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Congenital protein C deficiency (homozygous)
This inherited disorder typically manifests at birth or shortly after, causing widespread blood clot formation in vital organs. It is a serious condition requiring urgent management and affects infants with specific genetic changes.
Overview
Congenital protein C deficiency is a very rare inherited bleeding disorder characterised by a severe lack of functional protein C in the blood. Protein C is a vital natural anticoagulant, meaning it helps to prevent excessive blood clotting. When protein C is severely deficient, the body's ability to regulate clotting is significantly impaired, leading to uncontrolled and widespread clot formation [PMID:33678044]. This condition typically presents very early in life, often shortly after birth, with severe and life-threatening complications. It is distinct from heterozygous protein C deficiency, which is generally milder.
Symptoms & clinical features
Individuals with severe, homozygous congenital protein C deficiency often present in the neonatal period (first 28 days of life) with a condition called purpura fulminans [PMID:16538350]. This is a rapidly progressing disorder characterised by large, painful, purple skin lesions due to widespread small blood clots blocking blood vessels in the skin. These lesions can quickly lead to tissue death (necrosis) and scarring. Other symptoms can include serious blood clots (thrombosis) in organs such as the brain, liver, or kidneys, which can cause strokes, organ damage, or failure. Eye involvement can also occur, potentially leading to blindness. Without prompt treatment, these complications can be fatal.
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Affected organs
The primary organs affected in congenital protein C deficiency are those susceptible to widespread microvascular thrombosis. The skin is prominently affected, leading to purpura fulminans with extensive skin necrosis, particularly on the limbs and trunk [PMID:16538350]. The central nervous system, including the brain, can experience clot formation, potentially resulting in strokes or developmental problems. Internal organs like the liver, kidneys, and lungs can also be compromised by blood clots, leading to organ dysfunction or damage. The eyes are another site where clots can form, often affecting vision.
Risks & severity
Congenital protein C deficiency is a very severe condition with significant risks. The major risk is uncontrolled thrombosis, which can be life-threatening from birth if not recognised and managed promptly. Purpura fulminans, the characteristic skin manifestation, can cause extensive tissue damage and septicaemia-like symptoms. The risk of mortality is high without immediate intervention, and long-term complications can include neurological impairment, chronic skin issues, and organ damage. The severity of symptoms is directly related to the extremely low or absent levels of functional protein C [PMID:33678044].
Genetic causes
Congenital protein C deficiency is caused by pathogenic variants in the PROC gene. This gene provides instructions for making protein C, an important protein primarily produced in the liver. Protein C is a key component of the anticoagulant system, working to inactivate clotting factors Va and VIIIa, thus preventing excessive blood clot formation [PMID:33678044]. When both copies of the PROC gene have pathogenic variants (homozygous or compound heterozygous), it results in a severe deficiency of functional protein C. This severe reduction means the body cannot adequately regulate blood clotting, leading to the clinical features of the condition.
- PROC protein C, inactivator of coagulation factors Va and VIIIa
Inheritance pattern
This condition has an autosomal recessive inheritance pattern. This means that an individual must inherit two altered copies of the PROC gene - one from each parent - to be affected. If a person inherits only one altered copy and one normal copy, they are a carrier and typically do not show symptoms of the severe form of the condition; they might have heterozygous protein C deficiency, which is usually milder and may only become apparent with specific triggers. When both parents are carriers, there is a 1 in 4 (25%) chance with each pregnancy that their child will inherit two altered gene copies and develop congenital protein C deficiency.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosis of congenital protein C deficiency is usually suspected based on the characteristic clinical presentation, especially purpura fulminans in a neonate. Blood tests will show significantly reduced or undetectable levels of protein C activity and antigen. Confirmation of the diagnosis involves genetic testing, which identifies pathogenic variants in the PROC gene. In the UK, genetic testing for severe coagulation disorders, including protein C deficiency, falls under the NHS Genomic Medicine Service (GMS) pathways. Referrals for testing are typically made by specialist haematologists or paediatricians to their regional Genomic Laboratory Hub, often following consultation with clinical genetics services. The relevant R-code for protein C deficiency testing is R210 (Thrombophilia - genetic tests).
Management & lifestyle
Management for severe congenital protein C deficiency requires urgent and continuous treatment. Initial acute management involves rapid replacement of protein C, usually through plasma-derived or recombinant protein C concentrate, to control acute thrombotic episodes such as purpura fulminans [PMID:16538350]. Anticoagulant medications, such as heparin, may also be used in conjunction. Long-term management often involves prophylactic (preventative) protein C replacement therapy, potentially lifelong, to prevent recurrent clotting events. Regular monitoring by a specialist haematologist is essential. Individuals and families are supported by multidisciplinary teams within the NHS, including clinical geneticists and genetic counsellors, to understand the condition and its implications.
UK care pathway
In the UK, individuals with suspected or confirmed congenital protein C deficiency are managed through specialist NHS services. Diagnosis is typically confirmed via genetic testing coordinated by a regional Genomic Laboratory Hub, following a referral from a specialist clinician. The NHS Genomic Medicine Service (GMS) provides comprehensive care, including access to genetic counselling. Genetic counsellors offer support and information about the inheritance pattern, implications for family members, and future planning. The R210 test code covers genetic investigations for thrombophilia, including severe protein C deficiency.
Frequently asked questions
What is protein C and why is it important?
Protein C is a natural anticoagulant, a substance in your blood that helps prevent excessive clotting. It works by inactivating specific clotting factors. When protein C is severely deficient, the body cannot control blood clot formation effectively, leading to serious and widespread clots.
Can carriers of the PROC gene changes get this condition?
Individuals who carry one altered copy of the PROC gene are typically unaffected by the severe, homozygous form of congenital protein C deficiency. They may have heterozygous protein C deficiency, which is a milder form that might lead to an increased risk of clots, usually later in life or with specific triggers like surgery or trauma.
How is congenital protein C deficiency treated?
Treatment involves immediate replacement of protein C, usually with specific concentrates, to stop acute clotting episodes. This is often followed by ongoing preventative (prophylactic) protein C replacement therapy, potentially for life, along with monitoring by a specialist haematologist to prevent future blood clots.
What is purpura fulminans?
Purpura fulminans is a severe and rapidly progressing condition often seen in neonates with congenital protein C deficiency. It causes large, painful, purple skin lesions due to widespread small blood clots blocking vessels in the skin, which can lead to tissue death if not treated urgently.
How often does this condition occur?
Congenital protein C deficiency (homozygous form) is considered a very rare condition. The exact prevalence is not well established, but it is encountered extremely infrequently.