Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability… The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes’ function and platelet adhesion.
Pharmacol Res. 2020 Aug; 158: 104950.
Reprinted for educational purposes and social benefit, not for profit.
Patients affected by severe coronavirus induced disease-2019 (Covid-19) often experience hypoxemia due to alveolar involvement and endothelial dysfunction, which leads to the formation of micro thrombi in the pulmonary capillary vessels. Both hypoxemia and a prothrombotic diathesis have been associated with more severe disease and increased risk of death. To date, specific indications to treat this condition are lacking.
This was a single center, investigator initiated, compassionate use, proof of concept, case control, phase IIb study (NCT04368377) conducted in the Intermediate Respiratory Care Unit of L. Sacco University Hospital in Milano, Italy. Our objective was to explore the effects of the administration of anti-platelet therapy on arterial oxygenation and clinical outcomes in patients with severe Covid-19 with hypercoagulability.
We enrolled five consecutive patients with laboratory confirmed SARS-CoV-2 infection, severe respiratory failure requiring helmet continuous positive airway pressure (CPAP), bilateral pulmonary infiltrates and a pro-thrombotic state identified as a D-dimer > 3 times the upper limit of normal. Five patients matched for age, D-dimer value and SOFA score formed the control group.
Beyond standard of care, treated patients received 25 μg/Kg/body weight tirofiban as bolus infusion, followed by a continuous infusion of 0.15 μg/Kg/body weight per minute for 48 hours. Before tirofiban, patients received acetylsalicylic acid 250 mg infusion and oral clopidogrel 300 mg; both were continued at a dose of 75 mg daily for 30 days. Fondaparinux2.5 mg/day sub-cutaneous was given for the duration of the hospital stay. All controls were receiving prophylactic or therapeutic dose heparin, according to local standard operating procedures.
Treated patients consistently experienced a mean (SD) reduction in A-a O2 gradient of -32.6 mmHg (61.9, P = 0.154), -52.4 mmHg (59.4, P = 0.016) and -151.1 mmHg (56.6, P = 0.011; P = 0.047 vs. controls) at 24, 48 hours and 7 days after treatment. PaO2/FiO2 ratio increased by 52 mmHg (50, P = 0.172), 64 mmHg (47, P = 0.040) and 112 mmHg (51, P = 0.036) after 24, 48 hours and 7 days, respectively. All patients but one were successfully weaned from CPAP after 3 days. This was not true for the control group. No major adverse events were observed.
Antiplatelet therapy might be effective in improving the ventilation/perfusion ratio in Covid-19 patients with severe respiratory failure. The effects might be sustained by the prevention and interference on forming clots in lung capillary vessels and by modulating megakaryocytes’ function and platelet adhesion. Randomized clinical trials are urgently needed to confirm these results.
Although preliminary, these findings, combined with available ex vivo lung pathology, should stimulate the re-evaluation of megakaryocyte-platelet role in the pro-thrombotic state in Covid-19 patients and suggest possible alternative treatments that may involve antiplatelet therapy along with thrombosis prophylaxis. Still, which is the best therapeutic approach to face the thrombophilic diathesis of patients with severe Covid-19 remains unknown. Indeed, larger cohorts and randomized trials are urgently needed to answer this question.
Learn More about megakaryocyte proliferation in COVID-19:
- Only one tirofiban COVID Clinical Trial (Milan): NCT04368377
- Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series – The Lancet
- Pubmed Search: “megakaryocyte proliferation“
- Clinicopathological Study of Hematological Disorders After Thorotrast Administration in Japan
- New Insights Into the Differentiation of Megakaryocytes From Hematopoietic Progenitors
- Inhibition of Megakaryocyte Development in the Bone Marrow Underlies Dengue Virus-Induced Thrombocytopenia in Humanized Mice
- About tirofiban
- Aggrastat – FDA (Merck) – off patent.
- Aggrastat (Tirofiban) is an antiplatelet drug. It belongs to a class of antiplatelet drugs named glycoprotein IIb/IIIa inhibitors. Tirofiban is a small molecule inhibitor of the protein-protein interaction between fibrinogen and the platelet integrin receptor GP IIb/IIIa.
- The cost for Aggrastat intravenous solution (250 mcg/mL) is around $68 for a supply of 15 milliliters – Source: Drugs.com