Release of endogenous chondroitin sulfate and heparin as consequence of dysregulated proteolysis in COVID-19

Infection by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2), the pathogen responsible for COVID-19, is associated with immune-mediated responses that lead to dysregulated activation of proteolytic enzymes; these contribute to damage to the endothelium, thrombosis, hypercoagulability, and other hematologic complications that include thrombotic thrombocytopenia, a complication of severe COVID-19 as well as a potentially fatal adverse effect of COVID-19 vaccination. Here, it is demonstrated that proteolysis of plasma proteins leads to sequential release of endogenous glycosaminoglycans (GAGs), first chondroitin sulfate (CS), followed by heparin (HP). The extension and degree of what is called "proteolytic storm" determines whether only one endogenous type of GAGs (CS), or both (CS and HP), are released. Sulfated GAGs such as CS and HP exert a protective role against SARS-CoV-2 infection. However, sustained and excessive release of endogenous HP may be responsible for thrombotic thrombocytopenia just as it happens in HP-induced thrombocytopenia (HIT) a well-known side effect of HP administration that results in thromboembolisms in atypical sites, thrombocytopenia, and synthesis of autoantibodies directed against platelet factor 4 (PF4) that contribute to platelet aggregation. It is concluded that release of endogenous HP as consequence of dysregulated proteolysis occurring during COVID-19 or COVID-19 vaccination may play a fundamental role in the pathophysiology of the disease as well as in adverse reactions to vaccination.