Protein C deficiency

Protein C deficiency clinically presents as adult-onset venous thromboembolism or neonatal purpura fulminans. Heterozygous deficiency typically manifests in young to middle adulthood with deep vein thrombosis of the lower limbs or pulmonary embolism and confers an increased thrombotic risk (hazard ratio 1.6, 95% CI 1.3-1.9) compared with non-carriers. Less common presentations include venous thrombosis at unusual sites such as cerebral, mesenteric, or hepatic veins, and recurrent thromboembolic events across the lifespan. Homozygous or compound heterozygous deficiency is extremely rare and usually presents in the neonatal period as purpura fulminans with disseminated intravascular coagulation, characterised by rapidly progressing cutaneous purpura, microvascular thrombosis, and tissue ischaemia, with a severe clinical course. Heterozygous carriers exhibit highly variable presentation, with some affected from adolescence or early adulthood, often in the presence of additional acquired or inherited prothrombotic factors.

While the estimated prevalence of protein C deficiency in the general population is approximately 1/200, the prevalence of clinically overt deficiency is around 1/25,000.

Protein C deficiency is caused by germline pathogenic variants in PROC, which encodes protein C, an endogenous anticoagulant that, once activated by the thrombin-thrombomodulin complex on the endothelium, proteolytically inactivates coagulation factors Va and VIIIa. Pathogenic variants either reduce protein C synthesis, producing a quantitative (Type I) deficiency, or impair protein function with preserved antigen levels, producing a qualitative (Type II) deficiency. The resulting loss of anticoagulant activity removes a physiological brake on thrombin generation, predisposing affected individuals to venous thromboembolism. In up to 24% of patients with low PC levels, no abnormality in PROC is detected.

Protein C deficiency is inherited in an autosomal dominant manner. Each first-degree relative of an affected heterozygous individual has a 50% chance of inheriting the familial PROC pathogenic variant. Biallelic inheritance, which produces the severe neonatal phenotype, occurs in offspring of two heterozygous parents (recurrence risk 25%). Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis is established by demonstration of a reduced protein C activity in plasma in multiple measurements outside acute thrombosis or anticoagulant exposure. Determination of the protein C antigen is used to distinguish between type I (quantitative) and type II (qualitative) deficiency. Molecular analysis of the PROC gene is done to confirm the diagnosis and enable family screening.

• Genetic testing establishes the molecular cause of the disorder, enabling a definitive diagnosis where clinical and biochemical findings are suggestive but not conclusive.
• Knowledge of the genetic diagnosis informs individualized clinical management and forms the prerequisite for targeted medical care; decisions about specific measures rest with the treating physicians in consultation with the affected individual.
• Identification of the familial pathogenic variant enables predictive genetic testing of at-risk family members, permitting earlier recognition of carrier status and informed reproductive decision-making.

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