Hypercoagulability in pregnancy
|Hypercoagulability in pregnancy|
|Classification and external resources|
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. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.
Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to prevent post partum hemorrhage. Pregnancy changes the plasma levels of many clotting factors, such as fibrinogen, which can rise up to three times its normal value. Thrombin levels increase. Protein S, an anticoagulant, decreases. However, the other major anticoagulants, protein C and antithrombin III, remain constant. 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. Venous stasis may occur at the end of the first trimester, due to enhanced compliance of the vessel walls by a hormonal effect.
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. Pregnancy after the age of 35 augments the risk of VTE, as does multigravidity of more than four pregnancies. Several pregnancy complications, such as pre-eclampsia, cause substantial hypercoagulability.
General causes of hypercoagulability, about as common in pregnancy as in the general population, include both acquired ones such as antiphospholipid antibodies, and congenital ones, including factor V Leiden, prothrombin mutation, protein C and S deficiencies, and antithrombin III deficiency.
Prevention of thrombosis with anticoagulants 
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. Still, there seems to be no teratogenic effect of warfarin before six weeks of gestation. However, unfractionated heparin and low molecular weight heparin do not cross the placenta.
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 and a history of previous spontaneous abortions, 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.
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, and should not be administered when the pregnancy is confirmed. 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, prior to a planned conception. LMWH is as safe and efficacious as unfractionated heparin. A blood test including platelets and a clotting screen should be performed prior to administration of anticoagulant regimens in pregnancy.
Subcutaneous tinzaparin may be given at doses of 175 units of antifactor Xa activity per kg, based on prepregnancy or booking weight at approximately 16 weeks, and not the current weight. 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 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. 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. Similar issues are likely associated with the use of enoxaparin (a LMWH) in these high-risk individuals.
By risk score 
Prevention of DVT and other types of venous thrombosis may be required if certain predisposing risk factors are present. One example is based on the point system below, where points are summed to give the appropriate prophylaxis regimen.
Intermediate risk factors
Intermediate risk factors
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. 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. A total of 3 points increases the necessary duration of post partum prophylaxis to six weeks.
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. A previous distal DVT indicates a minimum of 12 weeks (three months) of therapeutic anticoagulation therapy. A previous proximal DVT or pulmonary embolism requires a minimum of 26 weeks (6.5 months) of therapy 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. In a very high risk, high-dose ante partum prophylaxis should be continued at least 12 weeks after delivery.
Major side effects of tinzaparin are osteoporosis (occurring in up to 1% of cases), thrombocytopenia (heparin-induced thrombocytopenia), haemorrhage, hair loss and drug allergy. Still, LMWHs are much less likely to cause heparin-induced thrombocytopenia than unfractionated heparin.
Anticoagulant therapy with LMWH is not usually monitored. LMWH therapy does not affect the prothrombin time (PT) or the INR, and anti-Xa levels are not reliable. It can prolong the partial thromboplastin time (APTT) in some women, but still, the APTT is not useful for monitoring.
To check for any thrombocytopenia, platelet count should be checked prior to commencing anticoagulant therapy, then seven to 10 days after commencement, and monthly thereafter. Platelet count should also be checked if unexpected bruising or bleeding occurs.
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. 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.
Anticoagulants in breastfeeding 
See also 
- 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.
- 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
- 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.
- Venös tromboembolism (VTE) - Guidelines for treatment in C counties. Bengt Wahlström, Emergency department, Uppsala Academic Hospital. January 2008
- Sathienkijkanchai A, Wasant P. (2005). "Fetal warfarin syndrome.". J Med Assoc Thai 88 (Suppl 8): S246–50. PMID 16856447.
- 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.
-  Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9th June 2006 [review June 2009]
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
Further reading 
-  Therapeutic anticoagulation in pregnancy. Norfolk and Norwich University Hospital (NHS Trust). Reference number CA3017. 9 June 2006 [review June 2009]