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Unscrambl(ase)ing COVID-19 SisobmorhT → Thrombosis

December 13, 2021
Naseema Gangat, MBBS

Dr. Naseema Gangat (@n_gangat), Editor of the 2021 ASH News Daily, is an associate professor of medicine in the Division of Hematology at Mayo Clinic in Rochester, Minnesota. She specializes in adult hematology and has a special interest in myeloproliferative neoplasms, myelodysplastic syndromes, and acute leukemia. She received her medical degree at Aga Khan University in Karachi, Pakistan, the city that also happens to be her hometown. She moved to the United States to pursue an internal medicine residency followed by hematology/oncology fellowship training at Mayo Clinic in Rochester. Dr. Gangat first got involved with ASH News Daily in 2018 as an Author. If the Burberry reference wasn’t a hint, Dr. Gangat is a proud “fashion-enthusiast” and regular attendee at London Fashion Week as well as Beverly Hills (Rodeo Drive) runway events — occasions known for being almost as exhilarating as the ASH annual meeting. 

The scientific community scrambles to decipher COVID-19–induced thrombosis, with more than 3,500 published studies on the subject. Although dysregulation of coagulation during SARS-CoV-2 infection and high rates of accompanying thrombosis are well described, with an estimated incidence of 14 to 22 percent, the postulated mechanisms of thrombosis remain elusive. The top culprits include inflammatory milieu, complement activation, endothelial injury, immune-mediated stimuli, neutrophil extracellular traps, antiphospholipid antibodies, and increased platelet activation, which result in “microthrombosis” or “immunothrombosis.” 

The COVID-19 clot unthickens at this year’s Plenary Scientific Session with the seminal discovery of a novel mechanism of COVID-induced thrombosis, bringing forth the prospect of targeted therapeutic intervention, exemplifying a true bench-to-bedside approach. I was fortunate to learn the backstory from lead laboratory investigator at the Beth Israel Deaconess Medical Center, Dr. Sol Schulman. He began by explaining, “Although tests like D-dimer capture the end result of coagulation activation, none of our standard clinical assays measure coagulation initiation or membrane procoagulant activity, which is tightly regulated by externalization of cell surface phosphatidylserine [PS].” One of the dominant mechanisms regulating PS externalization is the calcium-dependent phospholipid scramblase TMEM16F. Dr. Schulman’s team was excited to discover early in the pandemic that SARS-CoV-1 encoded an accessory protein ORF3a that was a predicted cation channel with high conservation between SARS-CoV-1 and -2. This led them to hypothesize that increased calcium permeability due to the ORF3a viroporin might dysregulate intracellular calcium homeostasis, trigger PS exposure, and enhance the activity of the tenase and prothrombinase complexes to drive coagulation. 

Jacob LudingtonIn his presentation, Dr Jacob Ludington (pictured), winner of the Mary Rodes Gibson Memorial Award, convincingly illustrates the above hypothesis through a series of experiments conducted in A549 pulmonary alveolar epithelial cells with synchronized ORF3a expression using a doxycycline-inducible system. Key findings included ORF3a-induced increased intracellular calcium and PS externalization without increased cell death; the latter process of PS externalization was accomplished through TMEM16F. Additionally, he demonstrated the critical role of ORF3a, in augmenting PS-dependent tissue factor procoagulant activity without a change in tissue factor expression in 53 lung autopsy specimens. Importantly, the pro-coagulant state induced by ORF3a was highly dependent on both PS and TMEM16F and was abrogated by either PS-binding protein lactadherin, or TMEM16F inhibition by either siRNA-mediated knockdown or drugs such as benzbromarone and CaCCinh-A01. Furthermore, the above observations were validated through live virus infection models devised together with the laboratory of Dr. Robert Schwartz at Cornell University, which demonstrated that ORF3a is both sufficient and necessary for augmentation of PS exposure and initiation of coagulation. 

The mechanism unveiled is exciting because it suggests potential therapeutic avenues, including the use of TMEM16F and ORF3a channel inhibitors. In support of the therapeutic relevance of these observations, Plenary introducer Dr. Andreas Greinacher, in his opening remarks astutely pointed out, “The current practice of anticoagulation with heparin blocks thrombin generation after PS exposure has occurred and causes bleeding complications.” Thus, the findings of this work open the door to counteract PS exposure without increasing bleeding risk at the same time. One potential TMEM16F inhibitor, an “unscramblase,” is the uricosuric agent benzbromarone, which is already available for the treatment of gout in 20 countries. Hence, we are cautiously optimistic that the drug can be promptly evaluated in the clinical setting, perhaps bringing us a step closer to mitigating morbidity and mortality associated with COVID-19 thrombosis. Undoubtedly, this work represents one piece of the COVID-19 puzzle and likely represents the beginning of the end. As British designer Anya Hindmarch reflected, “Often fear is the same emotion as excitement. It means you are breaking ground.”  

On a parting note, in accordance with conventional coagulation, here goes a pictorial rendition titled “Unscrambl(ase)ing COVID-19 Thrombosis,” which illustrates a putative virus-intrinsic mechanism for COVID-19–induced thrombosis. 















Dr. Gangat indicated no relevant conflicts of interest.

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