Guideline guideline Historically aPL have been detected as either a lupus antiWhilst these criteria are useful for

encouraging uniformity

coagulant (LA) or as anticardiolipin antibodies (aCL). LA is in clinical studies their uncritical application to the individGuidelines on the investigation and management of an in vitro phenomenon in which there is prolongation of a ual case in the clinic should be avoided; rather, the diagnosis phospholipid-dependent coagulation test that is not due to should depend upon a thorough assessment of the clinical antiphospholipid syndrome an inhibitor specific to a coagulation factor (see Section Lupus anticoagulant testing). It was originally thought

history, consideration of alternative causes of thrombosis or pregnancy morbidity and review of the laboratory data in the

that the LA phenomenon was due to autoantibodies against David Keeling, 1 Ian Mackie, 2 Gary W. Moore, 3 Ian A. Greer, anionic phospholipids interfering with the assembly of the Haematology tenase and prothrombinase complexes, and the aCL assay
1

light of knowledge of the limitations of the assays (see SecMichael Greaves 5 and British Committee for Standards in tion Detection of aPL in the clinical laboratory).

2 (see Section Solid aPL assays) was developed as an Oxford, UK, Oxford Haemophilia andphase Thrombosis Centre, Churchill Hospital, Haemostasis Research Unit, Haematology DepartClinical associations 3 alternative way of detecting these hypothetical antibodies. ment, University College London, London, UK, Centre for Haemostasis and Thrombosis, GSTS Pathology, Guys & St. Thomas 4 However it became in the early 1990s thatLiverpool, these tests UK and Hospitals, London, UK, clear University of Liverpool, wereUK detecting antibodies not to anionic phospholipids but Aberdeen, 5

In Medicine addition to and pregnancy morbidity there School of &thrombosis Dentistry, University of Aberdeen, 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 thromthe diagnosis and management of patients with antiphospbotic and pregnancy manifestations, none is specific to APS holipid syndrome individual patient circumstances (Miyakis et though al, 2006). Transverse myelopathy occurs in SLE may dictate an alternative approach. 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 associ-

to phospholipid binding proteins. The aCL enzyme-linked immunosorbent assay (ELISA) typically detects antibodies to b2 glycoprotein I (b GPI) (Galli et al, 1990; McNeil et al,
2

Keywords: antiphospholipid syndrome, antiphospholid 1990) and LA tests are sensitive to antibodies to b antibodies, thrombophilia b2 GPI) and also antibodies to prothrombin (Bevers et al,
1991).

GPI (anti-

b2 GPI is an apolipoprotein and a member of the complement control protein family; it binds to cell surface receptors and negatively charged surfaces. Among anti-b
2

Introduction

GPI it has

Features ofwith the migraine antiphospholipid syndrome (APS) ation is controversial with one recent study

been demonstrated that it is those that bind specifically to a

limited epitope domain 1 of the protein guideline (Gly40-Arg43) This guidance updateson and replaces the previous on that are most strongly associated with thrombosis (de Laat the investigation and management of antiphospholipid et al, 2005). Antiprothrombin antibodies weakly associsyndrome (APS) published in 2000 (Greaves et are al, 2000), with thrombosis; have a lowback affinity, thoughated where there have not they beenusually changes we refer to but in someappropriate. patients higher antibodies arewith produced them when Theaffinity guidance is updated refer- which cause the rare complication hypoprothrombinaemia. ence to relevant publications since of 2000. Publications known APS has been described as secondary if there is an associto the writing group were supplemented with additional autoimmune disorder, such as systemic lupusin erythepapersated identified by searching PubMed for publications matosus (SLE) rheumatoid arthritis, and primary if not. the last 11 years usingor the key words: lupus anticoagulant, In order to ensure consistency in research, consensus criteria anticardiolipin, antiphospholipid, b2glycoprotein I, antiprofor the diagnosis of APS have been agreed (Miyakis et thrombin and limits (clinical trial, randomized control trial, al, 2006) (Table I). core clinical journals, English lanmeta-analysis, humans, guage). 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
Clinical criteria

finding a relationship (Cavestro but others not The antiphospholipid syndrome (APS) et is al, an 2011) acquired (Montalban et al, 1992; Tietjen et al, 1998). Another controautoimmune condition. The clinical features are thrombosis versial concept is that APS may manifest as a disorder closely (venous, arterial and microvascular) and/or pregnancy mimicking sclerosis and responsive to anticoagulant complications andmultiple failure. It is important to recognize the therapy (Hughes, However, aPL be present in syndrome in the context 2003). of these problems andmay to institute some therapy cases ofto otherwise typical multiple sclerosis appropriate reduce the risk of recurrence. The (Heinzlef et al, 2002) perhaps representing an epiphenomenon in a reader is directed to reviews published since our previous disorder with an immune pathogenesis. Even more controguideline (Lim et al, 2006; Robertson & Greaves, 2006; Ruizversial is the suggestion that there may be a seronegative Irastorza et al, 2007; Giannakopoulos & Krilis, 2009; Gianform of APS (Hughes & Khamashta, 2003). The principal nakopoulos et al, 2009). 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 Definitions Antiphospholipid syndrome is diagnosed in a patient with 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,

Table I. Research criteria for defining the antiphospholipid syndrome. Adapted from Miyakis et al (2006). With permission, John Wiley & Sons, (see below) thrombosis and/or defined pregnancy morbidity Inc. 2006 International Society on Thrombosis and Haemostasis.

