Thromboembolism in pregnancy
        Main and The Obgyn Clinic of Hvidovre (danish)
        Pulmonary embolism 1-2 per 100,000 pregnancies is the major cause of maternal death in the developed world. Deep vein thrombosis (DVT), affects 1-2 of 1,000 pregnancies.

        Risk factors:
        • Age (double with age > 35)
        • Obesity
        • Operative deliveries (Cesarean section increase the risk 3-5 times))
        • Previous thromboembolism (5-12%)
        • Prolonged bed rest/immobilization
        • Preeclampsia after delivery (increase the risk 3-5 times).
        • Gross varicose veins
        • Parity greater than 4 in pregnancy (increase the risk 3 times but not post partum)
        • Thrombophilia increase risk at least 3 times and caused 50% of cases of DVT and pulmonary embolism in pregnancy
        Congenital Thrombophilia:
        • antithrombin III deficiency
        • Protein C deficiency
        • Protein S deficiency
        • Factor V Leiden
        • Prothrombin gene mutation

        Acquired Thrombophilia:
        Antiphospholipid Syndrom (Lupus anticoagulant, anticardiolipin antibodies, anti-ß2-glucoprotein)
        • Excessive blood loss
        • Paraplegia
        • Sickle cell disease
        • Inflammatory bowel disease and urinary tract infection
        • Dehydration

        D V T:
          Symptoms:
          • Left sided 85% and the ilio-femoral 72%
          • Leg pain or discomfort, swelling, tenderness and/or redness
          • Increase temperature, edema, lower abdominal pain
          • Elevated white cell count
          • Ultrasound Doppler
          • Low level of D-dimer suggest that there is no venous thromboembolism

        Diagnosis and who to treat:
          Golden standard venography 3140 mGy (Max recommended exposure in pregnancy = 50,000 mGy)
          Compression Duplex Ultrasound Doppler (DUS), Magnetic Resonance (MRV)
          DUS is excellent for proximal DVT, but may miss distal DVT
          If ultrasound is negative and high levels of clinical suspicion excist, the patient should continue anticoagulation and ultrasound repeated (in one week). If repeated testing is negative, anticoagulant treatment should be discontinued.
          When iliac vein thrombosis is suspected (bachpain and swelling of intire limp) MR or contrast venographi scould be considered.

          MRV should be avoided in 1 trimester because of lack of experience.

        PULMONARY EMBOLUS (PE):
        Symptoms:
        • Dyspnoea,
        • Tachypnea and tachycardia (important)
        • sometimes chest pain,
        • hemophysis,
        • fever,
        • panic,
        • cyanosis,
        • and signs of DVT

        Diagnosis:
        Ventilation - perfusion lung scan (V/Q) and compression Duplex chest X-ray Doppler ultrasound. Ventilation scan only has to be done if there is abnormal perfusion scan. A normal V/Q scan virtually exclude pulmonary embolus. If a scan shows low probability and ultrasound studies of legs Doppler are positive, PE is diagnosed.

        Even if the V/Q scan shows low probability and leg Doppler is negative, continue anticoagulation treatment and repeat testing in one week (pulmonary angiography (golden standard) and spiral CT should be considered (relative large amount of radiation to the fetus).

        If high suspicion, therapy and serial testing.

        Chest X-ray often normal (50%) but atelectasis, wedge-shaped infarction and pleural effusion can be seen. CTG, ECG is usually normal except for a sinus tachycardia. Right axis deviation, right bundle branch block, peaked P-waves in lead II due to right atrial dilation and SI, QIII, TIII may be seen.

        White cell count increases
        Artery blood gas and/or oxygen saturation decreases.
        Echocardiography only 30-40 % will have abnormalities (increased right ventricel, decreased right ventricel function and tricusspidal regurgilation.
        In massive PE unfractionated heparin is the prefered treatment and thrombolytic therapy or surgical embolectomi should be considered.
        A diagnose of DVT may indirectly confirm the diagnose of PE and since anticoagulant therapy is the same, further investigation may not be necessary.

        Drugs:
        Heparin does not cross, the placenta, but can cause osteoporosis and rarely thrombocytopenia. These side effects has not been seen in pregnant women on LMWH. The platelet count should be monitored after 5-10 days and then on a monthly basis to detect heparin-induced thrombocytopenia (HIT) ³ 50 % decrease, which is associated with further thrombotic complications. If Heparin given the last 100 days, HIT can develop after 1-3 days. A mild early form with mild thrombocytopenia > 65 is without risk.
        Pregnant women who develop heparin-induced thrombocytopenia and require continuing anticoagulant therapy should be managed with the heparinoid, danaparoid sodium or factor Xo inhibitors: ie fundaparmix under special advise.

