NORD gratefully acknowledges Steven Kang, MD, Clinical Associate Professor of Pathology and Blood Bank Director, State University of New York Downstate Medical Center, for assistance in the preparation of this report.
Protein C deficiency is a rare genetic disorder characterized by a deficiency of protein C, which is a natural anticoagulant. This means it helps to prevent the blood from clumping together (clotting) too much. There is a mild form in which affected individuals are at risk for developing blood clots, particularly a type of blood clot called deep vein thrombosis. This is a clot that forms in the legs. Although very rare, there is a severe form that is present at birth (congenital) and can potentially cause widespread small clots in the body and life-threatening complications in infancy. Protein C deficiency is caused by alterations (mutations) in the PROC gene. The milder form is caused by an alteration in one PROC gene and is inherited in an autosomal dominant manner. The severe form is caused by an alteration in both PROC genes and is inherited in an autosomal recessive manner.
Individuals with the mild form of protein C deficiency are at risk for developing blood clots, particularly in the veins (venous thromboembolisms). They are also at risk for a skin disease following treatment with a blood thinner called warfarin (warfarin-induced skin necrosis). Whether protein C deficiency increases the risk of blood clots in the arteries (arterial thrombosis) is not fully understood.
Infants with the severe forms of protein C deficiency (homozygous or compound heterozygous forms) can develop symptoms within hours to a few days after birth. They develop a potentially life-threatening condition called purpura fulminans. This condition is characterized by the formation of blood clots in blood vessels throughout the body. Blood clots affect the arms and legs most often, but can become widespread throughout the body (disseminated intravascular coagulation). Blood clots can block the normal flow of blood and lead to death (necrosis) of the surrounding tissue. Infants experience abnormal bleeding in affected areas and the formation of large, purple patches or spots on the skin and necrosis of the affected skin. Bruising and discoloration of the skin can be widespread over the body. Episodes of purpura fulminans may recur. Without treatment, purpura fulminans can be fatal.
People with the milder form of protein C deficiency may not show any symptoms (asymptomatic) until they reach adulthood. Others may remain asymptomatic. The most common symptom is deep vein thrombosis. This is a clot that forms in the deep veins of the legs. This can be painful and can cause the leg to swell, but the clots can form without pain or swelling too. A potential complication of this blood clot is that a piece of it can break off, travel through the bloodstream, and become lodged in the lungs. This can block the flow of blood to the lungs, a condition called pulmonary embolism. Blood clots can also form in the blood vessels that drain blood from the large and small intestines (mesenteric veins). Less often, blood clots may form in the cerebral veins, the main vein of the liver (portal vein), and other areas. Episodes of blood clots are often “triggered” or provoked by other risk factors such as surgery, pregnancy or immobilization or inactivity. Blood clots are more likely to develop as people with the milder form protein C deficiency get older.
Individuals with protein C deficiency are at risk of developing a condition called Warfarin-induced skin necrosis. The use of warfarin in affected individuals can lead to widespread skin lesions. The arms and legs, breasts and trunk are the most commonly affected areas. The lesions may be reddish or purple and, without treatment, will worsen until the affected skin breaks down.
Doctors do not know for sure whether people with protein C deficiency have an increased risk of developing blood clots in the arteries. This would increase their risk of having a cardiovascular issue such as a stroke.
Protein C deficiency is caused by an alteration (mutation) in the PROC gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
The PROC gene contains instructions for creating protein C. This protein is an anticoagulant; it works to keep the blood from clotting more than is needed. It also works to counteract inflammation. People with the milder forms of protein C deficiency may have abnormally low levels of protein C, or they may have normal levels, but the protein does not function as well as it’s supposed to. People with the severe forms have a severe deficiency of protein C in the body.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. The milder form of protein C deficiency is inherited in an autosomal dominant manner, which means that people inherit one altered copy of the PROC gene and one unaltered copy (heterozygous). The severe forms are inherited in an autosomal recessive manner, which means that people inherited two altered copies of the PROC gene. They may inherit the same alteration in both genes (homozygous), or they may inherit different alterations in each gene (compound heterozygotes).
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Protein C deficiency affects men and women in equal numbers. The prevalence of the milder form is about 1 in 200-500 people in the general population. Prevalence is the number of people in a population that have a disorder at a given time. The prevalence of severe protein C deficiency is about 1 in 500,000-750,000 people in the general population.
A diagnosis of protein C deficiency is based upon identification of characteristic symptoms (e.g. repeated blood clot formation), a detailed patient and familial history (e.g. history of blood clots in the family), a thorough clinical evaluation and certain specialized tests.
Clinical Testing and Workup
Doctors will run blood tests that will determine the activity of protein C in the blood. These tests are called assays and they measure the amount and activity of specific enzymes in the blood. Enzyme activity in infants with the severe form of protein C deficiency will range from 0% to 30%. In the mild form, the range is 30% to 70%.
Molecular genetic testing can confirm a diagnosis of protein C deficiency, but usually is not necessary. Molecular genetic testing can detect alterations (mutations) in the PROC gene known to cause this disorder, but is available only as a diagnostic service at specialized laboratories.
There are no standardized treatment protocols or guidelines for affected individuals. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with protein C deficiency.
Many individuals with mild forms of protein C deficiency will not need any treatment, except at times where there is an increased risk of blood clot formation such as during surgery, pregnancy, immobilization, or trauma. Some individuals with a strong family history to developing blood clots may receive preventive therapy (e.g. anticoagulant therapy).
Anticoagulant therapy is the use of drugs like heparin and warfarin that thin the blood and make it harder for the blood to clot. Special care must be taken if warfarin is used because of the risk of warfarin-induced skin necrosis. The duration of anticoagulant therapy varies based upon an individual patient’s specific situation.
In 2007, the US Food and Drug Administration approved the use of a protein C concentrate called Ceprotin for the treatment of individuals with severe protein C deficiency experiencing purpura fulminans or venous thrombosis. Infants with severe protein C deficiency who develop purpura fulminans require immediate treatment with Ceprotin. Fresh frozen plasma can be used if Ceprotin is unavailable. Some infants with severe protein C deficiency receive daily infusions of Ceprotin. One young child reported in the medical literature received continuous therapy through the use of an insulin pump.
In Europe, there is another drug that is a plasma-derived concentrate of protein C. This drug is called Protexel.
Warfarin-induced skin necrosis is a medical emergency. Warfarin should immediately be discontinued and affected individuals should be treated with vitamin K and therapeutic doses of heparin. In individuals with protein C deficiency, Ceprotin may be given to help normalize protein C activity. Fresh frozen plasma may be tried if Ceprotin is unavailable.
Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
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Manco-Johnson MJ, Bomgaars L, Palascak J, et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost. 2016;116:58-68. http://www.ncbi.nlm.nih.gov/pubmed/27052576
Taiaku S, Taniguchi-Ikeda M, Okazaki Y, et al. Prenatal genetic testing for familial severe congenital protein C deficiency. Hum Genome Var. 2015;2:15017. http://www.ncbi.nlm.nih.gov/pubmed/27081530
Piccini B, Capirchio L, Lenzi L, et al. Continuous subcutaneous infusion of protein C concentrate using an insulin pump in a newborn with congenital protein C deficiency. Blood Coagul Fibrinolysis. 2014;25:522-526. http://www.ncbi.nlm.nih.gov/pubmed/24509341
Knoebl PN. Severe congenital protein C deficiency: the use of protein C concentrates (human) as replacement therapy for life-threatening blood-clotting complications. Biologics. 2008;2:285-296. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2721356/
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