Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on “Two-Activation Theory of the Endothelium” and “Two-Path Unifying Theory” of Hemostasis
Abstract
:1. Introduction
2. Genesis of Endotheliopathy
2.1. Causes of Endotheliopathy
2.1.1. Complement System
2.1.2. Endothelial Molecular Pathogenesis
2.2. Genesis of Clinical Phenotypes in Endotheliopathy
2.2.1. Hemostasis Based on the Blood-Vessel Model
2.2.2. Vascular Injury Provoking Thrombosis
- The well-known role of ULVWF from ECs in the early phase of hemostasis in external bodily injury;
- The lack of participation of TF in hemostasis producing septic microthrombosis [4];
- TF unavailable in the EC injury but available from the SET/EVT in local bleeding vascular injury;
- Distinctly different disseminated microthrombosis occurring in the microvasculature in sepsis compared with localized macrothrombosis formed after fibrin clots occurring in a local large-vessel injury;
- The irrefutable hemostatic fundamental: “The hemostasis and thrombogenesis can be activated only by a vascular injury”.
- Damaged ECs from the blood-vessel wall following a vascular injury release ULVWF/FVIII in partnership, which are the essential components, along with platelets, in the formation of microthrombi strings. The process of ULVWF interacting with platelets is called “microthrombogenesis”;
- Damaged SET from the blood-vessel wall following a local vascular injury releases TF into circulation, which activates FVIIa and leads to the formation of fibrin clots via the extrinsic cascade with the sequential activation of FIX, FX, FV, FII, and fibrinogen to fibrin. The process is called “fibrinogenesis”;
- A local traumatic vascular injury involving ECs and SET produces both microthrombi strings and fibrin clots. The proposed theory is that the forming process of macrothrombosis must be the result of the “unifying mechanism of microthrombi strings and fibrin meshes”. This process is called “macrothrombogenesis”, in which neutrophil extracellular traps (NETosis) passively participate;
- The understanding of this unifying mechanism is very important in the understanding of arterial and venous combined micro–macrothrombosis, which is a process that should be called micro–macrothrombogenesis.
3. Endotheliopathic Syndromes
3.1. Consumptive Thrombocytopenia
3.2. Arterial Endotheliopathy vs. Venous Endotheliopathy
3.3. TTP-like Syndrome and ITP-like Syndrome
- TTP-like syndrome and ITP-like syndrome (e.g., most cases of ITP) are associated with thrombocytopenia, complement activation [45,46,47], and elevated VWF antigen/FVIII and ADAMTS13 insufficiency [10,48,49,50,51,52]. Interpretation: These changes are consistent with the activated complement system promoting endotheliopathy that leads to the exocytosis of ULVWF/FVIII, consumptive thrombocytopenia, and microthrombosis. However, microthrombosis occurs in the microvasculature in arterial endotheliopathy, as seen in TTP-like syndrome (i.e., aEA-VMTD), but it is commonly “silent” in venous circulation, as seen in ITP-like syndrome in venous endotheliopathy (i.e., vEA-VMTD);
- Despite thrombocytopenia, both are associated with the thrombophilic state [53,54,55,56]. Interpretation: TTP-like syndrome is already in the “microthrombotic state” within the microvasculature, and ITP-like syndrome is likely in “silent” microthrombotic state because the microthrombosis occurring in the venous system does not produce MAHA and MODS. However, acute venous thromboembolism (VTE), which is venous combined micro–macrothrombosis, can develop in ITP-like syndrome if additional venous vascular injury occurs, and especially in the intensive care unit (ICU) [14];
- Both have shown a beneficial response to therapeutic plasma exchange (TPE), intravenous immunoglobulins (IVIG), and rituximab [57,58,59,60,61,62,63,64]. Interpretation: The therapeutic benefit of these plasma therapies and anti-immune therapy suggests that both aEA-VMTD (TTP-like syndrome) and vEA-VMTD (ITP-like syndrome) share the same pathogenesis due to activated complement-associated endothewliopathy.
