- Email: [email protected]
Anaesthesia and the antiphospholipid syndrome: a review of 20 obstetric patients
International Journal of Obstrtrr Anesfhewu (1997) 6. 107-I 1 I 0 1997 Pearson ProfessmA Ltd
REVIEWARTICLE
Anaesthesia and the antiphospholipid syndrome: a review of 20 obstetric patients D. K. Ringrose Department of Anaesthesia,St Thomas’Hospital, London, UK SUMMARK The case notes of 20 obstetric patients with antiphospholipid syndrome delivering over a 4-year period were reviewed retrospectively. There were complete details for 22 singleton pregnancies. Obstetric complications in the pregnancies under review were frequent. Nine (47%) of the 19 women whose pregnancies reached the third trimester were delivered by caesarean section. During seven of the pregnancies there was significant prolongation of the phospholipid-dependent coagulation tests secondary to lupus anticoagulant and/or anticardiolipin antibodies. Four of these women received epidural blockade without sequelae. This finding, however,cannot provide valid evidencefor the safety or otherwise of epidural placement in this group of patients, since the series is small and the incidence of epidural haematoma is exceedingly rare in the obstetric population. Paradoxically, these patients are hypercoagulable.The estimated blood loss at these deliveries did not exceed600 m l. Eleven women (55%) had a previous history of thrombosis. Two women had thrombotic episodes during their pregnanciesand three had them post partum despite antithrombotic measures.
At St Thomas’ Hospital, The Lupus Arthritis Research Unit is a national referral centre for SLE and APS, and consequently about 10 mothers with APS deliver here per annum.
INTRODUCTION Antiphospholipid syndrome (APS) is characterized by the presence of autoantibodies to phospholipids. These are the lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), which are associated with recurrent venous or arterial thromboses,recurrent abortions and thrombocytopenia.’ Approximately half the patients with APS have systemic lupus erythematosus (SLE).’ Obstetric problems are frequent and include intrauterine growth retardation, recurrent m iscarriage, fetal death, preeclampsia,eclampsia, placental thrombosis and premature delivery.3 Another feature of APS is prolongation of the activated partial thromboplastin tim e (APTT) and kaolin cephalin clotting tim e (KCCT), both of which are phospholipid-dependent coagulation tests, beyond a level most anaesthetists would consider acceptable for epidural anaesthesia. The anaesthetist is likely to be involved with the care of these high risk parturients as there is a high incidence of operative delivery. The literature to date lacks any series on the anaesthetic management of these patients.
METHODS In a search through the records of the lupus pregnancy clinic, the case notes and anaesthetic charts of 20 obstetric patients with APS who were booked for delivery at St Thomas’ Hospital were found and reviewed retrospectively to determine their anaesthetic management and to record any complications that had arisen. The deliveries took place between late 1991 and early 1995. Incomplete sets of notes were not included, and some sets of notes for women with APS who had delivered during this period were no longer present in the lupus clinic records. RESULTS Patients There were 18 Caucasian women, one black African and one Indian. Their m e a n age was 30.5 years (range 20-40). There were 22 singleton pregnanciesincluding two second trimester intrauterine deaths and one
D. K. Ringrose MBBS, FRCA, Senior Registrar, Department of
Anaesthesia, Second Floor, New Guy’s House, Guy’s Hospital, St Thomas’ St, London SE1 9RT, UK. 107
108 International Journal of Obstetric Anesthesia Table 1. Obstetric complications in the present pregnancies
Number of pregnancies Preeclampsia Eclampsia Intrauterine growth retardation Oligohydramnios Placental abruption Acute fatty liver Emergency caesarean delivery No complications
1 1 4 1 2
1 5 9
Table 2. Delivery details for third trimester biiths
Mode of delivery Spontaneous Spontaneous Ventouse Forceps Caesarean Caesarean
Type of analgesia/anaesthesia
Number (n = 19)
% of total
None Epidural Epidural Epidural Epidural General anaesthesia
3 4 2 1 3 6
16 21 10 5 16 3
