Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis
Abstract
:1. Introduction
2. Endotheliopathy
3. Thrombocytopenia
4. Thrombosis
- Macrothrombosis includes DVT, VTE, CVST, PTE, splanchnic vein thrombosis (SVT) and Budd-Chiari syndrome, portal vein thrombosis, acute ischemic stroke, acute myocardial infarction, aortic thrombus and renal vein thrombosis, etc.
- Microthrombosis (i.e., VMTD) occurs in TTP, TTP-like syndrome, ARDS, diffuse encephalopathic stroke, microvascular myocardial infarction, hemolytic-uremic syndrome, transient ischemic attack, microaneurysm and thrombosis of retinal artery, MODS, and hepatic veno-occlusive disease.
- Heparin-induced thrombocytopenia with thrombosis syndrome, especially white clot syndrome, is a unique aberrant hemostatic disease without vascular injury.
- Gangrene syndrome associated with arterial combined micro-macrothrombosis includes symmetrical peripheral gangrene (SPG), purpura fulminans, Fournier’s gangrene in acute promyelocytic leukemia (APL), Burger’s disease, diabetic gangrene, Raynaud’s phenomenon, and acute necrotizing fasciitis.
- Fibrin clot disease occurs in APL as aberrant hemostatic disease without vascular injury.
- Acute “disseminated intravascular coagulation (DIC)” is a form of VMTD with hemorrhagic complication.
- Concurrent microthrombosis and macrothrombosis in both arterial and venous systems in paroxysmal nocturnal hemoglobinuria (PNH) is an unresolved disease yet.
5. Cerebral Venous Sinus Thrombosis
6. Pathogenesis of Venous Combined Micro-macrothrombotic Syndromes
7. Molecular Evidence of Venous Endotheliopathy
8. Diagnostic and Therapeutic Consideration
8.1. Diagnostic Perspective
8.2. Therapeutic Approach
8.3. “Special Note” on TTP-Like Syndrome and ADAMTS13 after COVID-19 Vaccines
9. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Clinical Phenotype | Arterial Endotheliopathy | Venous Endothelipathy |
---|---|---|
Underlying pathology | aEA-VMTD | vEA-VMTD |
Physiological/hemodynamic differences in the vascular network | Efferent circulation from the heart (oxygenated blood delivery to the organs) | Afferent circulation into the heart (deoxygenated blood delivery to the lungs) |
High pressure flow | Low pressure flow | |
High shear stress | Low shear stress | |
Capillary and arteriolar microvascular event | Venous and pulmonary microvascular event | |
Primary cause and result | ||
Vascular injury (ECs) | Sepsis-induced 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 venous system |
Activated hemostatic path | ULVWF path | ULVWF path |
Thrombosis component | Microthrombi strings | Microthrombi strings |
Clinical phenotypes | TTP-like syndrome
| ITP-like syndrome
|
Phenotypes | Distal DVT (de novo Venous Macrothrombosis) | Proximal/Central DVT (Combined Venous Micro-Macro thrombosis) |
---|---|---|
Disease examples | ||
Venous thrombosis | ||
DVT | Distal DVT | Proximal/central(catheter) DVT |
VTE | VTE; multiple PTE | |
Other complex venous thrombosis | IVCT; SVT; PVT; BCS; SVCT; CVST | |
Mechanisms of vascular injury | ||
Event | Local trauma (rarely with surgery/vascular access) | Underlying disease (vEA-VMTD (e.g., sepsis)) + local trauma (commonly with surgery/vascular access) |
Extent of vascular damage | Local ECs/SET injury | Disseminated ECs injury + local/regional ECs/SET injury |
Pathogenesis | ||
Activated thrombosis path | ULVWF and TF paths from local trauma | ULVWF path from systemic vEA-VMTD and TF path from regional trauma |
Thrombi character | Macrothrombus | Combined micro-macrothrombi composed of “microthrombi strings–fibrin meshes” |
Severity | Typically, solitary, benign, and self-limited | Serious and often with multiple/large thrombi |
Severe inflammation | Absent | May be present and can be severe |
Venous EA-VMTD | Absent | Commonly present (e.g., ITP-like syndrome) |
MOIS | Absent | May be present |
Diagnostic findings/markers | ||
Consumptive thrombocytopenia | Does not occur | Sometimes occurs |
ULVWF/VWF antigen | Normal | Overexpressed |
FVIII activity | Normal | Increased |
ADAMTS13 activity | Normal | Mild to moderately decreased |
D-dimer | Normal | Markedly increased |
Immune: ANA; APLA; Anti-DNA antibodies | Negative | May be positive |
