V. vulnificus-infected patients suffer from
hemolytic anemia and circulatory lesions, often accompanied by
venous thrombosis. However, the pathophysiological mechanism of
venous thrombosis associated with V. vulnificus
infection remains largely unknown. Herein, V. vulnificus
infection at the sub-hemolytic level induced shape change of human red blood cells (RBCs) accompanied by
phosphatidylserine exposure, and microvesicle generation, leading to the procoagulant activation of RBCs and ultimately, acquisition of prothrombotic activity. Of note, V. vulnificus exposed to RBCs substantially upregulated the rtxA gene encoding multifunctional autoprocessing repeats-in-toxin (MARTX) toxin. Mutant studies showed that V. vulnificus-induced RBC procoagulant activity was due to the pore forming region of the MARTX toxin causing intracellular Ca2+ influx in RBCs. In a rat
venous thrombosis model triggered by
tissue factor and stasis, the V. vulnificus wild type increased
thrombosis while the ΔrtxA mutant failed to increase
thrombosis, confirming that V. vulnificus induces
thrombosis through the procoagulant activation of RBCs via the mediation of the MARTX toxin.