therapeutic termination for eclampsia at 24 weeks. Among the 20 women, seven had been diagnosed with primary APS and 13 with the secondary syndrome associated with SLE. Type of delivery Obstetric complications were frequent with a high incidence of operative delivery (Tables 1 and 2). Ten women had vaginal deliveries, seven spontaneous and three instrumental, while nine had caesarean sections (Table 2). There were five emergency caesarean sections for fetal distress, of which one also had failure to progress and the remainder were elective. Coagulation profiles Seven women had abnormal coagulation profiles at delivery attributed to antiphospholipid antibodies (aPL) (Table 3). None of these had any signs of preeclampsia, and the fibrin degradation products and fibrinogen blood tests were all within normal limits. Six women had mild thrombocytopenia at delivery with platelet counts between loo-150 x 109/L. Anaesthesia Six general anaesthetics were given for caesarean deliveries (Table 2), one of which was elective and general anaesthesia was requested by the mother. In one of the emergency operations, although an epidural had been working well during labour, the block was inadequate
for surgery. The remaining four were for fetal distress and it was judged there was not enough time to institute regional anaesthesia. In addition, one of them had received subcutaneous heparin only 2 h previously and this was considered by the anaesthetist to be a contraindication to central neural blockade. There was one case of bronchospasm after intubation which produced transient hypoxaemia and resolved with deepening of anaesthesia. Another patient who had received general anaesthesia developed left-sided costophrenic consolidation with a productive cough during the postoperative period. Three women received epidural anaesthesia for caesarean section and seven received epidural analgesia during labour. All were without sequelae. Four of these had significant prolongation of their phospholipid-dependent coagulation tests for several months before delivery (Tables 2 and 3). None had received heparin within 24 h of epidural insertion. Thromhoprophylaxis and thrombosis Eleven women (55%) had a previous history of thrombosis. All the women in this series were given aspirin 75 mg during pregnancy, stopping at 38 weeks, and those with a previous history of thrombosis were treated with subcutaneous heparin as well. Seven women who delivered early received aspirin within 5 days of epidural insertion. Five patients experienced thrombotic episodes. One had a transient ischaemic episode affecting her speech and vision at 14 weeks gestation. She was
Anaesthesia and the antiphospholipid syndrome
109
Table 3. Coagulation profiles witbin 24 b of delivery of women with prolonged clotting tests attributed to aPL Patient
Delivery mode
Analgesia/anaesthesia
Platelets x 1OYL
KCCTR
1 2 3 4a 4b 5 6 7
C/S 20 week IUD us SVD Forceps c/s CIS SVD
GA DIA GA None EPID EPID EPID EPID
159 157 108 137 176 136 211 238
2.04 1.86 1.97 -
APTTR
INR
1.35 2.41 2.61 1.34
1.30 1.20 0.87 1.10 1.10 0.88 0.80 1.0
1.80
BT min
12 10
EBL (ml) 200 200 300 500 200 600 400 150
C/S: caesarean, SVD: spontaneous vaginal delivery, GA: general anaesthesia, EPID: epidural, DIA: diamorphine, IUD: intrauterine death, EBL: Estimated blood loss. Laboratory reference ranges: KCCTR: kaolin cephalin clotting time ratio 0.8-l .2, APTTR: activated partial thromboplastin time ratio 0.85-1.16, INR: international normalized ratio 0.84-1.16, BT: bleeding time < 10 min.
already receiving aspirin and was then given low molecular weight heparin (LMWH) and suffered no further episodes. Two patients had small pulmonary emboli after vaginal delivery. The diagnosis was confirmed by ventilation perfusion scans. Both patients had been given subcutaneous heparin before and after delivery and were subsequently anticoagulated with warfarin. Another patient who had been taking only aspirin developed a deep vein thrombosis 3 days after vaginal delivery which was confirmed by venography. One 3 1-year-old Caucasian woman suffered bilateral renal vein thrombosis after being induced at 24 weeks because of eclampsia. She had been given LMWH and aspirin during the pregnancy, and LMWH post partum. She subsequently went into renal failure and required peritoneal dialysis for 4 months to allow her renal function to recover.
