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

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

“…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.…”

“…5,12 Now, the underlying physiologic alteration of MODS in sepsis and other critical illnesses is identified as circulatory dysfunction occurring as a result of EA-VMTD. [11][12][13] This is an extremely important concept in the understanding for the pathogenesis of MODS as well as ARDS because we now know that the culprit of MODS is DIT, 1,[8][9][10][11][12] which pathogenesis based on "two-activation theory of the endothelium" as shown in Figure 1. 12,13 Clinical and pathological features.…”

“…The pathological features of ARDS are characterized by (1) diffuse alveolar damage associated with injury to alveolar lining and endothelial cells (ECs), (2) exudative pulmonary edema, and (3) hyaline membrane formation. [44][45][46] These pathologic changes are very similar, if not identical, in each ARDS caused by different pathogens and insults, including pneumonia-initiated SARS and MERS.…”

“…Acute respiratory distress syndrome (ARDS) is caused by severe pulmonary vascular dysfunction characterized by acute onset of dyspnea, tachycardia, hypoxemia associated with noncardiogenic pulmonary edema, and systemic inflammation. Although the exact pathophysiologic mechanism causing pulmonary vascular dysfunction has not been determined yet, it is a circulatory dysfunction often associated with moderate thrombocytopenia [1][2][3] and multi-organ dysfunction syndrome (MODS). [4][5][6] Because its pathogenetic mechanism is not clearly recognized, no effective therapeutic agent targeting the underlying pathologic disease has been procured to date.…”

“…8,10 Through the recognition of endothelial molecular pathogenesis, enough evidences have been accumulated that ARDS is one of the phenotypes of MODS occurring as a result of disseminated intravascular microthrombosis (DIT), which is the underlying pathology contributing to endotheliopathy-associated VMTD (EA-VMTD). 1,[9][10][11] The objective of this article is to analyze the clinical, pathological, and hematopathological features of ARDS and to account for involved pathophysiological mechanisms associated with endothelial dysfunction based on two hemostatic theories. In the end, this author will look into potential therapeutic option for the treatment of ARDS according to "theorybased medicine" instead of "evidence-based medicine" since clinical trials for ARDS have completely failed to find an effective therapeutic regimen.…”