        Osteoporosis after one-month treatment, lower risk with LMWH. Allergi > 2 %, most local site

        Warfarin:
        Crosses the placenta, no teratogenic effect before the 6 weeks of gestation. Embryopathy most often affected bone and cartilage (nasal and limb hypoplasia, chondrodysplasia). More seldom CNS maldeformation and optic nerve injury.
        The period of risk is between 6 and 12 weeks of gestation so no risk at conception. The risk may depend on dose (increase if dose > 5 mg/day). There is a significant risk of maternal (retroplacental) and fetal (intracerebral) bleeding when used in the third trimester, and particularly after 36 weeks gestation. No anticoagulation in milk.

        Treatment:
        • In generel there should be no difference in the treatment of DVT or pulmonary embolus during pregnancy. Therapeutic anticoagulant should be continued during pregnancy and at least 6 weeks postnatal and until at least 3 months of treatment has been given in total. If DVT/PE occurs postpartum and if no other risk factors then treatment should be 3 months for DVT and 6 months for PE.
        • In clinically strongly suspected DVT and/or PE treatment Heparin should be given until the diagnosis is excluded by effective testing (see above) unless treatment is strongly contraindicated.
        • The leg should be elevated and elastic compression stocking (TED) applied to reduce oedema.
        • Mobilization should be encouraged.
        • Duration of Treatment: Therapeutic doses of LMWH remaining of pregnancy and normally 6 weeks after delivery.

        Before anticoagulant treatment is commenced, hemoglobin, creatinin, APTT, INR, platelets. Arterial puncture in case of suspect pulmonary embolus. electrolytes and liver function test (to exclude renal or hepatic dysfunction which are cautious). P-Heparin in case monitoring is needed during treatment.

        Antenatal prophylactic and therapeutic doses of low-mulecular-weight Heparin
        Prophylaxis Enoxaparin 1000 units/mg (Klexane) Dalteparin (Fragmin) Tinzaparin B (Innohep)
        Normal body weight (50-90 kg) 40 mg daily 5000 units daily 4500 units daily
        Body weight < 50 kg 20 mg daily 2500 units daily 3500 units daily
        Body weight > 90 kga 40 mg 12-hourly 5000 units 12-hourly 4500 units 12-hourly
        Higher prophylactic dose 40 mg 12-hourly 5000 units 12-hourly 4500 units 12-hourly
        Therapeutic dose 1 mg/kg 12-hourly 90 units/kg hourly 90 units/kg hourly
        Danish recommandation 1,5 mg/kg 24 hoursly 175 units /24 hours
        * The dosage schedules for tinzaparin differ from the menufacturer's recommendation of once-daily dosage
        Taken from RCOG Guidelines No. 37


        For LMWH, firm guidelines regarding the need for monitoring have not been established but intermittent monitoring by anti-factor Xa assay 2-3 hours after LMWH injection starting in the second trimester is recommended by some. "The aim is a plasma Anti X-A level at 0.6 - 1.0 U/mL".

        Thrombophilia should be ruled out after pregnancy and one month after cessation of treatment (coagulation parameters are changed in pregnancy, e.g. low protein C).

        SUGGESTED PROTOCOL FOR COMMENCING WARFARIN TREATMENT IN THE PUERPERIUM (ADAPTED FROM BRITISH SOCIETY FOR HEAMATOLOGY GUIDELINES, 1998)

        Day of Warfarin
        Treatment        		 International
        Normalized Ratio        		 Warfarin Dose (mg)
        First . 7.0
        Second . 7.0
        Third <2.0
        2.0-2.1
        2.2-2.3
        2.4-2.5
        2.6-2.7
        2.8-2.9
        3.0-3.1
        3.2-3.3
        3.4
        3.5
        3.6-4.0
        >4.0         		7.0
        5.0
        4.5
        4.0
        3.5
        3.0
        2.5
        2.0
        1.5
        1.0
        0.5
        0.0
        Fourth <1.4
        1.4
        1.5
        1.6-1.7
        1.8
        1.9
        2.0-2.1
        2.2-2.3
        2.4-2.6
        2.7-3.0
        3.1-3.5
        3.6-4.0
        4.1-4.5
        >4.5        		 >8.0
        8.0
        7.5
        7.0
        6.5
        6.0
        5.5
        5.0
        4.5
        4.0
        3.5
        3.0
        Omit next day's dose then give 2 mg
        Omit two days doses then give 1 mg


        Propfylactic regime in prevention thromboembolic disease:

        Therapeutic dose routine measurement of peak anti-XA only recommended in women of extremes bodyweight (less than 50 kg and 90 kg or more with complicated factors for example with renal impairment or recurrent VTF) peak anti-XA activity 3 hours post injection of 0,5-1,2 units/ml.

