Web-Like Structures in COVID-19 STEMI Clots May Offer New Drug Target

In a novel approach that addresses questions typically broached at autopsy, researchers have shown that thrombi removed during primary PCI from patients with concomitant COVID-19 and STEMI offer clues to the abnormal clotting patterns seen in response to the virus.

Thrombi from five STEMI patients infected with SARS-CoV-2 had a high burden of web-like structures known as neutrophil extracellular traps (NETs) that could potentially become a new target for disrupting coronary clot formation caused by the virus, Ana Blasco, MD, PhD (Hospital Universitario Puerta de Hierro-Majadahonda, Spain), and colleagues suggest.

The median density of NETs was 61% in patients with STEMI and COVID-19 compared with 19% in historical STEMI controls prior to the pandemic (P < 0.001), the researchers reported last week in JAMA Cardiology.

The web-like NETs are composed of DNA and proteins that are typically released by neutrophils to ensnare pathogens. However, recent data from the United States and China have shown that many COVID-19 patients have high levels of certain markers of NETs in their blood, with higher levels among those on ventilators. The confirmation in this new study that NETs are found at high rates in STEMI patients with the virus adds to suspicions that unregulated NETs are a likely source of inflammation and microvascular thrombosis.

“This study reinforces the relevant role of NETs in the pathogenesis of SARS-CoV-2 infection. Based on our results, NETs seem to play a major role in coronary thrombosis in COVID-19 disease,” Blasco said in an email.

Commenting for TCTMD, Behnood Bikdeli, MD (Brigham and Women’s Hospital, Boston, MA, and Yale University School of Medicine, New Haven, CT), said that while strong conclusions cannot be drawn from such a small study, if true, the findings raise important questions about the therapeutic implications.

“Should we target the preemptive (prophylactic) antithrombotic strategies more intensely in those with ‘NETosis’? If so, how do we identify such a profile with simple bedside tests?” he noted in an email.

Bikdeli said there are currently more than 70 ongoing RCTs for various types of antithrombotic therapies in COVID-19 patients. Some of those studies are enrolling patients based on markers such as D-dimer, raising the question of whether peripheral assays could be used to identify increased levels of NETs.

NETs Found in All COVID-19 Patients

Blasco and colleagues examined intracoronary thrombi aspirated from four men and one woman with STEMI and COVID-19 who underwent primary PCI at their institution between March 23 and April 11, 2020. For the comparison group, they examined similar aspirates taken from 50 STEMI patients who had PCI between July and December 2015.

Every aspirate from the COVID-19 patients contained NETs compared with 68% of the historical controls. Examining the histology, Blasco and colleagues found that the thrombi from the COVID-19 group consisted primarily of fibrin, with some degree of polymorphonuclear cell infiltration.

None of the COVID-19 patients had fragments of atherosclerotic plaque or iron deposits suggesting previous episodes of plaque rupture. On the other hand, among the historical controls, 65% had evidence of plaque fragments in thrombi.

“The coagulation changes associated with COVID-19 suggest the presence of a hypercoagulable state that might increase the risk of thromboembolic complications,” Blasco and colleagues write. While increased D-dimer concentrations, modest decreases in platelet count, and prolongation of prothrombin time have been commonly documented in COVID-19 patients, they write, “None of these alterations was remarkable at the time of STEMI in this series, except in one patient who presented a high D-dimer concentration.” Interestingly, that patient was the only one among the five studied who died during hospitalization.

Despite the small sample size, Blasco et al add that “these findings would indirectly support the idea of an important role of neutrophils and NETs in coronary thrombus development in patients with COVID-19.”

To TCTMD, she said therapies that destabilize NETs, such as deoxyribonuclease (DNase) or alternative ways to block histone adhesion to other molecules, offer an interesting field of research.

“If proven effective and safe, some of these therapies could be feasible ways for the prevention of thrombotic disease in which NETs are involved,” Blasco said.

Bikdeli added that specific to drugs with antithrombotic properties, there is an ongoing RCT of dociparstat (Chimerix), a heparin derivative that may have anti-inflammatory and anticoagulant effects in addition to potentially reducing NETs.

Much of what has been learned thus far about the pathology of COVID-19 has come from autopsy studies. To TCTMD, Blasco said her study confirms that angioplasty in survivors is potentially an important source of information about COVID-19 and how it affects the cardiovascular system. 

“Indeed, thrombus aspiration during angioplasty offers the possibility of analyzing in vivo issues related to the thrombotic process in myocardial infarction,” she said. “A disadvantage is that the aspiration technique is unable to completely recover thrombotic material from most patients with STEMI, but it can be a useful source of information in this context.”