DISCUSSION
Anticardiolipin syndrome was first described in 1983 and has the following features: arterial and venous thromboses, strokes, migraine, livedo reticularis, recurrent abortions and occasional thrombocytopenia.4 Now it is more widely known as the antiphospholipid syndrome (APS) and may include other features such as valvular heart disease, labile hypertension, epilepsy, chorea, amaurosis fugax, multiinfarct dementia, myelitis, haemolytic anaemia, Budd-Chiari syndrome, Addison’s disease and early myocardial infarction.’ APS can occur alone (primary), or in patients who fulfil the criteria for SLE (secondary), although there appear to be few differences in antiphospholipidrelated complications. Between 10 and 34% of patients with SLE have APS.S To diagnose APS requires one or more of the following clinical findings: venous thrombosis, arterial
thrombosis, recurrent pregnancy loss and/or thrombocytopenia, together with moderate to high titres of IgG and/or IgM anticardiolipin antibody, or a positive LA test. The antiphospholipid tests must be positive on at least two occasions more than 3 months apart. It is common for women to test negative when they are not pregnant and positive in pregnancy. The association between aPL and recurrent spontaneous abortion is a consistent feature of APS. Intrauterine deaths tend to occur during the second and third trimesters, differing from the usual pattern of first trimester fetal loss. The pathological basis of this phenomenon is thought to be progressive thrombosis of the placental microvasculature leading to infarction and placental insufficiency, fetal growth retardation and, ultimately, fetal loss. The mechanism of thrombosis is unknown. However, recent studies have shown that a subset of aPL reacts with the serum protein 0, glycoprotein 1 and the phospholipid complex which is normally responsible for inhibiting factor XII activation, platelet activation and prothrombinase activity.6 Interfering with these mechanisms could predispose to thrombosis. However, the activated partial thromboplastin time ratio (APTTR) and kaolin cephalin clotting time ratio (KCCTR) phospholipid-dependent coagulation tests are prolonged beyond a level that most anaesthetists would consider acceptable for epidural placement. The prothrombin and thrombin times are usually normal. The presence of a prolonged APTTR or KCCTR secondary to aPL has not been found to be associated with increased blood loss in patients undergoing surgery.’ Estimated blood loss at delivery, although notoriously inaccurate, was no more than would be expected in the eight women with prolonged APTTR/KCCTR tests (Table 3). Other haematological abnormalities have been associated with aPL and may predispose to haemorrhage. Very rarely there may be antibodies to the clotting
110 International Journal of Obstetric Anesthesia factors II, VII, VIII and IX which can also prolong the APTTR/KCCTR tests and can be confirmed by factor assays.* Thrombocytopenia and a qualitative platelet abnormality may also occur. Six women (27%) in this survey had mild thrombocytopenia with platelet counts of 100-l 50 x 109/L. Elevated APTTR/KCCTR tests can often be identified early in pregnancy and should be sought if the patient is positive for LA or aCL. The cause must be determined early since the various assays and tests required to do this take time, and consultation between haematology and anaesthetic departments should take place well in advance of the delivery date.5 Four patients in this survey received uneventful epidural blockade even though their APTTR/ KCCTR tests were well above the upper limit of the laboratory reference range. This finding cannot, however, provide valid evidence of the safety or otherwise of epidural placement in this group of patients, since the series is small and epidural haematoma is exceedingly rare in the obstetric population, In the absence of coagulation defects secondary to clotting factor antibodies or platelet abnormalities, the in vitro phenomena of prolonged APTT or KCCT tests alone should not in theory predispose to haemorrhage or be a contraindication to epidural anaesthesia in patients with aPL. The use of central neural blockade may be further complicated by widespread use of aspirin, although the problem of epidural haematoma was not encountered in the CLASP study.9 All the women in this survey were given 75 mg aspirin a day, and seven received it within 5 days of epidural insertion without complication. The bleeding time is now generally regarded as a useless test in this situation. However, when