ANTIcoagulation in Severe COVID-19 Patients

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.


Eligibility Criteria:
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.