Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin
2011; Lippincott Williams & Wilkins; Volume: 124; Issue: 14 Linguagem: Inglês
10.1161/circulationaha.111.044412
ISSN1524-4539
AutoresBrea Lipe, Deborah L. Ornstein,
Tópico(s)Hemophilia Treatment and Research
ResumoHomeCirculationVol. 124, No. 14Deficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin Free AccessBrief ReportPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessBrief ReportPDF/EPUBDeficiencies of Natural Anticoagulants, Protein C, Protein S, and Antithrombin Brea Lipe, MD and Deborah L. Ornstein, MD Brea LipeBrea Lipe From Hematology/Oncology (B.L.) and Hemophilia and Thrombosis Center (D.L.O.), Dartmouth-Hitchcock Medical Center, Lebanon, NH; Departments of Medicine and Pathology, Dartmouth Medical School, Hanover, NH (D.L.O.). and Deborah L. OrnsteinDeborah L. Ornstein From Hematology/Oncology (B.L.) and Hemophilia and Thrombosis Center (D.L.O.), Dartmouth-Hitchcock Medical Center, Lebanon, NH; Departments of Medicine and Pathology, Dartmouth Medical School, Hanover, NH (D.L.O.). Originally published4 Oct 2011https://doi.org/10.1161/CIRCULATIONAHA.111.044412Circulation. 2011;124:e365–e368You or a family member may have developed a blood clot in one of the deep veins in the body (ie, a deep vein thrombosis, or DVT) or had a blood clot that traveled to the lungs (ie, a pulmonary embolism, or PE). As part of your medical care, your doctor may have evaluated you for conditions that may have contributed to developing a blood clot.Thrombophilia is a condition in which there is an increased tendency to form blood clots. It may be hereditary and conferred by genes inherited from one or more parents, or it may be acquired through situations such as surgery, cancer, pregnancy, or certain medications (eg, some contraceptive and menopausal hormone replacement products). The two most common hereditary thrombophilia conditions are the factor V Leiden and prothrombin 20210 gene mutations, both of which have been the subject of previous Cardiology Patient Pages.1,2 This Cardiology Patient Page will describe deficiencies in the natural anticoagulants, protein C, protein S, and antithrombin that may result in either hereditary or acquired thrombophilia.What Are the Natural Anticoagulants?Blood flows through blood vessels to deliver oxygen and nutrients to all the body's tissues. When a blood vessel is injured, a process called coagulation causes blood to form clots that stop the bleeding from the damaged blood vessel. Once coagulation begins, other substances in the blood, the natural anticoagulants, act as brakes to limit coagulation to the specific area of damage, thus avoiding formation of clots large enough to obstruct normal blood flow. There is a delicate balance at work to ensure that there is enough—but not too much—clotting ability in the blood. Too little clotting ability leads to bleeding problems, whereas too much clotting ability (thrombophilia) can lead to blood clot formation. The state of this balance between bleeding and clotting differs from person to person, and many things can upset the balance (Figure). Because the natural anticoagulants are required to help stop the clotting process, deficiencies of one of these substances can upset this balance and lead to thrombophilia. The most important natural anticoagulants are protein C, protein S, and antithrombin (which used to be called antithrombin III until its name was changed to antithrombin).Download figureDownload PowerPointFigure. The normal balance between clotting and bleeding is disrupted when there is a deficiency of one of the natural anticoagulants. There is a fine balance between clotting and bleeding in the blood. The substances that cause normal blood clots to form (called procoagulants) are carefully balanced by the natural anticoagulants (A) so that enough clotting occurs to prevent bleeding, but not so much as to trigger a large blood clot that obstructs a vein and prevents blood from flowing. When there is a deficiency in one of the natural anticoagulants (B, downward arrow), the balance is tipped in the direction of clotting such that individuals with these deficiencies have an increased propensity to form abnormal blood clots.What Causes Deficiencies of the Natural Anticoagulants?Low levels of the natural anticoagulants or natural anticoagulants that do not work properly can either be inherited or may occur during certain life events. Genes, including those for the natural anticoagulants, are inherited from your parents in 2 copies, 1 from your mother and 1 from your father. People born with deficiencies of one of the natural anticoagulants inherit one abnormal gene from either their mother or father. Rarely, people can inherit abnormal genes from both parents, but this often results in severe clotting problems that are diagnosed in infancy. People who have inherited normal levels of the natural anticoagulants may nevertheless develop deficiencies in certain situations, such as pregnancy, liver disease, severe infection or other illness, vitamin K deficiency, and certain medications, eg, estrogen, heparin, and warfarin. In addition, a recent blood clot may also reduce blood levels of the natural anticoagulants.How Is the Diagnosis Made?Testing is accomplished with a blood test to measure the levels and activity of the natural anticoagulants in your blood. Testing