Therapeutic approach per theory | No treatment or short-term anticoagulant | Anticoagulant and antimicrothrombotic/anticomplement agent (?) |
Pathology/Phenotypes | Arterial Micro-Macrothrombotic Syndrome (aEA-VMTD) | Venous Micro-Macrothrombotic Syndrome (vEA-VMTD) |
---|---|---|
Primary pathogenesis | ||
Cause example | Pathogen-associated endotheliopathy (SARS-CoV-2) | Pathogen-induced endotheliopathy (SARS-CoV-2) |
Vaccine-associated endotheliopathy (SARS-CoV-2 vaccines) | ||
Activated hemostatic path | ULVWF path via damaged ECs | ULVWF path via damaged ECs |
Involved vessels | Capillaries/arterioles | Veins/venules |
Underlying thrombophlia | ADAMTS13 insufficiency | ADAMTS13 insufficiency(?) |
Endothelial pathogenesis | Complement activation | Complement activation |
Phenotype and marker | ||
Thrombosis character | Arterial microvascular microthrombi | Venous microthrombi |
Clinical phenotype | TTP-like syndrome | ITP-like syndrome (“Silent” ITP) |
Consumptive thrombocytopenia | Consumptive thrombocytopenia | |
MAHA | MOIS | |
MODS/MOIS | ||
Endothelial markers | ULVWF ( ↑ VWF antigen ↑ FVIII activity) | ULVWF (↑ VWF antigen ↑ FVIII activity) |
Secondary pathogenesis | ||
Cause of additional vascular injury | From arterial vascular access in hospital | From venous vascular access in hospital |
From arterial vascular injury outside hospital | From incidental head injury (?) after vaccine (e.g., CVST) | |
Activated hemostatic path | TF path via damaged SET | TF path via damaged SET |
Affected vessels | Terminal arterial trees | Localized veins at injury site |
Molecular phenotype | Microthrombi and fibrin meshes | Microthrombi and fibrin meshes |
Pathologic phenotype | Numerous, minute macrothrombi shower composed of microthrombi and fibrin meshes in arterioles and capillaries in the digits, producing well-demarcated peripheral gangrene | Large, multiple, irregular, connected macrothrombi made of microthrombi and fibrin meshes in local or regional veins, producing DVT complex and venous stasis |
Clinical syndrome | Arterial micro-macrothrombosis (Gangrene syndrome) | Venous micro-macrothrombosis (complex DVT syndrome) |
Examples of syndromes | SPG, PF, ANF, diabetic gangrene, limb gangrene, Fournier’s disease, Burger’s disease, acrocyanosis) | VTE, CVST, IVCT, PTE, BCS, PVT, SVCT, SVT |
Combined Micro-Macrothrombosis due to aEA-VMTD (Gangrene Syndromes) (e.g., Sepsis) | Combined Micro-Macrothrombosis due to vEA-VMTD (Proximal/Central DVT) (e.g., Sepsis or after Vaccination) |
---|---|
Clinical features | Clinical features |
Fever/fatigue/myalgia | Fever/fatigue/myalgia |
TTP-like syndrome with thrombocytopenia and MAHA | ITP-like syndrome (“Silent” ITP) |
MODS (e.g., ARDS; encephalopathy) | MOIS (e.g., myocarditis; pericarditis) |
Gangrene syndromes (e.g., SPG; limb gangrene) | VTE (e.g., VTE; CVST; PTE; SVT) |
“Gangrene” | “Venous congestion syndrome” |
Laboratory changes (demonstrated) | Laboratory changes (demonstrated or expected) |
Endothelial (ULVWF path) markers | Endothelial (ULVWF path) markers |
Consumptive thrombocytopenia | Consumptive thrombocytopenia |
Overexpressed ULVWF/VWF antigen | Overexpressed ULVWF/VWF antigen |
Increased FVIII activity | Increased FVIII activity |
Increased thrombomodulin | Increased thrombomodulin |
Endothelial epiphenomenon | Endothelial epiphenomenon |
Positive ANA | Positive ANA |
Positive anti-dsDNA | Positive anti-dsDNA |
Positive anti-PL antibodies | Positive anti-PL antibodies |
Positive PF4 antibodies | Positive PF4 antibodies |
Tissue factor path markers | Tissue factor path markers |
Positive D-dimer | Positive D-dimer |
TF-bearing microvesicles in circulation | TF-bearing microvesicles in circulation (expected) |
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Chang, J.C.; Hawley, H.B. Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis. Medicina 2021, 57, 1163. https://doi.org/10.3390/medicina57111163
Chang JC, Hawley HB. Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis. Medicina. 2021; 57(11):1163. https://doi.org/10.3390/medicina57111163
Chicago/Turabian StyleChang, Jae C., and H. Bradford Hawley. 2021. "Vaccine-Associated Thrombocytopenia and Thrombosis: Venous Endotheliopathy Leading to Venous Combined Micro-Macrothrombosis" Medicina 57, no. 11: 1163. https://doi.org/10.3390/medicina57111163