faced with a patient requiring urgent central neural blockade, thrombelastography may provide an immediate assessment of haemostasis.” The presence of APS makes the pregnancy high risk. In 1985, a survey of the literature revealed 242 untreated pregnancies in 65 women with LA, of which 91% ended in fetal death.” In this survey, the survival rate in the earlier untreated pregnancies was only 20%. After 1989 at St Thomas’ Hospital, all pregnant women with APS were treated with low dose aspirin, and heparin as well if there was a history of previous thrombosis. This increased the live birth rate from 19% to 70%.3 Pregnancy alone is a risk factor for thromboembolism and occurs with a frequency of around 1 in 1000 in the general population with a further 2 per 1000 during the puerperium.” Fifty per cent of all cases of thrombosis in women with APS occur during pregnancy or while on oral contraceptives.13The association of APS with arterial thrombosis distinguishes it from many other hypercoagulation disorders. The
use of antithrombotic therapy in patients with APS can reduce the risk of thrombosis during pregnancy and puerperium to 12°h.3Unfractionated or LMWHs can be used for thromboprophylaxis during pregnancy since relatively little crosses the placenta. The LMWHs offer the advantage that levels can be monitored accurately with anti-Xa activity. The APTTR can be confusing in APS patients when using unfractionated heparin since it may already be prolonged by the antiphospholipid antibodies. Other advantages of LMW over unfractionated heparins are a higher antithrombotic:anticoagulation ratio which theoretically means less bleeding and a more selective antithrombotic effect, a longer half-life with a need for fewer injections per day, and less heparin-induced thrombocytopenia. Other thromboprophylactic measures such as the use of antiembolic stockings, the maintenance of normothermia and the avoidance of dehydration should be implemented for all women in labour with APS. The mobile ‘walking’ epidural may offer further protection from thrombosis. There is significant maternal morbidity peripartum in APS pregnancies from pulmonary embolism and cerebral infarction.14 In this survey there were two cases of pulmonary embolism and five of the 22 pregnancies (23%) were complicated by thrombotic episodes. Postoperative hypoxaemia may be an early sign of pulmonary embolism and merits immediate investigation. In conclusion, the presence of aPL confers a high degree of risk to both the mother and fetus, and optimal management should involve early specialist referral to a tertiary centre where the multidisciplinary expertise is available. ACKNOWLEDGEMENT I thank Professor F. Reynolds for advice and help with this survey.
REFERENCES 1. Hughes G R V. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344. 2. Khamashta M A, Cuadrado M J, Mujic F, Taub N A, Hunt B J, Hughes G R V. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-991. 3. Lima F, Khamashta M A, Buchanan N M M, Kerslake S, Hunt B J, Hughes G R V. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14: 131-136. 4. Hughes G R V. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BMJ 1983; 287: 108881089. antibodies: 5. Love P E, Santoro S A. Antiphospholipid anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682698. 6. McNeil H P, Simpson R J, Chesterton C N, Krilis S A. Antiphospholipid antibodies are directed against a complex
Anaesthesia and the antiphospholipid syndrome
7. 8. 9.
10.
antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein 1 (apolipoprotein H). Proc Nat1 Acad Sci USA 1990; 87: 41204124. Shapiro S, Thiagarajan P Lupus anticoagulant. Prog Hemost Thromb 1982; 6: 263-285. Espinoza L R, Hartmann R C. Significance of the lupus anticoagulant. Am J Hematol 1986; 22: 331-337. Collaborative Group. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Lowdose AspirinStudy in Pregnancy). Lancet 1994: 343; 619-629. Mallett S V, Cox D J A. Thrombelastography. Br J Anaesth 1992; 69: 307-313.
111
11. Branch D W, Scott J R, Kochenour N K, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985; 313: 1322-1326. 12. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task. Guidelines on the prevention, investigation and management of thrombosis associated with pregnancy. J Clin Path01 1993; 46: 489496. 13. Branch D W. Antiphospholipid syndrome: laboratory concerns, fetal loss and pregnancy management. Semin Perinatol 1991; 15: 230-237. 14. Branch D W, Andres R, Digre K B, Rote N S, Scott J R. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989; 73: 541-545.
