Hypercoagulability in pregnancy

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Hypercoagulability in pregnancy
Specialty Obstetrics

Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis (blood clots). Pregnancy itself is a factor of hypercoagulability (pregnancy-induced hypercoagulability), as a physiologically adaptive mechanism to prevent post partum bleeding. [1] However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial. [1]

Contents

Causes

Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to prevent post partum hemorrhage. [1] Pregnancy changes the plasma levels of many clotting factors, such as fibrinogen, which can rise up to three times its normal value. [2] Thrombin levels increase. [3] Protein S, an anticoagulant, decreases. However, the other major anticoagulants, protein C and antithrombin III, remain constant. [2] Fibrinolysis is impaired by an increase in plasminogen activator inhibitor-1 (PAI-1 or PAI) and plasminogen activator inhibitor-2 (PAI-2), the latter synthesized from the placenta. [2] Venous stasis may occur at the end of the first trimester, due to enhanced compliance of the vessel walls by a hormonal effect. [2]

Also, pregnancy can cause hypercoagulability by other factors, e.g. the prolonged bed rest that often occurs post partum that occurs in case of delivery by forceps, vacuum extractor or Caesarean section. [2] [4]

A study of more than 200,000 women came to the result that admission to inpatient care during pregnancy was associated with an 18-fold increase in the risk of venous thromboembolism (VTE) during the stay, and a 6-fold increase in risk in the four weeks after discharge, compared with pregnant women who did not require hospitalization. [5] The study included women admitted to hospital for one or more days for reasons other than delivery or venous thromboembolism. [5]

Pregnancy after the age of 35 augments the risk of VTE, as does multigravidity of more than four pregnancies. [2]

Pregnancy in itself causes approximately a five-fold increased risk of deep venous thrombosis. [6] Several pregnancy complications, such as pre-eclampsia, cause substantial hypercoagulability. [2]

Hypercoagulability states as a pre-existing condition in pregnancy include both acquired ones, such as antiphospholipid antibodies, and congenital ones, including factor V Leiden, prothrombin mutation, proteins C and S deficiencies, and antithrombin III deficiency.

Complications

Hypercoagulability in pregnancy, particularly due to inheritable thrombophilia, can lead to placental vascular thrombosis. [7] This can in turn lead to complications like early-onset hypertensive disorders of pregnancy, pre-eclampsia and small for gestational age infants (SGA). [7] Among other causes of hypercoagulability, Antiphospholipid syndrome has been associated with adverse pregnancy outcomes including recurrent miscarriage. [8] Deep vein thrombosis has an incidence of one in 1,000 to 2,000 pregnancies in the United States, [2] and is the second most common cause of maternal death in developed countries after bleeding. [9]

Prevention

Unfractionated heparin, low molecular weight heparin, warfarin (not to be used during pregnancy) and aspirin remain the basis of antithrombotic treatment and prophylaxis both before and during pregnancy. [10]

While the consensus among physicians is the safety of the mother supersedes the safety of the developing fetus, changes in the anticoagulation regimen during pregnancy can be performed to minimize the risks to the developing fetus while maintaining therapeutic levels of anticoagulants in the mother.

The main issue with anticoagulation in pregnancy is that warfarin, the most commonly used anticoagulant in chronic administration, is known to have teratogenic effects on the fetus if administered in early pregnancy. [11] [12] Still, there seems to be no teratogenic effect of warfarin before six weeks of gestation. [13] However, unfractionated heparin and low molecular weight heparin do not cross the placenta. [13]

Indications

In general, the indications for anticoagulation during pregnancy are the same as the general population. This includes (but is not limited to) a recent history of deep venous thrombosis (DVT) or pulmonary embolism, a metallic prosthetic heart valve, and atrial fibrillation in the setting of structural heart disease.

