Based on available data, do patients with COVID-19 face increased thrombotic and/or bleeding risk?

• The available data on thrombotic risk are quite limited (methodologically and otherwise) and based largely on case series from China (https://doi.org/10.1111/jth.14830), the Netherlands (https://doi.org/10.1016/j.thromres.2020.04.013), and France (https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf). Nonetheless, most experts agree that the signal for increased thrombotic risk is sufficient to recommend pharmacologic venous thromboembolism (VTE) prophylaxis in all hospitalized COVID-19 patients as long as there is no contraindication.
• One of the difficulties in determining the true incidence of thrombosis is that access to diagnostic testing may be limited (i.e., the patient may be too unstable, imaging may not be available for other reasons).
• In China, routine VTE prophylaxis is not given to hospitalized patients, which may at least partly explain the high VTE rate in that population. In a report from the Netherlands (where routine VTE prophylaxis is given) high rates of VTE were noted among ICU patients (https://doi.org/10.1016/j.thromres.2020.04.013). More than one-third of these patients, however, had a pulmonary embolism limited to subsegmental arteries. Regardless, it is important to remember that critical illness is associated with a substantial risk of VTE (8-10%) despite the use of prophylactic anticoagulants as shown in the PROTECT study (https://www.nejm.org/doi/full/10.1056/NEJMoa1014475). There may indeed be a higher risk among COVID-19 patients in the ICU, as suggested by a French cohort study (https://www.esicm.org/wp-content/uploads/2020/04/863_author_proof.pdf), but high-quality data are lacking.
• There is not a clear increased propensity for bleeding among COVID-19 patients with coagulopathy, though data are lacking. The coagulopathy found in severe COVID-19 appears to be associated with normal or increased fibrinogen levels. This contrasts with disseminated intravascular coagulopathy (DIC), which is characterized by low levels of fibrinogen, consumption of coagulation factors (and natural anticoagulants), severe thrombocytopenia, and bleeding with microvascular thrombosis.

What hemostasis/coagulation test(s), if any, should be ordered in patients with suspected or known COVID-19 absent evidence of thrombosis or bleeding? Should tests like D-dimer be ordered?

• As we are still gathering information about the nature of the coagulopathy associated with COVID-19, it is reasonable to measure D-dimer, PT, aPTT, and fibrinogen levels in hospitalized patients; importantly INR is not sufficiently sensitive for coagulopathy.
• Severe COVID-19 is associated with high D-dimer levels which appear to predict mortality. A relationship between elevated D-dimer levels and mortality, however, has been shown in previous cohorts of critically ill patients. Whether this is more significant in COVID-19 or more predictive of mortality in COVID-19 is currently unknown.
• It is also unknown whether antithrombotic treatments aimed at D-dimer thresholds improve outcomes. How elevated D-dimer levels should guide management is highly uncertain, but this information may be helpful for clinical monitoring, characterizing the coagulopathy, and conducting clinical trials to rigorously test management strategies. Therapeutic anticoagulation is not mandatory for all patients based only on an elevated D-dimer test and there is no evidence supporting use of D-dimer values to guide intensity of anticoagulation.

When should imaging studies be performed to evaluate for VTE in patients with COVID-19?

• Assessment for VTE should incorporate multiple elements of the patient condition, including interval history, physical exam and vital signs, currently administered treatments, and laboratory studies. The decision to order imaging for VTE should not be based on an elevated D-dimer alone.
• When possible, imaging confirmation of suspected VTE should be obtained to guide anticoagulation decisions. While this may not be possible in all settings, use of limited compression ultrasound (e.g., single limb, stopping once a clot is identified) may help to minimize exposure risk to vascular laboratory staff. In other settings, decisions may rely primarily on clinical evaluation and assessment of thrombotic vs. bleeding risk.

Is VTE prophylaxis for a hospitalized patient with COVID-19 any different from a patient without COVID-19? Is there a role for post-discharge thromboprophylaxis?

• The best answer is yes and no. On the one hand, all medically ill patients admitted to the hospital should trigger screening to evaluate the need for VTE prophylaxis. However, two preliminary findings seem to distinguish patients with COVID-19 from other hospitalized medically ill patients, at least based on early reports from China and Europe. First, COVID-19 patients admitted to the hospital may have an additional procoagulant state compared to other hospitalized patients, including activation of coagulation through various infectious and inflammatory mechanisms. Second, many of these VTE events are occurring in patients receiving standard dose VTE prophylaxis.
• All patients hospitalized with COVID-19 should receive pharmacologic VTE prophylaxis unless a specific contraindication (e.g., active bleeding) exists. Strategies to minimize frequent interactions between patients and health care providers (e.g., use of daily low-molecular-weight heparin rather than thrice-daily unfractionated heparin injections) may help to minimize infection risk and use of personal protective equipment when clinically appropriate.
• Use of higher-intensity, non-standard VTE prophylaxis can be considered for patients with COVID-19, but ideally should be done within the context of a clinical trial given current lack of efficacy evidence.
• Post-hospital VTE prophylaxis should be considered in patients with COVID-19. Experience from the MAGELLAN (https://www.nejm.org/doi/full/10.1056/NEJMoa1111096), APEX (https://www.nejm.org/doi/full/10.1056/NEJMoa1601747), and MARINER (https://www.nejm.org/doi/full/10.1056/NEJMoa1805090) studies suggest that in select patients without COVID-19, post-discharge thromboprophylaxis (particularly with a DOAC) may be beneficial if bleeding risk can be minimized. This may be even more important in COVID-19 because of the long duration of illness—a peak in symptoms around day 8-10 followed by a rather lengthy tail with increased likelihood of immobility and risk of superinfection. Use of a validated risk score (e.g., IMPROVE or IMPROVEDD score with D-dimer) may be particularly helpful in guiding decision-making.

Should therapeutic anticoagulation be used in patients with COVID-19 absent confirmed or suspected thrombosis (i.e., ACS, VTE, stroke)?

• There is substantial controversy about the use of escalated doses of anticoagulants to prevent thrombotic events in COVID-19. Some have advocated that anticoagulants may help prevent other complications such as respiratory deterioration and mechanical ventilation due to pulmonary microvascular thrombosis. However, because therapeutic anticoagulation is also associated with an increased risk of bleeding, it should ideally be used in the context of a randomized trial for prevention of thrombosis based on our current state of knowledge.

Clinical Topics: Anticoagulation Management, COVID-19 Hub, Pulmonary Hypertension and Venous Thromboembolism, Vascular Medicine, Anticoagulation Management and Venothromboembolism

Keywords: Anticoagulants, Heparin, Low-Molecular-Weight, Heparin, Venous Thromboembolism, Critical Illness, Fibrinolytic Agents, Fibrinogen, Patient Discharge, Superinfection, Respiration, Artificial, Netherlands, COVID-19, Coronavirus, Coronavirus Infections, International Normalized Ratio

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