should be done at least several weeks after an acute clotting episode and at least 3 to 6 weeks after stopping warfarin or heparin. Repeat testing should be done to confirm abnormal results, because false-positive results are common. For example, birth control pills and pregnancy often cause a falsely low level of protein S.What Are the Implications?Inherited deficiencies of the natural coagulants are uncommon. Protein C deficiency occurs in ≈1 of every 200 to 500 people, whereas protein S deficiency can be expected in ≈1 of every 500 individuals. Antithrombin deficiency is the least common of the 3 deficiencies, occurring in ≈1 of every 2000 to 5000 people.People with hereditary protein C or protein S deficiency have about a 2- to 11-fold increased risk for developing a DVT or PE in comparison with those without a deficiency. This translates roughly to a DVT or PE occurring in ≈1 of every 100 to 500 people with one of these deficiencies annually. Antithrombin deficiency is associated with a higher risk for developing a DVT and PE, and it is estimated that up to 50% of people with hereditary antithrombin deficiency will experience a blood clot in their lifetimes.Deficiencies of the natural anticoagulants are associated primarily with an increased risk for blood clots in veins, and seem to play little or no role in development of blood clots in arteries, eg, heart attack and stroke. However, a recent study suggests that protein C and protein S (but not antithrombin) deficiencies may be associated with an increased risk for forming arterial blood clots in people younger than 55 years.Although associated with an increased risk for forming blood clots, it is important to remember that many (perhaps most) people with deficiencies of the natural anticoagulants will never experience complications from the deficiency.How Are Deficiencies of the Natural Anticoagulants Treated?If you have had a DVT or PE, you were most likely treated with anticoagulants (blood thinners). Warfarin is currently the most commonly prescribed anticoagulant for long-term treatment after a DVT or PE, but it must be given initially with an additional injectable anticoagulant (usually heparin, low-molecular-weight heparin, or a similar drug) until the warfarin is fully effective. If you have protein C or protein S deficiency, you must never receive warfarin without first receiving another anticoagulant at the same time. Warfarin inhibits the body's own production of protein C and protein S. Therefore, initial treatment with warfarin alone in people with protein C or protein S deficiency may temporarily make clotting worse or precipitate a new clot or a severe skin rash known as skin necrosis. It is usually safe to take warfarin alone after 5 or more days of concurrent treatment with heparin, low-molecular-weight heparin, or a related drug, such as fondaparinux.After a first DVT or PE, the risk for developing a second clot is probably higher for individuals with a deficiency of one of the natural anticoagulants than for those without this deficiency. Although lifelong treatment with an anticoagulant is not always recommended after a first blood clot, the duration of anticoagulant treatment will depend on the exact type of natural anticoagulant deficiency you have, the circumstances of your clot, and other risk factors you may have. Therefore, anticoagulation duration will need to be carefully considered with your physician.If you have a deficiency of one of the natural anticoagulants but have never had a blood clot, then you will not routinely be treated with an anticoagulant. However, you should focus on reducing or eliminating other factors that may add to your risk of developing a blood clot in the future (Table 1). In addition, you may require temporary treatment with an anticoagulant during periods of particularly high risk, such as surgery or pregnancy. It is very important, therefore, that you let all your doctors know if you have such a deficiency.Table 1. Risk Factors for DVT and PEObesityImmobilizationSurgeryHospitalization for medical illnessTraumaProlonged travelCigarette smokingAdvancing age (risk doubles for every decade of life)PregnancyChronic illnesses Congestive heart failure (CHF) Chronic obstructive pulmonary disease (COPD) Cancer Inflammatory bowel diseases (eg, Crohn's disease, ulcerative colitis) Systemic lupus erythematosus and other rheumatologic disorders Myeloproliferative disordersHormone therapy Contraceptives Menopausal hormone replacement therapy (HRT)Other inherited or acquired alterations in the blood clotting systemDVT indicates deep vein thrombosis; PE, pulmonary embolism.What Are Special Considerations for Women With a Deficiency of One of the Natural Anticoagulants?Deficiencies of the natural anticoagulants demand special consideration during times of pregnancy or hormone use (oral contraceptives or menopausal hormone replacement therapy). Hormone use is associated with an increased risk for blood clots in the general population, but the risk is even higher for women with natural anticoagulant deficiencies. Although medications that contain estrogen appear to be associated with the highest risk, progestin-only contraceptives may also increase the risk somewhat. It is important to note that progestin-only contraceptives have a higher failure rate and thus a higher rate of pregnancy than combined oral