Anticoagulation Therapy during pregnancy

Pregnancy is associated with a hypercoagulable state due to enhanced production of certain clotting factors,
decrease in protein S activity, and inhibition of fibrinolysis.Thrombotic complications are a major cause of
maternal morbidity and mortality. The risk of thromboembolic complications is increased throughout
pregnancy, peaks at the first week postpartum, and remains elevated for the first 6 weeks postpartum.
Anticoagulation therapy during pregnancy is indicated for prevention or treatment of venous
thromboembolism, inherited thrombophilia, anti-phospholipid antibody syndrome, IUGR, and mechanical
heart valves.

LMWH: LMWH has become the drug of choice for the treatment of VTE in pregnancy and the puerperium.
In suspected DVT or PE, therapeutic LMWH should be given until the diagnosis is excluded by objective
testing.

Dosage: The recommended therapeutic dose is calculated on early pregnancy body weight (e.g. enoxaparin 1
mg/kg body weight twice daily, dalteparin 100 IU/kg body weight twice daily, or tinzaparin 175 IU/kg),
aiming for 4–6 h peak anti-Xa values of 0.6–1.2 IU/mL.

UFH: Typically, UFH is used in the acute treatment of massive pulmonary emboli

VKA and LMWH have advantages and disadvantages during pregnancy. However, comparison between
studies is hampered by reporting differences, and conclusions concerning the safety of low-dose VKA
(warfarin, 5mg daily) in the current literature are controversial.

VKAs cross the placenta and their use in the first trimester can result in embryopathy (limb defects and nasal
hypoplasia) in 0.6–10% of cases. Substitution of a VKA with UFH or LMWH in weeks 6–12 almost eliminates
the risk of embryopathy. There is evidence that the embryopathy risk with VKA is also dose dependent. The
risk was 0.45–0.9% in pregnancies with low-dose warfarin according to two recent systematic reviews. In
addition to the risk of embryopathy that is limited to the first trimester, there is a 0.7–2% risk of foetopathy
(e.g. ocular and central nervous system abnormalities and intracranial hemorrhage) when VKAs are used in
the second and third trimesters. Foetopathy has also been described with UFH but not with LMWH
throughout pregnancy. Vaginal delivery while the mother is on VKAs is contraindicated because of the risk
of foetal intracranial bleeding. Haemorrhagic complications in the mother occur with all regimens.

The efficacy and safety of several LMWH preparations was shown in a review of 2777 pregnant women
treated for DVT or PE.The risk of recurrent VTE with therapeutic doses of LMWH was 1.15%. The
observed rate of major bleeding was 1.98%. Heparin-induced thrombocytopenia is markedly lower with
LMWH than with UFH, as is heparin-induced osteoporosis (0.04%).In clinically suspected DVT or PE,
therapeutic LMWH should be given until the diagnosis is excluded by objective testing.

Monitoring is essential in patients treated with LMWH with mechanical valves. But the evidence is less clear
in patients with VTE. Given the need for dose increase as pregnancy progresses to maintain a certain
therapeutic anti-Xa level (peak: 0.7–1.2 U/mL) it seems reasonable to also determine anti-Xa peak levels
during pregnancy in patients with VTE. This appears particularly justified in view of the fact that PE
occurred in women receiving prophylactic doses of LMWH.As with the use of LMWH in women with
mechanical valves, using trough levels and adjusting the dosage frequency may be necessary to achieve
adequate anticoagulation.

UFH does not cross the placenta either, but is associated with more thrombocytopenia (platelet levels should
be measured every 2–3 days), osteoporosis, and more frequent dosing when given subcutaneously compared
with LMWH. Typically, UFH is used in the acute treatment of massive pulmonary emboli. It is also used
around the time of delivery if the maintenance of anticoagulation is critical and when the ability to reverse
anticoagulation urgently using protamine is advantageous. In this circumstance, LMWH should be switched
to IV UFH at least 36 h before the induction of labor or caesarean delivery is planned. UFH should be
discontinued 4–6 h before anticipated delivery and restarted 6 h after delivery if there are no bleeding
complications.

