Table 4 The summary of the main observations supporting the role of clopidogrel and ticagrelor in the pathogenesis of the first and the second flare [58, 59, 63,64,65,66, 75,76,77]
Observation | 1st flare | 2nd flare |
|---|---|---|
Suspected trigger | Clopidogrel | Ticagrelor |
The main clinical presentation | Urticaria Respiratory distress | Bowel dysfunction Hematuria |
Signs of common autoimmune disease | Lymphadenopathy Arthralgia | Lymphadenopathy Arthralgia |
Possible explanation of the main clinical presentation by drug pharmacodynamics/pharmacokinetics | Irreversible P2Y12 receptor binding might extend the severity of LMECB integrity loss (resulting in respiratory symptoms) Irreversible P2Y12 receptor binding might increase receptor desensitization and thus decrease expression of AQP (absence of gastrointestinal and renal symptoms) Higher glomerular filtration rate might decrease the drug passing through peritubular capillary network (absence of collecting duct cell injury) | Reversible P2Y12 receptor binding might not affect LMECB to the degree where it loses its integrity (absence of respiratory symptoms) Reversible P2Y12 receptor binding might decrease receptor desensitization and thus increase expression of AQP (leading to gastrointestinal and renal symptoms) Lower glomerular filtration rate might increase the drug passing through peritubular capillary network (presence of collecting duct cell injury) |
The possible leading underlying (non)immunological mechanism | DHR with involvement of IgE (urticaria) and T cells | DII bypassing IgE and T cells |
Possible pleiotropic drug effects via P2Y12 receptors | LMECB integrity loss | Increased transcription and translation of AQP genes Induction of ATP release from human red blood cells and proliferation of B cells |
Correlation between clinical and imaging/histopathologic findings | Urticaria—more histopathologic evidence consistent with UV Dyspnea—more reticulonodular opacities in both lungs | Isomorphic (non-glomerular) erythrocyturia—more hypodense changes largely involving kidney medulla Absence of large vessel vasculitis signs during hematuria |
Failure of standard immunosuppressive treatment | No | Yes |