On the Question of Venous Thromboembolism in COVID-19: Some Answers, More Questions and Our Experience

The coronavirus disease of 2019 (COVID-19) caused by the severe acute respiratory syndrome novel coronavirus (SARS-CoV-2) has wreaked havoc, due to its contagiousness and ability to manifest a deadly illness. Though hypoxemic respiratory failure due to bilateral extensive pulmonary infiltrates is the cause of death in 70% of fatal COVID-19 cases, the disease is by no means limited to the lungs.

As the new pandemic causing syndrome continues to be explored via scientific studies, it is now abundantly clear that COVID-19 is a pro-thrombotic illness.

We will focus on aspects of venous thromboembolism (VTE) related to COVID-19 in our inquiry into the coagulation abnormalities induced by SARS-CoV-2.

How Does It Happen?

SARS-CoV-2 is a single stranded enveloped RNA virus that obviously bears similarity to SARS-CoV-1, the original SARS epidemic causing virus in 2003. The data from that epidemic, as well as from COVID-19, suggests that unlike other RNA virus syndromes that cause hemorrhagic fever (Lassa, Ebola, and Dengue), there is increased thrombosis rather than bleeding diathesis.

The mechanism of this phenomenon, though not fully understood, is quite complex:  It involves an interplay of the inflammatory response from activated immune cells (macrophages, monocytes), pulmonary capillary endothelial glycocalyx damage, clotting cascade activation, fibrinolytic changes, and stimulation of cell death mechanisms.

The concept of this “immunothrombosis” at pulmonary capillary level leads to not only the worsening gas exchange seen alongside the cytokine surge of COVID-19, but also to the body’s response to attempt to degrade the clot fibrin by excessive fibrinolysis. Hence, the spike of degraded fibrin fragments (D-dimer) in the blood stream seems to correlate with severity of illness and the development of the systemic hypercoagulable state.

How Common Is It?

Current data suggests about a 40% risk of VTE in hospitalized COVID-19 (moderate to severe illness) patients. This is twice as much as what is documented for SARS-CoV-1.

How Is It Diagnosed?

Clinical suspicion thresholds and pretest probability scoring systems must be utilized as per standard hospitalized patients; however, the utility of D-dimer to assess feasibility to perform diagnostic testing for VTE is now in the forefront.

Based on the above pathophysiological description, rising D-dimer levels, especially in conjunction with systemic and laboratory markers of inflammatory surge (fever, leukocytosis, thrombocytosis, hyperferritinemia, C-reactive protein and lactate dehydrogenase elevations), may prompt diagnostic testing, including Doppler ultrasonography and CT-angiography.

How Is It Prevented?

Studies continue to evaluate the utility of different types and doses of pharmacological VTE prophylaxis. As far as type or formulation is concerned, expert opinion is not too divided. Low molecular weight heparin (LMWH) is preferred over unfractionated heparin (UFH), based on less frequent scheduling and therefore decreased exposure to staff administering the agent.

LMWH has to be used cautiously in worsening creatinine clearance, and UFH may be the agent of choice then. LMWH is also the agent preferred over fondaparinux, which is another attractive option due to once daily dosing. Direct oral anticoagulants (DOACs) are not preferred for VTE prophylaxis, due to safety profile, duration of action, dosage issues in renal failure, and other drug interactions.

As far as dose is concerned though, opinion has certainly not reached consensus. Standard dosing though recommended may not be adequate in this hypercoagulable milieu. Studies using higher doses of LMWH or UFH for VTE prevention have shown mixed results.

Higher dosing is being advocated for obese patients, those with other co-morbidities predisposing to VTE and importantly based on D-dimer values.

How Is It Treated?

Therapeutic anticoagulation using LMWH or UFH is utilized either after established VTE diagnosis or in many cases, empirically based on clinical probability scores as well as D-dimer values. The duration of VTE therapy remains uncertain. Current guidelines suggest continuing anticoagulation for up to three months for established VTE. This would require DOAC use after in-patient stay as the long-term agent of choice. Factor Xa inhibitors like apixaban and rivaroxaban are common choices.

Sub-massive or massive pulmonary embolism guidelines remain the same in COVID-19 patients, and existing algorithms incorporating systemic or catheter-directed thrombolysis remain in place.

How Was Our Experience?

Indiana experienced the initial wave of COVID-19 patients starting at the end of February 2020, and our ICU, already geared up for the pandemic, received 136 critically ill COVID-19 patients in the months of March and April. By the end of March, we were able to confirm the higher incidence of VTE in ICU patients based on our first-hand experience.

We published two studies related to VTE in COVID-19. 45 patients were included. Nineteen of 45 patients (42.2%) were found to have deep venous thrombosis (DVT). Sequential organ failure assessment scores were similar between the groups, but D-dimers were markedly higher in patients with DVT, both for maximum value and value on day of ultrasound (p < 0.01 for both). Choice of prophylactic regimen was not related to presence of DVT (p = 0.35). Based on our data, ultrasound evaluation is recommended if D-dimer is greater than 2,000 ng/mL (sensitivity 95%, specificity 46%) and empiric anticoagulation considered if D-dimer is greater than 5,500 ng/mL (sensitivity 53%, specificity 88 (Crit Care Med 2020 Jun 26;10.1097/CCM.0000000000004472).

Our second published study was on 109 COVID-19 ICU patients. We showed that elevated admission D-dimer and peak D-dimer were associated with VTE (p < 0.05). D-dimer greater than 2,600 ng/mL predicted VTE with an area under the receiver operating characteristic curve of 0.760 (95% CI, 0.661-0.858; p < 0.0001), sensitivity of 89.7%, and specificity of 59.5%. Twelve patients (11%) had thromboelastography performed, and 58% of these patients had a hypercoagulable study. The calculated coagulation index was hypercoagulable in 50% of patients with thromboelastography. (Crit Care Med 2020 May 27;10.1097/CCM.0000000000004466).

What Next?

There are currently 11 trials listed on ClinicalTrials.gov that are addressing various aspects of VTE in COVID-19. Randomized control trials evaluating different dosing regimens of VTE prophylaxis (high vs. low) based on length of stay, severity of illness, markers of inflammation and D-dimer levels are underway.

Similarly, trials using therapeutic anticoagulation empirically compared with standard care in COVID-19 are recruiting patients. Empiric use of agents like nafamostat mesylate and alteplase is being studied prospectively.

In conclusion, as we face this new complex disease and continue be challenged by the intricacies in human pathophysiology induced by SARS-CoV-2, VTE prevention and treatment has come to the forefront in managing severe COVID-19 patients. The link of large vessel thrombosis to microvascular pulmonary capillary thrombosis seen in autopsies indicate a wide spectrum of this immune-inflammatory-coagulation link. There will certainly be more to come on this in the near future.

Omar Rahman, MD, FCCM 
Assistant Professor of Medicine, Critical Care Medicine 
Indiana University School of Medicine/Indiana University Health