PROC – Hereditary thrombophilia due to congenital protein C deficiency

Hereditary protein C deficiency is an autosomal dominant thrombophilia characterized by reduced anticoagulant activity of protein C, leading to recurrent venous thromboembolism (deep vein thrombosis, pulmonary embolism) and, in biallelic cases, neonatal purpura fulminans. The PROC gene encodes a vitamin K–dependent serine protease zymogen activated by the thrombin–thrombomodulin complex, which inactivates factors Va and VIIIa to regulate coagulation.

Genetic studies have identified over 150 distinct PROC variants in more than 90 unrelated families, including missense, nonsense, frameshift, splice-site, and promoter mutations. Segregation of heterozygous PROC mutations with recurrent thrombosis has been documented in at least 46 affected relatives ([PMID:8704244]). In a Spanish cohort of 109 probands, 58 different PROC mutations were found, underscoring robust genetic causality ([PMID:31254973]).

The variant spectrum includes single‐nucleotide changes (e.g., c.1019C>T (p.Thr340Met)) and frameshifts; recurrent founder alleles have been reported—Arg147Trp in Taiwanese Chinese families ([PMID:15114590]) and W380G in Finnish patients. Heterozygous carriers typically present in adulthood with venous thromboembolism, while homozygotes or compound heterozygotes often manifest severe neonatal purpura fulminans.

Functional analyses demonstrate that many PROC mutations impair protein folding, secretion, gamma‐carboxylation, calcium binding, or receptor interactions. For example, Asp71Ala in the first EGF‐like domain markedly reduces cofactor activity and anticoagulant function ([PMID:8950780]). Nonsense and frameshift alleles triggering nonsense‐mediated decay further confirm loss‐of‐function as the primary mechanism.

No substantial conflicting evidence has emerged; all studies consistently support a loss‐of‐function pathogenic mechanism. The balance of genetic segregation, variant spectrum, and concordant in vitro and in vivo functional data establishes PROC deficiency as a definitive cause of hereditary thrombophilia due to congenital protein C deficiency.

Key Take-home: PROC genetic testing enables definitive diagnosis and informs lifelong anticoagulation strategies in patients and at-risk relatives.

References

• Blood • 1996 • Venous thromboembolism associated with double heterozygosity for R506Q mutation of factor V and for T298M mutation of protein C in a large family of a previously described homozygous protein C-deficient newborn with massive thrombosis. PMID:8704244
• American journal of hematology • 2004 • R147W mutation of PROC gene is common in venous thrombotic patients in Taiwanese Chinese. PMID:15114590
• Thrombosis and haemostasis • 2019 • Identification of 58 Mutations (26 Novel) in 94 of 109 Symptomatic Spanish Probands with Protein C Deficiency. PMID:31254973
• Thrombosis and haemostasis • 1996 • Functional consequences of mutations in amino acid residues that stabilize calcium binding to the first epidermal growth factor homology domain of human protein C. PMID:8950780

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