Abstract
Simple SummaryDVT is an intravascular blood clotting disorder that can be a life-threatening disease, particularly if it occurs in critically ill patients. Typically, distal DVT develops following a vascular injury associated with incidental trauma commonly involving lower extremities, which is transient and benign condition localized in the lower legs as solitary lesion. However, proximal/central DVT (i.e., venous thromboembolism) typically occurs in association with critical illnesses such as sepsis, diabetes, hypertension, cancer, autoimmune disease and others in the hospitalized patient, especially in the ICU. Recognition of different pathogenesis between distal DVT and proximal/central DVT is critically important because the prognosis is poorer in VTE. Its therapeutic approach should be different from distal DVT. The aim of this review is to identify the pathogenesis of two different types of DVT based on in vivo hemostatic mechanisms, which can explain their distinct phenotypes by clinical characteristics, laboratory data and imaging findings. An appropriate preventive measure can be put into the practice to avoid the onset of VTE. Additionally, should VTE be developed, proper and rational therapeutic regimen based on its pathogenesis can be designed for clinical trials to improve the outcome.Venous thrombosis includes deep venous thrombosis (DVT), venous thromboembolism (VTE), venous microthrombosis and others. Still, the pathogenesis of each venous thrombosis is not clearly established. Currently, isolated distal DVT and multiple proximal/central DVT are considered to be the same macrothrombotic disease affecting the venous system but with varying degree of clinical expression related to its localization and severity. The genesis of two phenotypes of DVT differing in clinical features and prognostic outcome can be identified by their unique hemostatic mechanisms. Two recently proposed hemostatic theories in vivo have clearly defined the character between “microthrombi” and “macrothrombus” in the vascular system. Phenotypic expression of thrombosis depends upon two major variables: (1) depth of vascular wall damage and (2) extent of the injury affecting the vascular tree system. Vascular wall injury limited to endothelial cells (ECs) in sepsis produces “disseminated” microthrombi, but intravascular injury due to trauma extending from ECs to subendothelial tissue (SET) produces “local” macrothrombus. Pathogen-induced sepsis activates the complement system leading to generalized endotheliopathy, which releases ultra large von Willebrand factor (ULVWF) multimers from ECs and promotes ULVWF path of hemostasis. In the venous system, the activated ULVWF path initiates microthrombogenesis to form platelet-ULVWF complexes, which become “microthrombi strings” that produce venous endotheliopathy-associated vascular microthrombotic disease (vEA-VMTD) and immune thrombocytopenic purpura (ITP)-like syndrome. In the arterial system, endotheliopathy produces arterial EA-VMTD (aEA-VMTD) with “life-threatening” thrombotic thrombocytopenic purpura (TTP)-like syndrome. Typically, vEA-VMTD is “silent” unless complicated by additional local venous vascular injury. A local venous vessel trauma without sepsis produces localized macrothrombosis due to activated ULVWF and tissue factor (TF) paths from damaged ECs and SET, which causes distal DVT with good prognosis. However, if a septic patient with “silent” vEA-VMTD is complicated by additional vascular injury from in-hospital vascular accesses, “venous combined micro-macrothrombosis” may develop as VTE via the unifying mechanism of the “two-path unifying theory” of hemostasis. This paradigm shifting pathogenetic difference between distal DVT and proximal/central DVT calls for a reassessment of current therapeutic approaches.
Highlights
Venous thrombosis is typically recognized as “macrothrombosis” involving the veinous vessels of the circulatory system
Distal deep venous thrombosis (DVT) is distinguishable from venous thromboembolism (VTE) by several clinical features (Table 1); first, it is usually diagnosed in the outpatient setting, but VTE often occurs and is diagnosed in the hospitalized and critically ill patients; second, it is small, solitary and localized disorder without inflammation, but VTE tends to be large and multiple lesions with local extension and commonly is associated with inflammation such as fever, chills and pain supporting the involvement of inflammatory pathway (Figure 2); third, it occurs typically without underlying disease, but VTE occurs with preexisting vascular disease such as septic endotheliopathy, hypertension, diabetes, polytrauma, autoimmune disease or cancer
When we look back the medical literature, vaccine-induced thrombocytopenia with thrombosis was mostly resulted in cerebral venous sinus thrombosis (CVST) but without direct implication to VTE
Summary
Venous thrombosis is typically recognized as “macrothrombosis” involving the veinous vessels of the circulatory system. Note: APL, acute promyelocytic leukemia; ANF, acute necrotizing fasciitis; AT arterial thrombosis; VCCS, venous circulatory congestion syndrome; CVST, cerebral venous sinus thrombosis; “DIC”, “false” disseminated intravascular coagulation; DVT, deep vein thrombosis; EA-VMTD, endotheliopathy-associated vascular microthrombotic diseases; ECs, endothelial cells; EVT, extravascular tissue; ITP, immune thrombocytopenic purpura; IVCT, inferior vena cava thrombosis; MODS, multiorgan dysfunction syndrome; PDIS, peripheral digit ischemic syndrome; PT, pulmonary thrombosis; PTE, pulmonary thromboembolism; SET, subendothelial tissue; SPG, symmetrical peripheral gangrene; TTP, thrombotic thrombocytopenic purpura; VTE, venous thromboembolism; a indicates extravascular blood clots The concept of this theory is derived from physiological changes of vascular wall damage in vascular model of in vivo hemostasis based on three hemostatic fundamentals [11].
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