REVIEWARTICLE
Anaesthesia and the antiphospholipid syndrome: a review of 20 obstetric patients D. K. Ringrose Department of Anaesthesia,St Thomas’Hospital, London, UK SUMMARK The case notes of 20 obstetric patients with antiphospholipid syndrome delivering over a 4-year period were reviewed retrospectively. There were complete details for 22 singleton pregnancies. Obstetric complications in the pregnancies under review were frequent. Nine (47%) of the 19 women whose pregnancies reached the third trimester were delivered by caesarean section. During seven of the pregnancies there was significant prolongation of the phospholipid-dependent coagulation tests secondary to lupus anticoagulant and/or anticardiolipin antibodies. Four of these women received epidural blockade without sequelae. This finding, however,cannot provide valid evidencefor the safety or otherwise of epidural placement in this group of patients, since the series is small and the incidence of epidural haematoma is exceedingly rare in the obstetric population. Paradoxically, these patients are hypercoagulable.The estimated blood loss at these deliveries did not exceed600 m l. Eleven women (55%) had a previous history of thrombosis. Two women had thrombotic episodes during their pregnanciesand three had them post partum despite antithrombotic measures.
At St Thomas’ Hospital, The Lupus Arthritis Research Unit is a national referral centre for SLE and APS, and consequently about 10 mothers with APS deliver here per annum.
INTRODUCTION Antiphospholipid syndrome (APS) is characterized by the presence of autoantibodies to phospholipids. These are the lupus anticoagulant (LA) and anticardiolipin antibodies (aCL), which are associated with recurrent venous or arterial thromboses,recurrent abortions and thrombocytopenia.’ Approximately half the patients with APS have systemic lupus erythematosus (SLE).’ Obstetric problems are frequent and include intrauterine growth retardation, recurrent m iscarriage, fetal death, preeclampsia,eclampsia, placental thrombosis and premature delivery.3 Another feature of APS is prolongation of the activated partial thromboplastin tim e (APTT) and kaolin cephalin clotting tim e (KCCT), both of which are phospholipid-dependent coagulation tests, beyond a level most anaesthetists would consider acceptable for epidural anaesthesia. The anaesthetist is likely to be involved with the care of these high risk parturients as there is a high incidence of operative delivery. The literature to date lacks any series on the anaesthetic management of these patients.
METHODS In a search through the records of the lupus pregnancy clinic, the case notes and anaesthetic charts of 20 obstetric patients with APS who were booked for delivery at St Thomas’ Hospital were found and reviewed retrospectively to determine their anaesthetic management and to record any complications that had arisen. The deliveries took place between late 1991 and early 1995. Incomplete sets of notes were not included, and some sets of notes for women with APS who had delivered during this period were no longer present in the lupus clinic records. RESULTS Patients There were 18 Caucasian women, one black African and one Indian. Their m e a n age was 30.5 years (range 20-40). There were 22 singleton pregnanciesincluding two second trimester intrauterine deaths and one
D. K. Ringrose MBBS, FRCA, Senior Registrar, Department of
Anaesthesia, Second Floor, New Guy’s House, Guy’s Hospital, St Thomas’ St, London SE1 9RT, UK. 107
108 International Journal of Obstetric Anesthesia Table 1. Obstetric complications in the present pregnancies
Number of pregnancies Preeclampsia Eclampsia Intrauterine growth retardation Oligohydramnios Placental abruption Acute fatty liver Emergency caesarean delivery No complications
1 1 4 1 2
1 5 9
Table 2. Delivery details for third trimester biiths
Mode of delivery Spontaneous Spontaneous Ventouse Forceps Caesarean Caesarean
Type of analgesia/anaesthesia
Number (n = 19)
% of total
None Epidural Epidural Epidural Epidural General anaesthesia
3 4 2 1 3 6
16 21 10 5 16 3
