Finding the Right Balance in COVID-19 Thromboprophylaxis

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APRIL 24, 2020 -- News this week that Broadway star Nick Cordera had one of his legs amputated due to thrombotic complications of COVID-19 brought to center stage what many physicians have been wrestling with for months.

Initial reports from China suggested hemostatic derangements, such as elevated D-dimer and prothrombin time, in patients with COVID-19. The second wave in Italy, Germany, and Spain brought reports of alarmingly high rates of venous and arterial thrombosis.

Soon after, clinicians began witnessing first-hand similar cases in New York City, recalled Behnood Bikdeli, MD, New York–Presbyterian Hospital/Columbia University Irving Medical Center and Yale University's Center for Outcomes Research and Evaluation, New Haven, Connecticut.

"There's so much confusion, so much heterogeneity in the way people are practicing — and granted, the evidence is not perfect — but I thought it's about time to provide a thorough assessment of the known literature but also some consensus-based recommendations," he told | Medscape Cardiology.

Together with Mahesh Madhavan, MD, also with New York–Presbyterian Hospital/Columbia University, they pulled together a 36-person international collaboration in 2 weeks. The resulting document was published April 15 in the Journal of the American College of Cardiology and endorsed by, among others, the International Society on Thrombosis and Haemostasis.

The report summarizes evidence on the pathogenesis, diagnosis, and management of thrombotic disease in patients with COVID-19, as well as how to manage patients with thrombotic disease without COVID-19.

The expert panel also highlights potential drug–drug interactions between investigational COVID-19 therapies and antithrombotic medications, and underscores the many unknowns still facing us.

The consensus is that COVID-19 may predispose patients to arterial and venous thrombotic disease but it not known whether there's an excess of clotting. There are no modern comparisons with historically matched ICU patients, who have had non-negligible thrombosis rates ranging from 5% to 20% and averaging about 7% to 7.5%, even despite thromboprophylaxis, said panel member Ido Weinberg, MD, medical director of VASCORE and comedical director of anticoagulation management services at Massachusetts General Hospital in Boston.


The numbers for COVID-19 patients have also been variable, he told | Medscape Cardiology. A publication from the Netherlands quoted a 31% cumulative incidence of thrombotic complications in COVID-19 ICU patients receiving at least standard thromboprophylaxis.

A pair of letters published April 24 in Radiology report that 23% of COVID-19 patients had acute pulmonary embolus (PE) on CT angiography at a US center as did 30% seen at a French tertiary care center.

However, a letter published last week on the first 393 patients at two New York hospitals, reported clotting complications in only 7.7% — a number reminiscent of that in the ICU population, Weinberg noted.

Both populations share traditional risk factors for thrombosis, such as older age and limited mobility. In COVID-19, there is also a very marked inflammatory response and critical illness. "Some of it [inflammation] is specific to coronaviruses but some of it is more general, and parsing it out specifically, I don't think we have the knowledge to do," he said.

Balancing VTE and Bleeding

Diagnosing VTE or pulmonary embolism (PE) may be challenging among patients with COVID-19, the experts note. Imaging studies may not be pursued because of the risk of transmitting infection or due to patient instability. Access to imaging may also be limited by the need to keep patients in a prone position.

Therapeutic anticoagulation is the mainstay of VTE treatment, but the optimal anticoagulation regimen is one of the biggest unknowns in this pandemic.

"Prophylaxis is crucial for most hospitalized patients," coauthor Madhavan told | Medscape Cardiology in an email. "[The] only reasons to avoid would be contraindications, which may involve active bleeding or extremely low platelet counts."

Prophylaxis therapy has been shown to prevent thrombotic events in many hospitalized patients prior to COVID-19, and there is some preliminary and limited evidence to say this extends to COVID-19 patients as well, he said.

For prophylaxis, patients typically receive low molecular weight (LMWH) or subcutaneous heparin. Many clinicians, however, are so concerned for undetected thrombi, that full-dose anticoagulation — often with parenteral agents such as unfractionated heparin or LMWH — are also being administered in many centers, Madhavan explained .


"We have certainly heard of cases where full-dose anticoagulation has unfortunately led to major bleeding events," he said. "It is important to note that while these patients are at elevated risk for thrombotic events, risk for bleeding is likely elevated in many as well, particularly in the critically ill patients with abnormal hemostatic parameters."

"Predicting the patients that may benefit from more intensive anticoagulation is very challenging and we need more studies and data to determine the right patients who may benefit from intensified anticoagulation," Madhavan said.

Weinberg also expressed concern for an elevated bleeding risk in patients receiving full-dose anticoagulation.

"Everyone is talking about the thrombosis but no one is talking about the bleeding," he said. "But there definitely is bleeding, including clinically significant bleeding, and [data] will be published soon."

Weinberg highlighted a small, retrospective paper, in which 11% of COVID-19 patients with a high risk for VTE, based on their Padua Prediction Score, also had a high risk of bleeding.

"I can tell you from the data I know that's unpublished yet, it pans out," he said.

Both LMWH and direct oral anticoagulants (DOACs) offer the advantage of not needing regular monitoring for efficacy, however, LMWH may be a better solution for hospitalized COVID-19 patients, Madhavan said.

"Given their longer half-life, the effect of DOACs can stick around the body and increase the likelihood of bleeding, especially in circumstances where procedures are needed/likely," he said.

The expert panel also point outs that DOACs can potentially interact with a number of medications, including investigational COVID-19 treatments.

For these reasons, Madhavan is switching his hospitalized COVID-19 patients, especially those that have the chance to decompensate, from DOACs to LMWH.

"For more stable patients that are likely to be discharged soon, keeping them on DOACs is not an unreasonable strategy," he added.

Although the Centers for Disease Control recently indicated a higher risk for severe COVID-19 in patients taking blood thinners, there is no evidence that antiplatelet agents or anticoagulants increase the risk of contracting or of developing severe COVID-19, the panel members said.

Medscape Medical News


J Am Coll Cardiol. Published April 15, 2020. Full tex

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