Increased plasma heparanase activity in COVID-19 patients

Abstract

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. Heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n=10) and COVID-19 patients (n=48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity associated with disease severity including the need for intensive care and mechanical ventilation, lactate dehydrogenase levels and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.

Beneficial non-anticoagulant mechanisms underlying heparin treatment of COVID-19 patients

“…Importantly, heparin/LMWH, and chemical heparin derivatives have proven to be potent HPSE inhibitors [ 21 , [32] , [33] , [34] ]. In line with this, in a recent preprint we showed that non-ICU patients receiving the LMWH dalteparin in a prophylactic dose of 5000 IU daily had a significantly lower HPSE activity, suggesting that clinically relevant inhibition of HPSE activity can already be reached using prophylactic-dose LMWH [26] . Taken together, we hypothesise that inhibition of increased HPSE activity by heparin/LMWH could be one of the main mechanisms to reduce severe clinical manifestations of COVID-19.…”

“…This suggests that increased HPSE activity may play a role in the severe clinical manifestations of COVID-19, including ARDS, and AKI. Notably, in a recent preprint we showed increased plasma HPSE activity in COVID-19 patients [26] .…”

“…Due to the multiple inflammatory and pathogenic mechanisms targeted by heparin/LMWH, it is warranted to conduct clinical studies that evaluate therapeutic doses of these compounds in COVID-19 patients. Although a prophylactic dose of LMWH is associated with a reduced HPSE activity in non-ICU COVID-19 patients [26] , regarding the other possible non-anticoagulant effects, no data is currently available as to whether heparin/LMWH in their usual prophylactic, or therapeutic dosage are effective to prevent viral entry, to neutralize cytokines and histones, and to interfere with leukocyte trafficking. In fact, the optimal anticoagulant dosing in patients with COVID-19 is currently uncertain.…”

Endothelium Infection and Dysregulation by SARS-CoV-2: Evidence and Caveats in COVID-19

“…Low-molecular-weight heparin (LMWH) is an anticoagulant medication commonly used to treat venous thromboembolism and inflammation [ 17 , 211 ]. LMWH is as an inhibitor of the endothelial glycocalyx-degrading enzyme heparanase, which is well known to exacerbate vascular leakage and inflammation, and may be involved in the development of ARDS in COVID-19 [ 212 ]. A study of 48 hospitalized COVID-19 patients found evidence of endothelial barrier destruction and increased plasma heparanase associated with disease severity [ 212 ].…”

“…LMWH is as an inhibitor of the endothelial glycocalyx-degrading enzyme heparanase, which is well known to exacerbate vascular leakage and inflammation, and may be involved in the development of ARDS in COVID-19 [ 212 ]. A study of 48 hospitalized COVID-19 patients found evidence of endothelial barrier destruction and increased plasma heparanase associated with disease severity [ 212 ]. However, anticoagulation therapy with LMWH was associated with a better prognosis in severe COVID-19 patients [ 211 , 212 ].…”