Novel Classification of Thrombotic Disorders Based on Molecular Hemostasis and Thrombogenesis Producing Primary and Secondary Phenotypes of Thrombosis

Abstract

Thrombosis, the common and deadliest disorder among human diseases, develops as a result of the intravascular hemostasis following an intravascular injury, which can be caused by a variety of trauma, non-traumatic insults or clinical illnesses. Thrombosis can occur at any location of the vascular system supplied by blood from the heart to large and smallest arterial and venous systems and may affect the function and anatomy of the organ and tissue. It more commonly occurs in the smaller circulatory system of the vascular tree such as arterioles and capillaries, and venules of the organs, especially in the brain, lungs, heart, pancreas, muscle and kidneys, and sinusoids of the liver. Thrombosis has been referred as the disease of "blood clots", which concept is incompletely defined, but represents many different hemostatic diseases from microthrombosis to fibrin clot disease, macrothrombosis, and combined micro-macrothrombosis. Thrombosis is produced following an intravascular injury via one or more combination of four different mechanisms of thrombogenesis: microthrombogenesis, fibrinogenesis, macrothrombogenesis and micro-macrothrombogenesis initiated by normal physiological hemostasis in vivo. The clinical phenotype expression of thrombosis is determined by: (1) depth of the intravascular wall injury, (2) extent of the injury affecting the vascular tree system, (3) physiological character of the involved vascular system, (4) locality of the vascular injury, and (5) underlying non-hemostatic conditions interacting with hemostasis. Recent acquisition of "two-path unifying theory" of hemostasis and "two-activation theory of the endothelium" has opened a new frontier in science of medicine by identifying the pathophysiological mechanism of different thrombotic disorders and also contributing to the better understanding of many poorly defined human diseases, including different phenotypes of stroke and cardiovascular disease, trauma, sepsis and septic shock, multiorgan dysfunction syndrome, and autoimmune disease, and others. Reviewed are the fundamentals in hemostasis, thrombogenesis and thrombosis based on hemostatic theories, and proposed is a novel classification of thrombotic disorders.

Keywords: combined micro-macrothrombosis; endotheliopathy; fibrin clot disease; fibrinogenesis; hemostasis; macrothrombogenesis; macrothrombosis; microthrombogenesis; microthrombosis; thrombogenesis; thrombosis; vascular microthrombotic disease.

Figure 1

Normal hemostasis in vivo based on “two-path unifying theory” (Reproduced and modified with permission from Chang JC. Thrombosis Journal. 2019;17:10). Following a vascular injury, hemostatic system in vivo activates two independent sub-hemostatic paths: microthrombotic (ULVWF path) and fibrinogenetic (TF path). The former is initiated by the damage of ECs and the latter by that of SET/EVT in external bodily injury and intravascular injury. In activated ULVWF path, ULVWF/FVIII are released and recruit platelets, and produce microthrombi strings via microthrombogenesis, but in activated TF path, TF is released and activates FVII. The TF-FVIIa complex produces fibrin meshes via fibrinogenesis of extrinsic coagulation cascade. The final path of in vivo hemostasis is macrothrombogenesis, in which microthrombi strings and fibrin meshes become unified together with the incorporation of NETs, including red blood cells, neutrophils, DNAs and histones. This unifying event “macrothrombogenesis” promotes the hemostatic plug and wound healing in external bodily injury and produces macrothrombus causing macrothrombosis in intravascular injury. Abbreviations: EA-VMTD, endotheliopathy-associated vascular microthrombotic disease: ECs, endothelial cells; EVT, extravascular tissue; NETs, neutrophil extracellular traps; SET, subendothelial tissue; TF, tissue factor; ULVWF, ultra large von Willebrand factor multimers.

