Pathogenesis of Two Faces of DVT: New Identity of Venous Thromboembolism as Combined Micro-Macrothrombosis via Unifying Mechanism Based on “Two-Path Unifying Theory” of Hemostasis and “Two-Activation Theory of the Endothelium”

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  Figure 1. Normal hemostasis based on “two-path unifying theory” (updated and reproduced with permission from Walters Kluwer Health, Inc., and Chang JC: Blood Coagul Fibrinolysis 2018; 29:573-584). 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]. Nature has endowed human with only “one” normal hemostatic system to be available to abrogate hemorrhage. Hemostasis protects humans from accidental bleeding in external bodily injury and provides physiologic wound healing. Additionally, it warns human to avoid unnecessary self-inflicted injury and hostile environmental insults which cause intravascular injury that can lead to deadly thrombotic disorder. This is a true irony of nature—the same hemostatic mechanism not only provides life-saving wound healing, but also can lead to life-threatening thrombosis. In normal hemostasis, there must be two sub-hemostatic paths (ULVWF path and TF path), which have to be unified to make normal physiologic hemostasis to produce macrothrombus. In ECs damage due to disease such as sepsis, only ULVWF path is activated and leads to…

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  Figure 2. Pathogenesis of vEA-VMTD. The pathogenesis of endotheliopathy is established based on the “two-activation theory of the endothelium” and is self-explanatory. In the venous system, the molecular responses triggering exocytosis of ULVWF multimers and FVIII and release of cytokines in endotheliopathy are expected to be the same to arterial system. However, the physiological effects between venous and arterial circulation are very different in their shear stress force, vascular directional flow and role of oxygen delivery as noted in the text. Thus, the clinical phenotype of aEA-VMTD is typically TTP-like syndrome and MODS with consumptive thrombocytopenia, which is clinically serious, but that of vEA-VMTD is “silent” ITP with consumptive thrombocytopenia. In severe sepsis, TTP-like syndrome implies sepsis is complicated by overt “arterial” microthrombosis”, but in mild sepsis, ITP-like syndrome suggests transient “venous” microthrombosis has had occurred and perhaps is continuously being resolved by ADAMTS13. This difference has a very important implication in the understanding of combined micro-macrothrombotic syndromes between gangrene-producing arterial combined…

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  Figure 3. Schematic illustration of cross section of blood vessel histology and hemostatic components (Reproduced and modified with permission from Chang JC. Clin Appl Thromb Hemost 2019 Jan–Dec; 25:1076029619887437) [11]. The blood vessel wall is the site of hemostasis (coagulation) to produce blood clots (hemostatic plug) and to stop hemorrhage in external bodily injury. It is also the site of hemostasis (thrombogenesis) to produce intravascular blood clot (thrombus) in intravascular injury that causes thrombosis. Its histologic components are divided into the endothelium, tunica intima, tunica media and tunica externa, and each component has its function contributing to molecular hemostasis. As illustrated, ECs damage triggers exocytosis of ULVWF and SET damage promotes the release of sTF from tunica intima, tunica media and tunica externa. EVT damage releases of eTF from the outside of blood vessel wall. This depth of blood vessel injury contributes to the genesis of different thrombotic disorders such as microthrombosis, macrothrombosis, fibrin clots/hematoma and thrombo-hemorrhagic clots. This concept is especially important in the understanding of different phenotypes of stroke and…

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  Figure 4. Genesis of two different DVT based on two-path unifying theory of hemostasis in vivo. Contemporary concept for every DVT is macrothrombosis in the venous system composed of blood clots containing fibrin clots, platelets, and NETs as a result of activation of TF-FVIIa complex-initiated coagulation cascade following vascular injury in the venous system. However, the exact mechanism producing macrothrombosis has not been determined, nor is the composition of macrothrombus proven. The “two-path unifying theory” of hemostasis and “two-activation theory of the endothelium” have been able to provide the exact role of major hemostatic components, including ULVWF, platelets, coagulation factors, and various cellular and molecular traps including NETs, in the vascular system. Based on hemostatic theories, two different phenotypes of DVT can be identified by their different pathogenesis and character of thrombosis. The genesis of distal DVT in Figure 4 (a) and that of proximal/central DVT (i.e., VTE) in Figure 4 (b) are summarized and elaborated in the text. Abbreviations: DVT, deep venous thrombosis; ECs, endothelial cells; MMT, micro-macrothrombosis; NETS, neutrophil extracellular traps;…

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  Figure 5. Pathogenesis of venous combined micro-macrothrombosis (Reproduced and modified with permission from Chang JC. Vasc Health Risk Manag. 2021, 17, 273–298) [4]. The Figure is self-explanatory. The pathogenesis of venous combined micro-macrothrombotic syndrome is the same as in arterial combined micro-macrothrombotic syndrome. Both are combined diseases of the underlying EA-VMTD caused by endotheliopathy occurring in sepsis or other illnesses and additional vascular injury caused by in-hospital vascular accesses. However, their clinical phenotypes are very different. In the venous system of sepsis, vEA-VMTD exists as “silent” microthrombi (e.g., ITP-like syndrome) and additional vascular injury produces fibrin meshes (fibrin clots). However, physiologically “silent” microthrombi and fibrin meshes can unify together via macrothrombogenesis and produce the clinical phenotype of proximal/central DVT (i.e., VTE). In the arterial system with different circulatory hemodynamic (i.e., shear stress flow) and physiologic function (i.e., oxygen delivery), “microangiopathic” microthrombi interact fibrin meshes and unify together via macrothrombogenesis at the multiple small arteries. It produces…