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
2. Pregnancy morbidity 1. Vascular thrombosis

Gynaecologists (RCOG), and the British Committee for Stan-

One or more clinical episodes of arterial, venous or small vessel thrombosis

including superficial, portal, renal, mesenteric and intracradards in Haematology (BCSH) Committee and comments (a) One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation nial veins. The most frequent site of arterial thrombosis in incorporated where appropriate. Thebirths GRADE system was normal neonate before the 34th week of gestation because of: (i) eclampsia or (b) One or more pre-term of a morphologically APS is in the cerebral vasculature resulting in transient used to quote levels and pre-eclampsia grades of evidence, details of which severe or (ii) recognized features of placental insufficiency cerebral ischaemia/stroke. Myocardial infarction is less comcan be found at http://www.bcshguidelines.com/BCSH_PRO(c) Three or more unexplained consecutive spontaneous miscarriages before the 10th week of gestation, with maternal anatomic or mon, although subclinical myocardial ischaemia may be CESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMEN hormonal abnormalities and paternal and maternal chromosomal causes excluded under-recognized (Sacre et al, 2010). Despite these clear Laboratory criteria DATION/43_GRADE.html. The objective of this guideline is associations between aPL and thrombosis, APS makes only a 1. healthcare Lupus anticoagulant (LA) present plasma, on two on or more occasions at least 12 weeks apart to provide professionals with in clear guidance minor contribution the overall burden 2. Anticardiolipin (aCL) antibody of immunoglobulin (Ig)G and/or IgM isotype in serum or plasma, present to in medium or high titre of disease from and Microvascular thrombosis in APS is least (i.e. >40GPL units or MPL units, or > the 99th centile), on two or more occasions,VTE at least 12 stroke. weeks apart but centile), may manifest astwo theor potentially lethal cata3. Anti-b2glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma (in common titre >the 99th present on more
occasions at least 12 weeks apart strophic antiphospholipid syndrome (CAPS). In CAPS there Correspondence: David Keeling, c/o BCSH Secretary, British Society Antiphospholipid antibody syndrome (APS) is present if at least one of the clinical criteria one of the laboratoryfailure criteria involving, are met is and typically multiorgan but not confined to, for Haematology, 100 White Lion Street, London N1 9PF, UK. E-mail: GPL bcsh@b-s-h.org.uk units, IgG antiphospholipid units; MPL units, IgM antiphospholipid units.

the lungs, brain and kidneys.

First published online 2012 8 Blackwell FebruaryPublishing 2012 Ltd British Journal of Haematology, 2012, 157, 4758

48 2012 Blackwell Publishing Ltd

British Journal of Haematology, 2012, 157, 4758 doi:10.1111/j.1365-2141.2012.09037.x

Guideline sustain. This guideline considers only thrombosis (primarily venous thromboembolism and arterial ischaemic stroke) and pregnancy morbidity, in APS. aPL and thrombosis. 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 41to162. 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 antib2 GPI the same authors found 7/14 studies showed a significant association with venous thrombosis but only in retrospective studies. In 2004 b
2

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-b2GPI (Pengo et al, 2010). aPL and pregnancy morbidity. 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-b
2

GPI and pregnancy

GPI dependent LA was shown to GPI was shown 2

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).

be associated with venous thrombosis (de Laat et al, 2004). The following year the presence of IgG anti-b 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-b2GPI and anti prothrombin antibodies are risk factors for DVT in a general population, the strongest association being for the combination of LA, ab
2

GPI 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-b
2

GPI were associated with thrombosis

whereas IgM anti-b GPI, IgG aCL and IgM aCL were not. 2 The authors proposed that anti-b GPI replace aCL measure2 ment 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-b
2

Pathophysiology
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-b poulos et al (2007) for a review). b
2 2

GPI 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. b
2

GPI-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 53 (95% confidence interval [CI] 14208) and for ischaemic stroke 431 (1221520). In women who had anti-b antibodies the risk of ischaemic stroke was 23(1437), but the risk of myocardial infarction was not increased (09, 05 16). 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-b
2 2

GPI (see Giannako-

GPI can exist in two con-

formations 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 b GPI the open conformation a cryptic epitope in the first domain becomes exposed, enabling antibody binding. Antibody-b complexes bind to a variety of receptors (e.g. Toll-like receptors 2 and 4, annexin A2, glycoprotein 1ba, 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 in ammatory 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 49
2 2

GPI, in GPI

GPI and greater for higher

than lower titre aCL. In one study, patients positive for a LA

2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 4758

Guideline prior to placentation. aPL appear to have a direct effect on trophoblasts, (Chamley et al, 1998; Nelson & Greer, 2008; Simioni,etal1999) 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,etal1999) and to inhibit complement activation in experimental APS (Girardi et al, 2004; Salmon & Girardi, 2004). 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.

Detection of aPL in the clinical laboratory

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).

Cut-off values, calculations and quality control (QC) for LA tests. 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 + 20 standard deviations (SD) (975th centile for normally distributed data) as a cut-off, but the recent
9

Preparation of plasma samples

Blood should be collected into 0109 mol/l trisodium citrate. Platelet contamination should be avoided by double centrifugation at 2000 g for 15 min at 1522C. This should yield plasma with a platelet count of <10 9 10 Plasma filtration through 02 lm filters is not recommended as this may generate microparticles (Favaloro, 2007). Ultracentrifugation (>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. /l.

International Society on Thrombosis and Haemostasis consensus document (Pengo et al, 2009) has recommended the 99th centile (mean + 23 SD for normally distributed data), which would improve specificity but reduce sensitivity. Most UK laboratories use the 975th 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,

Lupus anticoagulant testing

Classical findings for a LA are: 1 Prolongation of a phospholipid-dependent clotting test. 2 Demonstration of the presence of an inhibitor by mixing tests. 3 Demonstration of the phospholipid dependence of the inhibitor. 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. 50

2008) have been recommended. If previously established cutoff values (manufacturers value or different analyser) are available they may be validated in smaller numbers (2060) 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) 9 100 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 asLA-positive orLA-negative shouldbegiven. 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,
2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 4758

Guideline 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 in uence the sensitivity. Laboratories should also participate in an external quality assurance programme. 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.

