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CHOICE OF ANTITHROMBOTIC AGENT — There are three options for anticoagulation of peripartum women: unfractionated heparin, low molecular weight heparin, and warfarin. Use of each drug depends upon several factors, including gestational age, estimated date of delivery, and whether the woman is pre- or postpartum. Although aspirin is used to diminish platelet thromboxane synthesis and platelet aggregation in the uteroplacental vasculature, its ability to prevent thromboembolism in pregnant women has not been evaluated in a controlled trial.

Unfractionated heparin — Heparin is a complex glycosaminoglycan that exerts its anticoagulant effects by potentiating antithrombin activity, increasing levels of factor Xa inhibitor [34], and inhibiting platelet aggregation [35]. Unfractionated heparin is a heterogeneous mixture of high molecular weight (range 3000 to 30,000 Daltons, average 15,000 Daltons) negatively charged molecules, which precludes transfer of any significant quantity of drug across the placenta or into breast milk [36,37]. The half-life is 30 to 60 minutes for intravenous heparin and three hours for subcutaneous heparin.

Dose — The usual dose for antepartum prophylaxis is 5000 units subcutaneously every 12 hours adjusted to produce a heparin level of 0.1 to 0.2 U/ml or anti-factor Xa level of 0.1 to 0.2 U/ml six hours after injection (show table 5) [38]. An alternative method, which avoids monitoring, is to administer 5000 units subcutaneously every 12 hours in the first trimester, and then raise the dose to 7500 units in the second trimester, and 10,000 units in the third trimester. These doses have no or minimal effects on the activated partial thromboplastin time (aPTT). Some authors recommend following anti-factor Xa levels to guide VTE prophylaxis during pregnancy. One study observed that this standard heparin regimen was inadequate to achieve the desired anti-factor Xa therapeutic range in five of nine second-trimester pregnancies and in 6 of 13 third-trimester pregnancies [38].

However, women at very high risk of thrombosis, such as those with antithrombin deficiency or homozygous for the prothrombin or factor V Leiden mutation, should receive higher therapeutic heparin doses and require frequent monitoring of the aPTT. (See "Inherited thrombophilias in pregnancy").

Management of side effects — Potential side effects of heparin therapy include hemorrhage, osteoporosis, and thrombocytopenia.

Hemorrhage — The highest risk of hemorrhage is during labor and delivery, in the presence of a bleeding diathesis (abruption, pregnancy-related liver disease, concomitant aspirin therapy), and with obstetrical conditions associated with bleeding (eg, placenta previa, abruption) [39]. An increased risk of major hemorrhage is mostly confined to women receiving therapeutic doses of heparin. Lower dose prophylaxis as described above, is associated with minor bleeding, such as wound hematoma and oozing during surgery; postpartum uterine bleeding is not increased unless there is atony.
The management of bleeding during heparin therapy depends upon the location and severity of bleeding, the risk of associated with stopping the anticoagulant, and the duration of the aPTT. In most peripartum obstetrical patients, the heparin can be stopped and restarted, if indicated, after bleeding has been controlled. However, patients with a recent VTE may be candidates for insertion of an inferior vena cava filter. Although we would be reluctant to continue low dose prophylaxis in the face of clinical bleeding from a placenta previa or abruption, there are no data that addresses the volume of bleeding in these patients compared to those not on prophylaxis.

If urgent reversal of heparin effect is required, protamine sulfate can be administered by slow intravenous infusion (not greater than 20 mg/min and no more than 50 mg over any 10 minute period). The appropriate dose of protamine sulfate is dependent upon the dose of heparin given and the time of that dose. Full neutralization of heparin effect is achieved with a dose of 1 mg protamine sulfate/100 units heparin. However, because of the relatively short half life of intravenously administered heparin, the protamine sulfate dose must be calculated by estimating the amount of heparin remaining in the plasma at the time that reversal is required. Bolus doses of more than 25 to 50 mg of protamine sulfate are seldom required, and excessive dosing can have an anticoagulant effect. If heparin is given by subcutaneous injection, repeated small doses of protamine may be needed because of prolonged heparin systemic absorption from the subcutaneous depot. Patients who have previously received protamine (including diabetic patients under treatment with NPH insulin) have an approximately 1 percent risk of anaphylaxis when protamine sulfate is administered [40].

