Hypercoagulability in pregnancy

Hypercoagulability in pregnancy
Classification and external resources
ICD-10	O22.9, O99.1
ICD-9	649.3

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 postpartum hemorrhage.^[1] However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.^[1]

Causes

Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to prevent postpartum hemorrhage.^[1] Pregnancy changes the plasma levels of many clotting factors like fibrinogen, which can rise up to three times the 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 just 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]

There are also many pregnancy-related causes of hypercoagulability, e.g. the prolonged bed rest that often occurs postpartum that occurs in case of delivery by forceps, vacuum extractor or Caesarean section. ^[2] Pregnancy after the age of 35 augments the risk of VTE, as does multigravidity of more than 4 pregnancies. ^[2] Several pregnancy complications, like preeclampsia, cause substantial hypercoagulability.^[2]

General causes of hypercoagulability, that are approximately as common in pregnancy as in the general population, include both acquired ones such as antiphospholipid antibodies, and congenital ones, including Factor V Leiden mutation, prothrombin mutation, protein C and S deficiencies and antithrombin III deficiency.

Complications

Deep vein thrombosis has an incidence of 1 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.^[4]

Prevention of thrombosis with anticoagulants

While the consensus among physicians is that 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 anticoagulation 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.^[5][6] Still, there seems to be no teratogenic effect of warfarin before 6 weeks of gestation.^[7] On the other hand, unfractionated heparin and low molecular weight heparin (LMWH) do not cross the placenta.^[7]

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 SLE and a history of previous spontaneous abortions,^{[citation needed]} individuals who have a history of deep venous thrombosis (DVT) or pulmonary embolism (PE) associated with a previous pregnancy,^{[citation needed]} and even with individuals with a history of coagulation factor deficiencies and DVT not associated with a previous pregnancy.^[8]

Strategies

There is no consensus on the correct anticoagulation regimen during pregnancy. Treatment is tailored to the particular individual based on their risk of complications. Warfarin and other vitamin K inhibiting agents are contraindicated during the first trimester of pregnancy because of the teratogenic effects,^[9] and should not be administered when pregnancy confirmed.^[7] 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^[7] prior to a planned conception.^[10] LMWH is as safe and efficacious as unfractionated heparin.^[7] A blood test including platelets and a clotting screen should be performed prior to administration of anticoagulant regimens in pregnancy.^[7]

Subcutaneous tinzaparin may be given at doses of 175 units of anti-factor Xa activity per kg,^[7] based on pre-pregnancy or booking weight at approximately 16 weeks, and not the current weight.^[7] While unfractionated heparin is otherwise typically given in an intravenous formulation, this is inconvenient for the prolonged period of administration required in pregnancy.

Whether warfarin can be re-initiated after the twelfth week of pregnancy is unclear. In a recent retrospective analysis, it was suggested that resumption of warfarin after the first trimester is completed is associated with increased risk of loss of the fetus.^[11] However, this analysis included only individuals who were anticoagulated for mechanical heart valves, which generally require high levels of anticoagulation.

In pregnant women with mechanical heart valves, the optimal anticoagulation regimen is particularly unclear. It is clear from prior studies that anticoagulation with subcutaneous heparin in this setting is associated with a high incidence of thrombosis of the valve and death.^[12][13] Similar issues are likely associated with the use of enoxaparin (a low molecular weight heparin) in these high-risk individuals.^[14]

By risk score

Prevention of deep vein thrombosis and other types of venous thrombosis may be required if there are certain predisposing risk factors. One example is based on the point system below, where points are summed together to give the appropriate prophylaxis regimen.^[4]

Points	Risk factors
1 point Minor factors	Heterozygous for factor V Leiden mutation Heterozygous for factor II mutation Overweight, in this case defined as a BMI > 28 at early pregnancy[4] Caesarean section DVT heredity in a first-degree relative Age > 40 years Pre-eclampsia Hyperhomocysteinemia
2 points Intermediate risk factors	Protein S or C deficiency Immobilization (after e.g. bone fracture or prolonged bed rest
3 points Intermediate risk factors	Homozygous for factor V Leiden mutation Homozygous for factor II mutation
4 points Severe risk factors	Previous DVT Antiphospholipid syndrome without previous DVT Lupus anticoagulant
Very high risk	Artificial heart valves Antithrombin III deficiency Multiple previous thromboses Antiphospholipid syndrome with previous DVT Previous pulmonary embolism[7]

