Case Report: Severe protein S deficiency unmasks a cryptic PROC mutation with normal activity, triggering...

In young patients presenting with high-risk, idiopathic pulmonary thromboembolism (PTE), prompt identification of the underlying prothrombotic state is critical. Inherited deficiencies of protein C (PC) and protein S (PS) are predominant risk factors in Asians. However, routine functional assays for PC/PS activity may not capture the full genetic risk. Specifically, the clinical significance of a pathogenic PROC mutation in individuals with normal PC activity remains poorly defined. We hypothesize that in such individuals, the thrombogenic potential of a "cryptic" PROC defect may remain latent until unmasked by a profound cofactor deficiency, such as severe PS deficiency. This synergistic mechanism, and the catastrophic thrombosis it may precipitate, has not been previously documented.

A previously healthy 20-year-old male presented with sudden-onset high-risk pulmonary thromboembolism and obstructive shock. Despite systemic thrombolysis, he progressed to refractory shock and was successfully rescued with VA-ECMO bridging to percutaneous mechanical thrombectomy. Coagulation workup revealed severely reduced PS activity (28.3%); notably, protein C activity was normal at 99.7%. Genetic testing identified heterozygous pathogenic mutations in PROS1 (c.1680T > A, p.Tyr560Ter) and PROC (c.577_579delAAG, p.Lys193del), inherited from his asymptomatic parents respectively.

This case demonstrates that severe PS deficiency can unmask the thrombogenic potential of a pathogenic PROC mutation even in the setting of normal PC activity, revealing a previously underrecognized synergistic prothrombotic mechanism. It underscores the critical importance of systematic thrombophilia screening, including genetic testing for PROS1 and PROC, in young patients with high-risk PTE even when PC activity is normal.