Managing Thrombotic Complications in ICU Patients with COVID-19

By Shruti Gadre, MD

The prevalence of venous thromboembolism (VTE) is markedly higher in patients with COVID-19 in the intensive care unit (ICU). A meta-analysis of 66 studies and more than 28,000 patients with COVID-19 found that the rate of VTE in the entire population was 14% but about 23% in the ICU population.

However, at the end of 2020, both the International Society on Thrombosis and Haemostasis (ISTH) and the American College of Chest Physicians (CHEST) released consensus statements recommending against routine screening ultrasonography/echocardiography to rule out VTE in these patients. Why?

1. While the incidence of VTE was reportedly very high from the initial COVID-19 studies coming out of China, the rate of routine thromboprophylaxis administration in China is only about 20%.
2. A sizeable proportion of VTEs discovered were subsegmental pulmonary emboli or deep vein thrombi (DVT) in the calf — of questionable clinical significance.
3. The data, although welcome, were from small retrospective studies, not high-quality research published in peer-reviewed journals.
4. Routine screening could expose more healthcare personnel to the virus and increase demand on already limited resources.
5. The pathophysiology of these cases of VTE was thought to be different: Many may be in situ thrombosis rather than embolism, so appropriate treatment may be different.

When to consider testing for VTE

So, how do we reconcile this? While routine screening is not recommended, it is important to keep a high level of suspicion and low threshold to pursue an ultrasound, especially in patients with lines and catheters.

The presence of pulmonary embolism (PE) should be considered when a patient exhibits hemodynamic instability or poor gas exchange that is not fully explained or is out of proportion with the stage, duration and rate of progression of COVID-19 infection. For example, PE testing should be considered in a patient presenting with minimal pulmonary infiltrates and mild, short-term symptoms, but with syncope, shock, acute respiratory failure or signs of acute right ventricular failure. PE also should be considered if a patient develops acute shortness of breath, worsening oxygenation, hypotension or tachycardia, especially if imaging or clinical findings are not consistent with worsening COVID pneumonia. Data from France suggest that PE seen in patients with COVID-19 occurs at a median of six days.

Despite consensus statements, there are hospitals with screening protocols using D-dimer testing and point-of-care ultrasounds. At this time there is insufficient evidence to recommend using an elevated D-dimer or other laboratory data to guide screening for VTE.

Thromboprophylaxis in the ICU

It has been established that, in general, most ICU patients are at increased risk of thrombosis and that prophylactic anticoagulation reduces this risk. We can easily apply this data to the COVID-19 population.

Both low-molecular-weight heparin (LMWH) and unfractionated heparin (UFH) can be used for thromboprophylaxis. Societal consensus statements favor LMWH as it requires less-frequent administration, reducing caregiver exposure. Of course, renal injury and history of heparin-induced thrombocytopenia should be considered. Direct oral anticoagulants (DOACs) should be avoided due to high risk of rapid clinical deterioration, especially when concomitant therapy (antiviral and investigational treatment) is being administered, which can affect pharmacodynamics and bleeding risk.

Currently, most societies are recommending standard-dose prophylactic anticoagulation. It is important to limit skipped doses and escalate to intermediate dosing in obese patients according to current guidelines. Some hospitals have individualized risk-stratification protocols (often based on D-dimer levels) to escalate to intermediate dosing.

Treatment options after diagnosis of VTE

Once VTE has been diagnosed, consider these factors before determining which anticoagulant to use:

• Up to 20% of COVID-19 patients may have an elevated baseline partial thromboplastin time. Lupus anticoagulant has been reported in 40-90% of COVID-19 patients with a prolonged activated partial thromboplastin time (aPTT). Thus, if heparin is used for anticoagulation, anti-Xa assays are more useful than aPTTs.
• A large number of ICU patients with COVID-19 have renal dysfunction. As such, enoxaparin, DOACs and fondaparinux may not be appropriate or should be administered cautiously.
• Given the highly infectious nature of COVID-19, it may be important to limit caregiver exposure. Drips such as heparin, argatroban or bivalirudin may be less favorable. On the other hand, drugs with shorter half-lives (drugs that are easily titratable) give more flexibility to de-escalate/escalate therapeutics in the setting of bleeding or need for invasive revascularization.

Also, it is important to note that DOACs may have more drug-drug interactions than other parenteral agents. This may be more relevant for patients with comorbidities and patients on experimental treatments for COVID since all drug-drug interactions are not known.

Therefore, most society consensus statements recommend initial treatment with LMWH or UFH in the ICU. DOACs can be considered in an outpatient setting if there are no contraindications. Patients should receive treatment for at least three months.

While the pathophysiology of venous thrombosis may be different in COVID compared to other etiologies, at this point we have no reason to believe that the immediate risk of further deterioration from VTE is any different. Thus, our standard risk-stratification tools are still applicable.

To make treatment decisions, we can use the American Heart Association classification of low-risk, submassive and massive PE, or the European Society of Cardiology classification of low-, intermediate- and high-risk PE. Either way, low-risk patients do well with anticoagulation alone, while massive/high-risk patients need systemic thrombolysis if there are no contraindications. Intermediate-risk patients need to be monitored closely, and a fraction of them (along with massive PE patients with contraindications to systemic thrombolytics) may benefit from catheter-directed interventions. Catheter-based treatments follow the same protocols in COVID-19 patients as they do in other patients. The only difference is in infection-prevention protocols according to institutional practices.

Extended-duration thromboprophylaxis

Extended-duration thromboprophylaxis is generally not recommended for patients after discharge. Both ISTH and CHEST recommended against it prior to COVID-19 due to the results of multiple randomized controlled trials. APEX and MAGELLAN trials found that while administering DOACs for up to 45 days after discharge decreased absolute risk of venous thrombosis 0.5-2%, there was also a 2% increase in risk of major bleeding.

Having said this, it’s important to note that a patient admitted to the ICU does have a higher risk of thrombotic complications compared to a patient not admitted to the ICU. The absolute risk really depends on the patient population, but risk-stratification tools have been developed and validated. One tool is the IMPROVEDD score, which notes that an ICU stay increases risk of VTE post-discharge.

ICU patients also have a high risk of arterial thrombotic events post-discharge. A post-hoc analysis of the Mariner trial, which studied use of rivaroxaban for post-discharge extended thromboprophylaxis, revealed that if arterial and venous thrombotic events are combined (something we see frequently in COVID-19), the risk-benefit ratio favored use of extended-duration DOACs.

While not routine, it seems reasonable to at least consider extended-duration thromboprophylaxis in certain patients that may be high risk for thrombosis. Although no data specific to COVID-19 exist, it is reasonable to employ individualized risk stratification for thrombotic and hemorrhagic risk, followed by consideration of extended prophylaxis (for up to 45 days).

About the author: Dr. Gadre is a critical care specialist in Cleveland Clinic’s Respiratory Institute. This article is based on her presentation “Management of Thrombotic Complications in Patients with COVID-19” at the 2020 CHEST® Annual Meeting.