There may be a universal mechanism explaining
dyspnea after
ticagrelor and
elinogrel, namely,
transfusion-related acute lung injury (
TRALI). Indeed, recent clinical trials with
ticagrelor (DISPERSE, DISPERSE-II, and PLATO), and
elinogrel (INNOVATE PCI) revealed double-digit rates of
dyspnea after novel reversible
antiplatelet agents. In contrast,
dyspnea is not associated with conventional non-reversible agents such as
aspirin, or
thienopyridines (
ticlopidine,
clopidogrel, or
prasugrel) suggesting distinct mechanism of
shortness of breath after
ticagrelor and
elinogrel. The
adenosine hypothesis has been offered to explain such adverse association. However, despite obvious similarity between
ticagrelor and
adenosine molecules, the chemical structure of
elinogrel is entirely different. In fact,
ticagrelor is a cyclopentyl-triazolo-
pyrimidine, while
elinogrel is a
quinazolinedione. Since both agents cause
dyspnea, the
adenosine hypothesis is no longer valid. In contrast, the reversible nature of platelet inhibition attributable to both
ticagrelor and
elinogrel causing premature cell ageing, apoptosis, impaired turnover due to sequestration of overloaded, exhausted platelets in the pulmonary circulation are among potential autoimmune mechanism(s) resulting in the development of a
TRALI-like reaction, and frequent
dyspnea. Despite expected benefit for better
bleeding control, further development of reversible
antithrombins is severely limited due to the existence of a potentially universal serious adverse event, such as
TRALI-syndrome with
dyspnea as a predominant clinical manifestation. Since
TRALI is an established number one contributor to mortality after
blood transfusions,
ticagrelor death "benefit" in PLATO is challenged further.