Thrombocytopenia in critically ill patients due to vascular microthrombotic disease: pathogenesis based on “two activation theory of the endothelium”

The pathogenesis of thrombocytopenia in critically ill patients (TCIP) has not been established yet. Based on "two-activation theory of the endothelium", TCIP is a manifestation of platelet activation and consumption in association with endotheliopathy. Endotheliopathy occurs in many critical illnesses. An injury to vascular endothelial cells (ECs) from pathogen or insult leads to endothelial dysfunction, which initiates the activation of two distinctly independent molecular pathways (i.e., inflammatory and microthrombotic). The activation of inflammatory pathway occurs due to the release of inflammatory cytokines from injured ECs. Inflammatory cytokines mediate inflammation. The activation of microthrombotic pathway is induced by the activation of platelets and endothelial exocytosis of unusually large von Willebrand factor multimers (ULVWF). Activated platelets are recruited by exocytosed ULVWF, which are anchored to ECs, and together assemble microthrombi consisting of platelet-ULVWF complexes. This microthrombogenesis leads to consumptive thrombocytopenia (i.e., TCIP) and disseminated intravascular microthrombosis (DIT). DIT triggers vascular microthrombotic disease (VMTD), which manifestations include hypoxic multi-organ dysfunction syndrome, and thrombotic microangiopathy (TMA). The combined syndrome due to the activation of both inflammatory pathway and microthrombotiic pathway is called systemic inflammatory response syndrome (SIRS). Also, the true nature of "DIC" is endotheliopathy-associated DIT/VMTD (i.e., TTP-like syndrome).