Patient Education Blog

Protein C Deficiency

What is Protein C?

Protein C is a protein in our blood stream, which prevents blood from clotting too much.  It’s a sort of police protein that keeps our clotting in check.  If protein C levels are low, a person will have a tendency to clot more easily.  Elevated levels of protein C, on the other hand, appear to be irrelevant; they do not lead to an increased bleeding tendency.

What Problems Does Protein C Deficiency Cause?
Inherited protein C deficiency increases the risk for blood clots; acquired protein C deficiency usually does not.  There are 2 major causes for protein C values to be low: (a) an inherited deficiency due to a genetic abnormality (mutation), and (b) an acquired deficiency due to some other disease (Table Protein C Deficiency).  There are also several conditions under which a person temporarily has low protein C levels (see Table), but levels return to normal once the condition has resolved.  The distinction between inherited and acquired/temporary deficiency is important, to avoid a wrong diagnosis of “inherited protein C deficiency” when low values are found.  A definitive diagnosis of hereditary deficiency is sometimes difficult to make because of these interfering causes.  Repeat testing at a later time to confirm a low level is always advisable to make a definitive diagnosis.  Sometimes, family testing (testing of parents) is necessary to help clarify the diagnosis of inherited versus acquired deficiency.  Practical advice for any patient who carries the diagnosis of “protein C deficiency” is to question his/her diagnosis and to make sure the diagnosis was not based on a low level obtained while on warfarin or at the time of an acute clot.

(a)  Inherited Protein C Deficiency

How common is it? Who has it?  Inherited (congenital) protein C deficiency is a genetic disorder, and, thus, typically runs in families.  It is not very common. It occurs in 0.2 % of the general population, i.e. 1 out of 500 people has it.  Thus, there may be around 600,000 people with this disorder in the U.S.  It is inherited in a dominant pattern, which means that there is a 50 % chance that a child will have the disorder if one of the parents has it.  Men and women are equally affected.  It is independent of blood types.  We all inherit one protein C gene from our mother and one from our father. If a person has inherited one defective (mutated) protein C gene (from either mother or father), the person is said to be heterozygous for protein C deficiency.  If an individual has inherited 2 defective (mutated) genes, i.e. one defective gene from mother and another one from father, the person is homozygous.  Homozygous deficiency is extremely rare, occurring in approximately 1 in 1 million pregnancies. Often, the homozygous protein C deficient fetus does not survive, resulting in a miscarriage. For scientific purposes a classification of “type 1″ and “type 2” deficiency is used to distinguish different types of hereditary deficiency, but the distinction is clinically not relevant.

The risk for blood clots:  Individuals with protein C deficiency are at increased risk for blood clots in veins, such as clots in the veins of the leg (called deep vein thrombosis or DVT), and clots in the lung (called pulmonary embolism or PE).  Other venous clots may also occur: in the arm (upper extremity DVT), intestinal tract (portal vein thrombosis, Budd-Chiari syndrome, mesenteric vein thrombosis, etc.), or around the brain (cerebral venous thrombosis).  Protein C deficiency appears to be only a mild risk factor for clots in arteries (strokes and heart attacks).

The person with protein C deficiency who has had a blood clot:  Many physicians will recommend that an individual with inherited protein C deficiency who has had a DVT or PE, should be on indefinite blood thinning medication, i.e. typically warfarin (Coumadin®, Jantoven®).  If a person has protein C deficiency, but has never had a blood clot, the person is typically not given long-term blood thinners.  When deciding whether to treat with long-term warfarin or not, a number of factors need to be considered: does the person have additional risk factors for blood clots, such as obesity, smoking, a sedentary lifestyle, presence of an additional clotting disorder, or a family history of blood clots?  Also, the degree of protein C deficiency should be factored in.  Clearly, an individual decision needs to be made.

The person with protein C deficiency who has never had a blood clot:  Individuals with protein C deficiency who have never had a blood clot should receive brief courses of a low-dose blood thinner after surgery, during  prolonged immobility, or when a catheter is in one of the major veins of the body (central venous catheter), as these are times of increased risk for blood clots. Individuals should also not use estrogens (e.g., estrogen-containing birth control methods), as estrogens increase the risk for clots. Progestin-only contraceptives also have some risk for thrombosis and may also better be avoided.

Warfarin skin necrosis:  This is a rare complication of warfarin (Coumadin®, Jantoven®) therapy. More details on this disorder can be found here. It occurs within the first few days of beginning warfarin therapy.  Patients develop very painful skin areas, most commonly in the breasts, next commonly in buttocks, thighs and abdomen.  People at particular risk are those (a) who receive high initial doses of warfarin, and (b) who have an acute clot and receive heparin or low molecular weight heparin overlapping with warfarin for less than the recommended 5 days. Patients with underlying clotting disorder, such as protein C deficiency, may be at particular risk.

