High-dose tinzaparin in pregnancy and the need for urgent delivery

S. K. Backe and G. R. Lyons*

St James’s 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


    Abstract
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
The prolonged anticoagulant effects of high-dose low molecular weight heparin (LMWH) pose problems in pregnant women when unanticipated delivery is required. We present two pregnant women on therapeutic doses of LMWH whose labour did not progress smoothly. The Thrombelastograph® coagulation analyser was used to assess the coagulation status periodically. It influenced surgical and anaesthetic management and there was a safe outcome.

Br J Anaesth 2002; 89: 331–4

Keywords: measurement techniques, Thrombelastograph®; blood, anticoagulants, heparin; complications, deep vein thrombosis


    Introduction
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
Pregnancy is a hypercoagulable state that protects the mother against peripartum haemorrhage. There is an increased production of procoagulant factors VII, VIII, IX, X, XII, and fibrinogen, and a decrease in anticoagulants Protein S, C, and antithrombin III. However, this prothrombotic state predisposes to deep vein thrombosis (DVT) and pulmonary embolism, the latter being the most common cause of maternal death in the UK.1 2

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.


    Case report 1
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
A 36-yr-old Afro-Caribbean multipara (body mass index (BMI) 32, ex-smoker) was seen in the antenatal clinic at 8 weeks gestation. Six years previously she had arterial and venous thrombi, affecting the heart, kidney, and left leg, which were resistant to treatment with tissue plasminogen activator and heparin infusion. Left femoral artery thromboembolectomy was required. Her thrombophilia screen proved repeatedly normal. She improved on steroids and heparin and a vasculitic disorder was suspected. Four months later, during her first pregnancy, she was prescribed aspirin 75 mg once daily and dalteparin 5000 IU twice daily, in view of her past history of thrombosis. At 37 weeks, after an uneventful pregnancy, she had a planned Caesarean section. This was performed under regional anaesthesia, 12 h after her prophylactic dose of dalteparin. She was subsequently discharged on warfarin. Since that pregnancy, she had continued to take warfarin and had not experienced any thrombotic events.

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 kg–1. 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 (0.1–0.2 anti-Xa units ml–1; Fig. 2).



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Fig 1 A TEG® trace represents the formation of a blood clot over time with the start of clot initiation shown by the division of the trace from a straight line. The amplitude of the split is proportional to the clot strength. The TEG® trace of patient in case report 1 at 8 h post-tinzaparin administration is a straight line (in bold) which indicates a failure of clot initiation.

 


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Fig 2 The TEG® trace seen in bold is the trace of patient in case report 1 at 22 h post-tinzaparin of dose 175 IU kg–1 given subcutaneously. The division of the straight line shows the initiation of clot and the final clot strength is shown by the amplitude of the split. The effect of LMWH is shown on the TEG® trace in bold as a delay in clot initiation. The corresponding anti-Xa concetration is in the range our laboratory considers adequate for thromboprophylaxis. Both TEG® trace and anti-Xa concentration demonstrate the prolonged effect of a therapeutic dose of tinzaparin.

 
Prostin was administered to induce labour at 14:00 h. By 16:00 h (30 h post-tinzaparin) the r value of the TEG® data was in the normal range for pregnancy.10 A prophylactic dose of 40 mg enoxaparin was given at 16:30 h but, 30 min later, there were several episodes of fetal heart decelerations which were slow to recover. Artificial rupture of membranes was impossible because of a posterior cervix and she was taken to theatre for an emergency Caesarean section under general anaesthesia. A baby boy was born with an Apgar of 10 at 5 min and umbilical artery pH of 7.3. The intraoperative blood loss was about 700 ml.

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.


    Case report 2
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
A 34-yr-old Caucasian primigravida (BMI 26) was seen in the antenatal clinic at 4 weeks gestation. She had history of a pulmonary embolism 6 yr previously whilst on the oral contraceptive pill. A subsequent thrombophilia screen showed heterozygous factor II gene mutation. At 19 weeks gestation, because of her past history, she was started prophylactically on low-dose aspirin and enoxaparin 20 mg once daily. At 21 weeks she developed a DVT in the right femoral vein, which was confirmed by venogram. Enoxaparin was replaced with a therapeutic dose of tinzaparin 175 IU kg–1. Renal function was normal. She was referred to the antenatal anaesthetic assessment clinic and, with her cooperation, serial TEG® data and anti-Xa activity were monitored sequentially to get a 24 h profile.

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.


