Department of Cardiology, Ospedale L. Sacco, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157, Milano, Italy.
Division of Respiratory Diseases, Ospedale L. Sacco, ASST Fatebenefratelli-Sacco, Via G.B. Grassi 74, 20157, Milano, Italy.
Pharmacol Res. 2020 Aug;158:104950. doi: 10.1016/j.phrs.2020.104950. Epub 2020 May 23.
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.
患者患有严重的 2019 年冠状病毒病（COVID-19），常因肺泡受累和内皮功能障碍而导致低氧血症，从而导致肺毛细血管内微血栓形成。低氧血症和血栓形成倾向均与疾病更严重和死亡风险增加有关。迄今为止，尚无针对这种情况的具体治疗方法。这是一项由意大利米兰 L. Sacco 大学医院中级呼吸治疗病房的研究员发起的、同情使用的、概念验证的、病例对照的、IIb 期研究（NCT04368377）。我们的目的是探讨抗血小板治疗对患有高凝状态的严重 COVID-19 患者的动脉氧合和临床结局的影响。我们招募了五名连续的实验室确诊 SARS-CoV-2 感染、需要头盔持续气道正压通气（CPAP）的严重呼吸衰竭、双侧肺浸润和血栓形成状态的患者，该状态定义为 D-二聚体>正常上限的 3 倍。年龄、D-二聚体值和 SOFA 评分匹配的五名患者组成对照组。除标准治疗外，接受治疗的患者还接受了 25 μg/Kg/体重的替罗非班作为推注输注，然后以 0.15 μg/Kg/体重/分钟的速度连续输注 48 小时。在替罗非班前，患者接受乙酰水杨酸 250 mg 输注和口服氯吡格雷 300 mg；均以 75 mg/天的剂量连续使用 30 天。根据当地标准操作程序，所有对照者均接受预防性或治疗性剂量肝素。所有接受治疗的患者在治疗后 24、48 小时和 7 天，平均（SD）动脉-肺泡氧差分别降低-32.6 mmHg（61.9，P = 0.154）、-52.4 mmHg（59.4，P = 0.016）和-151.1 mmHg（56.6，P = 0.011；P = 0.047 与对照组）。治疗后 24、48 小时和 7 天，PaO2/FiO2 比值分别增加 52 mmHg（50，P = 0.172）、64 mmHg（47，P = 0.040）和 112 mmHg（51，P = 0.036）。所有患者（除 1 例外）在 3 天后均成功从 CPAP 脱机。但对照组并非如此。未观察到主要不良事件。抗血小板治疗可能有助于改善 COVID-19 严重呼吸衰竭患者的通气/灌注比。这种效果可能通过预防和干扰肺毛细血管内血栓形成以及调节巨核细胞功能和血小板黏附来维持。急需进行随机临床试验来证实这些结果。
