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Guidelines on the investigation and management of antiphospholipid syndrome

2012; Wiley; Volume: 157; Issue: 1 Linguagem: Inglês

10.1111/j.1365-2141.2012.09037.x

1365-2141

David Keeling, Ian Mackie, Gary Moore, Ian A. Greer, M. Greaves,

Heparin-Induced Thrombocytopenia and Thrombosis

This guidance updates and replaces the previous guideline on the investigation and management of antiphospholipid syndrome (APS) published in 2000 (Greaves et al, 2000), though where there have not been changes we refer back to them when appropriate. The guidance is updated with reference to relevant publications since 2000. Publications known to the writing group were supplemented with additional papers identified by searching PubMed for publications in the last 11 years using the key words: lupus anticoagulant, anticardiolipin, antiphospholipid, β2–glycoprotein I, antiprothrombin and limits (clinical trial, randomized control trial, meta-analysis, humans, core clinical journals, English language). The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the Royal College of Obstetricians and Gynaecologists (RCOG), and the British Committee for Standards in Haematology (BCSH) Committee and comments incorporated where appropriate. The 'GRADE' system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with antiphospholipid syndrome though individual patient circumstances may dictate an alternative approach. The antiphospholipid syndrome (APS) is an acquired autoimmune condition. The clinical features are thrombosis (venous, arterial and microvascular) and/or pregnancy complications and failure. It is important to recognize the syndrome in the context of these problems and to institute appropriate therapy to reduce the risk of recurrence. The reader is directed to reviews published since our previous guideline (Lim et al, 2006; Robertson & Greaves, 2006; Ruiz-Irastorza et al, 2007; Giannakopoulos & Krilis, 2009; Giannakopoulos et al, 2009). Antiphospholipid syndrome is diagnosed in a patient with thrombosis and/or defined pregnancy morbidity (see below) who has persistent antiphospholipid antibodies (aPL). Venous thrombosis in APS is most commonly lower limb deep vein thrombosis (DVT) and/or pulmonary embolism (PE) but any part of the venous system may be involved, including superficial, portal, renal, mesenteric and intracranial veins. The most frequent site of arterial thrombosis in APS is in the cerebral vasculature resulting in transient cerebral ischaemia/stroke. Myocardial infarction is less common, although subclinical myocardial ischaemia may be under-recognized (Sacre et al, 2010). Despite these clear associations between aPL and thrombosis, APS makes only a minor contribution to the overall burden of disease from VTE and stroke. Microvascular thrombosis in APS is least common but may manifest as the potentially lethal 'catastrophic antiphospholipid syndrome' (CAPS). In CAPS there is typically multiorgan failure involving, but not confined to, the lungs, brain and kidneys. Historically aPL have been detected as either a lupus anticoagulant (LA) or as anticardiolipin antibodies (aCL). LA is an in vitro phenomenon in which there is prolongation of a phospholipid-dependent coagulation test that is not due to an inhibitor specific to a coagulation factor (see Section '4.2'). It was originally thought that the LA phenomenon was due to autoantibodies against anionic phospholipids interfering with the assembly of the tenase and prothrombinase complexes, and the aCL assay (see Section '4.4') was developed as an alternative way of detecting these hypothetical antibodies. However it became clear in the early 1990s that these tests were detecting antibodies not to anionic phospholipids but to phospholipid binding proteins. The aCL enzyme-linked immunosorbent assay (ELISA) typically detects antibodies to β2–glycoprotein I (β2GPI) (Galli et al, 1990; McNeil et al, 1990) and LA tests are sensitive to antibodies to β2GPI (anti-β2GPI) and also antibodies to prothrombin (Bevers et al, 1991). β2GPI is an apolipoprotein and a member of the complement control protein family; it binds to cell surface receptors and negatively charged surfaces. Among anti-β2GPI it has been demonstrated that it is those that bind specifically to a limited epitope on domain 1 of the protein (Gly40-Arg43) that are most strongly associated with thrombosis (de Laat et al, 2005). Antiprothrombin antibodies are weakly associated with thrombosis; they usually have a low affinity, but in some patients higher