therapeutic termination for eclampsia at 24 weeks. Among the 20 women, seven had been diagnosed with primary APS and 13 with the secondary syndrome associated with SLE. Type of delivery Obstetric complications were frequent with a high incidence of operative delivery (Tables 1 and 2). Ten women had vaginal deliveries, seven spontaneous and three instrumental, while nine had caesarean sections (Table 2). There were five emergency caesarean sections for fetal distress, of which one also had failure to progress and the remainder were elective. Coagulation profiles Seven women had abnormal coagulation profiles at delivery attributed to antiphospholipid antibodies (aPL) (Table 3). None of these had any signs of preeclampsia, and the fibrin degradation products and fibrinogen blood tests were all within normal limits. Six women had mild thrombocytopenia at delivery with platelet counts between loo-150 x 109/L. Anaesthesia Six general anaesthetics were given for caesarean deliveries (Table 2), one of which was elective and general anaesthesia was requested by the mother. In one of the emergency operations, although an epidural had been working well during labour, the block was inadequate
for surgery. The remaining four were for fetal distress and it was judged there was not enough time to institute regional anaesthesia. In addition, one of them had received subcutaneous heparin only 2 h previously and this was considered by the anaesthetist to be a contraindication to central neural blockade. There was one case of bronchospasm after intubation which produced transient hypoxaemia and resolved with deepening of anaesthesia. Another patient who had received general anaesthesia developed left-sided costophrenic consolidation with a productive cough during the postoperative period. Three women received epidural anaesthesia for caesarean section and seven received epidural analgesia during labour. All were without sequelae. Four of these had significant prolongation of their phospholipid-dependent coagulation tests for several months before delivery (Tables 2 and 3). None had received heparin within 24 h of epidural insertion. Thromhoprophylaxis and thrombosis Eleven women (55%) had a previous history of thrombosis. All the women in this series were given aspirin 75 mg during pregnancy, stopping at 38 weeks, and those with a previous history of thrombosis were treated with subcutaneous heparin as well. Seven women who delivered early received aspirin within 5 days of epidural insertion. Five patients experienced thrombotic episodes. One had a transient ischaemic episode affecting her speech and vision at 14 weeks gestation. She was
Anaesthesia and the antiphospholipid syndrome
109
Table 3. Coagulation profiles witbin 24 b of delivery of women with prolonged clotting tests attributed to aPL Patient
Delivery mode
Analgesia/anaesthesia
Platelets x 1OYL
KCCTR
1 2 3 4a 4b 5 6 7
C/S 20 week IUD us SVD Forceps c/s CIS SVD
GA DIA GA None EPID EPID EPID EPID
159 157 108 137 176 136 211 238
2.04 1.86 1.97 -
APTTR
INR
1.35 2.41 2.61 1.34
1.30 1.20 0.87 1.10 1.10 0.88 0.80 1.0
1.80
BT min
12 10
EBL (ml) 200 200 300 500 200 600 400 150
C/S: caesarean, SVD: spontaneous vaginal delivery, GA: general anaesthesia, EPID: epidural, DIA: diamorphine, IUD: intrauterine death, EBL: Estimated blood loss. Laboratory reference ranges: KCCTR: kaolin cephalin clotting time ratio 0.8-l .2, APTTR: activated partial thromboplastin time ratio 0.85-1.16, INR: international normalized ratio 0.84-1.16, BT: bleeding time < 10 min.
already receiving aspirin and was then given low molecular weight heparin (LMWH) and suffered no further episodes. Two patients had small pulmonary emboli after vaginal delivery. The diagnosis was confirmed by ventilation perfusion scans. Both patients had been given subcutaneous heparin before and after delivery and were subsequently anticoagulated with warfarin. Another patient who had been taking only aspirin developed a deep vein thrombosis 3 days after vaginal delivery which was confirmed by venography. One 3 1-year-old Caucasian woman suffered bilateral renal vein thrombosis after being induced at 24 weeks because of eclampsia. She had been given LMWH and aspirin during the pregnancy, and LMWH post partum. She subsequently went into renal failure and required peritoneal dialysis for 4 months to allow her renal function to recover.
