COVID-19 and Pulmonary Embolism: Frequently Asked Questions
(Version 5.0; last updated January 29, 2021)
Input from Agnes Y. Y. Lee, MD, MSc; Maria deSancho, MD; Menaka Pai, MD, MSc; Menno Huisman, MD; Stephan Moll, MD; Walter Ageno, MD; and Lisa Bauman-Kreuziger, MD.
Note: Please review ASH's disclaimer regarding the use of the following information.
How do we diagnose pulmonary embolism (PE) if we cannot perform CTPA or V/Q lung scan because the patient must remain in isolation (e.g. due to risk of virus aerosolization, lack of personal protective equipment) or is too unstable?
When objective imaging is not feasible to confirm or refute a diagnosis of PE, clinicians must rely on clinical assessment based on history, physical findings and other tests. Observational data show that 7-39% of patients with COVID-19 infection who require mechanical ventilation have acute PE/DVT. Likelihood of PE is moderate to high in those with signs or symptoms of DVT, unexplained hypotension or tachycardia, unexplained worsening respiratory status, or traditional risk factors for thrombosis (e.g., history of thrombosis, cancer, hormonal therapy). If feasible, consider doing bilateral compression ultrasonography (CUS) of the legs, echocardiography or point-of-care ultrasonography (POCUS). These tests can confirm thrombosis if proximal DVT is documented on CUS or if a clot-in-transit is visualized in the main pulmonary arteries on echocardiography or POCUS, but they cannot rule out thrombosis if clot is not detected.
Does a normal D-dimer level effectively rule out PE/DVT?
Yes. The value of D-dimer testing is the ability to rule out PE/DVT when the level is normal. Although the false negative rate of D-dimer testing (i.e., PE/DVT is present but the result is normal) is unknown in this population, low rates of 1 – 2% using highly sensitive D-dimer assays have been reported in other high risk populations. Therefore, a normal D-dimer level provides reasonable confidence that PE/DVT is not present. (See ASH's FAQ document regarding COVID-19 and VTE/anticoagulation.) In addition, radiological imaging is not necessary when the D-dimer level is normal in the context of low pre-test probability. As ‘baseline’ D-dimer levels are higher in patients with COVID-19, current studies are evaluating whether a different (higher) cut-off value for D-dimer would be more useful in excluding VTE in these patients.
If D-dimer levels change from normal to abnormal, or rapidly increase on serial monitoring, is this indicative of PE/DVT?
An elevated D-dimer level does not confirm a diagnosis of PE/DVT in a patient with COVID-19 because the elevated D-dimer may result from the COVID-19 infection or other causes. If possible, CTPA and/or bilateral CUS should be performed to investigate for PE/DVT. It is important to determine if there are any new clinical findings that indicate acute PE/DVT and if there are other causes of high D-dimer levels, such as secondary infection, myocardial infarction, renal failure, or coagulopathy. (See ASH's FAQ document regarding COVID-19 and coagulopathy.) Published data have shown that the majority of patients with progressive, severe COVID-19 infection with acute lung injury/ARDS have very high D-dimer and fibrinogen levels, independent of the presence or absence of VTE. See below..
What are the risks and benefits of empiric therapeutic anticoagulation in COVID-19 patients?
Objective imaging to confirm a diagnosis of PE/DVT should, if possible, be done prior to starting therapeutic anticoagulation.
A large NIH multiplatform, adaptive-design trial that incorporates 3 global studies/networks (REMAP-CAP, ATTACC and ACTIV-4A) was set up to address the use of therapeutic anticoagulation. ACTIV-4A Inpatient and ATTACC enrolled patients within first 72 hours of hospitalization, while REMAP-CAP used a 48-hour cut-off for those needing organ support on admission and up to 14 days for those who were moderately ill. Patients were randomized in an adaptive fashion to receive different intensities of anticoagulation and/or antiplatelet agents. The primary outcome was a composite of 21-day “organ support-free” days, defined as number of hospital days not requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support, and in-hospital mortality. Thrombosis, bleeding and overall mortality were secondary outcomes. Patients who required therapeutic anticoagulation for other indications (e.g., mechanical heart valves) were excluded.