After adding any risk factors together, a total of 1 point or less indicates that no preventive action is needed.^[4] A total of 2 points indicates that short-term prophylaxis, e.g. with low molecular weight heparin, may be used in temporary risk factors, as well as administering prophylactic treatment 7 days postpartum, starting a couple of hours after birth.^[4] A total of 3 points increases the necessary duration of postpartum prophylaxis to 6 weeks.^[4]

A risk score of 4 points or higher means that there should probably be prophylaxis in the antepartum period, as well as at least 6 weeks postpartum.^[4] A previous distal DVT motivates a minimum of 12 weeks (3 months) of therapeutic anticoagulation therapy^[7] A previous proximal DVT or pulmonary embolism motivates a minimum of 26 weeks (6.5 months) of therapy^[7] If the therapy duration reaches delivery time, the remaining duration may be given postpartum, possibly extending the minimum of 6 weeks postpartum therapy.^[7] In a very high risk, there should be a high-dose antepartum prophylaxis, continued at least 12 weeks postpartum.^[4]

Women with antiphospholipid syndrome should have an additional low dose prophylactic treatment of Aspirin.^[4]

Cautions

All anticoagulants (including LMWH) should be used with caution in women with suspected coagulopathy, thrombocytopaenia, liver disease and nephropathy.^[7]

Major side effects of tinzaparin are osteoporosis (occurring in up to 1% of cases), thrombocytopenia (heparin-induced thrombocytopenia), haemorrhage, hair loss and drug allergy.^[7] Still, LMWHs are much less likely to cause heparin-induced thrombocytopenia than unfractionated heparin.^[7]

Regional anaesthesia is contraindicated in women on therapeutic anticoagulation, and should not be used within 24 hours of the last dose of tinzaparin. ^[7]

Monitoring

Anticoagulant therapy with LMWH is not usually monitored.^[7] LMWH therapy does not affect the prothrombin time (PT) or the INR, and Anti Xa levels are not reliable.^[7] It can prolong the Partial thromboplastin time (APTT) in some women, but still, the APTT is not useful for monitoring.^[7]

In order to check for any thrombocytopenia, platelet count should be checked prior to commencing anticoagulant therapy, then 7 to 10 days after commencement, and monthly thereafter.^[7] Platelet count should also be checked if unexpected bruising or bleeding occurs.^[7]

Reversal

Protamine reverses the effect of unfractionated heparin but only partially binds to and reverses LMWH. A dose of 1mg protamine/100IU 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.^[7] 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.^[7]

Anticoagulants in breastfeeding

Warfarin, heparin and LMWH do not seem to pass into breast milk, so these are not contraindicated in breastfeeding.^[7]

See also

• Valvular heart disease and pregnancy

References

1. ^ ^{a b c} Page 264 in: Gresele, Paolo (2008). Platelets in hematologic and cardiovascular disorders: a clinical handbook. Cambridge, UK: Cambridge University Press. ISBN 0-521-88115-3. 
2. ^ ^{a b c d e f g h} 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. PMID 2521425. 
4. ^ ^{a b c d e f g h i} Venös tromboembolism (VTE) - Guidelines for treatment in C counties. Bengt Wahlström, Emergency department, Uppsala Academic Hospital. January 2008
5. ^ Sathienkijkanchai A, Wasant P. (2005). "Fetal warfarin syndrome.". J Med Assoc Thai 88 (Suppl 8): S246–50. PMID 16856447. 
6. ^ 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. 
7. ^ ^{a b c d e f g h i j k l m n o p q r s t u v w x} [1] Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9th June 2006 [review June 2009]
8. ^ 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. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-31802005000600007&tlng=es&lng=en&nrm=iso. 
9. ^ Shaul WL, Emery H, Hall JG. (1975). "Chondrodysplasia punctata and maternal warfarin use during pregnancy.". Am J Dis Child 129 (3): 360–2. PMID 1121966. 
10. ^ 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. 
11. ^ 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. 
12. ^ 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. 
13. ^ 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. 
14. ^ 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. http://archinte.ama-assn.org/cgi/reprint/163/6/694.pdf. 

Further reading

• [2] Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9th June 2006 [review June 2009]