Hiding in plain sight? Understanding SCPCD

Severe congenital protein C deficiency (SCPCD) is a rare genetic disorder caused by mutations in the PROC gene characterised by extremely low or undetectable protein C levels (<1 IU/dL^-1).^1-4

The predicted global incidence of SCPCD is around 1 in 500,000–4 million, with a predicted prevalence of around 1 in 40,000–250,000^1-3,5

SCPCD diagnosis requires a multidisciplinary approach, which involves a combination of clinical evaluation, blood tests, and genetic testing. Accurate diagnosis is critical for timely management of SCPCD.³

SCPCD is a rare genetic disorder

SCPCD is a rare autosomal recessive disorder that usually presents within hours after birth.^2,6 The symptoms of SCPCD, which include purpura fulminans and venous, cerebral, and retinal thrombosis, are caused by excess blood coagulation due to a deficiency in protein C, a vitamin K-dependent anticoagulant that regulates thrombin activity.^2,3,6-8

Role of protein C in the anticoagulation pathway

The protein C pathway, a cofactor-dependent system, exerts protective anti-apoptotic and anti-inflammatory effects directly onto cells while facilitating anticoagulation.⁸

Protein C is mainly synthesised in the liver as an inactive zymogen, which is activated on endothelial cell surfaces (Figure 1).⁸

Figure 1. Activation of protein C.⁸ Abbreviations: APC, activated protein C; EPCR, endothelial protein C receptor; PC, protein C; TM, thrombomodulin.

Activated protein C exerts its anticoagulant activity through proteolytic cleavage and inactivation of factors Va and VIIIa, which are major cofactors involved in thrombin formation.⁸ This shuts down thrombin production, resulting in the prevention of blood coagulation (Figure 2).^8,9

Figure 2. Anticoagulant activity of protein C.^8,9 Abbreviation: APC, activated protein C.

Genetics of SCPCD

Congenital protein C deficiency is caused by loss-of-function mutations occurring on the protein C-encoding PROC gene, located on chromosome 2 (2q13–q14).^3,4 Heterozygous PROC mutations result in mild protein C deficiency, whereas severe deficiency (SCPCD) is caused by biallelic homozygous or compound heterozygous PROC mutations (Figure 3).^1,10,11

Figure 3. PROC gene mutations resulting in protein C deficiency.^1,10,11 Abbreviation: SCPCD, severe congenital protein C deficiency.

Individuals with SCPCD have inherited homozygous or compound heterozygous mutations in the PROC gene^1,10,11

Type I and type II protein C deficiency

More than 160 PROC mutations have been identified to date. Most result in type I protein C deficiency, while type II protein C deficiency accounts for only 15% of symptomatic deficiencies.^2,10,11

• Type I deficiency causes equivalent decreases in protein C activity and antigen levels, due to reduced synthesis or stability of normal protein C molecules^2,10,11
• Type II deficiency causes a greater reduction in protein C activity than antigen levels, due to synthesis of abnormal, reduced-activity protein C molecules^2,10,11

Patients with SCPCD may have type I or type II protein C deficiency, or a combination of both^5,11

Severity classification

Normal protein C activity levels in healthy individuals are ~40 IU dL^-1 in newborns (with a lower limit of normal of 25 IU dL^-1), ~60 IU dL^-1 at 6 months old, and range from 65–135 IU dL^-1 in adults. Goldenberg & Manco-Johnson classified protein C deficiency in adults as mild, moderate, or severe according to the protein C activity levels shown in Figure 4.²

Figure 4. Protein C activity levels by severity classification in adults. Values as reported by Goldenberg & Manco-Johnson. Haemophilia 2008.² *The classification of “mild” protein C deficiency varies by age, and is defined as protein C activity level >20 IU dL^-1 but below the age-appropriate lower limit of normal values.