affinity antibodies are produced which cause the rare complication of hypoprothrombinaemia. APS has been described as secondary if there is an associated autoimmune disorder, such as systemic lupus erythematosus (SLE) or rheumatoid arthritis, and primary if not. In order to ensure consistency in research, consensus criteria for the diagnosis of APS have been agreed (Miyakis et al, 2006) (Table 1). Whilst these criteria are useful for encouraging uniformity in clinical studies their uncritical application to the individual case in the clinic should be avoided; rather, the diagnosis should depend upon a thorough assessment of the clinical history, consideration of alternative causes of thrombosis or pregnancy morbidity and review of the laboratory data in the light of knowledge of the limitations of the assays (see Section '4'). In addition to thrombosis and pregnancy morbidity there have been many claims of other clinical associations with aPL. Thrombocytopenia, heart valve disease (which is most commonly occult), chorea, livedo reticularis/racemosa and nephropathy are likely associations, although like the thrombotic and pregnancy manifestations, none is specific to APS (Miyakis et al, 2006). Transverse myelopathy occurs in SLE and may be more frequent in those with aPL (Cervera et al, 2002). A purported association with infertility has not been substantiated (Buckingham & Chamley, 2009) and an association with migraine is controversial with one recent study finding a relationship (Cavestro et al, 2011) but others not (Montalban et al, 1992; Tietjen et al, 1998). Another controversial concept is that APS may manifest as a disorder closely mimicking multiple sclerosis and responsive to anticoagulant therapy (Hughes, 2003). However, aPL may be present in some cases of otherwise typical multiple sclerosis (Heinzlef et al, 2002) perhaps representing an epiphenomenon in a disorder with an immune pathogenesis. Even more controversial is the suggestion that there may be a seronegative form of APS (Hughes & Khamashta, 2003). The principal manifestations of APS, thrombosis and pregnancy failure, are common and in most cases have no autoimmune basis; as such the diagnosis of 'seronegative APS' would be difficult to sustain. This guideline considers only thrombosis (primarily venous thromboembolism and arterial ischaemic stroke) and pregnancy morbidity, in APS. In relation to venous thrombosis Galli et al (2003a,b) published two papers, which looked at the evidence for an association with aPL. There was evidence of an association with LA, odds ratios (OR) across studies ranging from 4·1 to 16·2. Although some studies suggested an association with aCL (Ginsburg et al, 1992; Schulman et al, 1998), others did not (Stegnar et al, 1991; Bongard et al, 1992; Oger et al, 1997) and overall Galli et al. concluded that aCL were not independently associated with DVT. For anti-β2GPI the same authors found 7/14 studies showed a significant association with venous thrombosis but only in retrospective studies. In 2004 β2GPI dependent LA was shown to be associated with venous thrombosis (de Laat et al, 2004). The following year the presence of IgG anti-β2GPI was shown to predict thrombosis in patients with LA (Zoghlami-Rintelen et al, 2005). An analysis of the Leiden Thrombophilia Study demonstrated that the presence of LA, anti-β2GPI and anti -prothrombin antibodies are risk factors for DVT in a general population, the strongest association being for the combination of LA, aβ2GPI and anti-prothrombin antibodies (de Groot et al, 2005). In a prospective population-based nested cohort study, aCL did not predict a first episode of venous thrombosis (Naess et al, 2006). In the WAPS study (Galli et al, 2007) IgG anti-β2GPI were associated with thrombosis whereas IgM anti-β2GPI, IgG aCL and IgM aCL were not. The authors proposed that anti-β2GPI replace aCL measurement and that only the IgG isotype should be tested for. With regard to arterial thrombosis the aforementioned reviews found that both LA and IgG aCL were associated with arterial thrombosis but that IgM aCL were not (Galli et al, 2003a,b). For anti-β2GPI they found 3/10 studies showed a significant association with arterial thrombosis and concluded that the evidence did not support an association with arterial events. β2GPI-dependent LA has been shown to be associated with arterial thrombosis (de Laat et al, 2004). In the RATIO (Risk of Arterial Thrombosis in Relation to Oral. Contraceptives) study of 175 patients with ischaemic stroke and 203 patients with myocardial