Purpura fulminans: Newborns with severe protein C deficiency (close to undetectable protein C blood levels) may develop diffuse and extensive skin necrosis  (tissue death), presenting as areas of black skin, fingers or toes. This is due to blood clots in the small veins of the skin and is termed purpura fulminans. Even when severe protein C deficiency is recognized promptly and long-term blood thinner therapy is instituted, additional blood clotting episodes commonly occur throughout life. This is partly due to the difficulty in consistently maintaining adequate anticoagulation levels in the blood throughout life. For this reason, other approaches have been considered (see Protein C Concentrates, below).

(b)  Acquired Protein C Deficiency

Acquired protein C deficiency is fairly common.  Low levels of protein C can be found in patients with the conditions listed in the table “Protein C Deficiency“. Table mentioned abov.  In adults, acquired protein C deficiency does not lead to an increased risk of blood clots; this is because in these conditions clotting factors other than protein C are frequently also lowered. In children, where infection is a common cause of acquired protein C deficiency, it is thought that acquired protein C deficiency increases the risk of blood clots, especially when levels are severely decreased.

Protein C is always low in the patient who takes warfarin (Coumadin®, Jantoven®).  There is no reason to test for it while a person is on warfarin.  A person needs to have been off warfarin for at least 14 days, before results return to the normal baseline and are reliable; if the patient is believed to be at high risk for developing another blood clot, the warfarin can be temporarily discontinued and another blood thinner given instead (such as low molecular weight heparins or Fondaparinux) that does not cause a decrease in protein C levels. That way, reliable protein C levels can be obtained. Some patients have been told they have “combined protein C and S deficiency”, but on review of their records it becomes clear that they were tested while on warfarin. Because protein C is produced in the liver, patients with liver disease may have low values of protein C.

In children and young adults, acquired protein C deficiency is sometimes seen in severe bacterial infections, such as meningitis. In some instances of extensive blood clotting in the deep veins (deep vein thrombosis = DVT) or lungs (pulmonary embolism = PE) in adults and children, levels of protein C temporarily decrease. Therefore, when a patient is tested during an acute clotting event, a severe infection, or on warfarin, low a low protein C level may a found. In this situation, a level should be repeated at a later time to determine whether the patient has a true and persistent protein C deficiency.

How Do You Test for Protein C Deficiency?

The best test to determine whether a person has protein C deficiency is a blood test called “protein C activity” or “functional protein C”.  Any physician’s office can order the test.  It is, however, not routinely performed by every clinical laboratory; a patient’s blood is typically sent to a specialized commercial laboratory or a larger medical institution for testing. Two different protein C tests can be done: (a) a protein C antigen level and (b) protein C activity level (also called “functional test”).  The protein C antigen test determines how much of the protein is present in the blood.  The protein C activity test determines whether the protein C that is present actually works.  Genetic testing does not need to be done in routine clinical practice.  There are many different mutations in the protein C gene that can lead to inherited protein C deficiency (over 160 have been described to date). Genetic testing is, therefore, not possible in routine clinical practice. It is reserved for special research studies.

Protein C Deficiency in Children

Parents of children with protein C deficiency need to be aware of the symptoms of blood clots, in case their child develops them.  Discussion between the expectant parents in whom one or both persons have protein C deficiency and the hematologist (“blood doctor”) and perinatologist (a physician who deals with unborns and newborns at higher than normal risk for complications) should be held prior to delivery.  Blood clots are uncommon in children with heterozygous protein C deficiency. Most newborn infants with heterozygous protein C deficiency do not need preventive treatment with heparin or protein C concentrate, but may benefit from particularly careful attention to hydration and their kidney and circulatory function.  Most children with heterozygous protein C deficiency do not develop blood clots unless there is an additional triggering event, such as surgery, trauma, a catheter, or severe infection.  Children known to have protein C deficiency may receive preventive therapy with blood thinners around trigger events. 

Protein C Deficiency and Pregnancy

Women with protein C deficiency are at particularly high risk for developing clots during pregnancy and after delivery.  The exact risk of developing blood clots during pregnancy in women with protein C deficiency is impossible to determine accurately and depends on whether a woman has additional risk factors for clots, such as overweight, a strong family history of clots or other clotting disorders. (a) Women who have never had a clot:  Approximately 1 out of 100 women with protein C deficiency will develop a blood clot during pregnancy, if blood thinners are not given. Individualized decisions as to which woman should receive blood thinner treatment during pregnancy or in the 6 weeks after delivery (postpartum) need to be made. There are two treatment choices: (a) either no blood thinners during the 9 months of pregnancy, but just diligent surveillance/observation, or (b) prophylactic (low) dose of a blood thinner injection. Most physicians would agree that a prophylactic dose of a blood thinner should be given for several weeks after delivery, such as for 6 weeks, as this is a period where women are at high risk for blood clots. (b) The woman who has had a blood clot before is at particularly high risk for another blood clot during pregnancy. Such a woman should receive blood thinner therapy during pregnancy and in the postpartum period. Having protein C deficiency may put a woman at higher risk for miscarriage and stillbirth, and certain pregnancy complications, such as preeclampsia, eclampsia, intrauterine growth restriction, and abruption of the placenta. However, as protein C deficiency is uncommon, it is not known whether there is truly an increased risk, how high that risk is if it is truly present, and whether giving blood thinners decreases that risk.