Warfarin is a vitamin K antagonist (VKA) that crosses the placenta. The American Heart
Association/American College of Cardiology guideline recommendations for use of VKAs during pregnancy
were revised in 2014 in recognition of the dose-dependent relationship with increased adverse outcomes. The
rates of embryopathy, miscarriage, and stillbirth occur with increased frequency with daily doses >5 mg.
Women with mechanical heart valves are at risk during pregnancy for valve thrombosis and hemorrhagic
complications, and anticoagulation must be meticulously monitored. Guidelines recommend that women
taking >5 mg of VKA during the first trimester should be switched to LMWH or unfractionated heparin by
the end of the sixth week of gestation to decrease the risk of embryopathy. The American Heart
Association/American College of Cardiology guidelines include an anticoagulation management algorithm of
women with mechanical heart valves during pregnancy. Fetal warfarin syndrome or “Di Sala syndrome”
primarily affects the fetus in the first trimester because warfarin crosses the placenta. It is associated with
facial dysmorphism such as nasal hypoplasia, skeletal abnormalities (limb hypoplasia and stippled epiphyses),
central nervous system abnormalities (ventral and dorsal midline dysplasia), and cardiac defects. Second and
third trimester effects include a ∼1% incidence of ocular and central nervous system abnormalities as well as
intracranial hemorrhage . Women who receive VKA throughout pregnancy should be changed to either
LMWH or unfractionated heparin at 36 weeks’ gestation in order to reduce the risk of fetal hemorrhage at
the time of vaginal delivery and delivery-associated maternal bleeding . Women who are using LMWH are
not candidates for regional anesthesia within 24 h of their last dose, so a timed delivery is helpful to prevent
complications of bleeding from long-acting injectable anticoagulants. Reversal of VKA in the mother does not
ensure reversal in the fetus, thus if a patient presents in labor while on a VKA, a cesarean delivery should be
performed to prevent fetal intraventricular hemorrhage during passage through the birth canal.

LMWH does not cross the placenta, and peak and trough anti-Xa levels must be followed meticulously during
pregnancy. Women are often at greatest risk of mechanical heart valve complications during the time of
transition from VKA to heparin. Mechanical valve thrombosis has been reported in 4.7% of pregnant women
with mechanical valves. In a recent meta-analysis of maternal and fetal outcomes in over 800 women with
mechanical heart valves on different anticoagulant strategies, Steinberg et al.Confirmed that VKA were
associated with the lowest risk of adverse maternal outcomes, whereas the use of LMWH was associated with
the lowest risk of adverse fetal outcomes.

Alternative anticoagulant strategies may be utilized in select cases. Fondaparinux is an indirect Factor Xa
inhibitor and is recommended by the ACOG in the setting of heparin-induced thrombocytopenia or heparin
allergy. At this time, there is insufficient data to recommend bivalirudin or the direct oral anticoagulants for
women in pregnancy.

Use of heparin and monitoring requirements

PHARMACOLOGY: Heparin must be given parenterally. It is usually administered SC or by continuous IV

infusion. When used for therapeutic purposes, the IV route is most often employed. If heparin is given SC for
treatment of thrombosis, the dose of heparin must be high enough to overcome the limited bioavailability
associated with this method of delivery. In the circulation, heparin binds to the endothelium and to plasma
proteins other than antithrombin. Heparin binding to endothelial cells explains its dose-dependent clearance. At
low doses, the half-life of heparin is short because it binds rapidly to the endothelium. With higher doses of
heparin, the half-life is longer because heparin is cleared more slowly once the endothelium is saturated.
Clearance is mainly extra renal; heparin binds to macrophages, which internalize and depolymerize the long
heparin chains and secrete shorter chains back into the circulation. Because of its dose-dependent clearance
mechanism, the plasma half-life of heparin ranges from 30 to 60 min with bolus IV doses of 25 and 100 units/kg,
respectively. Once heparin enters the circulation, it binds to plasma proteins other than antithrombin, a
phenomenon that reduces its anticoagulant activity. Some of the heparin-binding proteins found in plasma are
acute-phase reactants whose levels are elevated in ill patients. Others, such as high-molecular-weight multimers
of VWF, are released from activated platelets or endothelial cells. Activated platelets also release platelet factor
4 (PF4), a highly cationic protein that binds heparin with high affinity. The large amounts of PF4 found in the
vicinity of platelet-rich arterial thrombi can neutralize the anticoagulant activity of heparin. This phenomenon
may attenuate heparin’s capacity to suppress thrombus growth.

Because the levels of heparin-binding proteins in plasma vary from person to person, the anticoagulant
response to fixed or weight adjusted doses of heparin is unpredictable. Consequently, coagulation monitoring is
essential to ensure that a therapeutic response is obtained. This is particularly important when heparin is
administered for treatment of established thrombosis because a sub therapeutic anticoagulant response may
render patients at risk for recurrent thrombosis, whereas excessive anticoagulation increases the risk of
bleeding.

