Patients with serious infection are more likely to have COVID-19 associated coagulopathy than patients with mild infection. and those who die from COVID-19 are more likely to have met the ISTH criteria for DIC compared to survivors. Elevated D-dimer at admission and markedly increasing D-dimer levels (3- to 4-fold) over time are associated with high mortality, likely reflecting coagulation activation from infection/sepsis, cytokine storm and impending organ failure.¹

We recommend monitoring platelet count, PT/aPTT, D-dimer, and fibrinogen. Worsening of these parameters, specifically the D-Dimer, indicates progressive severity of COVID-19 infection and predicts that more aggressive critical care will be needed; experimental therapies for COVID-19 infection might be considered in this setting. Improvement of these parameters along with stable or improving clinical condition provides confidence that stepping down of aggressive treatment may be appropriate.¹

As for all coagulopathies, treatment of the underlying condition is paramount. Experience to date suggests that COVID-19 infection infrequently leads to bleeding despite abnormal coagulation parameters. Supportive care including blood product transfusion should be individualized. Blood component therapy should not be instituted on the basis of laboratory results alone, but reserved for those with active bleeding, requiring an invasive procedure, or who are otherwise at high risk for bleeding complications. Traditional risk factors for bleeding apply. There are no data to support any particular “safe” cut-off for hematological parameters and the thresholds below are for guidance only.

In patients who are not bleeding, there is no evidence that correction of laboratory parameters with blood products improves outcomes. Replacement might worsen disseminated thrombosis and further deplete scarce blood products.¹

Therapeutic anticoagulation is not required unless another indication for therapeutic anticoagulation is documented (e.g. VTE, atrial fibrillation, or mechanical valve). The efficacy of intermediate or full therapeutic anticoagulation for critically ill COVID-19 patients without documented VTE is under study.

In patients already on anticoagulation for VTE or atrial fibrillation, therapeutic doses of anticoagulant therapy should continue but may need to be held if the platelet count is less than 30-50 x 109/L or if the fibrinogen is less than 1.0 g/L. Individual patient assessment, however, is required to balance risks of thrombosis and bleeding.

Prophylactic dose LMWH is recommended for all hospitalized COVID-19 patients despite abnormal coagulation tests in the absence of active bleeding, and held only if platelet counts are less than 25 x 109/L, or fibrinogen less than 0.5 g/L. Abnormal PT or aPTT is not a contraindication for pharmacological thromboprophylaxis. Mechanical thromboprophylaxis should be used when pharmacological thromboprophylaxis is contraindicated. The effect of anticoagulation on patient outcomes is under investigation in many prospective trials.²

Acutely ill patients hospitalized with pneumonia, with or without COVID-19, possess several established risk factors for VTE including acute respiratory illness, active infection, an inflammatory state and diminished mobility. These patients may have additional clinical risk factors for VTE, such as advanced age (e.g., > 65 years), cancer, obesity, pregnancy, congestive heart failure, or history of prior VTE. Most, if not all, would qualify for in-hospital VTE prophylaxis according to existing evidence-based guidelines.

As COVID-19 itself may be associated with a prothrombotic state, VTE prophylaxis is of utmost importance. Additionally, more severely ill patients with COVID-19 who are admitted to the intensive care unit (ICU) may have severe mobility limitations as a result of being intubated, sedated, paralyzed, and potentially placed in a prone position.

An early study out of the Hubei Province in China³ suggests that in the absence of VTE prophylaxis, 25% of COVID-19 patients developed lower extremity DVT as assessed by surveillance doppler ultrasound of the lower extremities, which is higher than the 5–15% incidence seen in placebo arms of early studies of VTE prevention in medically ill hospitalized patients. In these early studies, use of pharmacologic VTE prophylaxis reduced the incidence of VTE by up to 60% without an increase in major bleeding.

A second study from the Netherlands⁴ found pulmonary embolism (PE) in 25 of 184 ICU patients with COVID-19 (13.6%), despite standard dose pharmacologic prophylaxis. A third study from Italy identified thromboembolic events (venous and arterial) in 7.7% of patients admitted with COVID-19, estimating a cumulative rate of 21%. While each of these studies are limited in their design, data collection, and/or statistical methodology, the importance of VTE prophylaxis cannot be understated for hospitalized patients with this illness.

Acutely ill patients hospitalized with pneumonia, with or without COVID-19, possess several established risk factors for VTE including acute respiratory illness, active infection, an inflammatory state and diminished mobility. These patients may have additional clinical risk factors for VTE, such as advanced age (e.g., > 65 years), cancer, obesity, pregnancy, congestive heart failure, or history of prior VTE. Most, if not all, would qualify for in-hospital VTE prophylaxis according to existing evidence-based guidelines.

As COVID-19 itself may be associated with a prothrombotic state, VTE prophylaxis is of utmost importance. Additionally, more severely ill patients with COVID-19 who are admitted to the intensive care unit (ICU) may have severe mobility limitations as a result of being intubated, sedated, paralyzed, and potentially placed in a prone position.