SCPCD is characterised by undetectable protein C levels (<1 IU dL^-1)²

Determining the underlying cause of protein C deficiency is key to an accurate diagnosis of SCPCD

As well as being a congenital disorder, protein C deficiency can be caused by non-genetic factors (referred to in the literature as ‘acquired protein C deficiency’), which may be due to other clinical conditions, such as:

• Increased consumption of protein C, e.g., due to sepsis following severe acute bacterial infection^1,3
• Decreased synthesis of protein C, e.g., due to vitamin K deficiency or liver disease³
• Antibody-mediated protein C clearance, e.g., as an autoimmune response to otherwise benign infections^1,3

A multidisciplinary approach involving clinical evaluation, blood tests, and genetic testing can help determine the underlying cause of protein C deficiency and diagnose SCPCD (Figure 5).^1-3,12-16

Figure 5. Differential diagnosis at a glance: How a multidisciplinary diagnostic approach can help distinguish between SCPCD and protein C deficiency caused by non-genetic factors.^1-3,12-16 Abbreviations: APTT, activated partial thromboplastin time; MRI, magnetic resonance imaging; PC, protein C; PS, protein S; SCPCD, severe congenital protein C deficiency.

Accurate diagnosis of SCPCD is critical for management³

References

1. Chalmers, 2011. Purpura fulminans: Recognition, diagnosis and management. https://doi.org/10.1136/adc.2010.199919
2. Goldenberg and Manco-Johnson, 2008. Protein C deficiency. https://doi.org/10.1111/j.1365-2516.2008.01838.x
3. Minford, 2022. Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTH. https://doi.org/10.1111/jth.15732
4. Patracchini, 1989. Sublocalization of the human protein C gene on chromosome 2q13-q14. https://doi.org/10.1007/BF00293902
5. Marlar and Mastovich, 1990. Hereditary protein C deficiency: A review of the genetics, clinical presentation, diagnosis and treatment. https://pubmed.ncbi.nlm.nih.gov/2103316/
6. Marlar, 1989. Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S, International Committee on Thrombosis and Haemostasis. https://doi.org/10.1016/s0022-3476(89)80688-2
7. Griffin, 1981. Deficiency of protein C in congenital thrombotic disease. https://doi.org/10.1172/jci110385
8. Lippincott Williams & Wilkins, 2012. Mosnier and Griffin. Chapter 19: Protein C, protein S, thrombomodulin, and the endothelial protein C receptor pathways. In: Hemostasis and thrombosis: Basic principles and clinical practice. https://www.wolterskluwer.com/en/solutions/ovid/hemostasis-and-thrombosis-basic-principles-and-clinical-practice-2713
9. UNI-MED Verlag, AG, 2008. Knoebl. Blood coagulation and inflammation in critical illness: The importance of the protein C pathway. https://www.uni-med.de/blood-coagulation-and-inflammation-in-critical-illness-the-importance-of-the-protein-c-pathway.html
10. StatPearls Publishing, 2024. Gupta and Patibandla. Protein C deficiency. https://www.ncbi.nlm.nih.gov/books/NBK542222/
11. Reitsma, 1995. Protein C deficiency: A database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. https://www.ncbi.nlm.nih.gov/pubmed/7482420
12. Khor and Van Cott, 2010. Laboratory tests for protein C deficiency. https://doi.org/10.1002/ajh.21679
13. Kottke-Marchant and Comp, 2002. Laboratory issues in diagnosing abnormalities of protein C, thrombomodulin, and endothelial cell protein C receptor. https://doi.org/10.5858/2002-126-1337-LIIDAO
14. Rhodes, 2017. Surviving Sepsis Campaign: International guidelines for management of sepsis and septic shock: 2016. https://doi.org/10.1007/s00134-017-4683-6
15. Tairaku, 2015. Prenatal genetic testing for familial severe congenital protein C deficiency. https://doi.org/10.1038/hgv.2015.17
16. Wacker, 2013. Procalcitonin as a diagnostic marker for sepsis: A systematic review and meta-analysis. https://doi.org/10.1016/S1473-3099(12)70323-7