DISCUSSION
Anticardiolipin syndrome was first described in 1983 and has the following features: arterial and venous thromboses, strokes, migraine, livedo reticularis, recurrent abortions and occasional thrombocytopenia.4 Now it is more widely known as the antiphospholipid syndrome (APS) and may include other features such as valvular heart disease, labile hypertension, epilepsy, chorea, amaurosis fugax, multiinfarct dementia, myelitis, haemolytic anaemia, Budd-Chiari syndrome, Addison’s disease and early myocardial infarction.’ APS can occur alone (primary), or in patients who fulfil the criteria for SLE (secondary), although there appear to be few differences in antiphospholipidrelated complications. Between 10 and 34% of patients with SLE have APS.S To diagnose APS requires one or more of the following clinical findings: venous thrombosis, arterial
thrombosis, recurrent pregnancy loss and/or thrombocytopenia, together with moderate to high titres of IgG and/or IgM anticardiolipin antibody, or a positive LA test. The antiphospholipid tests must be positive on at least two occasions more than 3 months apart. It is common for women to test negative when they are not pregnant and positive in pregnancy. The association between aPL and recurrent spontaneous abortion is a consistent feature of APS. Intrauterine deaths tend to occur during the second and third trimesters, differing from the usual pattern of first trimester fetal loss. The pathological basis of this phenomenon is thought to be progressive thrombosis of the placental microvasculature leading to infarction and placental insufficiency, fetal growth retardation and, ultimately, fetal loss. The mechanism of thrombosis is unknown. However, recent studies have shown that a subset of aPL reacts with the serum protein 0, glycoprotein 1 and the phospholipid complex which is normally responsible for inhibiting factor XII activation, platelet activation and prothrombinase activity.6 Interfering with these mechanisms could predispose to thrombosis. However, the activated partial thromboplastin time ratio (APTTR) and kaolin cephalin clotting time ratio (KCCTR) phospholipid-dependent coagulation tests are prolonged beyond a level that most anaesthetists would consider acceptable for epidural placement. The prothrombin and thrombin times are usually normal. The presence of a prolonged APTTR or KCCTR secondary to aPL has not been found to be associated with increased blood loss in patients undergoing surgery.’ Estimated blood loss at delivery, although notoriously inaccurate, was no more than would be expected in the eight women with prolonged APTTR/KCCTR tests (Table 3). Other haematological abnormalities have been associated with aPL and may predispose to haemorrhage. Very rarely there may be antibodies to the clotting
110 International Journal of Obstetric Anesthesia factors II, VII, VIII and IX which can also prolong the APTTR/KCCTR tests and can be confirmed by factor assays.* Thrombocytopenia and a qualitative platelet abnormality may also occur. Six women (27%) in this survey had mild thrombocytopenia with platelet counts of 100-l 50 x 109/L. Elevated APTTR/KCCTR tests can often be identified early in pregnancy and should be sought if the patient is positive for LA or aCL. The cause must be determined early since the various assays and tests required to do this take time, and consultation between haematology and anaesthetic departments should take place well in advance of the delivery date.5 Four patients in this survey received uneventful epidural blockade even though their APTTR/ KCCTR tests were well above the upper limit of the laboratory reference range. This finding cannot, however, provide valid evidence of the safety or otherwise of epidural placement in this group of patients, since the series is small and epidural haematoma is exceedingly rare in the obstetric population, In the absence of coagulation defects secondary to clotting factor antibodies or platelet abnormalities, the in vitro phenomena of prolonged APTT or KCCT tests alone should not in theory predispose to haemorrhage or be a contraindication to epidural anaesthesia in patients with aPL. The use of central neural blockade may be further complicated by widespread use of aspirin, although the problem of epidural haematoma was not encountered in the CLASP study.9 All the women in this survey were given 75 mg aspirin a day, and seven received it within 5 days of epidural insertion without complication. The bleeding time is now generally regarded as a useless test in this situation. However, when faced with a patient requiring urgent central neural blockade, thrombelastography may