Hiding in plain sight? How to spot SCPCD

Early recognition and management of severe congenital protein C deficiency (SCPCD) symptoms are key to preventing long-term morbidity and reducing mortality.¹ Urgent referral to a haematologist on presentation of purpura fulminans is critical.^1,2

SCPCD is a rare genetic disorder that usually presents within hours or days of birth, often resulting in death unless recognised and managed quickly^3,4

The symptoms of SCPCD are caused by insufficient levels of protein C, resulting in excess blood coagulation.³ The hallmark feature of SCPCD is purpura fulminans, which manifests as symmetrical ecchymotic skin lesions, with abnormal blood clotting and skin necrosis.^5,6 Lesions typically affect the extremities but have also been observed on the buttocks, abdomen, scalp, and soles of the feet. Additionally, lesions may develop at pressure points, at sites of puncture, and at sites where healing is occurring (Figure 1).^5,6

Diagnosing SCPCD can be challenging because purpura fulminans can also be caused by acquired protein C deficiency occurring after infection, meaning that the SCPCD phenotype mimics that of other more common conditions such as neonatal sepsis.^1,4 Distinguishing between congenital and acquired protein C deficiency is vital for proper management of SCPCD and requires a multidisciplinary diagnostic approach.^1,3,4,6-12

The first step in diagnosing neonates with SCPCD is recognising the symptoms¹

What is SCPCD?

SCPCD is an autosomal recessive disorder characterised by low or undetectable levels of protein C, an anticoagulant involved in thrombin regulation.^1,3 SCPCD is associated with high mortality rates in affected babies and can have long-term health consequences for survivors.^1,3

Symptoms of SCPCD

The symptoms of SCPCD (Figure 2) usually appear in the first hours and days of life, and are caused by a shift in the balance between pro- and anticoagulation factors due to protein C deficiency, leading to excess coagulation.^3-5

Differential diagnosis: Could it be SCPCD?

Diagnosing SCPCD in babies presenting with symptoms can be challenging because purpura fulminans can also occur as a result of non-genetic factors (referred to in the literature as ‘acquired protein C deficiency’), which may be due to other clinical conditions, such as:¹

• A sepsis-associated form of disseminated intravascular coagulation
• An autoimmune response following an otherwise benign infection

SCPCD is rare – the appearance of purpura fulminans in babies is more commonly associated with severe acute sepsis or bacterial infection; accurate identification of the underlying cause and prompt management is critical to ensure optimal outcomes^1,4

What should raise suspicion of SCPCD

If a newborn baby presents with purpura fulminans, or a combination of symptoms, additional risk factors for SCPCD should be considered that may help in determining a diagnosis.^1,3,16

• A history of miscarriage¹
• Consanguinity (relationship between blood relatives)^1,16
• A history of protein C deficiency (including non-severe forms) in the parents³

Early identification of purpura fulminans is critical

Purpura fulminans is a haematological emergency, and babies presenting with lesions are critically ill and require early management before progressive organ damage is sustained.¹

Hallmark features of SCPCD in newborns

What is the urgency in identifying and managing SCPCD? Professor Andrew Mumford explains the “hallmark feature of SCPCD” in newborns.

If identified quickly, early purpura fulminans may be reversible with treatment¹; however, left untreated, SCPCD-associated purpura fulminans can lead to life-threatening complications, with established lesions often rapidly progressing to cause extensive tissue death, requiring amputation of limbs/digits in up to 63% (n=10/16) of cases.^1,6,17 Without timely and appropriate management, purpura fulminans can lead to multi-organ failure and, ultimately, prove fatal.¹

A haematologist should be consulted immediately on presentation of purpura fulminans lesions^1,2

Testing for SCPCD

Differential diagnosis of congenital versus acquired protein C deficiency requires a multidisciplinary approach involving laboratory tests, family history, and genetic testing (Figure 3).^1,3,7-12

What’s next for patients with SCPCD?

In cases of uncertainty, such as with an ill preterm infant, repeated testing of the baby’s protein C levels may be necessary to confirm a diagnosis of SCPCD.⁴ Protein C levels can also be measured in the parents, and genetic testing performed to determine whether the baby has inherited a PROC gene mutation resulting in deficient or inactive protein C.^1,3,4

Early recognition and management of SCPCD symptoms are key to preventing long-term morbidity and reducing mortality.¹ Urgent referral to a haematologist on presentation of purpura fulminans is critical.^1,2

Spot the signs

Meet the expert

Professor Andrew Mumford

Professor Andrew Mumford is a Professor of Haematology at the University of Bristol and is affiliated with the University Hospitals Bristol NHS Foundation Trust, UK.

Disclosures: Received research funding, speaker fees, or consultancy fees from AbbVie, AstraZeneca, Novo Nordisk, Sysmex, and Takeda.

References

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2. Monagle, 2018. American Society of Hematology 2018 Guidelines for management of venous thromboembolism: treatment of pediatric venous thromboembolism. https://www.doi.org/10.1182/bloodadvances.2018024786
3. Goldenberg and Manco-Johnson, 2008. Protein C deficiency. https://www.doi.org/10.1111/j.1365-2516.2008.01838.x
4. Minford, 2022. Diagnosis and management of severe congenital protein C deficiency (SCPCD): Communication from the SSC of the ISTH. https://www.doi.org/10.1111/jth.15732
5. 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://www.doi.org/10.1016/s0022-3476(89)80688-2
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10. Rhodes, 2017. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016. https://www.doi.org/10.1007/s00134-017-4683-6
11. Tairaku, 2015. Prenatal genetic testing for familial severe congenital protein C deficiency. https://www.doi.org/10.1038/hgv.2015.17
12. Wacker, 2013. Procalcitonin as a diagnostic marker for sepsis: a systematic review and meta-analysis. https://www.doi.org/10.1016/S1473-3099(12)70323-7
13. Cassels-Brown, 1994. Ophthalmic manifestations of neonatal protein C deficiency. https://www.doi.org/10.1136/bjo.78.6.486
14. Ergenekon, 2000. Can leucocoria be the first manifestation of protrin C deficiency? https://www.doi.org/10.1136/bjo.84.1.117d
15. Fong, 2010. Cerebral palsy in siblings caused by compound heterozygous mutations in the gene encoding protein C. https://www.doi.org/10.1111/j.1469-8749.2010.03618.x
16. Shawky, 2013. Consanguinity and its relevance to clinical genetics. https://www.doi.org/10.1016/j.ejmhg.2013.01.002
17. Gürgey, 2005. Outcome in children with purpura fulminans: report on 16 patients. https://www.doi.org/10.1002/ajh.20435