    Discussion
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
LMWH therapy in pregnancy is a relatively recent advance in clinical practice.3 Two meta-analyses of randomized controlled trials indicate that LMWH are more effective and are associated with a lower haemorrhagic risk than unfractionated heparin in the initial treatment of DVT in non-pregnant patients.4 1113 Evaluation of LMWH in pregnancy in both prophylactic and therapeutic use is limited to small case series.3 14

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 50–70% 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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Fig 3 (A) The TEG trace of patient in case report 2 shows a late split and a poor amplitude when compared with the curve normally seen in pregnancy demonstrating hypocoagulability at 4 h after a therapeutic dose of tinzaparin. When protamine sulphate was added to the same sample in vitro (B) clot formation was quicker and stronger.

 
TEG® data have been used reliably to monitor heparin therapy in patients on cardio-pulmonary bypass17 and is shown to correlate equally well as anti-Xa activity with increasing dose of enoxaparin.18 There was a wide variation between the TEG® traces of our two patients, performed at 3–4 h after administration of therapeutic dose of LMWH. In the first patient the TEG® data showed inability to clot while, in the second, the coagulation was only slightly reduced. The corresponding anti-Xa concentrations in both patients were adequate.

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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Fig 4 The TEG® trace normally seen in pregnancy. The variables measured are: (1) r time (reaction time) which is the time of initial fibrin formation (measured as the time from start to a 1 mm deflection in the TEG® trace); (2) k time which reflects the period of rapid fibrin build-up and crosslinking (measured from the end of the r time to a 20 mm width deflection in the trace); (3) alpha angle which represents the speed of clot formation, fibrin crosslinking, and platelet-fibrin interaction and MA, which reflects a measure of the final clot strength and depends on fibrinogen concentration, platelet numbers and function.

 
In summary, LMWH in therapeutic doses can be an effective anticoagulant for 24 h and beyond. Guidelines recommend that the dose of LMWH is reduced before induction of labour. No guidance is given as to how women receiving this treatment should be managed in the event of a need for early urgent delivery. The extent of impairment of coagulation is sufficient to suggest that surgery may not be safe. In vitro assessment of protamine reversal in a single case suggests a benefit in an emergency situation. As of now, there are no guidelines for the reversal of LMWH using protamine sulphate to enable intervention. Current laboratory tests are unlikely to be adequate but the TEG® traces are able to give a rapid overview of the situation, and direct management.


    Acknowledgement
 
We are grateful to Dr Rowan Wilson for her advice in preparation of the manuscript.


    References
 Top
 Abstract
 Introduction
 Case report 1
 Case report 2
 Discussion
 References
 
1 Deparment of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Services, Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 1991–1993. London: HMSO, 1996

2 Deparment of Health, Welsh Office, Scottish Home and Health Department and Department of Health and Social Services, Northern Ireland. Confidential Enquiries into Maternal Deaths in the United Kingdom 1994–1996. London: HMSO, 1998

3 Thromboembolic Disease in Pregnancy and the Puerperium: Acute Management. Guideline No 28, published on behalf of the Guidelines and Audit Committee of the Royal College of Obstetricians and Gynaecologists, Glasgow, April 2001

4 Hirsh J, Levine M. Low molecular weight heparin. Blood 1992; 79: 1–17[ISI][Medline]

5 Hull RD, Raskob GE, Pineo GF, et al. Subcutaneous low molecular weight heparin compared with continuous intravenous heparin in the treatment of proximal-venous thrombosis. N Engl J Med 1992; 326: 975–82[Abstract]

6 Bertoli D, Borelli G. Peri and post natal teratology and reproductive studies of a LMWH in rats. Drug Res 1986; 36: 1260–3[Medline]

7 Forestier F, Daffos F, Toulemonde F. Low molecular weight heparin (CY 216) does not cross the placenta during the third trimester of pregnancy. Thromb Haemost 1987; 57: 234[ISI][Medline]

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10 Gorton H, Warren E, Simpson N, Lyons G, Columb MO. Thromboelastography (TEG)® identifies gender related differences in coagulation. Anesth Analg 2000; 91: 1279–81[Abstract/Free Full Text]

11 Nurmohamed MT, Rosendal FR, Buller HR, et al. LMWH versus standard heparin in general and orthopaedic surgery: a meta analysis. Lancet 1992; 340: 152–6[ISI][Medline]

12 Leizorovicz A, Haugh MC, Chapuis ER, Samama MM, Boissel JP. LMWH in prevention of perioperative thrombosis. BMJ 1992; 305: 913–20[ISI][Medline]

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18 Klein SM, Slaughter TF, Vail PT, et al. Thromboelastography as a perioperative measure of anticoagulation resulting from LMWH: a comparison with anti Xa concentrations. Anesth Analg 2000; 91: 1091–5[Abstract/Free Full Text]





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