Uptick in Heparin-Induced Thrombocytopenia in COVID-19 Complicates Care

There is a potential risk of heparin-induced thrombocytopenia (HIT) in patients with severe COVID-19 who received therapeutic doses of anticoagulation, according to a new French series suggesting an incidence rate that is higher than would be anticipated in ICU patients.

The findings have implications for the ongoing discussions over how and when, and with which agents, thrombosis risk in COVID-19 can be mitigated.

Among 86 patients with severe COVID-19 hospitalized at two ICUs, seven (8%) developed HIT and five of these patients had a severe thromboembolic event, including deep vein thromboses and stroke. HIT is a life-threatening immune-mediated drug reaction associated with decreases in the platelet count and a high risk of thrombosis. It is caused when platelet-activating antibodies bind to platelet factor 4 (PF4) and heparin complexes, explain Florence Daviet, MD (Assistance Publique-Hôpitaux de Marseille, France), and colleagues this week in Circulation.

The benefit-risk profile remains in favor of anticoagulation in my opinion. Florence Daviet

To TCTMD, Daviet said their ICU specializes in acute respiratory distress syndrome (ARDS) and extracorporeal membrane oxygenation (ECMO), and as such they received a number of patients with severe COVID-19-related pneumonia, some of whom required ECMO. “We quickly had the impression of observing more occurrence of HIT than usual in our patients, and this observation triggered our investigation,” she said in an email.

Given the evidence that severe COVID-19 is marked by a hypercoagulable state that predisposes patients to venous and arterial thrombotic events, the occurrence of HIT “could alter the risk-benefit balance of anticoagulation,” say investigators. Still, with the high risk of thrombosis among patients with severe COVID-19, anticoagulation is likely beneficial.

“The message of our work is to consider a possible higher incidence of HIT in severe COVID-19 patients [and] to closely monitor the platelets and to think early about the diagnosis of HIT,” said Daviet. “As the risk of thrombosis with significant mortality is high in these patients, the benefit-risk profile remains in favor of anticoagulation in my opinion.”

Making Sense of the Findings

Sanjum Sethi, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), who is part of his center’s pulmonary embolism response team (PERT), called the new report “fascinating” but urged caution interpreting the results.

“In the report, there was certainly a higher prevalence of HIT than what we see normally, but it’s a very small sample size,” Sethi told TCTMD. “So the findings need to be validated in a larger cohort. Secondly, COVID-19 certainly predisposes people—I should say we think it predisposes people—to arterial and venous complications, but the reality is that all these patients are critically ill, sedentary, hypoxic, and intubated in the ICU setting, which also predisposes them to clotting.”

The typical incidence of HIT in ICU patients is less than 1%, said Daviet, although it can range from 3% to 4% in patients supported by ECMO. In the present study, the researchers compared the 8% incidence of HIT in COVID-19 patients to a control cohort of ICU patients during the same 6-month period in 2019. During that period, the incidence of HIT among 447 patients was just 0.89%.

Critically ill patients are often treated with prophylactic anticoagulation to prevent thrombotic events, but there is a large suspicion that COVID-19 increases the risk of thrombosis beyond the typical risk factors accompanying critical illness, said Sethi.

Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA, and Yale University School of Medicine, New Haven, CT), said they also have encountered HIT in patients with severe COVID-19 treated with anticoagulation and that he agrees with the researchers about the need to be cautious about the potential risks when considering therapeutic anticoagulation, particularly in patients where such dosing might not be warranted. He noted that other reports have shown a higher-than-expected incidence of HIT in intubated COVID-19 patients, although this latest series is arguably the largest to date.

What we do today could help us inform practice tomorrow. Behnood Bikdeli

“HIT could be a catastrophic phenomenon, and usually we tend to think about it when somebody has a decrease in platelet count with multiple thrombotic events,” Bikdeli told TCTMD. The puzzling aspect of HIT with COVID-19 is that physicians may be uncertain if the thrombotic events are the result of thrombocytopenia or the virus, he said.

