Advances in the Understanding of Protein C and Protein S Deficiencies: from Molecular Mechanisms to Therapeutic Strategies

Abstract

Background: Protein C (PC) and Protein S (PS) deficiency, either inherited or acquired, are rare but a significant cause for thrombophilia. These vitamin K-dependent plasma glycoproteins collaborate in the anticoagulant pathway to regulate thrombin generation and maintain vascular integrity. Objective: To examine the molecular foundations, physiological processes, disease development, diagnostic methods, and treatment strategies related to Protein C and Protein S deficiencies, highlighting the latest findings on genetic variations, clinical manifestations, and therapeutic options. Methods: We conducted a thorough examination of the existing literature, encompassing peer-reviewed studies, clinical case reports, and respected haematology reference materials, concentrating on the genetic characteristics related to PC and PS deficiencies. Results: Protein C deficiency primarily results from pathogenic mutations in the PROC gene, while Protein S deficiency is caused by variations in the PROS1 gene. Both deficiencies increase the risk of venous thromboembolism (VTE) and, in severe instances, can lead to purpura fulminans and disseminated intravascular coagulation (DIC). Heterozygous forms exhibit variable penetrance and typically present as recurrent VTE. Confirming the diagnosis requires functional and antigenic assays, as well as molecular testing to detect any underlying mutations. Treatment options include anticoagulation using heparin or direct oral anticoagulants (DOACs), protein replacement therapy, and, in severe cases involving neonates, liver transplantation. Conclusion: Early detection and accurate molecular diagnosis of PC and PS deficiencies are essential for decreasing thrombotic morbidity and mortality. Standardization of diagnostic assays and personalized long-term anticoagulation regimens continue to be important factors for optimizing patient care.