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

Pregnancy-induced hypercoagulability is probably a physiologically adaptive mechanism to preventpost partum hemorrhage.^[1] Pregnancy changes the plasma levels of manyclotting factors, such asfibrinogen, 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 andantithrombin III, remain constant.^[2]Fibrinolysis is impaired by an increase inplasminogen activator inhibitor-1 (PAI-1 or PAI) andplasminogen activator inhibitor-2 (PAI-2), the latter synthesized from the placenta.^[2]Venous stasis may occur at the end of thefirst trimester, due to enhancedcompliance of the vessel walls by a hormonal effect.^[2]

Also, pregnancy can cause hypercoagulability by other factors, e.g. theprolonged bed rest that often occurspost partum that occurs in case of delivery byforceps,vacuum extractor orCaesarean section.^[2][4]

A study of more than 200,000 women came to the result that admission toinpatient care during pregnancy was associated with an 18-fold increase in the risk ofvenous 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 doesmultigravidity of more than four pregnancies.^[2]

Pregnancy in itself causes approximately a five-fold increased risk ofdeep venous thrombosis.^[6] Severalpregnancy complications, such aspre-eclampsia, cause substantial hypercoagulability.^[2]

Hypercoagulability states as apre-existing condition in pregnancy include both acquired ones, such asantiphospholipid antibodies, and congenital ones, includingfactor V Leiden,prothrombin mutation, proteins C and S deficiencies, andantithrombin III deficiency.

Hypercoagulability in pregnancy, particularly due to inheritable thrombophilia, can lead to placental vascular thrombosis.^[7] This can in turn lead to complications like early-onsethypertensive disorders of pregnancy,pre-eclampsia andsmall for gestational age infants (SGA).^[7] Among other causes of hypercoagulability,Antiphospholipid syndrome has been associated with adverse pregnancy outcomes including recurrentmiscarriage.^[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 ofmaternal death in developed countries after bleeding.^[9]

Unfractionatedheparin,low molecular weight heparin,warfarin (not to be used during pregnancy) andaspirin 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 developingfetus, changes in theanticoagulation 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 haveteratogenic effects on the fetus if administered in early pregnancy.^[11][12] Still, there seems to be no teratogenic effect of warfarin before sixweeks of gestation.^[13] However, unfractionated heparin and low molecular weight heparin do not cross the placenta.^[13]

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 ofdeep venous thrombosis (DVT) orpulmonary embolism, a metallicprosthetic heart valve, andatrial fibrillation in the setting of structural heart disease.

In addition to these indications, anticoagulation may be of benefit in individuals withlupus 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 ofrecurrent miscarriage, anticoagulation seems to increase thelive birth rate among those withantiphospholipid syndrome and perhaps those withcongenital thrombophilia but not in those with unexplained recurrent miscarriage.^[15]

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 othervitamin K-inhibiting agents are contraindicated during thefirst 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 unfractionatedheparin orlow molecular weight heparin (LMWH), such astinzaparin,^[13] prior to a plannedconception.^[17] LMWH is as safe and efficacious as unfractionated heparin.^[13] Ablood test includingplatelets and aclotting 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 ofthrombosis of the valve and death.^[19][20] Similar issues are likely associated with the use ofenoxaparin (a LMWH) in these high-risk individuals.^[21]

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]

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 dayspostpartum, starting a couple of hours after birth.^[9] A total of3 points increases the necessary duration ofpost partum prophylaxis to six weeks.^[9]

A risk score of four points or higher means prophylaxis in theante partum period is needed, as well as at least six weekspost partum.^[9] A previousdistal DVT indicates a minimum of 12 weeks (three months) of therapeutic anticoagulation therapy.^[13] A previousproximal 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 ofpost partum therapy.^[13] In a very high risk, high-doseante partum prophylaxis should be continued at least 12 weeks after delivery.^[9]

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

All anticoagulants (including LMWH) should be used with caution in women with suspectedcoagulopathy,thrombocytopaenia,liver disease andnephropathy.^[13]

Major side effects oftinzaparin areosteoporosis (occurring in up to 1% of cases),thrombocytopenia (heparin-induced thrombocytopenia),haemorrhage,hair loss anddrug 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]

Anticoagulant therapy with LMWH is not usually monitored.^[13] LMWH therapy does not affect theprothrombin time (PT) or theINR, and anti-Xa levels are not reliable.^[13] It can prolong thepartial 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]

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% ofanti-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]

• Valvular heart disease and pregnancy

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

• Anticoagulants
• Health issues in pregnancy
• Coagulopathies

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