infarction (Urbanus et al, 2009) the OR of LA for myocardial infarction was 5·3 (95% confidence interval [CI] 1·4–20·8) and for ischaemic stroke 43·1 (12·2–152·0). In women who had anti-β2GPI antibodies the risk of ischaemic stroke was 2·3 (1·4–3·7), but the risk of myocardial infarction was not increased (0·9, 0·5–1·6). Neither aCL nor antiprothrombin antibodies affected the risk of myocardial infarction or ischaemic stroke. There are fewer data on antibodies of IgA isotype but inclusion of IgA aCL tests does not improve diagnostic efficiency (Bertolaccini et al, 2001; Samarkos et al, 2006). In general, among aPL, the specificity for thrombosis is higher for LA than aCL or anti-β2GPI and greater for higher than lower titre aCL. In one study, patients positive for a LA in both a dilute Russell viper venom time (DRVVT) and a sensitive activated partial thromboplastin time (APTT) were more likely to have thrombosis than patients with only one positive LA test (Swadzba et al, 2011). IgM and IgA antibodies are poorly specific. In addition, among patients with thrombosis, the highest risk of recurrence is the relatively small cohort positive for all of LA, aCL and anti-β2GPI (Pengo et al, 2010). There is substantial evidence linking aPL to an increased risk of recurrent and late pregnancy loss (Ginsberg et al, 1992; Rai et al, 1995; Laskin et al, 1997; Robertson et al, 2006). LA has a stronger association with pregnancy loss than the other anti-phospholipid antibodies, while the importance of anti-β2GPI and pregnancy loss is uncertain (Opatrny et al, 2006). In the meta-analysis by Opatrny et al (2006), both IgG and IgM aCL were associated with recurrent fetal loss but it was not possible to determine the significance of isolated IgM aCL as studies have not distinguished between women having isolated IgM aCL and women having additional aPL antibodies. With regard to pre-eclampsia, placental abruption and fetal growth restriction (FGR), there is an association between these complications and the presence of aPL but this is less strong than with recurrent pregnancy loss (Branch et al, 2001; Robertson et al, 2006). Whether the association of aPL with thrombosis is causal has been contentious though studies in experimental animals do suggest that aPL are directly prothrombotic (Blank et al, 1991). Many mechanisms for thrombosis in APS have been suggested, such as increased expression of tissue factor on monocytes and endothelial cells (Branch & Rodgers, 1993; Amengual et al, 1998), interference in the protein C anticoagulant pathway (Malia et al, 1990; Atsumi et al, 1998a), inhibition of fibrinolysis (Atsumi et al, 1998b) and inhibition of annexin V binding to phospholipids (Rand et al, 1998). More recently attention has focused on anti-β2GPI (see Giannakopoulos et al (2007) for a review). β2GPI can exist in two conformations in plasma (Agar et al, 2010), a closed circular form and an open form. The circular conformation is maintained by interaction between the first and fifth domain of β2GPI, in the open conformation a cryptic epitope in the first domain becomes exposed, enabling antibody binding. Antibody-β2GPI complexes bind to a variety of receptors (e.g. Toll-like receptors 2 and 4, annexin A2, glycoprotein 1bα, and LRP8 in the LDL receptor family) on different cell types, including endothelial cells, platelets, monocytes and trophoblasts (de Groot & Meijers, 2011) and may trigger intracellular signalling and inflammatory responses. Pregnancy failure may be due to thrombosis in the placental bed, although alternative pathogenic mechanisms may apply, and may explain the tendency to very early losses prior to placentation. aPL appear to have a direct effect on trophoblasts, (Chamley et al, 1998; Nelson & Greer, 2008; Simioni, et al 2008) and there is evidence for activation of complement in pregnancy failure in experimental APS (Girardi et al, 2004; Salmon & Girardi, 2004) and in humans (Shamonki et al, 2007; Oku et al, 2009). These observations may explain the apparent efficacy of heparin in the prevention of early fetal losses in APS as heparin has been shown to exert potentially beneficial effects on trophoblasts in vitro (Simioni, et al 2008) and to inhibit complement activation in experimental APS (Girardi et al, 2004; Salmon & Girardi, 2004). The methodology for LA and solid phase aPL assays (e.g. aCL) was covered in detail in the previous BCSH guideline (Greaves et al, 2000). Blood should be collected into 0·109 mol/l trisodium citrate. Platelet contamination should be avoided by double centrifugation at 