St Jamess University Hospital, Beckett Street, Leeds LS9 7TF, UK*Corresponding author: The Royal Hospitals, Grosvenor Road, Belfast BT12 6BA, UK
Accepted for publication: March 6, 2002
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Abstract |
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Br J Anaesth 2002; 89: 3314
Keywords: measurement techniques, Thrombelastograph®; blood, anticoagulants, heparin; complications, deep vein thrombosis
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Introduction |
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Increasingly, pregnant women are treated with low molecular weight heparins (LMWH) for both prevention and treatment of thrombosis.3 LMWH commonly used in the UK are enoxaparin, dalteparin, and tinzaparin. The primary mode of action of LMWH is by binding to antithrombin III, thereby accelerating the inhibition of factor Xa, and to a lesser extent factor IIa. Plasma concentrations of anti-Xa activity at 4 h after the injection are used as a measure of its response. LMWH are widely believed to produce a predictable and reproducible response,4 when given in weight-adjusted doses, making laboratory monitoring and dose adjustment unnecessary. An advantage of LMWH in obstetrics, where the time scale for prophylaxis is much longer than in surgery, is increased bioavailability and longer half life, which together allow for once daily administration.5 Also, they do not cross the placental barrier.6 7 Comparative or controlled trials of LMWH use in pregnancy do not exist and treatment guidelines are extrapolated from studies and anecdotal reports from the general population. Fear of bleeding within the vertebral canal following regional block in patients receiving LMWH has prompted recommendations to postpone intervention for 12 h after injection. These guidelines8 are only valid for prophylactic and not therapeutic doses of LMWH.
We report two pregnant women who developed DVT while on a prophylactic dose of enoxaparin. They were subsequently managed with therapeutic doses of tinzaparin. The response to LMWH was measured using anti-Xa activity and Thrombelastograph® (TEG®) data and the results influenced peripartum management. These aspects are unreported previously and the implications for anaesthetists of high-dose tinzaparin in pregnancy are discussed.
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Case report 1 |
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Following her recent attendance at the antenatal clinic, warfarin was stopped and she was prescribed enoxaparin 40 mg once daily. Once established on LMWH therapy, a routine laboratory check on her factor Xa activity 6 h after injection, indicated a higher level of activity than needed for thromboprophylaxis. Her dose was reduced to 20 mg once daily. Two weeks later (16 weeks gestation) she developed a DVT in her left leg and enoxaparin was replaced with tinzaparin 175 IU kg1. As renal dysfunction can prolong the half-life of LMWH, her kidney function was periodically assessed and found to be normal.
She was referred to the antenatal anaesthetic clinic for assessment and, with her cooperation, TEG® analysis was performed in conjunction with anti-Xa activity, at 8 (Fig. 1) and 12 h after injection. The anti-Xa activity at 12 h post-injection at 34 weeks was predictive of bleeding9 and TEG® data showed a near absence of coagulation. She was admitted at 37 weeks following a routine Doppler scan which showed reduced liquor and no increase in fetal growth over the previous 8 days. She had taken her prescribed dose of tinzaparin at 10:00 h that day, before her admission. Four hours later a decision was made to expedite delivery, while acknowledging a high likelihood of an emergency Caesarean section. At 18:00 h (8 h post-tinzaparin) the TEG® data showed gross derangement in clotting and the obstetric team were advised that surgery would be hazardous. As the cardiotocograph was reactive, it was decided to delay delivery to the next day, anticipating that coagulation would then be normal. The following day at 08:00 h (22 h post-tinzaparin), TEG® data were still abnormal and anti-Xa activity was subsequently shown to be in the prophylactic range (0.10.2 anti-Xa units ml1; Fig. 2).
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Twenty five hours after surgery, she received 40 mg enoxaparin which was continued on a once daily basis, and she was subsequently discharged on warfarin.
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Case report 2 |
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With prior consultation with the obstetricians she was changed to enoxaparin 40 mg twice a day at 37 weeks, as it has a shorter duration of action. Her TEG® analysis showed no hypocoaguability, so the dose was increased to 80 mg twice a day. At 4 and 8 h post-enoxaparin the TEG® data were normal, although the corresponding anti-Xa concentrations suggested that she was adequately anticoagulated.