An early study out of the Hubei Province in China³ suggests that in the absence of VTE prophylaxis, 25% of COVID-19 patients developed lower extremity DVT as assessed by surveillance doppler ultrasound of the lower extremities, which is higher than the 5–15% incidence seen in placebo arms of early studies of VTE prevention in medically ill hospitalized patients. In these early studies, use of pharmacologic VTE prophylaxis reduced the incidence of VTE by up to 60% without an increase in major bleeding.

A second study from the Netherlands⁴ found pulmonary embolism (PE) in 25 of 184 ICU patients with COVID-19 (13.6%), despite standard dose pharmacologic prophylaxis. A third study from Italy identified thromboembolic events (venous and arterial) in 7.7% of patients admitted with COVID-19, estimating a cumulative rate of 21%. While each of these studies are limited in their design, data collection, and/or statistical methodology, the importance of VTE prophylaxis cannot be understated for hospitalized patients with this illness.

To the best of our knowledge, all published studies regarding VTE prophylaxis in patients with COVID-19 have been conducted in adult critically ill patients. Thus, there is no evidence to suggest that approaches other than standard regimens recommended in existing VTE prevention guidelines are indicated for non-critically ill patients.

In the study by Klok et al. ⁴ conducted among critically ill patients with COVID-19 in three ICUs across the Netherlands, the investigators found 25 symptomatic VTE events in 184 adult patients, all of whom received pharmacologic VTE prophylaxis. It should be noted that 2 of the 3 ICUs initially used lower than standard doses of low molecular weight heparin, and the doses were increased over time. Age and coagulopathy were independent predictors of thrombotic complications. This study suggests that critically ill adult COVID-19 patients may develop VTE with standard pharmacologic prophylaxis.

A study in France⁵ of 150 patients with COVID-19 and acute respiratory distress syndrome (ARDS) from 4 ICUs, receiving prophylactic (80%) or empiric treatment dose (20%) anticoagulation found 16.7% of patients suffered pulmonary embolism (PE) despite this therapy. This represents nearly a sixfold increase in PE compared to patients with ARDS not related to COVID-19. Presently there is no evidence for use of biomarkers such as D-dimer to guide intensification of anticoagulant dosing despite it being a marker of poor prognosis. However, it is important for providers and clinicians to stay apprised of emerging evidence and adjust practices accordingly.² Recommendations²

• For all non-critically ill hospitalized patients (i.e., not in an ICU) with confirmed or highly suspected COVID-19, it is recommended standard dose VTE prophylaxis as per existing societal guidelines for medically ill and surgical hospitalized patients.
• For critically ill patients (i.e., in an ICU) with confirmed or highly suspected COVID-19, it is suggested, increased doses of VTE prophylaxis (e.g., enoxaparin 40 mg subcutaneous twice daily, enoxaparin 0.5 mg/kg subcutaneous twice daily, heparin 7500 units subcutaneous three times daily, or low-intensity heparin infusion. This suggestion is based largely on expert opinion.
• For pregnant patients with confirmed or highly suspected COVID-19, it is recommend that providers collaborate closely with obstetric and anesthesia colleagues to determine optimal VTE prophylaxis dosing. Intermediate dosing regimens often used in the third trimester, as suggested by the American college of Obstetrics and Gynecology (ACOG) and RCOG, may be a reasonable option for pregnant patients with COVID-19.
• For patients that are improving and transferring out of the ICU to the medical ward, it is reasonable to de-escalate to standard VTE prophylaxis dosing.

Extending VTE prophylaxis beyond hospital discharge has not been widely adopted due to logistical challenges with implementation, bleeding risk, and large numbers needed to treat to prevent a single VTE event.

Consideration for post-hospital VTE prophylaxis may be reasonable on a case-by-case basis for patients with COVID-19 who are low bleed risk (e.g., IMPROVE bleed score <  7.0 and:

• Were admitted to the ICU, intubated, sedated, and possibly paralyzed for multiple days
• Have ongoing VTE risk factors at the time of discharge (e.g., diminished mobility, profound weakness, not at baseline physical status)

• Suggested that extended VTE prophylaxis is not necessary for all patients with COVID-19 who are being discharged from the hospital.
• Suggested that a multidisciplinary discussion occur at or near the time of discharge to determine if a patient has ongoing VTE risk factors, may benefit from extended post-hospital VTE prophylaxis, and has ensured access to VTE prophylactic medications.
• It is recommended to use a standardized patient selection approach that involves the patient in the decision-making process.
• If post-discharge prophylaxis is deemed reasonable, it is recommended use of an adequately studied and/or approved agent such as betrixaban, or rivaroxaban, or enoxaparin (adjusted as need based on weight, renal/liver function, and drug-drug interactions) and suggest limiting the total duration as used in the clinical trials (i.e. enoxaparin 6-14 days; rivaroxaban 31-39 days; betrixaban 35-42 days).