Sepsis and septic shock: endothelial molecular pathogenesis associated with vascular microthrombotic disease

Abstract

In addition to protective “immune response”, sepsis is characterized by destructive “endothelial response” of the host, leading to endotheliopathy and its molecular dysfunction. Complement activation generates membrane attack complex (MAC). MAC causes channel formation to the cell membrane of pathogen, leading to death of microorganisms. In the host, MAC also may induce channel formation to innocent bystander endothelial cells (ECs) and ECs cannot be protected. This provokes endotheliopathy, which activates two independent molecular pathways: inflammatory and microthrombotic. Activated inflammatory pathway promotes the release of inflammatory cytokines and triggers inflammation. Activated microthrombotic pathway mediates platelet activation and exocytosis of unusually large von Willebrand factor multimers (ULVWF) from ECs and initiates microthrombogenesis. Excessively released ULVWF become anchored to ECs as long elongated strings and recruit activated platelets to assemble platelet-ULVWF complexes and form “microthrombi”. These microthrombi strings trigger disseminated intravascular microthrombosis (DIT), which is the underlying pathology of endotheliopathy-associated vascular microthrombotic disease (EA-VMTD). Sepsis-induced endotheliopathy promotes inflammation and DIT. Inflammation produces inflammatory response and DIT orchestrates consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome (MODS). Systemic inflammatory response syndrome (SIRS) is a combined phenotype of inflammation and endotheliopathy-associated (EA)-VMTD. Successful therapeutic design for sepsis can be achieved by counteracting the pathologic microthrombogenesis.

Therapeutic plasma exchange in pediatric intensive care: Indications, results and complications

“…ADAMTS‐13 was detected in patients with severe sepsis and systemic inflammatory response syndrome and thus increased attention to TPE in treatment of sepsis . In studies investigating biomarkers in sepsis, there were significant decreases of C‐reactive protein, alfa‐1 antitripsin, and complement factor in plasma concentration of C3 following TPE treatment . There are some studies showing good response to TPE in thrombocytopenia‐associated multiple organ failure .…”

Acute Respiratory Distress Syndrome as an Organ Phenotype of Vascular Microthrombotic Disease: Based on Hemostatic Theory and Endothelial Molecular Pathogenesis

“…Indeed, ARDS is just one phenotype among MODS associated with increased microvascular permeability due to VMTD involving multiorgans. 5,9,12,24,34 This is also true for the current biorgan designation syndromes such as hepatorenal syndrome, cardiopulmonary syndrome, pulmonary-renal syndrome, hepatic encephalopathy, cardiorenal syndrome, and others. It should be emphasized that ARDS is not the cause of MODS, but all the organ phenotypes of MODS as well as ARDS are collateral syndromes provoked by VMTD.…”

“…Regardless, enough evidences have been presented that ARDS is a clinical disorder of pathologic hemostasis associated with activated coagulation system such as DIC. [1][2][3][4][5][8][9][10][11][12] However, this author has placed quotation marks on "DIC" because recent reinterpretation has identified the current concept of "DIC" was ill-founded because it was based on the hemostatic mechanism of activated tissue factor (TF) path, 1,8,9,11,12,28 which will be discussed briefly later in this article. Nonetheless, ARDS is one of the major organ phenotypic disorders among MODS contributing to the death associated with microthrombosis in critically ill patients due to diseases such as sepsis, trauma, and immune disorders.…”

“…According to hemostatic principles (Table 3), blood vessel damage limited to ECs in endotheliopathy Reproduced and modified from Chang. 12 Endothelial molecular pathogenesis of ARDS as one organ phenotype among various MODS is succinctly illustrated. The underlying pathologic nature of ARDS is a hemostatic disease due to endotheliopathy that promotes activation of two molecular pathways.…”

“…8,10,12,13 These two theories are congruous each other since the endothelium contributes to initial hemostasis and triggers molecular mechanism for thrombogenesis. In endotheliopathy, the pathologic nature of inflammation promoting inflammatory response 12 is recognized and the character of "microthrombi" leading to multiple hematologic phenotypes is identified. 9 In addition, the true mechanism of in vivo hemostasis in vascular injury and three different thrombogenetic mechanisms within hemostasis are uncovered.…”