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.

COVID-19 Sepsis: Pathogenesis and Endothelial Molecular Mechanisms Based on “Two-Path Unifying Theory” of Hemostasis and Endotheliopathy-Associated Vascular Microthrombotic Disease, and Proposed Therapeutic Approach with Antimicrothrombotic Therapy

“… 82 , 83 , 90 The result is consistent with key role of the enzyme in the pathogenesis of microthrombogenesis as proposed. 6 , 22 , 23 The laboratory findings have firmly supported the concept that COVID-19 sepsis is a hemostatic disease based on the following laboratory data. Consistently significant findings Normal or mild to moderate thrombocytopenia Uncommon but enough reported cases with MAHA Markedly increased ULVWF/VWF/VWF antigen expression 19 , 83 , 88–90 , 92 , 93 Markedly increased FVIII activity 19 , 90 , 92–95 Activated complement factors 9 , 15 , 16 Mild to moderately decreased activity of ADAMTS13 (25–75% of normal) 82 , 83 , 90 , 96–98 Increased fibrinogen in early stage of EA-VMTD or markedly decreased in advanced stage 30 , 68 , 82 , 84–86 , 88 , 89 Increased FDP(s)/D-dimer 68 , 83–91 , 93 Sometimes, significant abnormal findings Prolonged PT Prolonged aPTT Positive soluble fibrin monomer 68 , 91 …”

“…Finally, a novel “two-path unifying theory” of hemostasis was proposed and updated as shown in Figure 2 . 23 …”

“…This theory represents true hemostasis in vivo 99 and has been updated. 6 , 22 , 23 …”

“…These theories have already established the unique concept of EA-VMTD that is associated with activated unusually large von Willebrand factor (ULVWF) path of hemostasis, which is different from macrothrombosis and coagulopathy occurring as a result of combined activation of ULVWF and tissue factor (TF) paths. 23 The pathogenetic mechanism of macrothrombosis typified by pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) coexisting with ARDS in COVID-19 will be discussed from the concept of the hemostatic fundamentals. In the end, theory-based therapeutic approach will be proposed.…”

Causes of an elevated international normalized ratio in the intensive care unit and the implications for plasma transfusion

“…This is particularly the case with liver disease versus DIC, and patients assigned to the liver disease pattern had much higher levels of D-dimer than the other categories and we were unable to assign an ISTH DIC score. 45 We recognize that current concepts of the pathophysiology of DIC are evolving, 46,47 however, we choose the more traditional concept of Tissue Factor-FVIIa initiation of coagulation for DIC with factor consumption of FV, FVIII, fibrinogen, and ATIII. 47 Although low FV, fibrinogen, and ATIII levels were seen in many samples, the FVIII levels were all over 100% and thus these samples were assigned as a liver disease pattern and implying low hemostatic risk.…”