Protein C deficiency is a disorder that increases the risk of developing abnormal blood clots; the condition can be mild or severe.

Individuals with mild protein C deficiency are at risk of a type of blood clot known as a deep vein thrombosis (DVT). These clots occur in the deep veins of the arms or legs, away from the surface of the skin. A DVT can travel through the bloodstream and lodge in the lungs, causing a life-threatening blockage of blood flow known as a pulmonary embolism (PE). While most people with mild protein C deficiency never develop abnormal blood clots, certain factors can add to the risk of their development. These factors include increased age, surgery, inactivity, or pregnancy. Having another inherited disorder of blood clotting in addition to protein C deficiency can also influence the risk of abnormal blood clotting.

In severe cases of protein C deficiency, infants develop a life-threatening blood clotting disorder called purpura fulminans soon after birth. Purpura fulminans is characterized by the formation of blood clots in the small blood vessels throughout the body. These blood clots block normal blood flow and can lead to localized death of body tissue (necrosis). Widespread blood clotting uses up all available blood clotting proteins. As a result, abnormal bleeding occurs in various parts of the body, which can cause large, purple patches on the skin. Individuals who survive the newborn period may experience recurrent episodes of purpura fulminans.

Protein C deficiency is caused by mutations in the PROC gene. This gene provides instructions for making protein C, which is found in the bloodstream and is important for controlling blood clotting. Protein C blocks the activity of (inactivates) certain proteins that promote blood clotting.

Most of the mutations that cause protein C deficiency change single protein building blocks (amino acids) in protein C, which disrupts its ability to control blood clotting. Individuals with this condition do not have enough functional protein C to inactivate clotting proteins, which results in the increased risk of developing abnormal blood clots. Protein C deficiency can be divided into type I and type II based on how mutations in the PROC gene affect protein C. Type I is caused by PROC gene mutations that result in reduced levels of protein C, while type II is caused by PROC gene mutations that result in the production of an altered protein C with reduced activity. Both types of mutations can be associated with mild or severe protein C deficiency; the severity is determined by the number of PROC gene mutations an individual has.

Normal Function

The PROC gene provides instructions for making a protein called protein C that is important for controlling blood clotting. Protein C blocks the activity of two proteins that promote the formation of blood clots, called factor Va and factor VIIIa. Protein C is also involved in controlling inflammation. Inflammation is a normal body response to infection, irritation, or other injury.

Protein C is made in the liver and then released into the bloodstream. The protein remains turned off (inactive) until it attaches to a protein called thrombin, which converts it to activated protein C (APC). APC cuts (cleaves) the factor Va protein at specific sites, which partially or completely inactivates factor Va. (The inactive form is called factor V.) APC then works with factor V to inactivate factor VIIIa.

Health Conditions Related to Genetic Changes

Protein C deficiency

At least 270 mutations in the PROC gene have been found to cause protein C deficiency. Most of these mutations change single protein building blocks (amino acids) in protein C, which disrupts its ability to control blood clotting. Protein C deficiency can be divided into type I and type II based on the mutation in the PROC gene.

Protein C deficiency type I is caused by PROC gene mutations that result in reduced levels of protein C. Affected individuals do not have enough protein C to control blood clotting, which causes the increased risk for abnormal blood clots in protein C deficiency.

Mutations that cause protein C deficiency type II result in the production of an altered protein C with reduced activity. Individuals with this form of the condition have normal levels of protein C, but the protein is not able to interact with other molecules involved in blood clotting. If protein C cannot control blood clotting, abnormal blood clots may form.

Other Names for This Gene

• PC
• PROC1
• PROC_HUMAN
• protein C
• protein C (inactivator of coagulation factors Va and VIIIa)

Genomic Location

Protein C deficiency can be hereditary or acquired. Most cases of hereditary protein C deficiency are inherited in an autosomal dominant manner. This means that having only one mutated copy of the responsible gene in each cell (allele) is enough to cause mild protein C deficiency, although some may not have any symptoms. A mutated copy of the gene can be inherited from a person's mother or father.

People who inherit two mutated copies of the gene, one copy from each parent (autosomal recessive protein C deficiency) may have severe protein C deficiency. These few cases are inherited in an autosomal recessive way.

Mild protein C deficiency affects approximately 1 in 500 individuals. Severe protein C deficiency is rare and occurs in an estimated 1 in 4 million newborns.