Recommendation
The DRVVT and one other test should be employed for LA detection (2C), and the patient regarded as having a LA if either test is positive. A confirmatory step (e.g. using a high phospholipid concentration, platelet neutralizing reagent or LA-insensitive reagent) is needed to demonstrate phospholipid dependence (1A).

Solid phase aPL assays

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

LA detection in patients receiving anticoagulants. 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-b assays, these are sufficient for the diagnosis of APS. Assessment of clotting factor levels in the presence of LA. Factor assays may yield misleading results, particularly those for
2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 4758
2

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-b 2 GPI assays have greater specificity than aCL, but are poorly standardized. The purity and oxidation status of the antigenandmicrotitre plate type are criticaltoensurethattheclinically relevant anti-b 2 GPI 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 1of anti-b more evidenceisrequired. A calibration curve and IQC should be employed in every assay run for both aCL and anti-b
2 2

GPI,and may

offer bettersensitivity and specificityfor clinical events, although

GPI assays. IQC may be

performed using suitable normal or APS patient samples (local or commercial), or humanized monoclonal antibody preparations.

Which tests should be done?

LA is the most predictive test for thrombosis and the presence of IgG aCL or IgG anti-b
2

GPI 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. GPI

Recommendation
When testing for aPL is indicated, testing for LA and for IgG antibodies to b
2

GPI should be performed. The latter

can be detected either by an IgG aCL ELISA or an IgG 51

Guideline anti-b 2 GPI ELISA (2C). An aCL ELISA may detect antibodies to other phosphoilipid binding proteins as well as anti-b
2

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).

GPI.

In patients with thrombosis, measuring IgM antibodies does not add useful information (2B). In patients with pregnancy morbidity, the role of IgM antibodies is unclear (2C). Testing for IgA antibodies is not recommended (1B). When assessing clinical significance account should be taken of whether the patient has LA, aCL/anti-b2GPI, or both and of the isotype and titre in thesolidphasetests(1B).

Who should be tested for aPL and how should this affect management of patients Incidental finding of aPL
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 09% of unaffected controls (and 31% of cases) and anti-b
2

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.

GPI in 34% of controls (and

75% 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 (65%) 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 097%) (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 020%) (Giron-Gonzalez et al, 2004). However, a recent publication identified 104 subjects that were triple positive for LA, aCL and anti-b
2

Recommendation
We recommend testing for aPL in patients with unprovoked proximal DVT or PE after stopping anticoagulation (for at least 7 d) as the presence of aPL will in uence the balance of risks and benefits and support long-term anticoagulant therapy (2B).

GPI, and follow-

up for a mean of 45 years identified 25 first thromboembolic events (53% 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 275 per 100 patient-years for aspirin-treated subjects and 0 per 100 patient-years for the placebo-treated subjects (P = 083) (Erkan et al, 2007).

Which patients with ischaemic stroke should be tested for aPL and how should the result affect management?
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 doubleblind trial comparing warfarin (INR 1428) 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 099 (075131) and 094 (070128) 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
2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 4758

Recommendation
We recommend that primary thromboprophylaxis should not be used in those incidentally found to have aPL (2B).

Which patients with venous thrombosis should be tested for aPL and how should the result affect management?
Warfarin therapy carries a substantial risk of bleeding. Although the risk is greatest in the first weeks, it persists for 52

Guideline 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 I). The cohort studies previously referred to suggest that young patients (<50 years) with ischaemic stroke and APS may be at high risk of recurrence (patients who are triple positive for LA, aCL and anti-b
2

Anticoagulation in APS
As in all subjects with thrombosis, attention should be paid to modifiable risk factors such as smoking, obesity and exogenous female hormone use. Although there is developing interest in, and some rationale for, use of alternatives to anticoagulant drugs to reduce thrombosis risk in APS, specifically statins (Ferrara et al, 2003, 2004) and hydroxychloroquine (Edwards et al, 1997; Espinola et al, 2002; Rand et al, 2008), their use remains experimental at present. Intensity of anticoagulation in APS. A retrospective study of 147 patients (54% with venous thrombosis) suggested that a target INR of 35 was preferable to a target INR of 25 (Khamashta et al, 1995). Two subsequent prospective randomized trials have challenged this. Crowther et al (2003) randomized 114 patients with aPL and thrombosis (76% venous, 24% arterial) to a target INR of 25or35 and followed them for a mean of 27 years. Recurrences were 2/58 (34%) in the low intensity group and 6/56 (107%) in the high intensity group. For venous thrombosis the rates were 1/45 (22%) and 3/42 (71%), respectively. Finazzi et al (2005) randomized 109 patients with aPL and thrombosis (60% venous only, 31% arterial only, 9% both) to a target INR of 23or345 and followed them for a median of 36 years. Recurrences were 3/52 (58%) in the low intensity group and 6/54 (111%) in the high intensity group.

GPI have the highest

risk), and that anticoagulation with warfarin should be considered, but there is no strong evidence that it is more effective than aspirin. A small retrospective study followed eight patients with APS treated with aspirin for a median of 9 years after an ischaemic stroke: there were two recurrences in a total of 58 patient years on aspirin to give a recurrence rate of 35% per year, similar to the general stroke population (Derksen et al, 2003). In a further small study, 20 ischaemic stroke patients with aPL were randomized to either aspirin alone (n = 11) or aspirin plus warfarin (target INR 2 3) (Okuma et al, 2010). The cumulative incidence of stroke in patients with antiplatelet treatment only was statistically significantly higher than that in patients receiving the combination of antiplatelet and anticoagulation therapy. The authors suggested a larger study with more patients would be warranted. In the general stroke population, aspirin plus dipyridamole, or clopidogrel alone, are superior to aspirin alone.