Osteoporosis — Osteoporosis is most common with doses of heparin exceeding 15,000 U/day for more than six months [9,41-46]. Demineralization can result in the fracture of vertebral bodies or long bones, and the defect may not be entirely reversible [45-47].
Patients receiving such doses of heparin should receive 1500 mg of calcium and at least 400 IU vitamin D daily as prophylaxis against osteoporosis. They should also have bone densitometry studies performed after receiving six months of unfractionated heparin therapy exceeding 15,000 U/day. Evidence of osteoporosis should prompt referral to an endocrinologist familiar with treating osteoporosis in premenopausal patients. (See "Clinical use of heparin and low molecular weight heparin" and see "Drugs that affect bone metabolism", section on Heparin).

Thrombocytopenia — There are two types of heparin-related thrombocytopenia (HIT). Type I is common (10 to 20 percent of patients) and characterized by a small fall in platelet count that occurs within the first two days after heparin initiation, often returns to normal with continued heparin administration, and is of no clinical consequence [48]. The mechanism of the thrombocytopenia is nonimmune and appears to be due to a direct effect of heparin on platelet activation. Type 2 develops in fewer than 3 percent of patients, usually occurs 4 to 10 days after initiation of therapy, and is immune mediated; cessation of therapy is required to prevent serious thrombotic complications, such as white clot syndrome [9]. (See "Heparin-induced thrombocytopenia"). The diagnosis of HIT-2 can be confirmed by serotonin release assays, heparin-induced platelet aggregation assays, flow cytometry or solid phase immunoassays [49].
Because of the risk of thrombocytopenia in patients begun on heparin therapy, platelet counts should be checked within three days of initiation of treatment and followed weekly for three weeks.

Low molecular weight heparin — Low molecular weight heparins (LMWHs) are derivatives of unfractionated heparin that have a mean molecular weight of 4000 to 5000 daltons. Like unfractionated heparin, LMWH inactivates factor Xa, but has a lesser effect on thrombin. As a result, LMWHs do not prolong the aPTT. They are as effective as unfractionated heparin, with fewer side effects. A systematic review of the safety and efficacy of LMWH for thromboprophylaxis and treatment of VTE in pregnancy concluded these drugs were both safe and effective [50]. However, there is almost no information from randomized trials on efficacy in pregnant women [51]. (See "Low molecular weight heparin for venous thromboembolic disease").

LMWH has several clinical advantages over unfractionated heparin: higher bioavailability allows administration of a fixed dose without frequent laboratory monitoring, immune-mediated thrombocytopenia is rare, and bone loss may be lower. This was illustrated in the systematic review (64 studies including 2777 pregnancies) mentioned above which found no cases of HIT-2 and only a single case of an osteoporotic fracture [50]. Significant bleeding occurred in approximately 2 percent of pregnancies treated with LMWH and was usually due to obstetric causes. Bleeding occurred antepartum in 12 of the 55 cases, in association with delivery in 26, and in association with wound hematoma in 17.

The drug is more costly than unfractionated heparin, but overall cost of therapy is lower in some settings because home administration may avoid hospitalization. LMWH can be administered ante- or postpartum, but not intrapartum because their use may increase the risk of bleeding from needles or catheters employed for neuraxial anesthesia (see "Anesthesia" below). Use of LMWH does not pose a contraindication to breastfeeding.

Dose — A LMWH (dalteparin 2500 anti-factor Xa units subcutaneously daily, enoxaparin 30 mg subcutaneously twice daily, or tinzaparin 50 to 100 anti-factor Xa units/kg daily) is initiated. The data regarding the need for monitoring anti-factor Xa in pregnant patients receiving lower dose LMWH for prophylaxis are conflicting [38,52,53]. Although anti-factor Xa levels are not routinely measured in nonpregnant individuals, we recommend monitoring during pregnancy because of increased renal clearance in pregnancy, ongoing changes in maternal weight, and inadequate data establishing the optimum therapeutic dose in this population [54,55]. It is our practice to titrate the dose of LMWH to maintain prophylactic anti-factor Xa levels of 0.1 to 0.2 U/mL or therapeutic anti-factor Xa levels of 0.6 to 1.0 U/mL when assessed four hours after drug administration (show table 5).

and Factor X inhibitors