provide an immediate assessment of haemostasis.” The presence of APS makes the pregnancy high risk. In 1985, a survey of the literature revealed 242 untreated pregnancies in 65 women with LA, of which 91% ended in fetal death.” In this survey, the survival rate in the earlier untreated pregnancies was only 20%. After 1989 at St Thomas’ Hospital, all pregnant women with APS were treated with low dose aspirin, and heparin as well if there was a history of previous thrombosis. This increased the live birth rate from 19% to 70%.3 Pregnancy alone is a risk factor for thromboembolism and occurs with a frequency of around 1 in 1000 in the general population with a further 2 per 1000 during the puerperium.” Fifty per cent of all cases of thrombosis in women with APS occur during pregnancy or while on oral contraceptives.13The association of APS with arterial thrombosis distinguishes it from many other hypercoagulation disorders. The
use of antithrombotic therapy in patients with APS can reduce the risk of thrombosis during pregnancy and puerperium to 12°h.3Unfractionated or LMWHs can be used for thromboprophylaxis during pregnancy since relatively little crosses the placenta. The LMWHs offer the advantage that levels can be monitored accurately with anti-Xa activity. The APTTR can be confusing in APS patients when using unfractionated heparin since it may already be prolonged by the antiphospholipid antibodies. Other advantages of LMW over unfractionated heparins are a higher antithrombotic:anticoagulation ratio which theoretically means less bleeding and a more selective antithrombotic effect, a longer half-life with a need for fewer injections per day, and less heparin-induced thrombocytopenia. Other thromboprophylactic measures such as the use of antiembolic stockings, the maintenance of normothermia and the avoidance of dehydration should be implemented for all women in labour with APS. The mobile ‘walking’ epidural may offer further protection from thrombosis. There is significant maternal morbidity peripartum in APS pregnancies from pulmonary embolism and cerebral infarction.14 In this survey there were two cases of pulmonary embolism and five of the 22 pregnancies (23%) were complicated by thrombotic episodes. Postoperative hypoxaemia may be an early sign of pulmonary embolism and merits immediate investigation. In conclusion, the presence of aPL confers a high degree of risk to both the mother and fetus, and optimal management should involve early specialist referral to a tertiary centre where the multidisciplinary expertise is available. ACKNOWLEDGEMENT I thank Professor F. Reynolds for advice and help with this survey.
REFERENCES 1. Hughes G R V. The antiphospholipid syndrome: ten years on. Lancet 1993; 342: 341-344. 2. Khamashta M A, Cuadrado M J, Mujic F, Taub N A, Hunt B J, Hughes G R V. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993-991. 3. Lima F, Khamashta M A, Buchanan N M M, Kerslake S, Hunt B J, Hughes G R V. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996; 14: 131-136. 4. Hughes G R V. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. BMJ 1983; 287: 108881089. antibodies: 5. Love P E, Santoro S A. Antiphospholipid anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med 1990; 112: 682698. 6. McNeil H P, Simpson R J, Chesterton C N, Krilis S A. Antiphospholipid antibodies are directed against a complex
Anaesthesia and the antiphospholipid syndrome
7. 8. 9.
10.
antigen that includes a lipid-binding inhibitor of coagulation: beta 2-glycoprotein 1 (apolipoprotein H). Proc Nat1 Acad Sci USA 1990; 87: 41204124. Shapiro S, Thiagarajan P Lupus anticoagulant. Prog Hemost Thromb 1982; 6: 263-285. Espinoza L R, Hartmann R C. Significance of the lupus anticoagulant. Am J Hematol 1986; 22: 331-337. Collaborative Group. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Lowdose AspirinStudy in Pregnancy). Lancet 1994: 343; 619-629. Mallett S V, Cox D J A. Thrombelastography. Br J Anaesth 1992; 69: 307-313.
111
11. Branch D W, Scott J R, Kochenour N K, Hershgold E. Obstetric complications associated with the lupus anticoagulant. N Engl J Med 1985; 313: 1322-1326. 12. Maternal and Neonatal Haemostasis Working Party of the Haemostasis and Thrombosis Task. Guidelines on the prevention, investigation and management of thrombosis associated with pregnancy. J Clin Path01 1993; 46: 489496. 13. Branch D W. Antiphospholipid syndrome: laboratory concerns, fetal loss and pregnancy management. Semin Perinatol 1991; 15: 230-237. 14. Branch D W, Andres R, Digre K B, Rote N S, Scott J R. The association of antiphospholipid antibodies with severe preeclampsia. Obstet Gynecol 1989; 73: 541-545.