Disseminated intravascular coagulation: new identity as endotheliopathy-associated vascular microthrombotic disease based on in vivo hemostasis and endothelial molecular pathogenesis

Abstract

Disseminated intravascular coagulation (DIC) can be correctly redefined as disseminated intravascular microthrombosis based on "two-path unifying theory" of in vivo hemostasis. "DIC" is a form of vascular microthrombotic disease characterized by "microthrombi" composed of platelets and unusually large von Willebrand factor multimers (ULVWF). Microthrombotic disease includes not only "DIC", but also microthrombosis occurring in thrombotic thrombocytopenic purpura (TTP), TTP-like syndrome, and focal, multifocal and localized microthrombosis. Being a hemostatic disease, microthrombotic disease occurs as a result of lone activation of ULVWF path via partial in vivo hemostasis. In endothelial injury associated with critical illnesses such as sepsis, the vascular damage is limited to the endothelial cell and activates ULVWF path. In contrast, in intravascular traumatic injury, the local damage may extend from the endothelial cell to subendothelial tissue and sometimes beyond, and activates both ULVWF and tissue factor (TF) paths. When endotheliopathy triggers exocytosis of ULVWF and recruits platelets, ULVWF path is activated and promotes microthrombogenesis to produce microthrombi composed of microthrombi strings, but when localized vascular damage causes endothelial and subendothelial tissue damage, both ULVWF and TF paths are activated and promote macrothrombogenesis to produce macrothrombus made of complete "blood clots". Currently, "DIC" concept is ascribed to activated TF path leading to fibrin clots. Instead, it should be correctly redefined as microthrombosis caused by activation of ULVWF path, leading to endotheliopathy-associated microthrombosis. The correct term for acute "DIC" is disseminated microthrombosis-associated hepatic coagulopathy, and that for chronic "DIC" is disseminated microthrombosis without hepatic coagulopathy. TTP-like syndrome is hematologic phenotype of endotheliopathy-associated microthrombosis. This correct concept of "DIC" is identified from novel theory of "in vivo hemostasis", which now can solve every mystery associated with "DIC" and other associated thrombotic disorders. Thus, sepsis-associated coagulopathy is not "DIC", but is endotheliopathy-associated vascular microthrombotic disease.

Keywords: Disseminated intravascular coagulation; Disseminated intravascular microthrombosis; Endotheliopathy; Fibrin clots; Fibrinogenesis; Hemostasis; Hepatic coagulopathy; Macrothrombogenesis; Microthrombogenesis; TTP-like syndrome; Thrombosis; Thrombotic thrombocytopenic purpura; Vascular microthrombotic disease.

Fig. 1

Endothelial molecular pathogenesis of “DIC” (EA-VMTD). The molecular events of “DIC”, which is endotheliopathy-associated VMTD (i.e., TTP-like syndrome) with many associated clinical organ syndromes, can be explained by expanded ULVWF path as illustrated in the following “two-activation theory of the endothelium”. For example, in sepsis complement activation occurs and attacks pathogen as a part of innate immune response. In addition to lysis of pathogen by the terminal product C5b-9, it also may induce ECs damage and endothelial dysfunction to the host if endothelial membrane is unprotected by CD59. Endotheliopathy mediates both inflammatory pathway and microthrombotic pathway. Activated inflammatory pathway promotes inflammation and activated microthrombotic pathway triggers microthrombogenesis leading to EA-VMTD if ADAMTS13 is insufficient due to unbalanced excess of ULVWF from endothelial exocytosis or due to partial ADAMTS13 deficiency from heterozygous gene mutation of ADAMTS13 gene. EA-VMTD orchestrates thrombocytopenia, MAHA, and MODS, which are the clinical features of TTP-like syndrome/“DIC”. Abbreviations: AI, adrenal insufficiency; ALF, acute liver failure; ANP, acute necrotizing pancreatitis; ARDS, acute respiratory distress syndrome; ARF, acute renal failure; “DIC”, false disseminated intravascular coagulation; DES, diffuse encephalopathic stroke; DMI, diffuse myocardial infarction; EA-VMTD, endotheliopathy-associated VMTD; DIT, disseminated intravascular microthrombosis; ECs, endothelial cells; FHF, fulminant hepatic failure; HELLPs, hemolysis - elevated liver enzymes - low platelet syndrome; MAHA, microangiopathic hemolytic anemia; SIRS, systemic inflammatory response syndrome; MODS, multiorgan dysfunction syndrome; SS, septic shock; TTP, thrombotic thrombocytopenic purpura; ULVWF, unusually large von Willebrand factor multimers