In addition to these indications, anticoagulation may be of benefit in individuals with lupus erythematosus, individuals who have a history of DVT or PE associated with a previous pregnancy, and even with individuals with a history of coagulation factor deficiencies and DVT not associated with a previous pregnancy. [14]

In pregnant women with a history of recurrent miscarriage, anticoagulation seems to increase the live birth rate among those with antiphospholipid syndrome and perhaps those with congenital thrombophilia but not in those with unexplained recurrent miscarriage. [15]

Strategies

A consensus on the correct anticoagulation regimen during pregnancy is lacking. Treatment is tailored to the particular individual based on her risk of complications. Warfarin and other vitamin K-inhibiting agents are contraindicated during the first trimester of pregnancy because of the teratogenic effects, [16] and should not be administered when the pregnancy is confirmed. [13] Rather, women who are on chronic anticoagulation may be given the option of conversion to either unfractionated heparin or low molecular weight heparin (LMWH), such as tinzaparin, [13] prior to a planned conception. [17] LMWH is as safe and efficacious as unfractionated heparin. [13] A blood test including platelets and a clotting screen should be performed prior to administration of anticoagulant regimens in pregnancy. [13]

Subcutaneous tinzaparin may be given at doses of 175 units of antifactor Xa activity per kg, [13] based on prepregnancy or booking weight at approximately 16 weeks, and not the current weight. [13] While unfractionated heparin is otherwise typically given in an intravenous formulation, this is inconvenient for the prolonged period of administration required in pregnancy.[ citation needed ]

Whether warfarin can be reinitiated after the 12th week of pregnancy is unclear. In a recent retrospective analysis, resumption of warfarin after the first trimester is completed is associated with increased risk of loss of the fetus. [18] However, this analysis included only individuals who were treated with anticoagulants for mechanical heart valves, who generally require high levels of anticoagulation.

In pregnant women with mechanical heart valves, the optimal anticoagulation regimen is particularly unclear. Anticoagulation with subcutaneous heparin in this setting is associated with a high incidence of thrombosis of the valve and death. [19] [20] Similar issues are likely associated with the use of enoxaparin (a LMWH) in these high-risk individuals. [21]

Risk score

Prevention of DVT and other types of venous thrombosis may be required if certain predisposing risk factors are present. One example from Sweden is based on the point system below, where points are summed to give the appropriate prophylaxis regimen. [9]

PointsRisk factors
1 point
Minor factors
2 points
Intermediate risk factors
3 points
Intermediate risk factors
  • Homozygous for factor V Leiden mutation
  • Homozygous for factor II mutation
4 points
Severe risk factors
Very high risk

After adding any risk factors together, a total of one point or less indicates no preventive action is needed. [9] A total of two points indicates short-term prophylaxis, e.g. with LMWH, may be used in temporary risk factors, as well as administering prophylactic treatment seven days postpartum, starting a couple of hours after birth. [9] A total of 3 points increases the necessary duration of post partum prophylaxis to six weeks. [9]

A risk score of four points or higher means prophylaxis in the ante partum period is needed, as well as at least six weeks post partum. [9] A previous distal DVT indicates a minimum of 12 weeks (three months) of therapeutic anticoagulation therapy. [13] A previous proximal DVT or pulmonary embolism requires a minimum of 26 weeks (6.5 months) of therapy [13] If the therapy duration reaches delivery time, the remaining duration may be given after delivery, possibly extending the minimum of six weeks of post partum therapy. [13] In a very high risk, high-dose ante partum prophylaxis should be continued at least 12 weeks after delivery. [9]

Women with antiphospholipid syndrome should have an additional low-dose prophylactic treatment of aspirin. [9]

Cautions

All anticoagulants (including LMWH) should be used with caution in women with suspected coagulopathy, thrombocytopaenia, liver disease and nephropathy. [13]

Major side effects of tinzaparin are osteoporosis (occurring in up to 1% of cases), thrombocytopenia (heparin-induced thrombocytopenia), haemorrhage, hair loss and drug allergy. [13] Still, LMWHs are much less likely to cause heparin-induced thrombocytopenia than unfractionated heparin. [13]

Regional anaesthesia is contraindicated in women on therapeutic anticoagulation, and should not be used within 24 hours of the last dose of tinzaparin. [13]

Monitoring

Anticoagulant therapy with LMWH is not usually monitored. [13] LMWH therapy does not affect the prothrombin time (PT) or the INR, and anti-Xa levels are not reliable. [13] It can prolong the partial thromboplastin time (APTT) in some women, but still, the APTT is not useful for monitoring. [13]

To check for any thrombocytopenia, platelet count should be checked prior to commencing anticoagulant therapy, then seven to ten days after commencement, and monthly thereafter. [13] Platelet count should also be checked if unexpected bruising or bleeding occurs. [13]

