Protein S: function, regulation, and clinical perspectives.

Area of Science:

• Biochemistry
• Hematology
• Molecular Biology

Background:

• Protein S (PS) is a crucial natural anticoagulant involved in hemostasis.
• PS deficiency is a significant factor in acquired hypercoagulability, leading to conditions like myocardial infarction, stroke, and deep vein thrombosis.
• Despite its importance, the full spectrum of PS functions remains incompletely understood after decades of research.

Purpose of the Study:

• To review recent findings that enhance the understanding of Protein S functions.
• To elucidate the mechanisms of hypercoagulability associated with severe PS deficiency.

Main Methods:

• Review of recent scientific literature on Protein S.
• Analysis of newly discovered anticoagulant activities of Protein S.
• Correlation of PS levels with thrombotic risk in various conditions, including pregnancy and COVID-19.

Main Results:

• Protein S has been identified to directly inhibit Factor IXa (FIXa), a previously overlooked function.
• PS acts as a cofactor for Activated Protein C (APC) and Tissue Factor Pathway Inhibitor (TFPI).
• PS deficiency is linked to thrombophilia and venous thromboembolism (VTE), with potential implications for arterial thrombosis and recurrent pregnancy loss.

Conclusions:

• The hemostatic role of PS now encompasses direct regulation of FIXa activity, in addition to its established cofactor functions.
• Understanding the direct inhibition of FIXa by PS opens possibilities for developing PS-based therapeutics for deficiency-related thrombotic complications.
• Hypoxia, as seen in COVID-19, can decrease PS levels, exacerbating thrombotic risk.