Monitoring the Anticoagulant Effect: Heparin therapy can be monitored using the activated partial
thromboplastin time (aPTT) or anti-factor Xa level. Although the aPTT is the test most often used for this
purpose, there are problems with this assay. aPTT reagents vary in their sensitivity to heparin, and the type of
coagulometer used for testing can influence the results. Consequently, laboratories must establish a therapeutic
aPTT range with each reagent-coagulometer combination by measuring the aPTT and anti-factor Xa level in
plasma samples collected from heparin-treated patients. For most of the aPTT reagents and coagulometers in
current use, therapeutic heparin levels are achieved with a two- to threefold prolongation of the aPTT.
Anti-factor Xa levels also can be used to monitor heparin therapy. With this test, therapeutic heparin levels
range from 0.3 to 0.7 units/mL.

Up to 25% of heparin-treated patients with venous thromboembolism require >35,000 units/d to achieve a
therapeutic aPTT. These patients are considered heparin-resistant. It is useful to measure antifactor Xa levels in
heparin-resistant patients because many will have a therapeutic anti-factor Xa level despite a sub therapeutic
aPTT. This dissociation in test results occurs because elevated plasma levels of fibrinogen and factor VIII, both of
which are acute-phase proteins, shorten the aPTT but have no effect on anti-factor Xa levels. Heparin therapy in
patients who exhibit this phenomenon is best monitored using anti-factor Xa levels instead of the aPTT. Patients
with congenital or acquired antithrombin deficiency and those with elevated levels of heparin-binding proteins
may also need high doses of heparin to achieve a therapeutic aPTT or anti-factor Xa level. If there is good
correlation between the aPTT and the anti-factor Xa levels, either test can be used to monitor heparin therapy .

DOSING: For prophylaxis, heparin is usually given in fixed doses of 5000 units SC two or three times daily. With
these low doses, coagulation monitoring is unnecessary. In contrast, monitoring is essential when the drug is
given in therapeutic doses. Fixed-dose or weight based heparin nomograms are used to standardize heparin
dosing and to shorten the time required to achieve a therapeutic anticoagulant response. At least two heparin
nomograms have been validated in patients with venous thromboembolism and reduce the time required to
achieve a therapeutic aPTT. Weight-adjusted heparin nomograms have also been evaluated in patients with
acute coronary syndromes. After an IV heparin bolus of 5000 units or 70 units/kg, a heparin infusion rate of 12–
15 units/kg per hour is usually administered. In contrast, weight-adjusted heparin nomograms for patients with
venous thromboembolism use an initial bolus of 5000 units or 80 units/kg, followed by an infusion of 18
units/kg per hour. Thus, patients with venous thromboembolism appear to require higher doses of heparin to
achieve a therapeutic aPTT than do patients with acute coronary syndromes. This may reflect differences in the
thrombus burden. Heparin binds to fibrin, and the amount of fibrin in patients with extensive DVT is greater
than that in those with coronary thrombosis.

Low-Molecular-Weight Heparin: Consisting of smaller fragments of heparin, LMWH is prepared from

unfractionated heparin by controlled enzymatic or chemical depolymerization. The mean molecular weight of
LMWH is about 5000, one-third the mean molecular weight of unfractionated heparin. LMWH has advantages
over heparin and has replaced heparin for most indications .

MECHANISM OF ACTION: Like heparin, LMWH exerts its anticoagulant activity by activating antithrombin. With a mean
molecular weight of 5000, which corresponds to about 17 saccharide units, at least half of the pentasaccharide-containing
chains of LMWH are too short to bridge thrombin to antithrombin. However, these chains retain the capacity to accelerate
factor Xa inhibition by antithrombin because this activity is largely the result of the conformational changes in antithrombin
evoked by pentasaccharide binding. Consequently, LMWH catalyzes factor Xa inhibition by antithrombin more than
thrombin inhibition. Depending on their unique molecular weight distributions, LMWH preparations have anti-factor Xa to
anti-factor IIa ratios ranging from 2:1 to 4:1.

PHARMACOLOGY: Although usually given SC, LMWH also can be administered IV if a rapid anticoagulant
response is needed. LMWH has pharmacokinetic advantages over heparin. These advantages reflect the fact
that shorter heparin chains bind less avidly to endothelial cells, macrophages, and heparin-binding plasma
proteins. Reduced binding to endothelial cells and macrophages eliminates the rapid, dose-dependent, and
saturable mechanism of clearance that is a characteristic of unfractionated heparin. Instead, the clearance of
LMWH is dose-independent and its plasma half-life is longer. Based on measurement of anti-factor Xa levels,
LMWH has a plasma half-life of ~4 h. LMWH is cleared almost exclusively by the kidneys, and the drug can
accumulate in patients with renal insufficiency.

