Protein S: function, regulation, and clinical perspectives.

PURPOSE OF REVIEW: Protein S (PS) is an essential natural anticoagulant. PS deficiency is a major contributor to acquired hypercoagulability. Acquired hypercoagulability causes myocardial infarction, stroke, and deep vein thrombosis in millions of individuals. Yet, despite its importance in hemostasis, PS is the least understood anticoagulant. Even after 40 years since PS was first described, we are still uncovering information about how PS functions. The purpose of this review is to highlight recent findings that advance our understanding of the functions of PS and explain hypercoagulability caused by severe PS deficiency. RECENT FINDINGS: PS has long been described as a cofactor for Activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI). However, a recent report describes direct inhibition of Factor IXa (FIXa) by PS, an activity of PS that had been completely overlooked. Thrombophilia is becoming a more frequently reported disorder. Hereditary PS deficiency is an anticoagulant deficiency that results eventually in thrombophilia. In addition, PS deficiency is a predisposing factor for venous thromboembolism (VTE), but an effect of PS deficiency in arterial thrombosis, such as arterial ischemic stroke, is uncertain. Plasma PS concentration decreases in pregnant women. Inherited thrombophilias are important etiologies for recurrent pregnancy loss, and anticoagulation therapy is of benefit to women with recurrent pregnancy loss who had documented only PS deficiency.Hypoxia is a risk factor for VTE, and hypoxia downregulates plasma PS level. Importantly, COVID-19 can lead to hypoxemia because of lung damage from IL6-driven inflammatory responses to the viral infection. Because hypoxia decreases the abundance of the key anticoagulant PS, we surmise that the IL6-induced cytokine explosion combined with hypoxemia causes a drop in PS level that exacerbates the thrombotic risk in COVID-19 patients. SUMMARY: This review is intended to advance understanding of the anticoagulant function of an important plasma protein, PS. Despite 40+ years of research, we have not had a complete description of PS biology as it pertains to control of blood coagulation. However, the picture of PS function has become sharper with the recent discovery of FIXa inhibition by PS. Hemostasis mediated by PS now includes regulation of FIXa activity alongside the cofactor activities of PS in the TFPI/APC pathways. In addition, the direct inhibition of FIXa by PS suggests that PS, particularly a small derivative of PS, could be used to treat individuals with PS deficiencies or abnormalities that cause thrombotic complications.

Severe COVID-19 Is Characterized by an Impaired Type I Interferon Response and Elevated Levels of Arginase Producing Granulocytic Myeloid Derived Suppressor Cells.

COVID-19 ranges from asymptomatic in 35% of cases to severe in 20% of patients. Differences in the type and degree of inflammation appear to determine the severity of the disease. Recent reports show an increase in circulating monocytic-myeloid-derived suppressor cells (M-MDSC) in severe COVID 19 that deplete arginine but are not associated with respiratory complications. Our data shows that differences in the type, function and transcriptome of granulocytic-MDSC (G-MDSC) may in part explain the severity COVID-19, in particular the association with pulmonary complications. Large infiltrates by Arginase 1+ G-MDSC (Arg+G-MDSC), expressing NOX-1 and NOX-2 (important for production of reactive oxygen species) were found in the lungs of patients who died from COVID-19 complications. Increased circulating Arg+G-MDSC depleted arginine, which impaired T cell receptor and endothelial cell function. Transcriptomic signatures of G-MDSC from patients with different stages of COVID-19, revealed that asymptomatic patients had increased expression of pathways and genes associated with type I interferon (IFN), while patients with severe COVID-19 had increased expression of genes associated with arginase production, and granulocyte degranulation and function. These results suggest that asymptomatic patients develop a protective type I IFN response, while patients with severe COVID-19 have an increased inflammatory response that depletes arginine, impairs T cell and endothelial cell function, and causes extensive pulmonary damage. Therefore, inhibition of arginase-1 and/or replenishment of arginine may be important in preventing/treating severe COVID-19.

Role of vitamin D in treating COVID-19-associated coagulopathy: problems and perspectives.

Aggressive inflammatory response leading to hypercoagulability has been found to be associated with disease severity in COVID-19 patients and portends bad treatment outcome. A state of acute disseminated intravascular coagulation (DIC), along with pulmonary embolism and/or deep vein thrombosis, has been observed in critically ill ICU patients. Autopsy reports of COVID-19 patients demonstrated microthrombi in lungs and in other organs, as well as marked inflammatory changes, characteristic clinicopathological features that exacerbate disease severity. Vitamin D supplementation was recommended by many clinicians across the globe to improve clinical symptoms of COVID-19 patients, mainly because of its immunomodulatory roles on immune cells. Furthermore, vitamin D and its associated molecules are also known to directly or indirectly regulate various thrombotic pathways. We propose that vitamin D supplementation not only attenuates the risk of Acute Respiratory Disease Syndrome (ARDS) but it also may have a role in reducing coagulation abnormalities in critically ill COVID-19 patients. The overarching goal of this review is to discuss the effects of vitamin D on coagulation pathways and other intertwined processes leading to thrombosis. Many clinical trials are currently investigating the efficacy of vitamin D supplementation in reducing the risk of COVID-19 infection. However, randomized placebo control clinical trials are also necessary to ascertain the effect of vitamin D supplementation on reducing the risk of coagulopathy in COVID-19 patients.

COVID-19: a probable role of the anticoagulant Protein S in managing COVID-19-associated coagulopathy.

The COVID-19 pandemic has caused monumental mortality, and there are still no adequate therapies. Most severely ill COVID-19 patients manifest a hyperactivated immune response, instigated by interleukin 6 (IL6) that triggers a so called "cytokine storm" and coagulopathy. Hypoxia is also associated with COVID-19. So far overlooked is the fact that both IL6 and hypoxia depress the abundance of a key anticoagulant, Protein S. We speculate that the IL6-driven cytokine explosion plus hypoxemia causes a severe drop in Protein S level that exacerbates the thrombotic risk in COVID-19 patients. Here we highlight a mechanism by which the IL6-hypoxia curse causes a deadly hypercoagulable state in COVID-19 patients, and we suggest a path to therapy.