Recommendations
Routine screening for aPL in patients with ischaemic stroke is not warranted (1B). Young adults (<50 years) with ischaemic stroke should be screened for aPL (2C). For unselected stroke patients with a single positive aPL test result, antiplatelet therapy and warfarin are equally effective for preventing recurrent stroke (1B) and antiplatelet therapy is preferred on grounds of convenience. Young adults (<50 years) with ischaemic stroke and APS may be at high risk of recurrence and cohort studies suggest that anticoagulation with warfarin should be considered, but there is no strong evidence that it is better than antiplatelet therapy (2C).

Recommendation
The target INR for VKA therapy in APS should normally be 25 (target range 2030) (1A).

Monitoring oral anticoagulants in patients with a lupus anticoagulant

The majority of 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

Catastrophic APS
CAPS is an acute onset, life-threatening cause of multi-organ failure (Cervera et al, 2009). It is a rare condition that may complicate established APS or present de novo. There are no data from randomized trials to inform treatment, which is based upon the thrombotic features and autoimmune background. Combinations of treatments are typically used including anticoagulation with heparin/warfarin. Immunomodulatory therapies including plasmaphaeresis, intravenous human IgG, corticosteroids and rituximab have been employed.

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 43% of cases using Innovin, n = 400), which causes difficulty in establishing the true degree of anticoagula-

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Guideline tion; amidolytic factor X (FX) assays may be helpful (Tripodi et al, 2001; Moore et al, 2003). A therapeutic range of approximately 2040% FX corresponds to a therapeutic INR in LA-negative patients (Rosborough et al, 2010). diagnosis of APS, the data supporting the associations have been con icting 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

Recommendations
A baseline PT should be performed; if this is prolonged, an alternative PT reagent for which the baseline is normal should be used (1C). If there are problems identifying a suitable PT system for VKA control, the use of an amidolytic FX assay could be considered (2C).

Which patients with obstetric complications should be tested for aPL and how should the result affect management?
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 54

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).

Recommendations
Women with recurrent pregnancy loss ( 3 pregnancy losses) before 10 weeks gestation should be screened for aPL (1B). For women with APS with recurrent ( 3) pregnancy loss, antenatal administration of heparin combined with low dose aspirin is recommended throughout pregnancy (1B). In general, treatment should begin as soon as pregnancy is confirmed. For women with APS and a history of pre-eclampsia or FGR, low dose aspirin is recommended. Women with aPL should be considered for post-partum thromboprophylaxis (1B).

Disclaimer
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.

Acknowledgements and declarations of interest

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 con ict 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.