Figure 2

Pathogenesis of endotheliopathy based on “two-activation theory of the endothelium”. Endothelial molecular pathogenesis is initiated by the activated complement system following exposure to pathogen, toxin, drug, poison, venom, vaccine, polytrauma, hyperglycemia, severe hypertension, and others. Endotheliopathy releases inflammatory cytokines and hemostatic factors, and activates two clinically distinctive molecular pathways: inflammatory and microthrombotic. Both arterial endotheliolpathy and venous endotheliopathy provoke inflammation via inflammatory pathway leading to the inflammatory syndrome called MOIS due to cytokines, but arterial endotheliopathy promotes microthrombosis via microthrombotic pathway and produces aEA-VMTD due to activation of ULVWF path of hemostasis (shown in Figure 1). Arterial endotheliopathy is characterized by the triad of consumptive thrombocytopenia, MAHA, and MODS, which is called “TTP-like syndrome”, but venous endotheliopathy is characterized by ITP/“ITP-like syndrome” due to silent microthrombi with consumptive thrombocytopenia as explained in the text. The distinguishing features are caused by different anatomy, physiological function and hemodynamic characteristics between arterial system and venous system. These are very important pathological features in the understanding of the complexity of variable thrombotic phenotypes occurring endotheliopathic syndromes. Abbreviations: EA-VMTD, endotheliopathy-associated vascular microthrombotic disease; ITP, immune thrombocytopenic purpura; MAC, membrane attack complex; IFN, interferon; IL, interleukin; MAHA, microangiopathic hemolytic anemia; MODS, multiorgan dysfunction syndrome; MOIS, multiorgan inflammatory syndrome; TNF, tumor necrosis factor; TTP, thrombotic thrombocytopenic purpura; aEA-VMTD, arterial EA-VMTD; vEA-VMTD, venous EA-VMTD; ULVWF, ultra large von Willebrand factor.

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). The blood vessel wall is the site of hemostasis (coagulation) in vivo to produce blood clots (hemostatic plug) and stop hemorrhage in the external bodily injury. It is also the site of hemostasis (thrombogenesis) to produce intravascular blood clots (thrombus) in the intravascular injury to cause 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 the exocytosis of ULVWF/FVIII and SET damage promotes the release of sTF from the tunica intima, tunica media and tunica externa. EVT damage releases of eTF from the outside of blood vessel wall. This depth of blood vessel wall injury contributes to the genesis of different thrombotic disorders such as microthrombosis, macrothrombosis, fibrin clots, thrombo-hemorrhagic clots and various endotheliopathic syndromes. This concept based on the blood vessel wall model is especially important in the understanding of different phenotypes of stroke and heart attack. Abbreviations: EVT, extravascular tissue; eTF, extravascular tissue factor; SET, subendothelial tissue; sTF, subendothelial tissue factor; RBC, red blood cells; ULVWF, ultra large von Willebrand factor.

