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Protein C Deficiency

Inherited protein C deficiency is considered a stronger thrombophilia. It increases the risk for venous and arterial thromboembolism, and possibly for early and late pregnancy loss and other adverse pregnancy outcomes (preeclampsia, IUGR, placental abruption).  There are 2 major causes for low protein C values: (a) an inherited deficiency, and (b) acquired and sometimes transient deficiencies (see table).  A definitive diagnosis of hereditary deficiency can be 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 is necessary to help clarify the diagnosis of inherited versus acquired deficiency.  In the patient who carries the diagnosis of  “protein C deficiency” it is always worthwhile to question the diagnosis until review of history timing of testing clarifies the diagnosis was not based on a low level obtained while on warfarin or at the time of the acute thrombotic event.

How to Test for Protein C Deficiency?
A “Protein C activity”, also referred to as “functional protein C” should be obtained to determine whether a person has protein C deficiency.  There is no clinical utility in also ordering a protein C antigen. While obtaining both the activity and antigen test helps distinguish between type 1 deficiency (quantitative deficiency, in which both activity and antigen are decreased) and type 2 deficiency (dysfunctional protein C; protein C activity is low, the antigen is normal), such distinction is only of academic interest. Clinically it is not relevant – either type is associated with an increased risk for thrombosis. Similarly, there is no utility in obtaining a protein C panel or profile, containing a protein C activity and antigen. The antigen test should deleted from such panels. There are more than 160 known mutations in the protein C gene that lead to inherited protein C deficiency. Genetic testing, therefore, is not done in routine clinical practice. It is reserved for research studies. Elevated levels of protein C appear to be irrelevant; they do not lead to an increased bleeding tendency.  Results of antigen and activity tests are typically expressed in “percent”.  Normal ranges differ from lab to lab, but are typically in the order of 80 – 120 %.  Healthy, full-term newborns have much lower protein C levels than adults – a level of 35% is typical, and as low as 20% is normal for this ­­age. In premature newborns, levels are typically even lower. The average protein C level at 6 months of age is approximately 60 %. Adult levels are not reached until sometime between early childhood and puberty.

Inherited Protein C Deficiency

Prevalence:  Protein C deficiency is somewhat uncommon: it occurs in 0.2 % of the general population. Thus, there may be around 600,000 people with protein C deficiency in the U.S.  It is inherited in an autosomal dominant pattern. Most individuals with inherited protein C deficiency have a heterozygous mutation.  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.

The risk for thrombosis: Individuals with protein C deficiency are at increased risk for venous thromboembolism, mostly leg DVT and PE.  However, other venous thromboses may also occur: superficial thrombophlebitis,  arm DVT, splanchnic vein thrombosis  (portal vein thrombosis, Budd-Chiari syndrome, mesenteric vein thrombosis), or cerebral venous thrombosis.  Protein C deficiency appears to be a mild risk factor for  arterial thrombosis [ref].

The person with protein C deficiency who has had a blood clot:  The patient with inherited protein C deficiency who has had an unprovoked (idiopathic) DVT or PE should be on indefinite anticoagulation, unless anticoagulation is not tolerated well. Whether this recommendation is also true for the patient who had a VTE associated with a major transient risk factor (major trauma, major surgery) is not clear. Individualized decisions need to be made, taking into consideration the triggering factor and other thrombosis risk factors (weight, smoking, family history, sedentary lifestyle, presence of additional thrombophilias, etc). Also, the degree of protein C deficiency could be factored in. Whether the patient who has an arterial thrombotic event in the absence of arteriosclerosis or arteriosclerosis risk factors and who is found to have protein C deficiency is better treated with warfarin or aspirin is not known.