2012 Blackwell Publishing Ltd British Journal of Haematology, 2012, 157, 4758

Guideline

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p re gn an c y: a ran d o mi z e d , c o n tro l l ed tr i al of tr e atm en t . O bste tri c s a nd G y n ec ol og y , 10 0, 40 8 41 3. F aval or o, E. J. (20 07) Pr e an al yti c al var i abl e s i n c o agu lat io n t es ti n g. B l ood Co ag ul a ti on an d Fi b ri n oly s i s, 18 , 86 89 . F er r ara, D. E . , Li u , X . , Es p i no l a, R. G ., Me ro n i , P .L . , A bu kh al af, I ., Harr i s, E .N. & P i e ra nge l i , S .S . ( 200 3) I nh i b it i on of th e t hr o mb og e ni c an d i n amm ato r y p ro p er ti e s o f an ti p ho sp h ol i p i d an ti bo d i e s by u vast ati n i n an i n vi vo an i m al m od e l . Ar thr it is an d R he u mati s m, 48 , 327 2 32 79. F er r ara, D. E ., Sw e r li c k, R ., C asp e r, K ., Me r on i , P . L ., V e ga- Oste r tag, M. E . , H arr i s, E . N. & P i er an ge l i , S. S. (2 004 ) F lu vas tati n in h i bi ts up - re gu l ati o n o f ti s su e fac to r e xp r es si o n by an ti p ho sp h o li p i d an ti b od i e s o n e n do th e l ia l c e ll s . Jou rn al of T hr ombo si s an d Hae mo stasi s , 2, 155 8 15 63. F in az z i , G . , Ma rc h i ol i , R ., Bran c ac c i o, V. , Sc h in c o , P . , W i sl o ff, F. , Mu si al , J. , Bau do , F. , Be rr e tti n i , M. , T es ta, S. , D An ge l o , A ., To gn on i , G . & Bar b ui , T. ( 20 05) A ran d o mi z e d c l in i c al tr i al of h i gh- i n te n si ty w ar fari n vs . c o n ve n ti on al an ti th ro m bo ti c th e rap y fo r th e p r e ve nt io n of r e c ur r en t th ro m bo si s i n pat i en ts wi th th e an ti p ho sp h o li p i d syn d ro m e ( WA P S) . Jou rn al o f Th rom bosi s an d Hae mo stasi s , 3, 84 8 853 . G al li , M. , Co m fu ri u s, P. , M aass e n, C. , H em k e r, H . C ., de Bae ts , M .H ., van Bre d a Vr i e sm an , P . J. , Bar bu i , T. , Z waa l, R. F. & Be ve r s, E .M. (1 990 ) A nti c ar d io l i pi n an ti b od i e s (A CA ) d ir e c te d n ot to c ard i o li p i n bu t to a pl as ma pr o te i n co fac to r [ se e c o m me n ts ]. L an ce t, 3 35, 154 41 547 . G al li , M ., L u c i an i, D., B er to l in i , G . & Barb u i, T. ( 200 3a) An ti - be ta 2- gl yc o pr o te i n I, an ti p ro th ro m bi n ant i bo di e s , an d th e r i sk o f thr o mb o si s i n t he an ti p ho sp h o li p i d s yn dr om e . B loo d, 102 , 27 17 27 23. G al li , M ., L u c i an i, D., B er to l in i , G . & Barb u i, T. ( 200 3b ) L up u s an ti c oagu l an ts ar e s tro n ge r r i sk fac to rs for t hr o mb o si s th an ant ic ar d i ol i p in an ti b od i e s i n th e ant i ph o sp h ol i pi d syn d ro m e : a sys te m ati c r e vi e w o f th e l i te ra tu re . B l ood , 101 , 18 27 183 2. G al li , M. , Bo rr e l li , G . , Jac ob se n , E . M., M arfi s i, R . M. , Fi n az z i , G ., Mar c h i ol i , R. , Wi s lo ff, F ., M arz i al i , S . , M or bo e u f, O . & Ba rb ui , T. ( 200 7) Cl i n i c al si g ni fi c an c e of d i ffe r en t anti p h os p ho l i pi d an ti b od i e s i n th e W AP S ( w arfar i n i n t he an ti ph o sp h ol i p i d s yn dr o me ) stu d y. B loo d, 11 0, 117 8 118 3. G ard i n e r, C. , Mac k i e , I. J. , Mal i a, R .G . , J on e s, D. W ., Wi n te r , M ., Le e m i n g, D ., Tab er n e r, D. A. , Mac h i n , S .J . & G re ave s , M . (20 00 ) T he i m p or tan c e o f lo c al ly d e ri ve d r e fe re n c e r an ge s an d st and ar di z e d c alc u l ati o n o f di l u te Ru ss e ll s vi p e r ve n om ti m e r es u lt s i n sc r e e ni n g fo r l u p us an ti c o agu lan t. B ri ti sh J our n al of Ha em atol og y , 1 11 , 12 30 12 35. G i an nak op o u lo s , B. & K ri l i s, S .A . ( 20 09) Ho w I tr e at th e a nti p h os p ho l ip i d syn d ro m e . B l ood , 11 4, 202020 30. G i an nak op o u lo s , B. , P ass am, F . , R ahg oz ar , S . & K ri l i s, S. A. ( 20 07) C ur re n t c o n c e pts