2000 g for 15 min at 15–22°C. This should yield plasma with a platelet count of 5000 g) as the second centrifugation step is not recommended for the same reasons (Sletnes et al, 1992). Samples should not be repeatedly thawed and refrozen. Preliminary routine coagulation tests are helpful in eliminating undiagnosed coagulopathies and anticoagulant treatment. Classical findings for a LA are: Two test systems of different principles should be employed to ensure that weak LA is detected and to improve specificity, though patients are regarded as having a LA if one test is positive. Clinical evidence based on associations with thrombosis suggests that the DRVVT has good utility and should be one of these tests. The other test will usually be an APTT using a reagent with proven LA sensitivity, a modified APTT, or a dilute prothrombin time. A mixing test may be used to detect an inhibitor and a confirmatory step (e.g. using a high phospholipid concentration, platelet neutralizing reagent or LA-insensitive reagent) is needed to demonstrate phospholipid dependence. If the APTT is suggestive of LA but the DRVVT is negative, a confirmatory step in the APTT (or a further type of high specificity test employing screen and confirmatory assays) is needed to fulfil the criteria for LA. Mixing tests are a criterion for LA and improve the specificity. However, they introduce a dilution factor and may make weak LA samples appear negative. In the absence of any other causes of prolonged clotting times, such samples should be considered LA positive if the screen and confirmatory tests on undiluted plasma give positive results (Clyne et al, 1993; Male et al, 2000; Thom et al, 2003; Moore & Savidge, 2006). Whenever possible, this should be confirmed by testing a fresh sample. Given that there are differences in sensitivity and specificity between reagents (Denis-Magdelaine et al, 1995; Lawrie et al, 1999; Moore & Savidge, 2004) cut-off values for LA positivity should be specific for the given reagent and model of coagulometer (Lawrie et al, 1999; Gardiner et al, 2000). These values may be available from the manufacturer, but local validation is advised. Historically, laboratories have used the mean + 2·0 standard deviations (SD) (97·5th centile for normally distributed data) as a cut-off, but the recent International Society on Thrombosis and Haemostasis consensus document (Pengo et al, 2009) has recommended the 99th centile (mean + 2·3 SD for normally distributed data), which would improve specificity but reduce sensitivity. Most UK laboratories use the 97·5th centile. To estimate either with accuracy a large number of normal samples is needed and commercial frozen normal plasma sets, which must be sufficiently platelet-poor, may be useful in this respect. The inaccuracy of the reference interval estimation with small sample sizes is under-appreciated and sample sizes of 200 (Altman, 1991) and a minimum of 120 (Horowitz et al, 2008) have been recommended. If previously established cut-off values (manufacturer's value or different analyser) are available they may be validated in smaller numbers (20–60) of normal subjects (Horowitz et al, 2008). A normal plasma pool (NPP) (n ≥ 6) should be tested with each batch of samples and the patient screen and confirm results should be expressed as ratios against this. The method for calculating the degree of correction (in the confirm step) that has been recommended by the manufacturer should be used, provided that this takes into account the NPP clotting time. This should either employ the percentage correction of ratio = ((screen ratio – confirm ratio)/screen ratio) × 100 as previously described (Greaves et al, 2000), or a normalized test/confirm ratio = screen ratio/confirm ratio. When reporting the results, the method, cut-off value, and an interpretation as LA-positive or LA-negative should be given. Internal QC (IQC) must be performed with each batch of tests, using LA-negative and -positive plasmas. QC plasmas should be prepared in the same way as test samples. For the positive QC, plasma from a patient with well documented, unequivocal APS and LA may be used. Commercial QC plasmas should be matched with the reagents and validated, as differences in buffering between plasmas and reagents can lead to erroneous results while platelet contamination of plasma pools will influence the sensitivity. Laboratories should also participate in an external quality assurance programme. LA testing is not recommended in patients receiving vitamin K antagonists (VKA) because exclusion of a LA