The old but new: Can unfractioned heparin and low molecular weight heparins inhibit proteolytic activation and cellular internalization of SARS-CoV2 by inhibition of host cell proteases?

Abstract

The pathogenic infectivity of the virus requires the S1 subunit of the spike (S) protein to bind the host cell receptor, angiontensin converting enzyme (ACE2). While the binding to host cell receptor is the first step of infection, the entrance of the virus into the cell needs the cleavage of S1-S2 subunits to expose S2 for fusion to cell membrane via host proteases including cathepsins, cell surface transmembrane protease/serine (TMPRSS) proteases, furin, trypsin and factor Xa. Previous in vitro studies have shown that factor Xa inhibition can decrease viral infectivity. We suppose that host cell proteases including furin (as expressed highly in lungs), factor Xa and cathepsin are possible targets to decrease viral burden, therefore unfractioned heparin and low molecular weight heparin-LMWH (specifically dalteparin and tinzaparin for their anti inflammatory action) can be potential inhibitors of multiple endoproteases involved in virus infectivity. Our hypothesis needs to be tested in in vitro and clinical studies, however as we are in an urgent situation as the burden of SARS-CoV2 is increasing all around the world, we recommend the usage of unfractioned heparin or LMWH in intensive care unit (ICU) and non-ICU hospitalized patients with the risk-benefit judgement of the clinician. Whether our hypothesis is clinically applicable and successful in decreasing viral infection will be evaluated for further studies.

Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID‐19

“…The next step requires cleavage of the S1‐S2 subunits, which then allows the S2 subunit to fuse with the cell membrane to promote viral entry into the host cell 9 . While a number of proteases can cleave the S protein subunits, factor Xa is a major contributor to this reaction 11 …”

“…The receptor is also located in the kidney, heart, gastrointestinal tract, as well as on lymphocytes. Once ACE2 binds to the S1 subunit on SARS‐CoV‐2, the receptor is downregulated 11–14 . This produces an abundance of ATII, which can cause direct lung damage itself 15 …”

Potential Therapeutic Roles for Direct Factor Xa Inhibitors in Coronavirus Infections

“…Importantly, FXa inhibitors are generally associated with less rebound hypercoagulation that is more common with heparins and direct thrombin inhibitors [50,51]. In fact, while heparins appear to be gaining significant interest in treating COVID-19 patients [52,53], a recent study has documented evidence of heparin resistance in critically ill patients [54]. This suggests that alternative anticoagulants are in urgent Together, given the established efficacy and safety of direct FXa inhibitors as anticoagulants, and the pathogenesis of the ongoing viral pandemic, it is anticipated that these drugs can play a major role in treating the reported coagulopathies so as to mitigate the illness manifestations and reduce the death rate of COVID-19 patients.…”

Cardiac Arrhythmias in Critically Ill Patients With COVID-19: A Brief Review

“…It has been postulated that heparin actually can provide the additional advantage of inactivating a protease that is related to viral infectivity, and both unfractionated heparin and low-molecular-weight heparin have short half-lives and a low degree of drug-drug interactions, thus making them attractive first-choice agents for critically ill patients. 63 Regarding oral anticoagulation, warfarin may not be preferred in these patients due to the many pharmacokinetic/dynamic alterations that can occur. Interruptions in tube feeding and varying vitamin K content, as well as initiation/discontinuation of antibiotics, steroids, and antiviral medications, can lead to fluctuations in the international normalized ratio.…”