o n th e p atho ge n e si s of t he an ti p h os ph o li p i d syn d ro m e . B l ood, 1 09 , 422 43 0. G i ann ak op o ul o s, B. , P as sam , F. , I oan n ou , Y. & Kr i l is , S .A . ( 200 9) H ow w e d i agn os e t he an ti p ho sp h ol i p i d syn d ro m e . B lo od, 1 13, 9 85 99 4. G i ns be r g, J. S. , Bri l l -E d war d s, P . , J oh n sto n , M. , De n bu r g, J .A ., An d re w , M., Bu rr ow s , R .F ., Be n se n , W . , Ci vi d i n o, A. & L on g, A . A. ( 19 92) Re l ati o ns hi p o f an ti ph o sp h ol i p i d an ti b od i e s t o p re gn an c y l o ss i n pat ie n ts w i th s ys te mi c l up u s e ryt he m ato su s : a c r os s- se c ti o na l s tu dy . B l ood , 80 , 975 9 80. G i ns bu r g, K . S. , L i an g, M .H ., Ne w c om e r, L ., G ol d h abe r , S. Z. , Sc h u r, P . H. , He n n e ke n s, C. H. & Stam p fe r, M. J. ( 199 2) A n ti c ard i ol i p i n an ti b od i e s an d th e ri s k for i s ch e m i c st ro ke and v e no u s th ro m bo si s [ se e c om m e nt s] . An n al s of I nte rn al Me di c in e , 11 7, 99 7 100 2. G i rar di , G . , Re d e c ha, P . & Sal mo n , J. E . (2 004 ) He p ari n p re ve n ts an t ip h os p ho l i pi d an ti bo d yi nd u c e d fe tal lo s s b y i n hi b i ti n g c om p l e me n t ac ti vati o n . Natu re Me d ic i ne , 1 0, 12 22 12 26. G i ro n -G o nz al e z , J. A. , Gar c i a d e l Ri o, E . , Ro dr i gu e z , C. , Ro dr i gu e z -Mar to re l l , J. & S e rr ano , A . (2 004 ) An ti p ho sp h o li p i d syn d ro m e an d asym p to mat ic c arr i e rs o f an ti ph o sp h ol i p i d ant ib o dy : p ro sp e c ti ve a nal ys i s of 40 4 i nd i vi d ual s . Jou rn al of Rh e um atol og y , 31 , 15 60 156 7. G re ave s , M., C oh e n , H ., Mac H i n, S . & Mac k i e , I . (2 000 ) G ui d e l in e s o n th e i n ve sti gat i on an d m an age m e nt of t he an ti p ho s ph o li p i d syn d ro m e . B ri ti sh J our na l Hae m atol og y , 10 9, 7 04 715 . G re e r , I. A. & Ne l so n- P i e rc y, C . ( 200 5) L ow - mo l e c u lar -w e i gh t h e par i n s fo r th r om b op r op h yla xi s an d tr e atm e nt o f ve n ou s th r om b oe m bo l i sm in p re gn an c y: a s yste m ati c re vi e w o f saf et y an d e ffi c ac y. B l ood, 1 06 , 401 40 7. He i n z le f, O. , We i l l , B. , Jo h an et , C ., Saz do vi tc h , V . , Cai l l at- Zu c man , S. , To ur n i e r- Las se r ve , E . & Ro u ll e t, E . ( 200 2) An ti c ar di o l i pi n an ti b od i e s in p ati e nts wi th m ul ti p l e s c le r os i s d o n ot r e pr e se n t a s u bg ro up of p ati e n ts ac c or d i ng to c li n i c al , fam i li al , an d b i o lo gi c al c h ar ac te ri s ti cs . J our na l of Ne ur ol og y , Ne ur osu rg e ry an d Ps y ch i atr y , 72 , 647 64 9. Ho ro w i tz , G. L ., A l tai e , S ., Bo yd , J. C. , Ce r i ott i, F . , G arg, U., Ho rn , P . , P e s ce , A. , Si n e , H .E . & Zako w sk i , J. ( 200 8) De fi n i n g, E stab l i sh i ng , an d Ve r i fyi n g R efe r e n c e In te r val s i n t he C l i ni c al L ab or ato ry : A p pr ov e d G u i d el i n e T hi r d Ed i ti o n . CL SI d o cu m e n t C 28 -A 3c . C li n i c al an d L abo r ato ry Stan d ard s In st i tut e , Wayn e , P A, U SA. Hu gh e s, G . R. ( 200 3) Mi gr ai n e , m e m or y l o ss , an d m ul ti p l e s c le r os i s. Ne u ro lo gi c al fe atu re s o f t he an ti ph o sp h ol i p i d (H u gh es ) sy nd r om e . P ostg r ad ua te Me di c al Jou r na l, 7 9, 818 3. Hu gh e s, G .R . & K h am ash ta, M .A . ( 200 3) S e ro n eg ati ve an ti p h os p ho l ip i d s yn dr om e . A nn al s of th e Rh eu ma ti c Di s ea se s, 62 , 112 7. Ic h i kaw a, K. , Tsu ts um i , A. , Ats u mi , T. , M atsu u ra , E ., Ko b ayash i , S. , Hu gh e s , G . R. , K ha mas h ta, M . A. & K oi ke , T. ( 199 9) A c h i me r i c an ti b od y wi t h th e hu m an gam m a1 c o ns tan t r e gi on as a p ut ati ve sta nd ar d fo r as says to d e te c t IgG b et a2- gl yc op r ote i n I -d e p en