Prasugrel in Severe COVID-19 Pneumonia

Severe respiratory failure and multi-organ damage in coronavirus disease 2019 (COVID-19)
patients have not a unitary pathophysiological interpretation. There is evidence of an
association between the clinical entity of the disease and its severity with the plasma
levels of D-dimer and inflammatory indexes. On the basis of retrospective investigations
there is accumulating evidence of alterations in the haemostatic parameters that with
increased D-dimer values, increased coagulation time and platelets may be predictors of worse
prognosis. A systematic survey conducted in the coronavirus disease 2019 (COVID-19) Centre of
the AOUI Verona, as part of the Database and Study on the role of platelets in the clinical
manifestations of COVID-19 (Ethics Committee CESC Verona and Rovigo approved) revealed by
means of computerized tomography (CT) angiograph in patients with a persistent respiratory
deficit and very high D-dimer values mainly multiple, bilateral vascular occlusions involving
the segmental and subsegmental branches of the pulmonary arteries. This finding is suggestive
of a frequent and clinically relevant thrombotic process in a appreciable number
(approximately 20%) of patients with COVID-19 pneumonia hospitalized in medical wards. It is
a well-established clinical notion that acute and chronic inflammatory diseases may favour
the onset of venous thromboembolic events in hospitalized patients. Thromboprophylaxis with a
fixed dose of heparin/low molecular weight heparin (LMWH) is recommended for medical patient
with concomitant neoplasia or inflammatory disease. It is conceivable that under conditions,
such as SARS-CoV2 pneumonia, an inflammation-dependent thrombotic process takes place and
that platelet activation may play a pathogenic role both in the thrombotic process and in the
amplification of the inflammatory process. In fact, there is experimental evidence that
platelet activation in inflammation would lead to accelerated coagulation and a thrombotic
vascular occlusion, with similarities to what is widely documented in atherothrombosis and
thrombotic microangiopathies. The administration of antiplatelet drugs represents the
cornerstone for the prevention and treatment of arterial thromboembolism in atherosclerotic
disease and has also shown some limited efficacy also in the context of venous and arterial
thromboembolism associated with atrial fibrillation. Preliminary observations indicate that
the use of purinergic receptor P2Y12 inhibitors during pneumococcal pneumonia may improve the
inflammatory process and respiratory function in humans. There are currently no validated
protocols for thrombosis prevention in the field of pulmonary viral diseases, in particular
COVID-19. There is adequate scientific rationale to consider the use of a P2Y12 inhibitor
antiplatelet drug for the prevention of thrombosis in the pulmonary circulation and the
attenuation of pulmonary inflammation. The use of a P2Y12 inhibitor is motivated by numerous
experimental demonstrations of the anti-inflammatory activity of P2Y12 inhibitors and by the
evidence of improvement of respiratory function parameters both in humans and experimental
models. Prasugrel could be considered as an ideal candidate drug for administration in
Covid-19 patients because of its higher efficacy in acute coronary syndrome compared to
clopidogrel. Interactions of prasugrel with drugs used for the treatment of SARS-CoV2 are
limited. The hypothesis underlying the present study project is that in Covid-19 platelet
activation occurs via an inflammation-dependent mechanism and that early antithrombotic
prophylaxis in non-critical patients, like those admitted to medical wards, could reduce the
incidence of pulmonary thrombosis as well as respiratory and multi-organ failure,
contributing to improve clinical outcome of the patients with pneumonia caused by SARS-CoV2
viruses. The anticoagulant activity exerted by a fixed dose of enoxaparin (4000U/day),
recommended in patients with the clinical features described, according to a note of the
"Italian Medicines Agency" (AIFA), together with the prevention of thrombogenic activity of
platelets by means of a P2Y12 inhibitor could prevent aggravation of COVID-19 patients to a
greater extent than enoxaparin alone given at the same dose. Early initiation of treatment
should mitigate the presentation of pneumonia. The proposed treatment is feasible in all
COVID-19 patients, regardless of the treatment regimen used for their condition (antivirals,
anti-inflammatory drugs, antibiotics), except for specific contraindications to the use of
prasugrel, or placebo if patients are treated with antiplatelet drugs.