In the study, the seven patients with HIT had antibodies to PF4/heparin and the diagnosis was confirmed using the heparin-induced platelet aggregation test. Bikdeli said the standard criteria for confirming the diagnosis of HIT is a functional assay, such as a serotonin-release assay used typically in the United States. From clinical perspective, seeking a diagnosis of HIT based on a reduction in platelets, clinical risk scores, and PF4 antibody testing is “reasonable,” said Bikdeli, but he would have liked to have seen HIT confirmed, particularly in the context of COVID-19, with the functional assay.

“All of this is to say the published report is very interesting, but it’s based off a presumptive diagnosis and not a confirmed diagnosis,” he said.

Theodore Warkentin, MD (McMaster University, Hamilton, Canada), who has previously published a review of COVID-19 and hypercoagulation seen with HIT, pointed out that five of the seven patients with HIT developed thrombotic complications. “This high rate of thrombosis is consistent with the patients having 'true' HIT,” he said in an email. Like Daviet and colleagues, Warkentin stated that clinicians should be vigilant for HIT given the frequent use of heparin in COVID-19 patients.

‘Liberal’ Use of Therapeutic Anticoagulation

For Sethi and Bikdeli, the new report also highlights the use of aggressive anticoagulation in patients with severe COVID-19 given the potential for venous and arterial thrombotic complications.

At Columbia, they established a consensus across numerous specialties early in the COVID-19 pandemic to look at intermediate-dose anticoagulation against prophylactic dosing in the IMPROVE-COVID study of patients with severe COVID-19. The new French series identifying HIT “speaks to one of the potential harms of giving heparin more liberally,” said Sethi. “Maybe we need to temper that just a little bit. I think the key will be finding out which patients will benefit from the aggressive anticoagulation approach and which patients can be treated a little more conservatively. I don’t think that’s really been elucidated yet.”

“I completely agree that indiscriminate use of escalated doses of anticoagulation would not be the best thing to do,” added Bikdeli. “I strongly urge all clinicians and investigators that if they are planning to give an escalated dose, do it in a prospective research setting, ideally a randomized trial. What we do today could help us inform practice tomorrow.”

I think the key will be finding out which patients will benefit from the aggressive anticoagulation approach and which patients can be treated a little more conservatively. Sanjum Sethi

At their center, Daviet said severe COVID 19 patients received either enhanced prophylactic anticoagulation or therapeutic anticoagulation based on laboratory criteria for hypercoagulability, clinical risk factors for thrombosis, such as obesity or comorbid cancer, or a clinical diagnosis of thrombosis. Patients who required ECMO all received therapeutic anticoagulation. “In practice, the vast majority of patients received therapeutic anticoagulation,” she said in an email. The patients were switched to either argatroban or danaparoid after the HIT diagnosis.

Several studies of anticoagulant therapy in COVID-19 are ongoing, including multiple large-scale trials comparing different anticoagulant dosing regimens, such as ATTACC and the National Institutes of Health-sponsored ACTIV-4.

Bikdeli, along with Parham Sadeghipour, MD (Rajaie Cardiovascular Medical and Research Center, Tehran, Iran), is leading the INSPIRATION study, which is also testing intermediate-dose (enoxaparin 50 mg/day and higher based on weight and creatinine clearance) against standard-dose anticoagulation (40 mg/day unless adjusted for obesity or creatinine clearance).  

As reported by TCTMD, a recent review sums up the recent evidence related to use of anticoagulants and antiplatelets in the setting SARS-CoV-2 and other viruses, proposing an algorithm to help guide clinicians in their use of different antithrombotic therapies in different settings.

Right now, it’s uncertain which patients might be at risk for HIT, said Daviet. While obesity is a risk factor, only two of the seven patients who developed HIT were considered obese. Further studies, say researchers, are warranted to confirm the higher-than-usual incidence of HIT and to better understand the pathophysiology. Sethi agreed, adding that clinicians need “finer tools” be better understand which patients would benefit from aggressive anticoagulation.

“I don’t think the [French] report proves anything, but it raises a lot of questions,” said Sethi.