3.4. Endotheliopathic Inflammatory Syndromes
- Organ-designated endotheliitis, which is called multiorgan inflammatory syndrome (MOIS) [13] (e.g., myocarditis, pericarditis, encephalitis, pneumonitis, thyroiditis, hepatitis, nephritis, pancreatitis, adrenalitis, myositis, lymphadenitis, and others);
- Systemic inflammatory response syndrome (SIRS) [6];
- Cytokine storm/cytokine release syndrome [65];
- Multisystem inflammatory syndrome in child (MIS-C) [66];
- Multisystem inflammatory syndrome in adult (MIS-A) [67];
- Kawasaki disease [68];
- Polyarteritis nodosa [69];
- Acute necrotizing fasciitis [70];
- Thromboangiitis obliterans [71];
- Localized endothelial inflammatory syndromes (e.g., Sjogren’s syndrome, temporal arteritis, Crohn’s disease, Grave’s diseases, Hashimoto’s thyroiditis, Alzheimer’s disease, amyotrophic lateral sclerosis, myasthenia gravis, diabetic endotheliitis, rheumatoid endotheliitis, and others);
- Focal, local, regional, or disseminated endotheliitis/angiitis/vasculitis;
- Angiodysplasia/hemangiomatosis/telangiectasia/atrio-venous malformation.
3.5. Endotheliopathy-Associated Vascular Microthrombotic Disease
3.5.1. Examples of “Suspected” or Proven Endotheliopathy-Associated Microthrombotic Syndromes
Focal, Multifocal, Local, or Regional EA-VMTD [11,12]
- Hereditary disease in early life
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- Hereditary hemorrhagic telangiectasia/Osler–Weber–Rendu syndrome;
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- Capillary arterio-venous malformation syndrome;
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- Hereditary neurocutaneous hemangiomatosis;
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- Hereditary endotheliopathy, retinopathy, nephropathy and stroke (HERNS) syndrome;
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- Kasabach–Merritt syndrome with kaposiform hemangioendothelioma;
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- Fabry disease with endothelial dysfunction due to α-galactosidase A deficiency;
- Acquired disease in later life
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- Susac syndrome with encephalopathy, retinopathy, and audiopathy;
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- Vascular dementia due to multifocal endotheliopathy associated with cognitive dysfunction;
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- Retinal microaneurysm in diabetes;
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- Degos disease associated with skin papules [75];
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- Henoch–Shoenlein purpura with subcutaneous hemorrhage and renal failure [76];
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- Heyde’s syndrome associated with aortic stenosis and intestinal angiodysplasia [77];
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- Critical-illness-associated endotheliopathy;
- Sepsis-associated endotheliopathy (e.g., pathogens, including bacteria, viruses, fungi, rickettsia, and parasites) [6];
- Chemical-/toxin-associated endotheliopathy (e.g., drug, toxin, vaccine, poison, and venom);
- Pregnancy-associated endotheliopathy (e.g., gestational thrombocytopenia; hemolysis, elevated liver enzymes, low platelets [HELLP] syndrome; preeclampsia; abruptio placenta; placenta previa; amniotic fluid embolism; dead fetus syndrome);
- Cancer-associated endotheliopathy (e.g., breasts, stomach, and lungs);
- Polytrauma-associated endotheliopathy (e.g., car accident);
- Transplant-associated endotheliopathy (e.g., kidneys, heart, bone marrow, and stem cells) [83];
- Autoimmune disease-associated endotheliopathy (e.g., systemic lupus erythematosus (SLE) [84];
- Diabetic endotheliopathy due to plasma glycated CD59.
Organ/Multiorgan Dysfunction Syndromes
- Reye’s syndrome with possible hepatic encephalopathy with MODS [85];
- Transfusion-related acute lung injury (TRALI) (possible consumptive thrombocytopenia-associated pulmonary artery endotheliopathy causing ARDS) [86];
- Subacute bacterial endocarditis (SBE) (consistent with inflammatory syndrome and microthrombosis due to endotheliopathy) [87];
- Veno-occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) consistent with hepatic venous endotheliopathy [88];
- Microvascular myocardial infarction (MVMI) due to diffuse microvascular microthrombosis [89];
- Acute necrotizing pancreatitis, often with arterial endotheliopathy [92];
- Waterhouse–Friderichsen syndrome due to adrenal microvascular microthrombosis and hemorrhage [93];
- Acute renal failure (ARF)/hemolytic-uremic syndrome (HUS) [94];
- Goodpasture syndrome with pulmonary renal syndrome with ADAMTS13 insufficiency [95];
- Idiopathic pulmonary hypertension with pulmonary arterial endotheliopathy and microtubule dysfunction [98];
- Primary biliary cirrhosis with endothelial transformation;
- Felty syndrome with the overexpression of VWF (?);
- EA-VMTD with hepatic coagulopathy (old term: “acute DIC”) [8];
- Paroxysmal nocturnal hemoglobinuria;
- Combined organ syndromes with recognized terms (e.g., hepatorenal syndrome, hepatic encephalopathy, cardio-pulmonary syndrome, pulmonary encephalopathy, pulmonary-renal syndrome, and cardio-renal syndrome);
- MODS [6].