LMWH exhibits about 90% bioavailability after SC injection. Because LMWH binds less avidly to heparin-binding
proteins in plasma than heparin, LMWH produces a more predictable dose response, and resistance to LMWH is
rare. With a longer half-life and more predictable anticoagulant response, LMWH can be given SC once or twice
daily without coagulation monitoring, even when the drug is given in treatment doses. These properties render
LMWH more convenient than unfractionated heparin. Capitalizing on this feature, studies in patients with
venous thromboembolism have shown that home treatment with LMWH is as effective and safe as in-hospital
treatment with continuous IV infusions of heparin. Outpatient treatment with LMWH streamlines care, reduces
health care costs, and increases patient satisfaction.

MONITORING: In the majority of patients, LMWH does not require coagulation monitoring. If monitoring is
necessary, anti-factor Xa levels must be measured because most LMWH preparations have little effect on the
aPTT. Therapeutic anti-factor Xa levels with LMWH range from 0.5 to 1.2 units/mL when measured 3–4 h after
drug administration. When LMWH is given in prophylactic doses, peak anti-factor Xa levels of 0.2–0.5 units/mL
are desirable.

Indications for LMWH monitoring include renal insufficiency and obesity. LMWH monitoring in patients with a
creatinine clearance of ≤50 mL/min is advisable to ensure that there is no drug accumulation. Although weight-
adjusted LMWH dosing appears to produce therapeutic anti-factor Xa levels in patients who are overweight, this
approach has not been extensively evaluated in those with morbid obesity. It may also be advisable to monitor
the anticoagulant activity of LMWH during pregnancy because dose requirements can change, particularly in the
third trimester. Monitoring should also be considered in high-risk settings, such as in patients with mechanical
heart valves who are given LMWH for prevention of valve thrombosis, and when LMWH is used in treatment
doses in infants or children.

DOSING: The doses of LMWH recommended for prophylaxis or treatment vary depending on the LMWH
preparation. For prophylaxis, once-daily SC doses of 4000–5000 units are often used, whereas doses of 2500–
3000 units are given when the drug is administered twice daily. For treatment of venous thromboembolism, a
dose of 150–200 units/kg is given if the drug is administered once daily. If a twice daily regimen is used, a dose
of 100 units/kg is given. In patients with unstable angina, LMWH is given SC on a twice-daily basis at a dose of
100–120 units/kg.

The aPTT assesses the intrinsic and common coagulation pathways; factors XI, IX, VIII, X, V, and II; fibrinogen;
prekallikrein; high-molecular-weight kininogen; and factor XII (Fig. 61-6).

The aPTT reagent contains phospholipids derived from either animal or vegetable sources that function as a
platelet substitute in the coagulation pathways and includes an activator of the intrinsic coagulation system,
such as non particulate ellagic acid or the particulate activators kaolin, celite, or micronized silica. The
phospholipid composition of aPTT reagents varies, which influences the sensitivity of individual reagents to
clotting factor deficiencies and to inhibitors such as heparin and lupus anticoagulants. Thus, aPTT results will
vary from one laboratory to another, and the normal range in the laboratory where the testing occurs should be
used in the interpretation. Local laboratories can relate their aPTT values to the therapeutic heparin
anticoagulation by correlating aPTT values with direct measurements of heparin activity (anti-Xa or protamine
titration assays) in samples from heparinized patients, although correlation between these assays is often poor.
The aPTT reagent will vary in sensitivity to individual factor deficiencies and usually becomes prolonged with
individual factor deficiencies of 30–50%.

Mixing studies are used to evaluate a prolonged aPTT or, less commonly PT, to distinguish between a factor
deficiency and an inhibitor. In this assay, normal plasma and patient plasma are mixed in a 1:1 ratio, and the
aPTT or PT is determined immediately and after incubation at 37°C for varying times, typically 30, 60, and/or 120
min. With isolated factor deficiencies, the aPTT will correct with mixing and stay corrected with incubation. With
aPTT prolongation due to a lupus anticoagulant, the mixing and incubation will show no correction. In acquired
neutralizing factor antibodies, notably an acquired factor VIII inhibitor, the initial assay may or may not correct
immediately after mixing but will prolong or remain prolonged with incubation at 37°C. Failure to correct with
mixing can also be due to the presence of other inhibitors or interfering substances such as heparin, fibrin split
products, and paraproteins.

References: Harrison’s principles of internal medicine 20 th edition, 2017AHA/ACC guideline for the management of
patients with valvular heart disease, 2018 ESC (European society of cardiology) guideline for the management of
cardiovascular disease in pregnancy

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