Figure 4

Pathogenesis of thrombosis producing its primary and secondary phenotypes based on “two-path unifying theory of hemostasis. Thrombogenesis following an intravascular injury may take two different paths. For example, in sepsis the intravascular injury is limited to ECs but disseminated. The damage releases ULVWF/FVIII and activates ULVWF path (microthrombotic pathway) that produces microthrombi strings, eventually leading to microthrombosis (e.g., aEA-VMTD). However, in a local trauma the intravascular injury is extended from ECs to SET/EVT but localized, which releases TF and small amount of ULVWF/FVIII and activates TF path (traumatic pathway) that produces blood clots composed of fibrin meshes, small amount of ULVWF/FVIII and platelets, and NETs, leading to macrothrombosis (e.g., DVT). Sometimes the septic patient with disseminated microthrombi strings due to endotheliopathy admitted to ICU could also develop another unrelated serious vascular damage to SET/EVT due to an indwelling vascular device in ICU care, which releases TF and promote fibrinogenesis that forms fibrin meshes. In this case, combined micro-macrothrombi composed of ternary components of ULVWF/FVIII, platelets, and fibrin meshes could be formed and lead to combined micro-macrothrombosis shown in the Figure with clinical phenotypes. The thrombosis due to EA-VMTD and another vascular injury is a complex form of micro-macrothrombosis. Their thrombogeneses are logical and has been explained in the text and my previous publications [14,25]. Abbreviations: AAT, aortic arch thrombosis; aEA-VMTD, arterial endotheliopathy-associated vascular microthrombotic disease; AIS, acute ischemic stroke; AMI, acute myocardial infarction; ARDS, acute respiratory distress syndrome; BCS, Budd-Chiari syndrome; DES, diffuse encephalopathic stroke; CVST, cerebral venous sinus thrombosis; DVT, deep venous thrombosis; ECs, Endothelial cells; EVT, extravascular tissue; HERNS, hereditary endotheliopathy, retinopathy, retinopathy and stroke syndromes; HUS, hemolytic-uremic syndrome; ICU, intensive care unit; ITP-LS, ITP-like syndrome; IVCT/SVCT, inferior vena cava thrombosis/superior vena cava thrombosis; MODS, multiorgan dysfunction syndrome; NETs, neutrophil extracellular traps; PDIS, peripheral digit ischemic syndrome; PNH, paroxysmal nocturnal hemoglobinuria; PT, pulmonary thrombosis; PTE, pulmonary thromboembolism; PVT, portal vein thrombosis; RAT, renal artery thrombosis; SET, subendothelial tissue; SOS, sinus obstruction syndrome; SPG, symmetrical peripheral gangrene; SVT, splanchnic vein thrombosis; TF, tissue factor; TIA, transient ischemic attack; TTP-LS, TTP-like syndrome; ULVWF, ultra large von Willebrand factor; VOD, veno-occlusive disease; VTE, venous thromboembolism.

Figure 5

Pathogenesis of multiple thrombotic disorders encountering in COVID-19 sepsis. Unlike other sepsis, including bacterial, viral, fungal, rickettsial and parasitic sepsis, COVID-19 has been highlighted by the mystery of extensive thrombotic diseases, which has included ARDS, DVT, VTE, PTE, complicated gangrene syndromes such as SPG, limb gangrene and acrocyanosis, which pathogeneses are summarized and thrombotic syndromes are exemplified in the bottom section of the Figure even though all of these syndromes have been rarely but previously described in other sepsis as well. This author does not think these thrombotic syndromes are the unique feature of COVID-19 but more likely have occurred as the result of intensive intervention utilizing numerous vascular devices and accesses in ICU following the directive from hyped psychology of political and medical communities in pandemic and also were highlighted by enthusiastic publications of the cases in medical literature. To emphasize the importance of vascular damage contributing to the heightened role inducing thrombogenesis in ICU setting, I have summarized the pathogenesis of several thrombotic syndromes that have occurred in COVID-19 infection. This Figure can be easily applied to other sepsis in place of COVID-19 sepsis. Abbreviations: ANF, acute necrotizing fasciitis; ARDS, acute respiratory distress syndrome; BCS, Budd-Chiari syndrome; CVST, cerebral venous sinus thrombosis; DVT, deep venous thrombosis; ECs, endothelial cells; EVT, extravascular tissue; ICU, intensive care unit; ITP, immune thrombocytopenic purpura; IVCT/SVCT, inferior vena cava thrombosis/superior vena cava thrombosis; MAHA, microangiopathic hemolytic anemia; MODS, multiorgan dysfuncion syndrome; MMT, micromacrothrombosis; MVT, mesenteric vein thrombosis; PTE, pulmonary thromboembolism; PVT, portal vein thrombosis; SET, subendothelial tissue; SPG, symmetrical peripheral gangrene; SVT, splanchnic vein thrombosis; TF, tissue factor; TTP, thrombotic thrombocytopenic purpura; ULVWF, ultra large von Willebrand factor; aEA-VMTD, arterial endotheliopathy-asasociated vascular microthrombotic disdase; vEA-VMTD, venous EA-VMTD; VCCS, venous circulatory congestion syndrome; VTE, venous throm-boembolism.