d e n t an ti c ard i o li p i n an d an ti be ta2 -gl yc o p ro te i n I an ti b od i e s. A rth ri ti s an d Rhe u mat i sm, 4 2, 24 61 24 70. Io ri o , A ., Ke ar on , C. , F i l ip p u c c i, E ., Mar c uc c i , M., Mac u ra, A . , P e ngo , V . , Si r agu sa, S . & P al are t i, G . (2 010 ) Ri sk o f r e c u rr e nc e afte r a fi r st e pi s od e of sym p tom ati c ve no u s thr o mb o e mb ol i s m pr ovok e d by a tran s ie n t r i sk fac to r: a s yste m ati c re vi e w . Ar ch i ve s o f In te rn al Med i ci n e, 17 0, 1 710 171 6. Jo uh i kai n e n , T. (19 90 ) De te c ti o n of lu p u s an ti c oagu lan t by me an s o f d il u te R us se l l s v ip e r ve n om ti me i s affe c te d by o ra l an ti c o agu lan t th e r apy. B lo od C oag u l ati on a nd F ib ri n ol y si s, 1, 627 63 2. Ke ar on , C. , Kah n , S. R. , Agn e l l i, G . , G o ld h abe r , S ., Ras ko b, G . E . & Co m er o ta, A .J . ( 200 8) A nt i th ro mb o ti c the r ap y for ve n ou s th ro mb o e mb ol i c di s e ase : Am e r ic an C ol l e ge o f Ch e s t P hy si c i an s E vi de n c e -Ba se d C l in i c al P rac ti c e Gu i d e li n e s ( 8th E di ti o n ). C he st, 1 33 , 454 S5 45S . Kh am ash ta, M. A ., C u adr ad o, M. J. , Mu j i c , F. , Tau b, N.A . , Hu nt , B .J . & H u ghe s , G .R . ( 19 95) Th e man age m e n t o f thr o mb o si s i n th e an ti p h os ph o l i pi d -an ti b od y syn d ro m e [s e e c om m e n ts] . New En g l an d Jou rn al of M ed i ci n e, 3 32 , 993 9 97. Kr n ic - Bar ri e , S. , O C on n or , C .R ., L o on e y, S. W ., P ie r an ge l i , S. S. & Har ri s , E .N. (19 97 ) A re tr osp e c ti ve re vi e w o f 61 p ati e n ts w i th an ti p h os p ho l i pi d syn d ro m e . A nal ys i s of fac to r s i n u e n c in g re c u rr e n t th r om bo s is . Ar ch i ve s of In ter na l Me di c i ne , 15 7, 2 101 21 08. Ku tte h , W . H. & E rm e l , L .D. (1 996 ) A c l i ni c al tri al for th e t re atm e n t of an ti p h os ph o li p i d ant ib o dyass oc i ate d re c u rr e n t pr e gn anc y l o ss w i th l o w er do se h e p ari n and asp i r in . Am er i ca n Jou r nal of Re prod u cti ve I mmu n ol og y , 35 , 402 40 7. Las ki n , C .A . , Bom b ard i e r, C. , Han n ah , M. E ., M an de l , F. P . , R i tc hi e , J. W ., F are w e ll , V ., F ari n e , D., Sp i tz er , K ., F i e ld i n g, L ., S ol o ni n ka , C. A. & Y eun g, M. ( 19 97) P re d n i so ne an d as p ir i n i n wo m e n wi th au to an ti bo d ie s an d un e xp l ai ne d re c u rr e n t fe tal l os s. Ne w E n g la nd Jou rn al of Med i ci n e , 337 , 14 81 53. Las ki n , C. A. , Sp i tz e r, K .A ., C l ark , C . A. , Cr ow th e r, M. R. , G i n sb e rg, J. S. , H awk e r, G .A . , K i ngd o m , J. C. , Bar re tt , J. & G e nt , M. ( 200 9) L o w m ol e c u la r we i gh t he p ar i n an d asp i r in for re c u rr e nt p re g nan c y l os s: re s u lts fro m t he ra nd o mi z e d , c o n tro l le d H e pA SA Tr i al . Jou rn al of Rhe u mato log y , 36 , 2 79 28 7. Law r i e, A. S. , Mac k ie , I. J. , P ur d y, G . & M ac hi n , S. J. (1 999 ) Th e s e ns i ti vi ty an d sp e c i fic i ty of c o mme r c i al r e age nt s fo r th e d e te c ti o n o f l u p us ant i c oagu l an t s h ow m ar ke d d i ffer e n c e s i n pe r for m an c e b e tw e en p h oto -o p ti c al and me c h an i c al c oa gu lo m e te rs . Th rom bosi s an d Ha e most asi s, 8 1, 7 58 762 . Le vi n e , S. R. , Br e y, R .L . , Ti l l e y, B. C ., Th om p so n , J. L. , S ac c o, R. L. , S ci ac c a, R. R. , Mu r ph y, A . , L u, Y., Co sti g an, T .M ., R hi n e , C ., Le vi n , B. , Tr i pl e tt, D.A . & Mo h r, J .P . ( 20 04) A nt i ph o sp ho l i pi d ant i bo di e s an d s ub se q u e nt th ro m bo - oc c l u si ve e ve nt s in pat ie n ts w i th i sc h e m i c st ro ke . JA MA, 291 , 5765 84. Li e s tol , S ., Jac o b se n , E .M. & Wi s lo ff, F . ( 20 02) Di lu te p ro th r om bi n ti m e -b ase d l u pu s r ati o te st.

