Protein C Deficiency

What protein C does

Protein C circulates in an inactive form. When clotting starts, thrombin bound to a protein called thrombomodulin activates protein C. Activated protein C, helped by protein S, switches off two key clotting factors (factor Va and factor VIIIa), limiting how much clot forms. It needs vitamin K to be made correctly.

When protein C is low, this natural brake is weaker, so clots form more easily.

Types of protein C deficiency

Inherited

• heterozygous (one faulty gene): levels about 50% of normal. Many people have no clots. Risk of venous clots is several times higher than average, rising with additional risk factors
• homozygous or compound heterozygous (two faulty genes): very low or absent protein C. Causes neonatal purpura fulminans, widespread clotting and skin necrosis within hours to days of birth, and eye or brain damage. Very rare

Inheritance is autosomal dominant for mild forms. Two subtypes exist: type I (low amount) and type II (normal amount but poor function).

Acquired

• liver disease
• vitamin K deficiency
• warfarin treatment (protein C falls quickly when warfarin starts)
• severe infections and sepsis, disseminated intravascular coagulation
• after surgery or a large clot
• some chemotherapy drugs

Symptoms

Most people have no symptoms until a clot forms:

• deep vein thrombosis: leg swelling, pain, warmth and redness
• pulmonary embolism: breathlessness, chest pain, rapid heartbeat
• clots in unusual places: brain veins, abdominal veins, arm veins
• recurrent clots
• warfarin necrosis: painful skin patches turning purple and black in the first days of warfarin
• in newborns: purpura fulminans

Arterial clots, such as heart attack and stroke, are not clearly linked to inherited protein C deficiency.

Who should be tested

Thrombophilia testing is not recommended for everyone with a clot. The American Society of Hematology suggests considering it when results would change management, for example:

• a clot at a young age without a clear cause
• a strong family history of clots
• clots in unusual sites
• warfarin skin necrosis
• women with a family history of thrombophilia planning pregnancy or estrogen use

Diagnosis

• protein C activity (functional) test: the main screening test
• protein C antigen test: helps distinguish type I from type II
• genetic testing (PROC gene) in selected cases
• timing matters: levels are falsely low during an acute clot, on warfarin, in liver disease, vitamin K deficiency and sepsis. Testing is best done at least 2 weeks after stopping warfarin and after recovery from a clot, and abnormal results should be repeated
• newborns naturally have lower protein C, so age-specific ranges are used
• other thrombophilias, such as factor V Leiden, protein S and antithrombin deficiency, are often tested at the same time

Treatment

Treating a clot

• anticoagulation with heparin, a direct oral anticoagulant or warfarin, for at least 3 months
• warfarin precaution: always start with heparin overlap and avoid high loading doses, to prevent warfarin skin necrosis
• long-term anticoagulation may be recommended after an unprovoked or recurrent clot

Preventing clots

• preventive anticoagulation during high-risk times: major surgery, long immobility, and pregnancy and after birth
• avoiding estrogen-containing contraception and hormone therapy when possible
• staying active, keeping hydrated and moving on long trips

Severe deficiency

• protein C concentrate (FDA-approved for severe congenital deficiency) or fresh frozen plasma for purpura fulminans
• long-term treatment with protein C concentrate or anticoagulants
• liver transplant in rare cases

Pregnancy

Pregnancy increases clotting risk. People with protein C deficiency are often given low molecular weight heparin during pregnancy and for 6 weeks after birth, depending on personal and family history. Warfarin is avoided in pregnancy because it can harm the baby.

Frequently asked questions

What is protein C deficiency?

Protein C deficiency is a condition in which the body has too little protein C, or protein C that does not work properly. Protein C is a natural blood thinner, so a deficiency increases the risk of blood clots in the veins.

Is protein C deficiency inherited?

It can be inherited, usually from one parent, causing mild to moderate deficiency. It can also be acquired from liver disease, vitamin K deficiency, warfarin or severe infection. Rare severe inherited forms come from both parents.

What are the symptoms of protein C deficiency?

Most people have no symptoms until a blood clot forms. Clots can cause leg swelling and pain, or breathlessness and chest pain if they travel to the lungs. Newborns with severe deficiency develop rapidly spreading purple skin patches.

Why is warfarin risky with protein C deficiency?

Warfarin lowers protein C faster than it lowers clotting factors. In the first days, this can temporarily increase clotting in the skin's small vessels, causing warfarin-induced skin necrosis. Starting warfarin with heparin and avoiding high initial doses prevents it.

Do I need blood thinners for protein C deficiency?

Not necessarily. Many people with mild deficiency never have a clot and do not need daily blood thinners. Anticoagulants are used to treat clots, sometimes long-term after unprovoked clots, and preventively during high-risk times such as surgery and pregnancy.