Enhanced platelet inhibition treatment improves hypoxemia in patients with severe Covid-19 and hypercoagulability. A case control, proof of concept study

Abstract

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.

Keywords: Antiplatelet; Coagulation; Coronavirus; Covid-19; D-dimer; Respiratory failure.

Graphical abstract

Fig. 1

Changes in oxygenation parameters in treated patients and controls. Changes in PaO2/FiO2 (Panel A), A-a O2 gradient (Panel B) and PaO2 (Panel C) after anti-platelet therapy administration are shown at different time-points. Values are reported as means and vertical bars are standard deviations. * p-value < 0.05.

Fig. 2

Changes in respiratory support in treated patients and controls. Variations in the respiratory support after the initiation of study treatment (left) and in controls (right). Each line identifies a patient. Three patients from the treated group (patient #2, patient #3 and patient #5) were weaned from CPAP after three days, and patient #5 was weaned from O2 therapy after seven days. Patient #1 assessment stopped 48 hours after study protocol initiation because he was transferred to the ICU and intubated because of progressive respiratory distress secondary to sepsis. The substantial and rapid increase in PaO2 and PAO2/FIO2 in patient #1 soon after treatment with tirofiban appears disproportionate compared with the variations observed in other patients. The latter was probably secondary to a concomitant increase in cardiac output secondary to impeding sepsis rather than a direct and isolated effect of the experimental treatment. PaO2 = arterial partial pressure of oxygen; FiO2 = fraction of inspired oxygen; A-a O2 = alveolar-arterial gradient of oxygen. For details please see Table 1.