        Life threating PTE unfractionated intravenous heparin: Loding dose 80 units/kg followed by continuous IV infusion of 18 units/kg/hour. If thrombolysis is planned the loading dose is omitted. APTT 4-6 hours after loading dose, 6 hours after any dose change and then at least daily target APTT 1,5-2,5 times average control values

        Aspirin 75 mg be given when LMWH are indicated.

        In spontaneous in women recicving therapeutic dose of subcutanes unfractionated Heparin carefully monitoring the APTT is required. Heparin subcutaneous discontinued 6 hours before and IV Heparin 6 hours before induction or regional anaesthecia.

        Previous thromboemboli:
        1. Previous thromboembolic with transient risk factors (i.e. surgery, bed rest ect). Careful observation during pregnancy.

          2. LMWH one week before term to 6 weeks post partum (If only previous crus thrombosis observation is enough).
        2. Previous idiopathic thromboemboli during pregnancy and intake of oral contraceptive, other risk factors of long duration, congenital thrombofilia (antithrombin, protein C and protein S, factor V Leiden, prothrombin G202110 mutation, antiphospholipid antibodies: (cardiolipin antibodies, lupus anticoagulans) hyperhomocysteinaemi (5 mg follic acid).
        3. Women in antikoagulation treatment because of previous thromboemboli.

        LMWH from beginning of pregnancy to 6 weeks post partum.
        Intermediate dose in case of antithrombin deficiency, homozygocity for Factor V Leidin or prothrombin G202110 mutation or a combination of 2 or more risk factors as well as first degree relative with risk factors for thromboembolic desease and severe thromboembolic events.

        Thrombophilia and no case of thromboembolia, observation or LMWH:
        LMWH is required in cases of antithrombin deficity, homozygocity for factor V Leiden or prothrombin G202110 or combination of 2 or more inherited risk factors.

        From one week before term to 6 weeks post partum, congenital antithrombin deficiency (low risk protein S and C deficiency as well lupus antikoagulans and cardiolipin antibodies in high titer.

        Anticoagulation in case of previous pregnancy complications
        Antiphosfolipid antibodies and previous two abortions after 10 gestational week, IUGR, fetal death, abruption or preeclampsia.

        Amniocentesis:
        Heparin should be discontinued the night before and resume 6 hours post amniocentesis.

        Prophylaxis in patiens with mechanical heart valves:
        1. Heparin from 0-16 (13)/52
          Warfarin from 16-32-36/52
          Heparin from 32-36/52 to delivery
          Warfarin postpartum
        2. When changing from Heparin to Warfarin, do not D/C LMWF until INR has been therapeutic for more than 2 days.
          When changing from Warfarin to Heparin consider doing this as an inpatient.
        3. Consider warfarin throughout pregnancy particularly if the patient needs < 5 mg.

        Prevention of Osteoporosis
        Calcium supplementation (1,500 mg in divided doses daily), Vitamin D (800 U daily) and weight bearing exercises (e.g. walking) are recommended for women using Heparin to minimize the osteopenic effects of this drug.

        Labour, epidural and cesarean sectio:
        The woman should be advised that once she is established in labor or thinks that she is in labor, she should not inject any further heparin. She should be reassessed on admission to hospital and further doses should be prescribed by medical staff.
        Epidural/spinal Therapeutic doses of LMWH are replaced by profylactic dosis 24 hours before labour.
        Epidural/spinal can be applied or catheter removed 12 hours after injection of profylactic dose (or P-Heparin <0,20 klU/l).
        New profylactic dose given not earlier than 2 hours before application or removel of catheter.
        Warfarin should be given 24 hours after delivery and is recommended if anticoagulation is expected to be more than 6 weeks post partum.

        Cesarean Section:
        For delivery by elective Cesarean Section, the woman should receive a thromboprophylactic dose of LMWH on the day (evening) prior to deliver. On the day of delivery, the morning dose should be omitted and the operation performed that morning. The thrombophylactic dose of LMWH should be given three hours postoperatively ( four hours after removal of the epidural catheter, if appropriate), and the treatment dose recommenced that evening

        There is an increase risk of wound haematoma following Cesarean section prophylactic heparin (around 2%) especially if given two hours before surgery.

        If patients receiving therapeutic dose of LMWH, wound drains should be considered at Cesarean section and the skin incision should be closed with staples or interrupted sutures to allow drainage of any haematoma.

