Anti-Activated Factor X Profiles in Pregnant Women Receiving Antenatal Thromboprophylaxis with Enoxaparin

Thromboembolic disease is a major contributor to maternal mortality in the United Kingdom [1]. Since approximately 50% of events occur in the antenatal period, addressing the issue of postpartum thromboprophylaxis alone is unlikely to have a significant impact on the incidence of this condition. Women at particular risk of thromboembolic disease include those with a past history of a thromboembolic event(s), particularly those with congenital or acquired thrombophilia. Such women merit consideration for antenatal thromboprophylaxis. Because warfarin is a known teratogen and can also have adverse effects later in pregnancy, heparin has traditionally been the drug of choice for such prophylaxis.There is increasing interest in the use of low molecular weight (LMW) heparins in obstetric practice. These agents have been shown to have superior efficacy in reducing the incidence of thromboembolic complications in patients undergoing orthopaedic surgery when compared to unfractionated (UF) heparin [2], and also have a reduced risk of haemorrhagic complications compared to UF heparin. In addition, LMW heparins have increased bioavailability and a longer half-life [3]making once daily administration possible, a feature which many patients find attractive. Furthermore, of particular relevance to long-term use in pregnancy, these agents have less risk of heparin-induced thrombocytopenia [4]and may have less effect on bone density [5]than UF heparin.LMW heparins affect activated factor X (FXa) preferentially, and assaying for anti-FXa activity is the most commonly used method for assessing LMW heparin concentrations ex vivo [6]. The aim of this study was to establish anti-FXa activity following thromboprophylaxis with enoxaparin in pregnancy, in particular the timing of peak anti-FXa activity.A group of 16 women had an anti-FXa profile performed at the commencement of antental thromboprophylaxis, employing enoxaparin (Clexane; Rhone-Poulenc Rorer, UK) 40 mg daily. The median age of the women was 29.5 years (range 20–39) and there were 13 parous and 3 primigravid women. The women were divided into two groups according to gestational age: <20 completed weeks (median 13.5, range 6–19) or >20 completed weeks (median 24, range 22–30) (n = 8 each group). The indications for antenatal thromboprophylaxis were previous postnatal deep vein thrombosis (DVT)/previous thromboembolic event (PTE) (five cases), previous antenatal DVT (three cases), and PTE without pregnancy (six cases), acquired thrombophilia (one case), and one case of knee joint replacement in pregnancy following osteomyelitis in the area of a previous joint replacement for osteosarcoma.Venous blood was sampled prior to subcutaneous injection of enoxaparin, and at 1-, 2-, 3-, 6- and 12-hour intervals following administration. The blood was collected in 3.8% trisodium citrate (9:1 v.v) and placed immediately on ice prior to transfer for assay of anti-FXa activity. Samples were spun at 2,500 g at 4°C for 15 min. Plasma was separated and stored in 1-ml aliquots at –70°C. Anti-FXa assays were performed using a chromogenic substrate assay (Chromogenix ATI, Diagen FX, S2222).Analysis of variance (ANOVA) was used to analyse the data. Correlation was assessed by simple regression analysis. In addition, simple regression analysis was used to establish any association between gestation and peak anti-FXa activity.Anti-FXa activity (U/ml) is displayed in figure 1. In both groups anti-FXa activity was significantly higher at 1, 2, 3 and 6 h posttreatment compared with pretreatment levels (p < 0.05), and anti-FXa activity at 12 h was not significantly different from pretreatment levels. Peak anti-FXa activity was achieved at 3 h posttreatment (respectively 0.326 and 0.264 U/ml for the <20-week and >20-week groups). There was no association between gestational age and peak anti-FXa activity (r2 = 0.086, p = 0.272). There was one case of venous thromboembolism at 6 weeks postpartum in a patient with a previous history of DVT and multiple PTE, who admitted non-compliance with her postnatal warfarin therapy. There were no problems with excessive bruising at the injection site, no haemorrhagic problems in relation to delivery, and no thrombotic complications in any of these patients during prophylaxis with enoxaprin.LMW heparins have negligible effect on global clotting studies and measurements of anti-FXa activity is most commonly employed to monitor treatment with these agents. Anti-FXa profiles in the present study, employing prophylactic doses of LMW heparin, have demonstrated peak anti-FXa activity at 3 h postinjection. This is in keeping with the pharmacokinetic studies of Aiach et al. [7]in the non-pregnant population. The risk of haemorrhage associated with heparin treatment has been shown to correlate with anti-FXa activity. In one study [8], employing enoxaparin 30 mg twice daily for thromboprophylaxis, no haemorrhagic complications were encountered when anti-FXa activity was between 0.1 and 0.2 U/ml 6 h postinjection. When anti-FXa activity is greater than 0.4 U/ml the risk of bleeding increases significantly [9]. In the current study, investigating prophylactic doses of enoxaparin, the peak anti-FXa activity was always <0.4 U/ml, and no haemorrhagic problems were encountered.There have been a number of reports on the use of LMW heparins in pregnancy decribing their efficacy as thromboprophylactic agents, and their lack of major complications [10, 11]. We have presented data regarding the laboratory monitoring of enoxaparin administered in the antenatal period demonstrating that peak activity was achieved at the same interval as in the non-pregnant situation [7]and appears to be in an appropriate range for prophylaxis. It has been suggested that monitoring of anti-FXa activity is not required when heparin is administered in prophylactic doses [12]and it has become our practice to check a 3-hour anti-FXa level following commencement of LMW heparin prophylaxis, with no further anti-FXa monitoring provided this peak level is less than 0.4 U/ml. In this study, with albeit small numbers, anti-FXa activity in response to enoxaparin 40 mg was not affected by gestational age. This is in keeping with the finding of the largest series reported to date of 69 pregnancies in which heparin levels (anti-FXa assay) were not affected by gestational age [11].This study provides information about the pharmacokinetics of LMW heparin in pregnancy, and establishes that peak anti-FXa activity occurs at 3 h postadministration of enoxaparin which is important for determining the safety of this agent in individual patients. We acknowledge that we cannot comment on the pharmacokientics of LMW heparin beyond 30 week’s gestation. It is likely that any effect of pregnancy in the third trimester would be a reduction in anti-FXa activity as a result of plasma volume expansion. This would be unlikely to affect the safety of enoxaparin, but may have implications for its efficacy, although clinical outcomes reported to date do not suggest this.