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.

Keywords: Anti-microthrombotic therapy; C5b-9 (membrane attack complex [MAC]); Disseminated intravascular coagulation (“DIC”, ill-founded DIC); Disseminated intravascular microthrombosis (DIT); Endotheliopathy; Microthrombogenesis; Multiorgan dysfunction syndrome (MODS); TTP-like syndrome; Therapeutic plasma exchange (TPE); Unusually large von Willebrand factor multimers (ULVWF); Vascular microthrombotic disease (VMTD).

Fig. 1

Physiological and pathological response mechanisms in sepsis. In sepsis, host response is characterized by two mechanisms. One is physiologic defensive mechanism through immune system, and the other is pathologic destructive mechanism through endothelial system. The physiologic response and pathologic clinical syndromes are notated in the Figure. Now, we know that complement system, protecting the host through innate immune system, could trigger harmful endothelial pathogenesis. This dual role of the complement must be nature’s rule just like normal hemostasis, which protects human lives in external bodily injury, but also may harm human lives in intravascular injury through thrombogenesis. Abbreviations: APC antigen presenting cell, “DIC” disseminated intravascular coagulation, DIT disseminated intravascular microthrombosis, EA-VMTD endotheliopathy-associated vascular microthrombotic disease, MAHA microangiopathic hemolytic anemia, MODS multiorgan dysfunction syndrome, MOF multiorgan failure, NO nitric oxide, IF interferon, IL interleukin, LPS lipopolysaccharide, SIRS systemic inflammatory response syndrome, TNF tumor necrosis factor, TTP thrombotic thrombocytopenic purpura

Fig. 2

Three different paths of thrombogenesis that can occur within normal hemostasis. (Reproduced and updated with permission from Chang JC. Blood Coagul Fibrinoplysis. 2018; 29:573–84). Two different thrombotic paths, microthrombotic (ULVWF) and fibrinogenic (TF), are initiated in normal hemostasis, but later the two paths must unify to conclude normal hemostasis with passive role of NETs; it stops the bleeding in external bodily injury and produce the thrombosis in intravascular injury. However, in the different level (depth) of intravascular injury, thrombogenesis takes two different paths. If the level of intravascular injury is confined to the endothelium, lone ULVWF path become activated and causes microthrombosis (i.e., VMTD) because TF path is not activated. On the other hand, if the level of intravascular injury extends from the endothelium to SET/EVT, TF path becomes also activated and causes macrothrombosis (e.g., DVT). In one theoretical situation, if only SET/EVT is injured, available TF is supposed to activate TF path, but in reality this injury does not cause thrombosis without breached endothelium. However, in pathologic hemostasis, aberrant TF activation occurs and produces fibrin clots (i.e., true DIC) in APL due to TF expression in intravascular space from leukemic promyelocytes. APL is a consumption coagulopathy due to lone activation of TF path. This logic is based on “two-path unifying theory”. Please see Figure 2, showing 3 different thrombosis disorders via microthrombogenesis, fibrinogenesis, macrothrombogenesis, which are annotated in bold face. Each thrombognesis occurs when ULVWF path, TF path or combined paths are activated depending upon the levels of damage in intravascular injury (endothelium and SET/EVT). The characters of microthrombi, fibrin clots and macrothrombus from different paths are very different and produce distinctly different clinical thrombotic disorders [20]. Abbreviations: APL acute promyelocytic leukemia, DIC disseminated intravascular coagulation, DVT deep vein thrombosis, EVT extravascular tissue, NET neutrophil extracellular traps, SET subendothelial tissue, TF tissue factor, ULVWF unusually large von Willebrand factor multimers, VMTD vascular microthrombotic disease

Fig. 3

Endothelial molecular pathogenesis and microthrombogenesis in sepsis. (Based on “two-activation theory of the endothelium”). (Reproduced and modified from Thrombosis Journal 2018;16:20). Endothelial molecular pathogenesis is succinctly illustrated. Endotheliopathy activates two main pathways. Activation of inflammatory pathway produces cytokines, which main function is the modulation of inflammation, including fever and myalgia. Activation of microthrombotic pathway causes much more deadly septic syndromes via generalized EA-VMTD/DIT. Abbreviations: CNSD central nervous system dysfunction, DIC disseminated intravascular coagulation, DIT disseminated intravascular microthrombosis, EA-VMTD endotheliopathy-associated VMTD, FHF fulminant hepatic failure, MAHA microangiopathic hemolytic anemia, SIRS systemic inflammatory response syndrome, TCIP thrombocytopenia in critically ill patients, TTP thrombotic thrombocytopenic purpura, ULVWF unusually large von Willebrand factor multimers, * cell-mediated immune cells are T lymphocyte, macrophage, monocyte, neutrophil, and dendritic cell

Fig. 4

Pathogenesis of multiorgan dysfunction syndrome in sepsis-associated vascular microthrombotic disease. The pathogenesis of MODS in sepsis is summarized. Any organ can be involved by VMTD. However, MODS is much more common in vital organs such as the lungs with ARDS, the brain with CNSD, and the kidneys with acute renal failure. The illustration is self-explanatory. Abbreviations: AAI acute adrenal insufficiency, ALF acute liver failure, aHUS atypical hemolytic uremic syndrome, AP acute pancreatitis, ARDS acute respiratory distress syndrome, ARF, acute renal failure, CNSD central nervous system dysfunction, CMVD coronary microvascular disease, FHF fulminant hepatic failure, HCPS hantavirus cardio-pulmonary syndrome, HE hepatic encephalopathy, HPS hantavirus pulmonary syndrome, HRS hepato-renal syndrome, HUS hemolytic-uremic syndrome, NOMI non-occlusive mesenteric ischemia syndrome, PDIS peripheral digit ischemic syndrome, RML rhabdomyolysis, SS, stroke syndrome, TSS toxic and septic shock syndrome, WFS Waterhouse-Friderichsen syndrome

Fig. 5

Pathogenesis of septic shock: acute adrenal insufficiency model. Abbreviations: AAI acute adrenal insufficiency, DIT disseminated intravascular microthrombosis, ECs endothelial cells, MAC membrane attack complex, MAHA microangiopathic hemolytic anemia, MODS multiorgan dysfunction syndrome, TTP thrombotic thrombocytopenic purpura, ULVWF unusually large von Willebrand factor multimers

Fig. 6

Combined micro-macrothrombotic syndrome in EA-VMTD showing well demarcated symmetrical peripheral gangrene. This photo demonstrates peripheral digit ischemic syndrome in a young man with severe meningococcemia who developed classical “DIC” (TTP-like syndrome). Following a surgical procedure. Severe symmetrical well-demarcated dry gangrenes developed in the fingers of both hands. He survived, but lost gangrenous parts of fingers. This syndrome can be explained by combined micro-macrothrombotic syndrome per “two-path unifying theory” as noted in the text