Systemic Syndromes
- TTP-like syndrome (consistent with arterial EA-VMTD) [5];
- Systemic lupus erythematosus (SLE) (consistent with inflammatory cutaneous endotheliopathy and MODS associated with EA-VMTD) [101];
- Kawasaki disease (consistent with inflammatory and lymphocutaneous syndrome in vaccine-induced venous endotheliopathy, and rarely with arterial endotheliopathy) [103];
- Malignant hypertension with hypertensive encephalopathy [104];
Combined Micro–Macrothrombotic Syndromes [6,10,13,14]
- Peripheral gangrene syndromes associated with arterial endotheliopathy and additional in-hospital arterial vascular injury (e.g., symmetrical peripheral gangrene (SPG), Fournier’s disease, Buerger’s disease, gas gangrene, diabetic gangrene, acute necrotizing fasciitis, Raynaud’s phenomenon, “coumadin”-associated gangrene syndrome, and envenomation syndrome);
3.5.2. Pathogenesis of Combined Micro–Macrothrombotic Syndromes [10,13,14]
3.5.3. What Should We Have to Know about the Pathogenesis of EA-VMTD?
- EA-VMTD is a hemostatic disease caused by the activation of ULVWF path of hemostasis;
- It is characterized by increased ULVWF/VWF/VWF antigen expression and increased FVIII activity due to the release from damaged ECs;
- It is associated with platelet consumption and the formation of microthrombi strings, and it may trigger microvascular hemolysis due to the increased shear-stress effect on the red cells, and especially in the arterial system (i.e., MAHA);
- It is often associated with the insufficiency of the ULVWF-cleaving enzyme ADAMTS13 secondary to its gene mutation or polymorphism, or excessive exocytosis of ULVWF over the cleaving capacity of ADAMTS13 in the endothelial damage;
- EA-VMTD orchestrates MODS, such as encephalopathy, ARDS, MVMI, acute necrotizing pancreatitis, rhabdomyolysis, hepatic dysfunction, acute renal failure, and sometimes multifocal microvascular microthrombosis with clinically significant phenotypes, such syndromes as retinal microaneurysm, TIA, Heyde’s syndrome, HERNS syndrome, and Susac syndrome.
3.6. Epiphenomenon
3.6.1. Positive Anti-PF4 Antibodies and Anti-PL Antibodies
3.6.2. Endothelial Epiphenomenon
4. Practical Diagnostic Criteria and Diagnostic Perspective for Endotheliopathy
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
References
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Hemostasis | Coagulation | Thrombosis | |
---|---|---|---|
Term concept | Philosophical | Physiological | Structural |
Implied meaning | Natural process in vivo | Artificial process in vitro Physiologic process at bleeding site | Pathological process in vivo |
Involved site | Blood-vessel wall | Test tube Extravascular trauma to vessel wall | Intravascular lumen |
Products | Hemostatic plug | Fibrin mesh/fibrin clot * | Microthrombi/macrothrombi |
Critical role | Vascular-wall injury | Coagulation test Hemorrhage | Physiologic thrombogenesis |
Components | Endothelium SET EVT Blood in circulation | TF/thromboplastin Coagulation proteins/serine proteases | ULVWF/FVIII from ECs Platelets+ from circulation Coagulation proteins/serine proteases TF from SET/EVT |
Phenotypes | Determined by the level of vascular damage | Determined by participating coagulation factors | Determined by ULVWF, platelets, TF, hemostatic factors, and unifying mechanism |
Inciting example | Endotheliopathy Vascular injury | Coagulation tests for PT and aPTT | VMTD/MODS due to microthrombosis EA-VMTD: TTP-like syndrome: “DIC” Arterial macrothrombosis VTE Combined micro–macrothrombosis |
(1) Hemostatic Principles | ||
| ||
(2) Major Participating Components | ||
Components | Origin | Mechanism |
(1) ECs/SET/EVT | Blood-vessel wall/EVT | Protective barrier |
(2) ULVWF | ECs | Endothelial exocytosis/anchoring and microthrombogenesis |
(3) Platelets | Circulation | Adhesion to ULVWF strings/assembling and microthrombogenesis |
(4) TF | SET and EVT | Release from tissue due to vascular injury/leading and fibrinogenesis |
(5) Coagulation factors | Circulation | Activation of coagulation factors/forming and macrothrombogenesis |
