New Target to Combat COVID-Related Thrombosis?

Megan Brooks

November 04, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

More than half of patients hospitalized with COVID-19 have prothrombotic antiphospholipid (aPL) autoantibodies in their blood, which could contribute to venous and arterial thromboembolism commonly seen in COVID patients, new research indicates.

"In patients with COVID-19, we continue to see a relentless, self-amplifying cycle of inflammation and clotting in the body. Now we're learning that autoantibodies could be a culprit in this loop of clotting and inflammation that makes people who were already struggling even sicker," investigator Yogendra Kanthi, MD, from the University of Michigan's Frankel Cardiovascular Center in Ann Arbor, and the National Heart, Lung, and Blood Institute, said in a news release.

While it's "too soon to change clinical practice, it could be that these antibodies will allow for better personalization in the treatment of COVID-19. For example, individuals with positive antibody tests might benefit from strong anticoagulants," co-investigator Jason Knight, MD, PhD, with University of Michigan Medicine, told theheart.org | Medscape Cardiology.

The study was published online November 2 in Science Translational Medicine.  

Antiphospholipid antibodies abnormally target phospholipids and phospholipid-binding proteins and their presence is key to the diagnosis of antiphospholipid syndrome. However, aPL antibodies can also arise transiently in patients with critical illness and various infections; case series have recently detected aPL antibodies in COVID-19 patients.

To investigate further, the Michigan team measured eight types of aPL antibodies in serum from 172 patients hospitalized with COVID-19. 

They found that 89 patients (52%) tested positive for at least one type of aPL antibody based on the manufacturer's cut-off and 52 (30%) tested positive using a more stringent cutoff (titer ≥40 units). 

"Moderate-to-high" titers were evident in roughly two thirds of positive samples.

The majority of positive samples were associated with three types of aPL autoantibodies: anti-phosphatidylserine/prothrombin (aPS/PT) IgG (24% of samples), anticardiolipin (aCL) IgM (23%), and aPS/PT IgM (18%).

Therapeutic Implications

"Higher titers of aPL antibodies were associated with neutrophil hyperactivity including the release of neutrophil extracellular traps (NETs), higher platelet counts, more severe respiratory disease, and lower clinical estimated glomerular filtration rate," the researchers report.

They note that studies from the general thrombosis literature have shown that activated neutrophils, and in particular NET formation, contribute to the generation of blood clots in arterial, venous, and microscopic vascular beds. NETs have also been recently implicated in the development of antiphospholipid syndrome.

Therapies that target NET formation may have a role in treating thrombotic disease, including potentially COVID-19. Dipyridamole, for example, suppresses aPL antibody-mediated NETosis and mitigates venous thrombosis in mice, the researchers note.

And in the current study, they showed that dipyridamole suppressed COVID-19 patient IgG-mediated NET release from neutrophils in vitro

The researchers have launched a randomized clinical trial called DICER to test the efficacy of dipyridamole, "a safe, generic, and inexpensive drug to break the endless cycle of inflammation and thrombosis that makes patients with COVID-19 sicker," Kanthi told theheart.org | Medscape Cardiology.

The researchers also suggest more systematic exploration of plasmapheresis in the subgroup of COVID-19 patients with high titers of aPL antibodies.

It will also be important to define the extent to which convalescent plasma may harbor aPL antibodies or other prothrombotic autoantibodies in addition to protective anti-SARS-CoV-2 antibodies, they say.

A limitation of the current analysis is that aPL antibodies were not tested on a defined day of hospitalization, but rather when a serum sample became available to the research laboratory.

"Future studies should endeavor to systematically track aPL antibodies over the full course of hospitalization of COVID-19 patients, and perhaps especially at and after the time of discharge," the study team suggests.

The study had no specific funding. The authors have disclosed no relevant financial relationships.

Sci Transl Med. Published November 2, 2020. Full text

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