Reversal

Protamine reverses the effect of unfractionated heparin, but only partially binds to and reverses LMWH. A dose of 1 mg protamine / 100 IU LMWH reverses 90% of its anti-IIa and 60% of anti-Xa activity, but the clinical effect of the residual anti-Xa activity is not known. [13] Both anti-IIa and anti-Xa activity may return up to three hours after protamine reversal, possibly due to release of additional LMWH from depot tissues. [13]

See also

Related Research Articles

<span class="mw-page-title-main">Anticoagulant</span> Class of drugs

Anticoagulants, commonly known as blood thinners, are chemical substances that prevent or reduce coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood. As a class of medications, anticoagulants are used in therapy for thrombotic disorders. Oral anticoagulants (OACs) are taken by many people in pill or tablet form, and various intravenous anticoagulant dosage forms are used in hospitals. Some anticoagulants are used in medical equipment, such as sample tubes, blood transfusion bags, heart–lung machines, and dialysis equipment. One of the first anticoagulants, warfarin, was initially approved as a rodenticide.

<span class="mw-page-title-main">Thrombosis</span> Medical condition caused by blood clots

Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.

<span class="mw-page-title-main">Pulmonary embolism</span> Blockage of an artery in the lungs

Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathing in, and coughing up blood. Symptoms of a blood clot in the leg may also be present, such as a red, warm, swollen, and painful leg. Signs of a PE include low blood oxygen levels, rapid breathing, rapid heart rate, and sometimes a mild fever. Severe cases can lead to passing out, abnormally low blood pressure, obstructive shock, and sudden death.

<span class="mw-page-title-main">Venous thrombosis</span> Blood clot (thrombus) that forms within a vein

Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).

<span class="mw-page-title-main">Antiphospholipid syndrome</span> Medical condition

Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease. Diagnosis is made based on symptoms and testing, but sometimes research criteria is used to aid in diagnosis. The research criteria for definite APS requires one clinical event and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, and/or anti-cardiolipin antibodies.

Factor V Leiden is a variant of human factor V, which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoagulant protein that normally inhibits the pro-clotting activity of factor V, is not able to bind normally to factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans. It is named after the Dutch city of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of Pieter Hendrick Reitsma. Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population. It is an autosomal dominant genetic disorder with incomplete penetrance.

<span class="mw-page-title-main">Deep vein thrombosis</span> Formation of a blood clot (thrombus) in a deep vein

Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms. The most common life-threatening concern with DVT is the potential for a clot to embolize, travel as an embolus through the right side of the heart, and become lodged in a pulmonary artery that supplies blood to the lungs. This is called a pulmonary embolism (PE). DVT and PE comprise the cardiovascular disease of venous thromboembolism (VTE). About two-thirds of VTE manifests as DVT only, with one-third manifesting as PE with or without DVT. The most frequent long-term DVT complication is post-thrombotic syndrome, which can cause pain, swelling, a sensation of heaviness, itching, and in severe cases, ulcers. Recurrent VTE occurs in about 30% of those in the ten years following an initial VTE.

Low-molecular-weight heparin (LMWH) is a class of anticoagulant medications. They are used in the prevention of blood clots and treatment of venous thromboembolism and in the treatment of myocardial infarction.

<span class="mw-page-title-main">Heparin-induced thrombocytopenia</span> Low platelet count due to heparin, associated with a risk of thrombosis

Heparin-induced thrombocytopenia (HIT) is the development of thrombocytopenia, due to the administration of various forms of heparin, an anticoagulant. HIT predisposes to thrombosis. When thrombosis is identified the condition is called heparin-induced thrombocytopenia and thrombosis (HITT). HIT is caused by the formation of abnormal antibodies that activate platelets, which release microparticles that activate thrombin, leading to thrombosis. If someone receiving heparin develops new or worsening thrombosis, or if the platelet count falls, HIT can be confirmed with specific blood tests.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

<span class="mw-page-title-main">Rivaroxaban</span> Anticoagulant drug

Rivaroxaban, sold under the brand name Xarelto among others, is an anticoagulant medication used to treat and prevent blood clots. Specifically it is used to treat deep vein thrombosis and pulmonary emboli and prevent blood clots in atrial fibrillation and following hip or knee surgery. It is taken by mouth.

