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, 63–66, 75–77]

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