Coronavirus disease 2019 (COVID-19), a viral respiratory illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may predispose patients to thrombotic disease due to a state of profound inflammation, platelet activation, and endothelial dysfunction leading to respiratory distress and increased mortality. The incidence of macrovascular thrombotic events varies from 10 to 30% in COVID-19 hospitalized patients depending on the type of arterial or vein thrombosis captured and severity of illness . Observational results in patients receiving routine low-dose prophylactic anticoagulation (LD-PA), several institutions have recently released guidance statement to prevent macrovascular thrombotic events with dose escalation anticoagulation. In these recommendations, high-dose prophylactic anticoagulation (HD-PA) and therapeutic anticoagulation (TA) can be employed either empirically or based on the body mass index and increased D-dimer values. No randomized trial has validated this approach, and other recent recommendations challenge this approach. Microvascular thrombotic events are also of major concern in critically ill patients with COVID-19, even in the absence of obvious macrovascular thrombotic events. A large review of autopsy findings in COVID-19-related deaths reported micro thrombi in small pulmonary vessels. More generally, COVID-19-induced endothelitis and coagulopathy across vascular beds of different organs lead to widespread microvascular thrombosis with microangiopathy and occlusion of capillaries. Thus, in severe COVID-19 patients requiring oxygen therapy without initial macrovascular thrombotic event, a HD-PA or a TA could be beneficial by limiting the extension of microvascular thrombosis and the evolution of the lung and multi-organ microcirculatory dysfunction. In a large observational cohort of 2,773 COVID-19 patients, a lower in-hospital mortality in ventilated patients receiving TA as compared to those receiving PA (29.1% vs. 62.7%). Our hypothesis is dual: i) first, that TA and HD-PA strategies mitigate microthrombosis and each limit the progression of COVID-19, including respiratory failure and multi-organ dysfunction, with in fine a decreased mortality and duration of disease, as compared to a low-dose PA; ii) second, that TA outperforms HD-PA in this setting.

Inclusion Criteria:

• Age ≥ 18 years ;

• Severe COVID-19 pneumonia, defined by:

  • A newly-appeared pulmonary parenchymal infiltrate; AND
  • a positive RT-PCR (either upper or lower respiratory tract) for COVID-19 (SARS-CoV-2); AND
  • WHO progression scale ≥ 5 (on The Who ordinal scale)

• Written informed consent (patient, next of skin or emergency situation).

• In view of the exceptional and urgent situation, affiliation to a social security scheme will not be a criterion for inclusion.

Exclusion Criteria:

• Pregnancy and breast feeding woman;
• Postpartum (6 weeks);
• Extreme weights (<40 kg or >100 kg);
• Patients admitted since more than 72 hours to the hospital (if the WHO ordinal scale is 5 at time of inclusion) or since more than 72 hours to the intensive care unit (if the WHO ordinal scale is 6 or more at time of inclusion);
• Need for therapeutic anticoagulation (except for COVID-related pulmonary thrombosis);
• Bleeding event related to hemostasis disorders, acute clinically significant bleed, current gastrointestinal ulcer or any organic lesion with high risk for bleeding
• Platelet count < 50 G/L;
• Within 15 days of recent surgery, within 24 hours of spinal or epidural anesthesia;
• Any prior intracranial hemorrhage, enlarged acute ischemic stroke, known intracranial malformation or neoplasm, acute infectious endocarditis;
• Severe renal failure (creatinine clearance <30 mL/min);
• Iodine allergy;
• Hypersensitivity to heparin or its derivatives including low-molecular-weight heparin;
• History of type II heparin-induced thrombocytopenia;
• Chronic oxygen supplementation;
• Moribund patient or death expected from underlying disease during the current admission;
• Patient deprived of liberty and persons subject to institutional psychiatric care;
• Patients under guardianship or curatorship;
• Participation to another interventional research on anticoagulation.

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