is problematic whilst the international normalized ratio (INR) is in the therapeutic range. If it is thought to be helpful in determining the advisability of long-term anticoagulation, brief discontinuation of VKA therapy for diagnostic purposes is not a high risk strategy in most instances. When LA testing is required for patients receiving oral anticoagulants, the utility of the DRVVT is disputed (Jouhikainen, 1990; Olteanu et al, 2009) and tests performed on undiluted plasma may be misleading. Performing screening and confirmatory steps on equal volume mixtures of patient and normal plasma may be informative. If the screening step on the mixture is abnormal, this may be taken as grounds for considering that an inhibitor is present and the confirmatory step will demonstrate phospholipid dependence. Due to the dilution effect, negative testing in mixing studies does not exclude the presence of a LA. The taipan snake venom time is a useful secondary test to DRVVT in patients receiving oral anticoagulants, with high specificity for LA (Moore et al, 2003; Parmar et al, 2009), It can be used with a platelet neutralization procedure or ecarin time as confirmation. LA tests should not be performed if the patient is receiving therapeutic doses of unfractionated heparin, because this may cause erroneous results (Schjetlein et al, 1993; Lawrie et al, 1999; Liestol et al, 2002). Low dose subcutaneous unfractionated heparin and low molecular weight heparin (LMWH) have less effect on the DRVVT and most commercial reagents contain a heparin neutralizang reagent sufficient to cover prophylactic doses. Platelet neutralization procedures should be avoided in samples containing heparin due to the potential for false positive LA results (Exner, 2000). If positive results are obtained from aCL or anti-β2GPI assays, these are sufficient for the diagnosis of APS. Factor assays may yield misleading results, particularly those for intrinsic pathway factors based on 1-stage methods. Assays should be performed at several dilutions as poor parallelism indicates interference by the inhibitor and unreliable results. In this situation, using higher dilutions of the test sample can sometimes restore parallelism, but the standard curve must also be extended. Alternatively a LA-insensitive APTT reagent can be used for 1-stage assays. Another option is to use an assay system that is less dependent on phospholipid concentration, such as a 2-stage assay or certain chromogenic substrate assays. It should be recognized that some patients with factor inhibitors may also have a LA. Detailed guidance for the performance of aCL assays has recently been published (Pierangeli & Harris, 2008). Key features are the use of 10% adult bovine serum or fetal calf serum as a blocking agent and sample diluent and polyclonal (Pierangeli & Harris, 2008) or humanized monoclonal (Ichikawa et al, 1999) antibody calibrators with values in IgG or IgM antiphospholipid units (GPL units, MPL units). Normal cut-off values should be established in healthy subjects using the 99th centile but it should be noted that the definition of APS used for research requires levels greater than the 99th centile or >40 GPL units. Anti-β2GPI assays have greater specificity than aCL, but are poorly standardized. The purity and oxidation status of the antigen and microtitre plate type are critical to ensure that the clinically relevant anti-β2GPI epitopes are exposed; humanized monoclonal antibodies, such as HCAL and EY2C9, have been recommended as calibrants (Tincani et al, 2004; Reber et al, 2008) but are not commercially available. Assays have recently been developed that employ recombinant domain 1 of anti-β2GPI, and may offer better sensitivity and specificity for clinical events, although more evidence is required. A calibration curve and IQC should be employed in every assay run for both aCL and anti-β2GPI assays. IQC may be performed using suitable normal or APS patient samples (local or commercial), or humanized monoclonal antibody preparations. LA is the most predictive test for thrombosis and the presence of IgG aCL or IgG anti-β2GPI in those who are LA-positive increases the specificity. There is nothing to suggest that measuring IgM antibodies in patients with thrombosis adds useful information. Tests should be repeated after an interval of 12 weeks to demonstrate persistence. Incidental detection of aPL is common, e.g. in the Leiden thrombophilia study, a population-based case control study of VTE, LA was present in 0·9% of unaffected controls (and 3·1% of cases) and