<span class="mw-page-title-main">Activated protein C resistance</span> Medical condition

Activated protein C resistance (APCR) is a hypercoagulability characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis, which resulting in medical conditions such as deep vein thrombosis and pulmonary embolism. The most common cause of hereditary APC resistance is factor V Leiden mutation.

<span class="mw-page-title-main">Protein C deficiency</span> Medical condition

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.

Antithrombin III deficiency is a deficiency of antithrombin III. This deficiency may be inherited or acquired. It is a rare hereditary disorder that generally comes to light when a patient suffers recurrent venous thrombosis and pulmonary embolism, and repetitive intrauterine fetal death (IUFD). Hereditary antithrombin deficiency results in a state of increased coagulation which may lead to venous thrombosis. Inheritance is usually autosomal dominant, though a few recessive cases have been noted. The disorder was first described by Egeberg in 1965. The causes of acquired antithrombin deficiency are easier to find than the hereditary deficiency.

<span class="mw-page-title-main">Tinzaparin sodium</span> Pharmaceutical drug

Tinzaparin is an antithrombotic drug in the heparin group. It is a low molecular weight heparin (LMWH) marketed as Innohep worldwide. It has been approved by the U.S. Food and Drug Administration (FDA) for once daily treatment and prophylaxis of deep vein thrombosis (DVT) and pulmonary embolism (PE).

Blood clots are a relatively common occurrence in the general population and are seen in approximately 1-2% of the population by age 60. Typically, blood clots develop in the deep veins of the lower extremities, deep vein thrombosis (DVT) or as a blood clot in the lung, pulmonary embolism. A very small number of people who develop blood clots have a more serious and often life-threatening condition, known as thrombotic storm (TS). TS is characterized by the development of more than one blood clot in a short period of time. These clots often occur in multiple and sometimes unusual locations in the body and are often difficult to treat. TS may be associated with an existing condition or situation that predisposes a person to blood clots, such as injury, infection, or pregnancy. In many cases, a risk assessment will identify interventions that will prevent the formation of blood clots.

Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. Two copies increases the risk to up to 20 in 1,000 per year. Most people never develop a blood clot in their lifetimes.

Direct thrombin inhibitors (DTIs) are a class of anticoagulant drugs that can be used to prevent and treat embolisms and blood clots caused by various diseases. They inhibit thrombin, a serine protease which affects the coagulation cascade in many ways. DTIs have undergone rapid development since the 90's. With technological advances in genetic engineering the production of recombinant hirudin was made possible which opened the door to this new group of drugs. Before the use of DTIs the therapy and prophylaxis for anticoagulation had stayed the same for over 50 years with the use of heparin derivatives and warfarin which have some well known disadvantages. DTIs are still under development, but the research focus has shifted towards factor Xa inhibitors, or even dual thrombin and fXa inhibitors that have a broader mechanism of action by both inhibiting factor IIa (thrombin) and Xa. A recent review of patents and literature on thrombin inhibitors has demonstrated that the development of allosteric and multi-mechanism inhibitors might lead the way to a safer anticoagulant.

<span class="mw-page-title-main">Thrombosis prevention</span> Medical treatment

Thrombosis prevention or thromboprophylaxis is medical treatment to prevent the development of thrombosis in those considered at risk for developing thrombosis. Some people are at a higher risk for the formation of blood clots than others, such as those with cancer undergoing a surgical procedure. Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk.