Fig. 2

a Normal hemostasis based on “two-path unifying theory”. (Updated and reproduced with permission from Walters Kluwer Health, Inc., and Chang JC: Blood coagulation Fibrinolysis 2018; 29:573–584). The concept of this theory is derived from physiologic changes associated with the different levels of vascular wall damage in vascular injury as explained in three essentials in normal hemostasis (Table 3). The nature has endowed human with only “one” normal hemostatic system. Hemostasis protects lives from unnecessary bleeding in external bodily injury and aids in self-wound healing. It also warns human to avoid unnecessary self-inflicted injury and hostile environmental insult that can cause intravascular injury leading to deadly thrombotic disorders. This is true irony of nature that exactly same normal hemostasis not only provides wound healing but also can lead to life-threatening thrombosis. As explained in the text, two sub-hemostatic paths (ULVWF and TF) are initiated in vascular injury, which have to be unified to lead to normal blood clotting in external bodily injury and trigger macrothrombus in intravascular injury. In a certain disease (e.g., sepsis), only ULVWF path is activated as seen in “DIC”, and in another disease (e.g., APL), only TF path is activated as seen in true “DIC”. The former produces EA-VMTD and the latter produces fibrin clot disease. If both paths were activated simultaneously in local traumatic vascular injury, the unifying process of two hemostatic paths is called macrothrombogenesis, which produce macrothrombus. These three paths of thrombogeneses are explained in the text [3, 4]. Abbreviations: APL, acute promyelocytic leukemia; “DIC”, false disseminated intravascular coagulation; EA-VMTD, endotheliopathy-associated vascular microthrombotic disease; EVT, extravascular tissue; SET, subendothelial tissue; NETs, neutrophil extracellular traps; TF, tissue factor; ULVWF, unusually large von Willerand factor multimers. b Three paths to thrombogenesis based on “two-path unifying theory”. (Reproduced with permission from Walters Kluwer Health, Inc., and Chang JC: Blood coagulation Fibrinolysis 2018; 29:585–595). Figure 2b illustrates three different thrombogenetic paths in “two-path unifying theory of hemostasis” (microthrombogenesis, fibrinogenesis and macrothrombogenesis) to form respective blood clots. Each pathogenesis occurs when ULVWF path, TF path or combined path is utilized depending upon the levels of vascular wall damage following intravascular injury (ECs, SET, and EVT). The characters of the thrombi/fibrin clots from different paths are very different and produce distinctly different clinical phenotypic thrombotic disorders. In “DIC”, microthrombogenesis occurs due to lone activation of ULVWF path and leads to EA-VMTD, which hematologic phenotype is TTP-likes syndrome. Abbreviations: “DIC”, false disseminated intravascular coagulation; EA-VMTD, endotheliopathy-associated vascular microthrombotic disease; ECs, endothelial cells; EVT, extravascular tissue; SET, subendothelial tissue; NETs, neutrophil extracellular traps; TF, tissue factor; ULVWF, unusually large von Willebrand factor multimers

Fig. 3

Schematic illustration of cross section of blood vessel and hemostatic components. (Reproduced and modified with permission from Chang JC. Clin Appl Thromb Hemost 2019 Jan-Dec; 25:1076029619887437). The most important part in the understanding of hemostasis in vivo is cognizance of the histological structure of the blood vessel and its role of vascular physiology in vascular injury. The reason is thrombosis cannot occur without vascular injury as explained in Table 3 and shown in novel “two-path unifying theory” of hemostasis [3, 4]. In intravascular injury, the local damage of ECs causes localized exocytosis of ULVWF to activate ULVWF path and damage extending into SET causes localized release of sTF to activate TF path. Both paths together lead to macrothrombogenesis and produce macrothrombus (e.g., DVT; pulmonary embolism; acute ischemic stroke). Should intravascular trauma extend further into EVT with additional release of eTF and bleed beyond EVT as seen in thrombo-hemorrhagic stroke, it produces macrothrombosis and hemorrhage (i.e., thrombo-hemorrhagic syndrome). Abbreviations: EVT, extravascular tissue; eTF, extravascular tissue factor; SET, subendothelial tissue; sTF, subendothelial tissue factor; RBC, red blood cells; ULVWF, unusually large von Willebrand factor multimers