anti-β2GPI in 3·4% of controls (and 7·5% of patients) (de Groot et al, 2005). Even when persistent, incidental antibodies have been thought to be associated with a low rate of thrombosis, e.g. 36 (6·5%) of 552 normal blood donors were found to have IgG aCL (eight remained positive for 9 months) but none had thrombosis during the 12 month follow-up (0% 95% CI 0–9·7%) (Vila et al, 1994). In a larger study, 178 asymptomatic carriers of aPL were followed up for 36 months and no episode of thrombosis was detected (0% 95% CI 0–2·0%) (Giron-Gonzalez et al, 2004). However, a recent publication identified 104 subjects that were triple positive for LA, aCL and anti-β2GPI, and follow-up for a mean of 4·5 years identified 25 first thromboembolic events (5·3% per year)(Pengo et al, 2011). Aspirin did not significantly affect the incidence of thromboembolism, consistent with a randomized trial in which thromboprophylaxis with aspirin was ineffective: in 98 individuals with aPL but no clinical manifestations randomized to receive aspirin (n = 48) or placebo (n = 50) the acute thrombosis incidence rates were 2·75 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for the placebo-treated subjects (P = 0·83) (Erkan et al, 2007). Warfarin therapy carries a substantial risk of bleeding. Although the risk is greatest in the first weeks, it persists for the duration of exposure. Initial treatment is for at least 3 months, thereafter decisions regarding the continuation of treatment long-term after an episode of VTE should be based on an individual assessment of the risk-benefit ratio. The risk of recurrence is significantly higher after an unprovoked event (Iorio et al, 2010). Retrospective studies have shown a high incidence of thrombosis recurrence in patients with aPL (Rosove & Brewer, 1992; Khamashta et al, 1995; Krnic-Barrie et al, 1997). In these studies, 80/147 (Khamashta et al, 1995), 39/70 (Rosove & Brewer, 1992) and 23/61 (Krnic-Barrie et al, 1997) had venous thrombosis. In the prospective Duration of Anticoagulation (DURAC) study a single aCL positive test doubled the risk of a recurrence (Schulman et al, 1998). In patients with venous thrombosis, a finite duration of treatment is recommended for patients with a transient risk factor but long-term anticoagulation is considered in those with an unprovoked event (Kearon et al, 2008). We do not recommend testing for aPL in patients with venous thrombosis due to a transient risk factor as we do not think there is sufficient evidence to recommend long-term anticoagulation even if the patient has aPL. If it is decided to stop anticoagulation after unprovoked proximal DVT or PE, testing for aPL is indicated as their presence will increase the risk of recurrence favouring long-term anticoagulation. As a result of retrospective and observational studies it was thought that stroke associated with aPL carried a high risk of recurrence (with the likelihood of consequent permanent disability or death) and should be treated with long-term warfarin (Rosove & Brewer, 1992; Khamashta et al, 1995; Krnic-Barrie et al, 1997). The Antiphospholipid Antibodies and Stroke Study (APASS) (Levine et al, 2004) was a prospective cohort study within the Warfarin versus Aspirin Recurrent Stroke Study (WARSS), a randomized double-blind trial comparing warfarin (INR 1·4–2·8) with aspirin. 720 out of 1770 stroke patients (41%) were aPL positive (13% LA, 20% aCL, 7% both) and aPL did not predict recurrence: OR 0·99 (0·75–1·31) and 0·94 (0·70–1·28) for the patients on warfarin and aspirin, respectively. It should be noted that tests for aPL were only performed on a single occasion and that IgG aCL > 21 GPL units was regarded as positive. For patients with a single positive aPL test result and prior stroke, aspirin and moderate-intensity warfarin appear equally effective for preventing recurrent stroke. We have no high quality evidence for young patients with stroke who have APS according to the Miyakis et al (2006) criteria (Table 1). The cohort studies previously referred to suggest that young patients ( 95%) with APS have a normal prothrombin time (PT) in the absence of other coagulopathies or anticoagulant use. When the PT is prolonged, it is sometimes due to hypoprothrombinaemia, but it has been suggested that the PT/INR may be falsely increased by interference of LA with the phospholipid component of the PT reagent, particularly where recombinant tissue factor is employed and purified phospholipids are used for relipidation. Certain reagents, such as Innovin and Thromborel R (Tripodi et