She continued on this dose until her next admission, which was at 40 weeks for a planned induction of labour. She had peripheral oedema and in the antenatal ward she was found to be hypertensive with raised diastolic pressure of 104 mm Hg and 3+ of proteinuria. She self-administered 80 mg enoxaparin at approximately 20:00 h and at 23:00 h she was given 1 mg prostin to initiate labour. At 09:00 h the following morning the prostin and enoxaparin were repeated. She went into labour 4 h later and at 14:00 h (5 h post-enoxaparin), the TEG® trace was normal. Anti-thromboembolic stockings were used throughout labour.
At 14:30 h, she received an epidural for analgesia. A healthy baby girl with Apgar scores of 9 and 10 at 1 and 5 min, respectively, was born by spontaneous vaginal delivery. A postpartum haemorrhage in the region of 1 litre because of an atonic uterus was treated with oxytocics. Approximately 12 h after the bleeding settled she received enoxaparin, which was continued once daily. She was subsequently discharged on warfarin.
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Discussion |
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Recent Royal College of Obstetrics and Gynaecology (RCOG) guidelines suggest that women who have had DVT during their pregnancy require anticoagulation until 6 weeks after delivery. They recommend LMWH to be started in therapeutic doses and the dosage reduced to a prophylactic level at the time of labour and delivery. This recognizes the need for normal coagulation for labour and at delivery. These guidelines do not address the possibility of an unanticipated premature labour or requirement for an unplanned Caesarean section in women receiving therapeutic doses of LMWH.
Tinzaparin given subcutaneously is used frequently in a therapeutic role, and can have a prolonged anticoagulant effect, which at therapeutic doses lasts for 24 h.15 A dilemma arises when fetal interests require urgent delivery but maternal coagulation is grossly deranged. In our first case, this issue had not been considered and there was no management plan for this eventuality. Surgical delivery without adequate coagulation was considered to be hazardous to the mother, but to postpone delivery whilst coagulation returned to normal carried risks for the fetus. Fortunately, the fetus did not come to any harm despite the postponement of delivery by 28 h. In the past when unfractionated heparin has been used, the anticoagulant effect could be completely reversed with protamine, and the process titrated by measuring activated partial thromboplastin time (aPTT). The reversal effect of protamine on LMWH has been studied only in volunteers and in non-pregnant patients. It is known to effectively reverse more than 90% of the anti-IIa activity and 5070% of the anti-Xa activity.16 aPTT is the test recommended by the manufacturers for monitoring protamine reversal but this considers only anti-IIa activity. We examined the reversal effect of protamine in the second patient by in vitro studies using TEG® analysis (Fig. 3A and B). The in vitro test suggested that protamine could be effective but clearly to extrapolate this in vivo would be an oversimplification.
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LMWH vary in their ratio of anti-Xa:IIa activity. It is 1.8:1 with tinzaparin, 3.7:1 with enoxaparin, and 2:1 with dalteparin. Other potential influences of LMWH on haemostasis are inhibition of platelet function, factor IXa and thrombin, enhancement of fibrinolytic activity, and tissue factor pathway inhibitor. Thus, from the standpoint of the clinician, using anti-Xa activity, a single isolated point in the coagulation cascade, to monitor heparin that has multiple sites of activity can be misleading.
The TEG® measures whole blood coagulation from the initiation of clotting to the final stages of clot lysis or retraction. The equipment is ward based, easy to use and produces a reliable result in 30 min. In comparison, the measurement of the anti-Xa activity is similarly not universally available and results cannot be obtained within the relevant clinical time scale. The TEG® offers additional information compared with common laboratory tests as it measures the interaction of various components of the clotting process. The variables measured are r, k, alpha angle, maximum amplitude (MA), and time to maximum amplitude (tMA) (Fig. 4). Of these, the r value correlates well with heparin concentration in vivo.18
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Acknowledgement |
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References |
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