References

  1. 1 2 3 Page 264 in: Gresele, Paolo (2008). Platelets in hematologic and cardiovascular disorders: a clinical handbook. Cambridge, UK: Cambridge University Press. ISBN   978-0-521-88115-9.
  2. 1 2 3 4 5 6 7 8 Hypercoagulability during Pregnancy Lab Lines. A publication of the Department of Pathology and Laboratory Medicine at the University of Cincinnati. September/October 2002 Volume 8, Issue 5
  3. ↑ de Boer K, ten Cate JW, Sturk A, Borm JJ, Treffers PE (1989). "Enhanced thrombin generation in normal and hypertensive pregnancy". Am J Obstet Gynecol. 160 (1): 95–100. doi:10.1016/0002-9378(89)90096-3. PMID   2521425.
  4. ↑ "Venous Thromboembolism (Blood Clots) and Pregnancy". Centers for Disease Control and Prevention. 20 August 2020. Retrieved 24 October 2020.
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  6. ↑ Eichinger, S.; Evers, J. L. H.; Glasier, A.; La Vecchia, C.; Martinelli, I.; Skouby, S.; Somigliana, E.; Baird, D. T.; Benagiano, G.; Crosignani, P. G.; Gianaroli, L.; Negri, E.; Volpe, A.; Glasier, A.; Crosignani, P. G. (2013). "Venous thromboembolism in women: A specific reproductive health risk". Human Reproduction Update. 19 (5): 471–482. doi: 10.1093/humupd/dmt028 . PMID   23825156.
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  8. ↑ McNamee, Kelly; Dawood, Feroza; Farquharson, Roy (1 August 2012). "Recurrent miscarriage and thrombophilia". Current Opinion in Obstetrics and Gynecology. 24 (4): 229–234. doi:10.1097/GCO.0b013e32835585dc. PMID   22729089.
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  10. ↑ Giannubilo, SR; Tranquilli, AL (2012). "Anticoagulant therapy during pregnancy for maternal and fetal acquired and inherited thrombophilia". Current Medicinal Chemistry. 19 (27): 4562–71. doi:10.2174/092986712803306466. PMID   22876895.
  11. ↑ Sathienkijkanchai A, Wasant P (2005). "Fetal warfarin syndrome". J Med Assoc Thai. 88 (Suppl 8): S246–50. PMID   16856447.
  12. ↑ Schaefer C, Hannemann D, Meister R, Eléfant E, Paulus W, Vial T, Reuvers M, Robert-Gnansia E, Arnon J, De Santis M, Clementi M, Rodriguez-Pinilla E, Dolivo A, Merlob P (2006). "Vitamin K antagonists and pregnancy outcome. A multi-centre prospective study". Thromb Haemost. 95 (6): 949–57. doi:10.1160/TH06-02-0108. PMID   16732373. S2CID   33278534.
  13. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 Archived 12 June 2010 at the Wayback Machine Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9 June 2006 [review June 2009]
  14. ↑ Couto E, Nomura ML, Barini R, Pinto e Silva JL (2005). "Pregnancy-associated venous thromboembolism in combined heterozygous factor V Leiden and prothrombin G20210A mutations". Sao Paulo Med J. 123 (6): 286–8. doi: 10.1590/S1516-31802005000600007 . PMID   16444389.
  15. ↑ De Jong, P. G.; Goddijn, M.; Middeldorp, S. (2013). "Antithrombotic therapy for pregnancy loss". Human Reproduction Update. 19 (6): 656–673. doi: 10.1093/humupd/dmt019 . PMID   23766357.
  16. ↑ Shaul WL, Emery H, Hall JG (1975). "Chondrodysplasia punctata and maternal warfarin use during pregnancy". Am J Dis Child. 129 (3): 360–2. doi:10.1001/archpedi.1975.02120400060014. PMID   1121966.
  17. ↑ James AH, Grotegut CA, Brancazio LR, Brown H (2007). "Thromboembolism in pregnancy: recurrence and its prevention". Semin Perinatol. 31 (3): 167–75. doi:10.1053/j.semperi.2007.03.002. PMID   17531898.
  18. ↑ Kim BJ, An SJ, Shim SS, Jun JK, Yoon BH, Syn HC, Park JS (2006). "Pregnancy outcomes in women with mechanical heart valves". J Reprod Med. 51 (8): 649–54. PMID   16967636.
  19. ↑ Iturbe-Alessio I, Fonseca MC, Mutchinik O, Santos MA, Zajarías A, Salazar E (1986). "Risks of anticoagulant therapy in pregnant women with artificial heart valves". N Engl J Med. 315 (22): 1390–3. doi:10.1056/NEJM198611273152205. PMID   3773964.
  20. ↑ Salazar E, Izaguirre R, Verdejo J, Mutchinick O (1996). "Failure of adjusted doses of subcutaneous heparin to prevent thromboembolic phenomena in pregnant patients with mechanical cardiac valve prostheses". J Am Coll Cardiol. 27 (7): 1698–703. doi: 10.1016/0735-1097(96)00072-1 . PMID   8636556.
  21. ↑ Ginsberg JS, Chan WS, Bates SM, Kaatz S (2003). "Anticoagulation of pregnant women with mechanical heart valves" (PDF). Arch Intern Med. 163 (6): 694–8. doi: 10.1001/archinte.163.6.694 . PMID   12639202.
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