        I. Prevention of Post-Thrombotic Syndrome
          Graduated elastic compression stockings should be worn on the affected leg for two years after the acute event to reduce the risk of post-thrombotic syndrome if swelling persist. A RCT in non-pregnant patients has shown that such therapy can reduce the incidence of post thrombotic syndrome from 23% to 11%

          Treatment of Patients on Anticoagulation Who Needs Acute Surgery/CS:
          1. All such patients should have their INR reversed unless they either have a mechanical mitral valve or have a DVT/PE within the previous two months, in which case the INR should only reduced to around 2.
          2. An urgent order for 6-12 units (1 unit = 145 cc) of fresh frozen plasma (15 mls/kg) should be placed and the blood bank contacted to ensure the fastest possible delivery (thawing of 4-6 units takes 20 minutes.
          3. Two IV's should be inserted and the FFP infused at maximum speed (5 to 10 minutes per unit) unless the patient's cardiovascular status precludes this.
          4. Blood for STAT INR should be drawn 15 minutes after the infusion of the last FFP to document that the INR has been reversed.
          5. Bleeding or active major bleeding where instant reversal is warranted or inpatients who cannot tolerate the fluid load of FFP infusion give r-Factor VIIa: 20 mG/kg IV as bolus over 5 min (< 10 ml). It works instantly; do repeat INR after 15 minutes.
          6. If bleeding does not stop, repeat the dose every 2 hours. Repeat INR 6 hours after last dose. If > 1.5, repeat bolus r-Factor VIIa.

        II. Elective Surgery
          Prophylaxis for perioperative management of patients on Warfarin.

          A. Low Risk TE Stop Warfarin 4 days (Target INR near normal).
          DVT prophylaxis if required for procedure.
          Restart Warfarin postop.
          B. Moderate Risk TE Add Heparin 5000 s.c. bid (Enaxoparin 40 mg s.c.) 2 days prior to surgery,
          continued postop until INR is therapeutic.
          C. High Risk TE Stop Warfarin 3-4 days (Target INR 1.3-1.5) Full heparinization as INR < therapeutic
          Stop Heparin (IV for valves) 6 hr, or LMWH (for VTE) 12 hrs prior to surgery
          Restart IV Heparin 12 hr postop (consult Surgeon).
          Continue until INR therapeutic.
          Restart Warfarin within 24 hr postop (consult Surgeon).
          D. Patients with low risk Decrease Warfarin (Target INR bleeding 1.3-1.5) 4-5 days preop .
          Restart Warfarin postop with Heparin 5000 s.c. if necessary.

        III. Antiheparin Agents
        Protamine Sulfate
        In the situation of Heparin overdosage, since blood Heparin concentrations decrease rapidly after administration, adjust the Protamine dosage depending upon the duration of time since heparin administration as follows:

        Time Elapsed Dose of Protamine (mg) to Neutralize 100 units of Heparin
        Immediate 1-1.5
        30-60 min. 0.5-0.75
        > 2 h 0.25-0.375

        If Heparin administered by deep s.c. injection, use 1-1.5 mg Protamine per 100 units Heparin; this may be done by a portion of the dose (e.g. 25-80 mg) given slowly IV followed by the remaining portion as a continuous infusion over 8-16 hours (the expected absorption time of the s.c. Heparin dose).

        Administration:
        For I.V. only: incompatible with cephalosporins and penicillins; administer slow IVP (50 mg over 10 minutes); rapid I.V. infusion causes hypotension;inject without further dilution over 1-3 minutes, maximum of 50 mg in any 10-minute period.

        References:
        (1) British Society for Haematology. Guidelines on Oral Anticoagulation. Third Eidtioh. Br J Hematol 1998;101:374-87.

        (2) Brandjes DP,Buller HR, Hejboer H, Hulsman MV, et al. Randomized trial of effect of compression stockings in patients with symptomatic proximal venous thrombosis. Lancet 1997;349:759-6.

        (3) Clinical Green Top Guidelines 2003. Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management. Royal College of Obstetrics & Gynecologists. 2007

        (4) Guidelines for prevention of thromboembolic events in valvular heart disease. European Society of Cardiology. Journal of Heart Valve Disease 1993;2:398-410.

        (5) Nielsen-Piercy C. Handbook of Obstetric Medicine. Second Edition, by Martin Dunitz, Ltd., published in the United Kingdom in 2002.

        (6) Sanson B, Lensin A.W.A,, Prins, M.H. et al. Safety of low-molecular weight heparin in pregnancy. A systematic review. Thromb Haemost 1999;81:668-672. (7) www.uptodate.com 2007

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