Protein C Deficiency and Surgery or Trauma

Individuals with protein C deficiency need very good DVT prevention (“prophylaxis”) with blood thinners at times of minor or major surgery. Major surgery and trauma are risk factors for blood clots (deep vein thrombosis or pulmonary embolism) in anybody; but they are an even greater risk for the person with protein C deficiency.  Extra attention to DVT prophylaxis is, therefore, indicated, typically with one of the blood thinning drugs.  If trauma or excessive risk for bleeding (for example neurosurgery) does not allow physicians to give the blood thinner, protein C concentrate can be considered.

Treatment: Protein C Concentrates

A protein C concentrate (Ceprotin®) was approved by the FDA in 2007.  High doses of intravenous protein C concentrates can help thin the blood and protect from blood clots.  Since a person with protein C deficiency is at increased risk for blood clots during (a) surgery, (b) delivery, (c) prolonged immobility, such as acute illness and hospital admission, or (d) overwhelming infection in the blood stream, called sepsis, intravenous protein C concentrate might, theoretically, be beneficial in these situations to decrease the risk for blood clots. A human plasma–derived, viral-inactivated protein C concentrate manufactured by Baxter (Ceprotin; Baxter BioScience Glendale, California) has been licensed in the United States and Europe.  In Europe, Ceprotin has been licensed and available to patients since 2001. A second plasma-derived concentrate (Protexel; LFB, Lille, France) is also available in Europe.

No guidelines exist as to which patients should receive protein C concentrate. Typically, treatment is given only at times of increased risk for clotting, or when the blood thinner heparin by itself cannot be safely given because it would lead to an increased risk for bleeding.  These situations are major surgery, major trauma, and delivery. However, in some patients, protein C concentrate has been used on a regular basis in severe protein C patients who have had severe bleeding complications on long-term blood thinner therapy. By giving protein C and “blood thinners” together, one may be able to reduce the dose of daily blood thinners and hopefully reduce the risk for future severe bleeding episodes. In addition, protein C concentrate is also used for purpura fulminans in infants with protein C deficiency.

Family Testing

Other family members should consider getting tested.  If a person has been diagnosed with protein C deficiency and has none of the acquired factors or disorders that cause acquired protein C deficiency (see Table above), an inherited deficiency may be present.  It is then appropriate to inform other family members (children, parents, siblings) of the diagnosis.  These family members should consider getting tested, and a protein C activity test should be performed in them.

Key Issues

  • If you have been diagnosed with protein C deficiency: question the diagnosis.  Be aware that misdiagnosis may occur if the timing of testing and interpretation of the result was incorrect, particularly if you were tested while on warfarin (Coumadin®, Jantoven®).
  • If you have been diagnosed with an inherited protein C deficiency, inform other family members of the diagnosis. They should consider getting tested.
  • If you have inherited protein C deficiency, consider being evaluated by a blood clotting specialist (typically a hematologist) at a specialized Thrombosis Center.
  • Know the symptoms of blood clots in the legs (deep vein thrombosis=DVT) or lung (pulmonary embolism=PE) and make lifestyle changes (lose weight, stop smoking, consider stopping estrogen therapy).
  • If you have inherited protein C deficiency, make sure you get very good DVT prophylaxis in risk situations (surgery, major trauma, prolonged immobility, pregnancy).
  • Questions or comments about protein C deficiency? Go to the online Clot Connect Support Forum, category “Thrombophilia (clotting disorders).

References

  1. Goldenberg NA et al. Protein C deficiency. Haemophilia. 2008 Nov;14(6):1214-1221.
  2. Bates SM et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy. American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2008;133:844S-886S.
  3. The American College of Obstetricians and Gynecologists Practice Bulletin. Inherited thrombophilias in pregnancy. Number 113,July 2010, page 1-11.
  4. Mahmoodi BK et al. Hereditary deficiency of protein C or protein S confers increased risk of arterial thromboembolic events at a young age: results from a large family cohort study. Circulation. 2008 Oct 14;118(16):1659-1667.
  5. Rodger MA, et al. Inherited thrombophilia and pregnancy complications revisited. Obstet Gynecol. 2008;112:320-324.
  6. Website of the manufacturer of protein C concentrate, Baxter: www.ceprotin.com.

For Health Care Professionals: A blog with information on protein C deficiency written for health care professionals can be found here.

Acknowledgement:  This blog entry was written in collaboration with Dr. Neil Goldenberg, Departments of Pediatrics and Medicine, Mountain States Regional Hemophilia and Thrombosis Center, University of Colorado and The Children’s Hospital, Aurora, CO.

Disclosure: The authors have no financial conflict of interest relevant to this educational post.

Last updated:  June 22nd, 2011

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