The person with protein C deficiency who has never had a blood clot:  The person who has protein C deficiency, but never had a thrombotic event,  is typically not treated with long-term anticoagulation, but should receive brief courses of prophylactic anticoagulation after surgery (major and minor), during  prolonged immobility, with central venous catheters, possibly even during casts and extremity immobilizer treatment and during long-distance airline travel. Women should not use estrogens (e.g., estrogen-containing birth control methods), and progestin-only contraceptives may also better be avoided, except for progestin-releasing IUD.

Warfarin skin necrosis  Patients with underlying stronger thrombophilias, such as protein C deficiency, may be at particular risk for developing warfarin skin necrosis. Care should be taken to (a) not start a patient on very high doses of warfarin. A 5 mg or  7.5 mg qd regimen in the initial few days may be preferable over 10 mg qd starting doses. Also, diligent attention should be paid to overlapping warfarin and the parenteral anticoagualant for at least 5 days and until the INR is above 2.0. More details on warfarin skin necrosis can be found here.

Purpura fulminans: Newborns with severe protein C deficiency (close to undetectable protein C blood levels) may develop diffuse and extensive skin necrosis, including gangrene of digits. This is an indication for protein C concentrates.

(b)  Acquired Protein C Deficiency

Acquired protein C deficiency is fairly common.  Low plasma levels can be found in patients with the conditions listed in the table. In adults, acquired protein C deficiency does not lead to hyper-coagulability, as coagulation factors other than protein C are frequently also lowered in these conditions. 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.  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 thrombotic event if not on anticoagulants, the warfarin can be temporarily discontinued and a parenteral anticoagulant given (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 patients with acute thrombosis levels of protein C can temporarily decrease. Therefore, a level should be repeated at a later time to determine whether the patient has a true and persistent protein C deficiency.

Protein C Deficiency and Pregnancy

Women with protein C deficiency are at particularly high risk for DVT and PE during pregnancy and after delivery.  The risk is also influenced by whether a woman has additional risk factors for clots, such as overweight, a strong family history of clots or other clotting disorders.

  1. Women who have never had a thrombotic event:  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 [ref ]: (a) either no anticoagulation during the 9 months of pregnancy, but diligent surveillance, or (b) prophylactic dose of a anticoagulation. Prophylactic anticoagulation should be given for several weeks after delivery, such as for 6 weeks.
  2. The woman who has had a thrombosis before is at particularly high risk for another thrombotic event during pregnancy. Such a woman should receive anticoagualtion 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 [ref ]. 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 anticoagulants decrease that risk.

Protein C Deficiency and Surgery or Trauma

Individuals with protein C deficiency need very good DVT prophylaxis at times of minor surgery or major surgery. If trauma or excessive risk for bleeding (for example neurosurgery) does not allow anticoagulants to be given, protein C concentrate can be considered.

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 and perinatologist should be held prior to delivery.  Most newborns with heterozygous protein C deficiency do not need prophylactic treatment with heparin or protein C concentrate, but may benefit from particularly careful attention to hydration and their renal and circulatory function. Most children with heterozygous protein C deficiency do not develop thrombosis 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 Concentrates

A human plasma–derived, viral-inactivated protein C concentrate manufactured by Baxter (Ceprotin; Baxter BioScience Glendale, California) was approved by the FDA in 2007.  In Europe, Ceprotin has been licensed and available to patients since 2001. Another plasma-derived concentrate (Protexel; LFB, Lille, France) is also available in Europe.  No professional guidelines exist as to which patients should receive protein C concentrate. Treatment can be considered at times of increased thrombotic risk when an anticoagulant by itself cannot be safely given because of an increased bleeding risk risk, such as neurosurgery, major surgery, major trauma, and delivery. 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 full-dose long-term anticoagulant therapy. By giving protein C and anticoagulants together, one may be able to reduce the intensity of anticoagulant therapy 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 acquired protein C deficiency has been ruled out.  The appropriate test to obtain in these family members is a protein C activity (= functional protein C).

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.

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.

For Patients:  This same information, written for patients and other non-health care professionals, can be found here.

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

Last updated:  June 16th, 2011

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