a coagulopathy associated with leptospirosis has been described. In an animal study, Leptospira infected hamsters had a prolonged PT, APTT, and a thrombin time in all organ extracts, especially in the lung and the liver, probably due to interference with the prothrombinase complex [34]. Platelet dysfunction, coagulopathy, and thrombocytopenia might be contributing to the increased bleeding observed in leptospirosis.…”

Virulent Leptospira interrogans Induce Cytotoxic Effects in Human Platelets in vitro Through Direct Interactions

“…In the presence of soluble factors in the plasma (PRP), the leptospires and platelets appear to form clusters or microaggregates. We speculate that soluble plasma factors might protect platelets from detachment and that the Leptospira -platelet microaggregates might be the result of fibrin generation, as these bacteria activate the coagulation cascade by various platelet-independent mechanisms in vitro ( Vieira et al, 2016 , 2017 , 2020 ). Microaggregation of platelets treated with leptospires was not observed in the flow cytometry studies because platelets were diluted and not under stirring conditions to avoid contact (and aggregation).…”

Weil’s disease with haemoptysis and acute respiratory distress syndrome

“…PLTs dysfunction caused by increased binding with von Willebrand factor and fibrinogen, is another possible mechanism of haemorrhagic diathesis in patients with leptospirosis 46. In experimental models, Leptospira infection disturbs normal coagulation through X-like and thrombin-like factor increased activity, which is accelerated in the prothrombinase complex 47. Increased production of the pro-inflammatory mediator bradykinin and pro-coagulant microvesicles activate both extrinsic and intrinsic coagulation cascades 48…”