Study Affirms Thrombotic Risk in COVID-19

The now well-recognized risk of thrombotic events seen in patients with COVID-19 treated at various hot spots around the United States also was seen at two Cleveland Clinic sites, one in northeast Ohio and the other in south Florida, a new study shows.

Among patients treated between March 13 and May 13, 2020, the rate of acute thrombotic events—including venous thromboembolism (VTE), stroke, and MI—was 5.2% in the hospitalized cohort and 8.8% in the ICU cohort, according to researchers led by Ayman Elbadawi, MD (University of Texas Medical Branch, Galveston).

Those rates, though higher than usual, are lower  than what has been seen in hospitals in COVID-19 hot spots around the United States. One study from New York City, for instance, showed that 16% of hospitalized COVID-19 patients had thrombotic events.

The fact that the two areas included in the Cleveland Clinic analysis were not considered epicenters during the study period—and New York City was—might explain the discrepancy, senior author Scott Cameron, MD, PhD (Cleveland Clinic, OH), told TCTMD. “It’s possible that if you have the same type of patient in an epicenter with fewer resources, it would stand to reason that you’re going to have higher adverse events such as venous thromboembolism and maybe worse outcomes.”

It could also be that the breadth of expertise across specialties—which includes the largest vascular medicine department in the country—that can be called upon to provide the most up-to-date care played a role in the more-favorable patient outcomes, Cameron said.

And finally, based on the awareness that VTE is one of the biggest killers of hospitalized patients, Cleveland Clinic has ensured that preventive steps are taken in all. “In the COVID-19 era, we were especially well prepared for those patients because we were so aggressive at prophylaxis,” which might have contributed to the lower-than-expected thrombotic event rates, Cameron said.

The findings were reported in a research letter published online September 29, 2020, ahead of print in Arteriosclerosis, Thrombosis, and Vascular Biology.

Higher White Blood Cell Count Tied to Thrombosis

The investigators looked at data on 3,678 adults who tested positive for SARS-CoV-2 and were treated in the ambulatory or hospitalized setting at the two Cleveland Clinic sites in the first few months of the pandemic. About one-quarter (24.3%) were hospitalized, and 8.0% had to be admitted to an ICU.

In the hospitalized group, 2.7% of patients had VTE, 1.2% acute ischemic stroke, and 1.2% acute MI. The corresponding figures in the ICU cohort were 5.1%, 1.7%, and 2.4%.

Those with thrombotic events more frequently required respiratory support (57.8% vs 37.1%), pressors (28.9% vs 14.9%), and hemodialysis (31.1% vs 15.0%), and they had a longer length of stay (7.5 vs 6.0 days). In-hospital mortality was numerically—but not significantly—higher in patients with thrombotic events (17.5% vs 12.0%; P = 0.21).

Looking for factors independently associated with thrombotic events, the researchers found only one after multivariable adjustment: higher white blood cell count (OR 1.10; 95% CI 1.02-1.19). Surprisingly, Cameron said, that was driven by neutrophils and not lymphocytes. “Typically lymphocytes are what we expect to track with how well someone is responding to a virus,” he explained. “This is highly unusual for you to have a viral infection but then have the neutrophil count be the only predictor . . . of whether they’re going to get thrombotic events.”

What that means, he said, “is that while people are focusing on mechanisms of thrombosis, it’s critical that they keep in mind that systemic inflammation, in ways that we’ve never seen before, seems to be very prominent in this disease.”

Of note, D-dimer concentration was not independently associated with thrombotic risk, contrary to what has been seen in other studies. Cameron pointed out that at some hospitals, D-dimer is being used to guide whether patients receive a prophylactic or treatment dose of anticoagulation. “We have absolutely zero data for it,” he said. “And antithrombotic agents, particularly unfractionated heparin, have risks. And if there’s no data, we simply don’t do it.”

Rationale for Anticoagulant and Antiplatelet Therapies

That variation in practice from center to center is a reflection of the lack of solid evidence on which to base decisions around antithrombotic therapy.

In a review published online September 28, 2020, ahead of print in the International Journal of Cardiology, lead author Cosmo Godino, MD (IRCCS San Raffaele Scientific Institute, Milan, Italy), and colleagues go through the evidence related to use of anticoagulants and antiplatelets in the setting of infection with SARS-CoV-2 and other viruses. The idea for the review, written primarily in April and May, was sparked by the observation that patients with severe COVID-19 seemed to have a thromboinflammatory syndrome, presenting with MI, pulmonary embolism, and the like.

Godino et al also present an algorithm to help guide clinicians in their use of antiplatelet and anticoagulant therapy in COVID-19 patients across the spectrum of severity. “It is crucial to start anticoagulant therapy and to think about anticoagulant therapy as soon as possible in patients with severe or critical condition,” Godino told TCTMD, noting that “at the moment, we believe that anticoagulants are more important than antiplatelet therapy in COVID patients.”

One of the most important aspects of the review, according to Cameron, is a table that lists various antiplatelet and anticoagulant agents along with potential mechanisms of benefit in COVID-19 and drug-drug interactions.

So your suspicion for pulmonary embolism should be extraordinarily high in a patient with COVID-19 even if they’re on a heparin prophylactic dose. Scott Cameron

Cameron also liked the discussion over potential beneficial effects derived from different types of heparin, including anti-inflammatory and possibly direct antiviral effects, as well as the fact that the authors did not put a heavy focus on putting patients on anticoagulation after discharge if they had a thrombotic event. That’s good because there is emerging evidence that there is no additional risk of VTE after discharge in patients with COVID-19, he said.

The overall message regarding use of antithrombotic therapy in COVID-19 is that “every hospitalized patient should have venous thromboembolism prophylaxis, including patients with COVID-19,” Cameron said.

“Be aware that a lot of thrombosis with patients with COVID-19 occurs in situ. So you might get blood clots showing up in the lung with the absence of blood clots in the leg, and the reason for that is immunothrombosis or activation of white blood cells in concert with platelets. That appears to be a prominent [feature] in this disease,” he continued. “So your suspicion for pulmonary embolism should be extraordinarily high in a patient with COVID-19 even if they’re on a heparin prophylactic dose, and that may mean imaging patients if they’re not behaving according to what you think the normal clinical trajectory is.”

In a high-risk patient, low-molecular-weight heparin is as good as unfractionated heparin but works faster. Unfractionated heparin doesn’t reach therapeutic levels in the blood for about half a day, whereas it takes about an hour or 90 minutes with low-molecular-weight heparin. Also, unfractionated heparin requires a blood draw every 6 hours, so using low-molecular-weight heparin will reduce the risk of infectious exposure for healthcare workers tasked with drawing blood and monitoring anticoagulant levels, Cameron said.

As for antiplatelets, their potential utility for patients with COVID-19 is a major open question, both Godino and Cameron said. Cameron said there are several studies showing that neutrophil extracellular traps (NETs) seem to be a common feature of COVID-19. “Basically white blood cells are throwing out extracellular DNA and that’s activating platelets and it’s activating the coagulation cascade,” he explained.

There are currently 14 clinical trials evaluating antiplatelets in COVID-19 that have been registered, he said. One is looking at dipyridamole. “I do think that the mechanism of action of dipyridamole, because it blocks platelets and it also inhibits inflammation, could potentially be an important finding if it stands up to the rigors of randomized controlled trials,” Cameron said. But he cautioned against off-label use of antiplatelets in the meantime: “It’s too soon, and we as an institution are not encouraging that practice.”