al, 2001) appear to be more sensitive to LA. Where the baseline PT is elevated, alternative, LA-insensitive PT reagents should be employed. Point-of-care devices should be used with caution for INR determination in APS (Briggs et al, 2008; Perry et al, 2010). Most manufacturers list APS as a specific exclusion to their use. In rare patients with prolongation of the baseline PT (one study (Moore et al, 2005) found this in 4·3% of cases using Innovin, n = 400), which causes difficulty in establishing the true degree of anticoagulation; amidolytic factor X (FX) assays may be helpful (Tripodi et al, 2001; Moore et al, 2003). A therapeutic range of approximately 20–40% FX corresponds to a therapeutic INR in LA-negative patients (Rosborough et al, 2010). The investigation and treatment of women with recurrent pregnancy loss is covered in an RCOG guideline (http://www.rcog.org.uk/files/rcog-corp/GTG17recurrentmiscarriage.pdf). The pregnant state may have some effect on tests for aPL, suggesting that investigation should be pursued between pregnancies where possible (Topping et al, 1999). Antithrombotic interventions are used to reduce the incidence of pregnancy complications. In APS this management is supported by clinical trials (Kutteh & Ermel, 1996; Rai et al, 1997) and systematic review (Empson et al, 2005), which reported that unfractionated heparin (UFH) in combination with low dose aspirin reduces the incidence of pregnancy loss in women with a history of recurrent loss. Although data are limited, increasing the dose of UFH (combined with low dose aspirin) does not appear to decrease the risk of pregnancy loss further (Kutteh & Ermel, 1996; Empson et al, 2005). Low dose aspirin therapy alone has not been shown to reduce pregnancy loss compared with routine care or placebo (Cowchock & Reece, 1997; Tulppala et al, 1997; Pattison et al, 2000; Empson et al, 2005). In contrast to UFH, the combination of LMWH and low dose aspirin did not result in a reduced rate of pregnancy loss compared with aspirin alone (Farquharson et al, 2002; Empson et al, 2005; Laskin et al, 2009). Although LMWH has replaced UFH in pregnancy because of a more favourable safety profile and once daily dosing (Greer & Nelson-Piercy, 2005) there are few data comparing LMWH and UFH. However, in two small pilot studies the combination of LMWH and low dose aspirin appeared equivalent to UFH and low dose aspirin in preventing recurrent pregnancy loss (Stephenson et al, 2004; Noble et al, 2005). Although there is limited evidence of efficacy, LMWH has largely replaced UFH in obstetric practice for treatment of recurrent miscarriage in APS because of safety and ease of use. Despite inclusion of fetal death placental insufficiency and severe early pre-eclampsia in the consensus criteria for diagnosis of APS, the data supporting the associations have been conflicting to date and there is a lack of robust evidence to guide treatment (Branch, 2011). Low dose aspirin is established for prevention of FGR and pre-eclampsia and is appropriate to use in women with APS and a history of these complications. However there is a lack of evidence to demonstrate that adding UFH or LMWH carries additional benefit for secondary prevention of these late pregnancy complications in women with APS. Thus, while such therapy may be considered, based on an extrapolation from recurrent pregnancy loss evidence, at present this practice is not supported by the limited evidence available. An RCOG guideline recommends that women with previous thrombosis and APS should be offered both antenatal and 6 weeks of post-partum thromboprophylaxis and that women with persistent aPL with no previous VTE and no other risk factors or fetal indications for LMWH may be managed with close surveillance antenatally but should be considered for LMWH for 7 d postpartum (http://www.rcog.org.uk/files/rcog-corp/GTG37aReducingRiskThrombosis.pdf). While the advice and information in these guidelines is believed to be true and accurate at the time of going to press, neither the authors, the British Society for Haematology nor the publishers accept any legal responsibility for the content of these guidelines. All authors contributed to the search for papers, interpretation of data, and drafting the paper and all approved the submitted final version. None of the authors have declared a conflict of interest. Task force membership at time of writing this guideline was Dr D Keeling, Dr H Watson, Dr A Mumford, Dr I Jennings, Prof M Laffan, Dr E Chalmers, Dr M Makris, Dr RC Tait, Prof I Walker, Dr E Gray.