For patients requiring ICU level of care at enrollment (severe state): As of December 21, 2020, enrollment of patients requiring ICU level of care was paused due to an interim pooled analysis demonstrating futility (OR 0.76; 0.60 – 0.97) of full dose anticoagulation in reducing the need for organ support and mortality, compared with usual care prophylactic dose anticoagulation, in this specific subgroup. ICU level of care was defined as requiring high flow nasal oxygen, invasive or noninvasive mechanical ventilation, vasopressor therapy, or ECMO support. Peer-reviewed publication is pending (see preliminary data in Table). However, given the concern for safety (numerically higher mortality and bleeding; probability of therapeutic dose is harmful is 98.5%), we discourage the empiric use of full dose heparin or LMWH in this specific subgroup of COVID-19 patients who do not have other indications for therapeutic anticoagulation, outside of a clinical trial.
For hospitalized patients not requiring ICU level of care at enrollment (moderate state): On January 22, 2021, the NIH announced that full dose anticoagulation is superior to usual care prophylactic dose anticoagulation (proportional OR 1.5; 1.1 – 2.2) in reducing the need for organ support and mortality in moderately ill hospitalized COVID-19 patients. Moderately ill patients were defined as those who required hospitalization but not ICU level of care (see above) at the trial enrollment time point. Preliminary, non-adjudicated data on thrombotic and bleeding outcomes have been made public (see Table). Consequently, until peer-reviewed data are available, we recommend using clinical judgment, with careful consideration of the risk of bleeding and the eligibility criteria used in these studies, in managing individual patients.
Table: Pre-publication, interim, non-peer reviewed data from the Multiplatform Trial
|Moderate State||Severe State|
|Therapeutic||Usual Care||Therapeutic||Usual Care|
|Need for organ support*||~16%||~23%||N/A||N/A|
|Mortality||40/699 (5.7%)||54/699 (7.7%)||160/453 (35.3%)||144/442 (32.6%)|
|Thrombotic events ƚ||16/853 (1.9%)||24/742 (3.2%)||31/460 (6.7%)||53/448 (11.8%)|
|ISTH Major bleeding||14/853 (1.6%)||7/742 (0.9%)||17/460 (3.7%)||8/448 (1.8%)|
*a post-hoc analysis, ƚ includes DVT, PE, MI, ischemic stroke, other thrombotic event
Planning for continuing enrollment in these multiplatform trials is in process, while other studies are continuing in evaluation of other dosing regimens and interventions, such as intermediate dose anticoagulation or antiplatelet agents. We encourage participation in ongoing clinical trials and epidemiologic studies, and will update this FAQ as more data become available.
Are there any clinical scenarios of suspected thrombosis in which empiric therapeutic anticoagulation would be considered in COVID-19 patients?
In cases where there are no contraindications for therapeutic anticoagulation AND there is a very high clinical suspicion of thrombosis BUT no possibility of performing imaging studies to diagnose PE or DVT, empiric anticoagulation has been proposed in the following scenarios:
- Intubated patients who develop sudden clinical and laboratory findings highly consistent with PE, such as desaturation, tachycardia, increased central venous pressure or pulmonary artery wedge pressure, or evidence of right heart strain on echocardiogram, especially when chest X- ray and/or markers of inflammation are stable or improving.
- Patients with physical findings consistent with thrombosis, such as superficial thrombophlebitis, peripheral ischemia or cyanosis, thrombosis of dialysis filters, tubing or catheters, or retiform purpura (branching lesions caused by thrombosis in the dermal and subcutaneous vasculature).
- Patients with respiratory failure, particularly when D-dimer and/or fibrinogen levels are very high, in whom PE or microvascular thrombosis is highly suspected and other causes are not identified (e.g., ARDS, fluid overload).
If a patient is empirically started on anticoagulation for suspected PE, how long should they be anticoagulated? What if later investigation shows no evidence of PE?
All patients with COVID-19 who are started on empiric therapeutic anticoagulation for presumed or documented PE should be given a minimum course of 3 months of the therapeutic regimen (provided the patient tolerates treatment without serious bleeding). Thrombus resolution can occur within a few days of effective anticoagulation, so negative results from delayed testing should not be interpreted as implying PE or DVT was not previously present. At 3 months, therapeutic anticoagulation can stop, provided the patient has recovered from COVID-19 and has no ongoing risk factors for thrombosis or other indications for anticoagulation (e.g. prolonged immobilization or atrial fibrillation).
For additional information, see:
- Moores et al Prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19: CHEST Guideline and Expert Panel Report
- Barnes et al. Thromboembolism and Anticoagulant Therapy During the COVID-19 Pandemic: Interim Clinical Guidance from the Anticoagulation Forum.
- International Society of Thrombosis and Hemostasis
- Bikdeli et al. COVID-19 and Thrombotic or Thromboembolic Disease: Implications for Prevention, Antithrombotic Therapy, and Follow-up. JACC.
- Antithrombotic therapy in patients with COVID-19