contraceptives containing both estrogen and progestin. In addition, progestin-only contraceptives have an increased risk of irregular bleeding that may lead some women to discontinue the medication. The levonorgestrel-secreting intrauterine device (Mirena) is not associated with an increased risk for developing blood clots and is often recommended for women with thrombophilia or a history of blood clots. Although the levonorgestrel intrauterine device also has a risk of irregular bleeding, the first-year failure rate carries a much lower risk of pregnancy than other contraceptive methods. Women should review the risks and benefits of the various options with their doctors before deciding on hormone use.During pregnancy and for the first 4 to 6 weeks after delivery, there is an increased risk for developing blood clots in all women. This rate is higher for those with than for those without a deficiency of one of the natural anticoagulants. There may also be an increased risk for early and late term miscarriages. Women with a deficiency of one of the natural anticoagulants who are planning a pregnancy should work closely with their obstetrician, hematologist, and/or thrombosis expert consultant to determine the appropriate treatment during and after pregnancy.Who Should Be Tested for Deficiencies of the Natural Anticoagulants?You may consider testing if you develop a blood clot and have a family member with a deficiency of one of the natural anticoagulants or if you have unexplained or recurrent DVTs or PEs without a family history. Other situations may arise in which testing can be considered after discussion with your physician. Testing healthy relatives of people with a natural anticoagulant deficiency is controversial and should be discussed carefully with your physician. Advantages of testing may include increased awareness of the risk factors for and symptoms of blood clots. Disadvantages include possible anxiety regarding a diagnosis that may never produce symptoms, lack of insurance coverage for inappropriate testing, and unnecessary withholding of certain medications, like oral contraceptives or hormone replacement therapy.How Do I Minimize the Risk Caused by Deficiencies of the Natural Anticoagulants?Although the genetic risk from natural anticoagulant deficiencies cannot be altered, individuals can make lifestyle modifications to reduce additional risk factors. A major risk factor for blood clots is obesity, for example, which poses a more potent risk than some of the hereditary thrombophilias. Tips for reducing risk for DVT and PE are listed in Table 2.Table 2. Steps to Take to Minimize the Risk for Developing a DVT or PEMaintain an ideal body weightEngage in regular physical activityDo not smokeAvoid long periods of immobility (>2 h) Get up to walk around or stretch during airplane flights or long car trips Consider the use of elastic compression stockings that provide moderate compression (15–20 mm Hg) Drink water to maintain hydration Avoid alcohol and caffeine during travelIf you are planning to have surgery Alert your doctor to any genetic risk factors Work with your doctors to identify strategies to reduce your riskRecognize the symptoms of a DVT or PE and seek medical attention should they occur Shortness of breath and/or chest pain Unexplained pain, swelling, and/or redness of a limbDVT indicates deep vein thrombosis; PE, pulmonary embolism.ConclusionsNatural anticoagulant deficiencies are rare and are either inherited at birth or acquired sometime during life. Natural anticoagulant deficiencies are one of many conditions that can increase the risk for developing a DVT or PE (Table 1), but many people with such a deficiency will never develop blood clots. Although the inherited risks cannot be altered, many things can be done to decrease an individual's overall risk of developing blood clots (Table 2). A heart healthy lifestyle is of paramount importance to minimizing thrombosis risk. Recognizing the symptoms of a DVT or PE allows for prompt treatment to minimize the risk of lasting side effects. Finally, it is important to work with your doctor to understand your individual risk, preventive strategies, and therapeutic options in the event of a DVT or PE.Additional Resources1. Heit J. Thrombophilia: common questions on laboratory assessment and management. Hematology Am Soc Hematol Educ Program. 2007:127–135.2. Foy P, Moll S. Thrombophilia: 2009 update. Curr Treat Options Cardiovasc Med. 2009;11: 114–128.3. Middeldorp S, van Hylckama Vlieg A. Does thrombophilia testing help in the clinical management of patients? Br J Hematol. 2008;143:321–335.4. Dalen JE. Should patients with venous thromboembolism be screened for thrombophilia? Am J Med. 2008;121:458–463.5. National Blood Clot Alliance. Website of the nonprofit patient organization, NBCA. Available at: http://stoptheclot.org.6. North American Thrombosis Forum. Website of the nonprofit organization, NATF. Available at: www.NATFonline.org.DisclosuresNone.FootnotesCorrespondence to Deborah L. Ornstein, MD, Hemophilia & Thrombosis Center, Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756. E-mail [email protected]orgReferences1. Ornstein DL, Cushman M. Factor V Leiden. Circulation. 2003; 107:e94–e97LinkGoogle Scholar2. Varga EA, Moll S. Prothrombin 20210 mutation (factor II mutation). 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