(3) Vascular Injury and Hemostatic Phenotypes | ||
Injury-Induced Damage | Involved Hemostatic Path | Level of Vascular Injury and Examples |
(1) Endothelium | ULVWF | Level 1 damage—microthrombosis (e.g., TIA [focal]; Heyde’s syndrome [local); EA-VMTD [disseminated]) |
(2) Endothelium/SET | ULVWF + sTF | Level 2 damage—macrothrombosis (e.g., AIS; DVT; PTE; AA) |
(3) Endothelium/SET/EVT | ULVWF + eTF | Level 3 damage—macrothrombosis with hemorrhage (e.g., THS; THMI) |
(4) EVT alone | eTF | Level e damage—fibrin clot disease (e.g., AHS (e.g., SDH; EDH); ICH; organ/tissue hematoma) |
Hemostatic Phenotypes | Causes | Genesis |
(1) Hemorrhage | External bodily injury | Trauma-induced external bleeding (e.g., accident; assault; self-inflicted injury) |
(2) Hematoma | Internal EVT injury | Obtuse trauma-induced bleeding (e.g., tissue and cavitary hematoma; hemarthrosis) |
(3) Thrombosis | Intravascular injury | Intravascular injury (e.g., atherosclerosis; diabetes; indwelling venous catheter; surgery; vascular access) |
Thrombosis Mechanism | Microthrombogenesis | Fibrinogenesis | Macrothrombogenesis |
---|---|---|---|
Utilizing hemostatic path | ULVWF path | TF path | Combined ULVWF and TF path |
Examples | Sepsis (bacterial, viral, fungal, rickettsial, parasitic) Polytrauma, surgery, transplant Toxin, drug, venom, vaccine Pregnancy Diseases (autoimmune, cancer, diabetes) | APL SDH EDH | DVT (distal) VTE (central DVT/PTE) Arterial thrombosis Peripheral gangrene |
Thrombosis character | Microthrombi strings | Fibrin clots | Macrothrombus Combined micro–macrothrombi |
Vascular lesion and phenotype example | Focal—retinal microaneurysm Local—hepatic VOD Multifocal—HERNS, Susac syndrome Disseminated—EA-VMTD/MODS | Disseminated—true DIC | Local—distal DVT, arterial thrombosis, AIS |
Complex vascular/ hematologic phenotypes | Venous—venous microthrombi (ITP-like syndrome) Arterial—arterial microthrombi (TTP-like syndrome, MODS) | Venous/arterial—DIC (fibrin clot disease) | Combined micro–macrothrombosis Venous—VTE, PTE, CVST Arterial—SPG, limb gangrene |
Clinical Phenotype | Arterial Endotheliopathy | Venous Endotheliopathy |
---|---|---|
Underlying pathology | aEA-VMTD | vEA-VMTD |
Physiological/hemodynamic difference | Efferent circulation from the heart (oxygen delivery) High-pressure flow High shear stress Capillary and arteriolar microvascular events | Afferent circulation into the heart (CO2 disposal) Low-pressure flow Low shear stress Venous and pulmonary microvascular events |
Primary cause | ||
Vascular injury (ECs) | Sepsis-induced arterial microvascular endotheliopathy | Sepsis-induced venous endotheliopathy Vaccine-induced venous endotheliopathy |
Vascular pathology site | Disseminated aEA-VMTD at the microvasculature | Transient or “silent” vEA-VMTD at the venous system |
Activated hemostatic path | ULVWF path | ULVWF path |
Thrombosis component | Microthrombi strings in the microvasculature | Microthrombi strings in the venous system |
Microthrombotic event | Disseminated VMTD | Silent microthrombosis with efficient (?) microthrombolysis |
Clinical phenotypes | TTP-like syndrome
| ITP-like syndrome
|
Clinical Features
|
Laboratory and Molecular Features
|
Diagnostic Blood Tests
|
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Chang, J.C. Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on “Two-Activation Theory of the Endothelium” and “Two-Path Unifying Theory” of Hemostasis. Medicina 2022, 58, 1311. https://doi.org/10.3390/medicina58091311
Chang JC. Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on “Two-Activation Theory of the Endothelium” and “Two-Path Unifying Theory” of Hemostasis. Medicina. 2022; 58(9):1311. https://doi.org/10.3390/medicina58091311
Chicago/Turabian StyleChang, Jae C. 2022. "Molecular Pathogenesis of Endotheliopathy and Endotheliopathic Syndromes, Leading to Inflammation and Microthrombosis, and Various Hemostatic Clinical Phenotypes Based on “Two-Activation Theory of the Endothelium” and “Two-Path Unifying Theory” of Hemostasis" Medicina 58, no. 9: 1311. https://doi.org/10.3390/medicina58091311