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In te g rate d L A t es ti n g w i th re c o mb i n an t ti ss u e th r om bo p l asti n . Th rom bosi s Res ea rc h, 10 5, 17 7 1 82. L i m , W. , C ro wt he r , M. A. & E i ke l bo om , J .W . ( 200 6) Man age m e n t o f an ti p h os ph o l ip i d an ti b od y syn d ro m e: a sys te m ati c r e vi e w. J AMA , 295 , 1 050 10 57. Mal e , C ., L e c h ne r , K. , Sp e i se r , W . & P abi n ge r , I. ( 200 0) Tr ans i e nt lu p u s an ti c o agu la nt s i n c hi l d re n : s te p wi s e d i sap p e aran c e o f di ag no st i c fe atu r e s. Th rom bosi s an d Hae m ostas is , 83 , 174 17 5. Mal i a, R .G . , K i tc he n , S ., G re ave s , M. & P re s ton , F . E . (1 990 ) I nh i b it i on o f ac ti vate d pr o te i n C an d i ts c ofac t or pr o te i n S by ant i ph o sp h ol i pi d an ti b od i e s [s e e c om m e n ts] . B ri ti s h J our na l Ha em atol og y , 7 6, 10 1 107 . Mc Ne i l , H. P . , S i mp s on , R. J. , Ch e st er m an , C . N. & K ri l i s, S. A. (1 990 ) A nt i- p ho s ph o li p i d an ti b od i e s ar e d i re c te d agai n st a c om p le x an ti ge n th at i n c lu d e s a l i p id - bi n d in g i n h i bi to r o f co agu l ati o n: be ta 2- gl yc o pr o te i n I ( apo l i po p ro te i n H) . P roc ee d in g s of t he Nati on al A ca de my o f Sci e n ce s of t he Un it ed Sta tes of Am e ri ca , 8 7, 41 20 412 4. Mi yak i s, S. , L oc k sh i n, M. D., Ats u mi , T. , Bran c h , D. W ., Bre y, R. L. , C e rv e ra, R. , De r kse n , R . H. , d e G r oo t, P .G . , K o i ke , T., Me r on i , P .L . , R e be r , G . , S ho e n fel d , Y. , T i nc an i , A. , V lac h o yi ann o p ou l os , P . G . & K ri l i s, S. A. ( 200 6) In te rn ati o n al co n se n s us stat e me n t o n an u p dat e o f th e c las si fi c ati o n c r it e ri a for de fi n i te ant ip h os p ho l i pi d syn d ro m e ( AP S ). Jou rn al of T hr ombos i s an d Ha em ostas i s, 4 , 295 30 6. Mo n tal ban , J., Ce r ve ra, R. , F on t, J ., Or di , J ., Vi an n a, J. , H aga, H .J ., T in to r e , M. , Kh am ash ta, M .A . & H ug he s , G .R . ( 19 92) L ac k of ass oc i ati o n b e tw ee n an ti c ard i o li p i n an ti b od i e s an d mi gr ai n e i n sys te m i c lu p u s e r yth em at os us . Neu ro log y , 42 , 6 81 682 . Mo o re , G . W. & Savi d ge , G .F . ( 200 4) He te r o ge ne i ty o f R us se l l s vi pe r ve n o m affe c ts th e s e n si ti vi ty o f th e d i l u te Ru s se l l s vi p e r ve n om ti me to l u pu s an ti c o agu lan ts . B l ood Coa g ul at io n an d F i br i nol y si s , 15, 2 79 28 2. Mo o re , G .W . & S avi dg e, G . F. (2 006 ) Th e d i lu ti o n e ffe c t o f e q u al vo lu m e m i xi n g s tu di e s c om p ro m i se s c on fi rm ati o n of in h i bi ti o n by lu p u s an ti c o agu lan t s e ve n w h e n m i xtu r e sp e c ifi c r e fe re n c e r an ge s are app l i e d. Thr omb osi s Re se arc h, 118 , 52 3 528 . Mo o re , G .W . , Sm i th , M .P . & Savi d ge , G . F. ( 200 3) Th e E c ari n ti m e i s an i m p ro ve d co n fi rm ato ry te s t fo r th e Tai p an sn ake ve n om ti m e i n w ar fari n i z e d pa ti en ts w i th l u p us an ti c o agu la nt s. B l ood C oag u la ti on an d Fi br i no ly s is , 14 , 30731 2. Mo o re , G . W. , Ran gar aj an , S. , Ho ll an d , L. J. , He n l e y, A . & Savi d ge , G . F. (2 005 ) L ow fre q u en c y o f e l e vate d p ro th ro m bi n ti m e s i n p ati e nt s w i th l u pu s ant i co agu l an ts w h e n u s i ng a re c o mb i n ant th r om bo p l asti n r e age n t: im p l i cat i on s for d os i ng an d mo n i tor i n g o f or al an ti c o agu l an t th er ap y. B r i tis h J our n al of B i ome d ic al S ci e nc e , 6 2, 151 8; q ui z 47. Nae s s, I. A. , Ch ri s ti an se n , S .C . , C an ne g ie t er , S. C. , R os e nd aal , F .R . & Ham m e rs tro e m , J. ( 200 6) A p ro sp e c ti ve s tu dy of a nti c ar d io l i pi n an ti b od i e s as a ri s k fac to r fo r ve n ou s t hr om b os i s i n a ge n e ral p op u l ati on ( th e H UNT st ud y) . J our na l of Th rom bosi s an d Hae mo stasi s , 4, 444 9. Ne l so n , S. M. & G r e e r, I.A . ( 20 08) Th e p o te nt i al r ol e o f he p ari n i n ass i ste d co n c e pt io n . Hu ma n Re pr odu c ti on Upd ate , 14, 6 23 64 5. No bl e , L . S. , Ku tt e h, W . H. , L ash e y, N. , F ran k li n , R . D. & He rr ad a, J . ( 20 05) A nti p h os p ho l i pi d an ti b od i e s as so c iat e d w i th re c u rr e nt pr e gn anc y l o ss : p ro sp e c ti ve , mu l ti c e nt e r, co n tr ol l e d p i lo t s tu dy c o mp ar i ng tr e atm e nt w i th lo w -m ol e c u l ar- w ei gh t h e par i n v er su s un fr ac ti on ate d h ep ar i n. F er ti li ty an d Ste ri l i ty , 83 , 68 46 90. Oge r , E ., Le r ny er , C ., Du e ym e s, M., L e M oi gn e , E . , Br es so l e tte , L ., E s c offr e , M. , Yo ui n o u , P . & Mo tti e r, D. (1 997 ) A ss oc i ati o n b e tw e e n I gM an ti c ard i o li p i n an ti bo d i e s an d d e e p ve n ou s th ro m bo si s i n p ati e n ts w i th ou t s yst em i c l up u s e ry the m ato su s . Lu pu s, 6 , 455 4 61. Ok u, K . , A ts um i , T. , Boh gak i , M ., A me n gu al , O. , K ataok a, H. , H or i ta, T ., Yas ud a, S. & K o i ke , T. ( 200 9) C om p le m e n t ac ti vat i on i n p ati e n ts w it h p ri m ary ant ip h o sp ho l i pi d syn d r om e . A nn al s of th e Rhe u mati c D i se as es , 68 , 1 03 01 035 . Ok um a, H. , Ki t agaw a, Y. , Yas ud a, T., To ku ok a, K . & Takag i , S . ( 201 0) Co m par i so n be tw e e n s i n gle an ti p lat el e t the r ap y an d c om b i nat i on o f an ti p l ate l e t a nd an ti c oagu l ati o n t he r apy fo r s e c on d ary p re ve n ti o n i n i sc h e m i c str o ke p ati e n ts w i th an ti p ho sp h o li p i d syn d ro me . In te rn ati on al Jo ur na l of Me di c al Sc i e nc es , 7, 151 8. Ol te an u , H ., Dow n e s, K. A. , P at el , J. , P r apr ot ni k , D. & S aro d e , R. ( 20 09) W ar fari n d o e s no t in te r fe re w it h l up u s an ti c oagu l an t d e te c ti o n b y d i l ute Ru s se l l s vi p e r ve n o m ti m e . Cl i n i cal la bor ator y , 55 , 13 81 42. Op atr ny , L ., Davi d , M. , K ah n , S. R. , S h ri e r, I. & Re y, E . (2 006 ) A sso c i ati o n b e twe e n an ti ph o sp h ol i p i d an ti bo di e s an d r e cu r re n t fe tal l os s i n w om e n w it ho u t au to i mm u n e di s e ase : a m e taan al ysi s . J our n al of Rh eu m atol og y , 33 , 221 4 22 21. P ar mar , K ., L e fko u , E ., Dou gh ty, H ., C o nn o r, P. & Hu n t, B.J . ( 200 9) T he u ti l i ty of th e Tai p an sn ak e ve n o m as say i n as se ss i ng l u p us an ti c o agu l an t s tatu s i n i nd i vi d u als r e c e iv in g o r no t r e c e i vi n g an o r al vi ta mi n K an tago n i st. B l ood Co ag ul a ti on an d Fi br i nol y si s , 20, 271 27 5. P atti s on , N .S ., C h aml e y, L . W. , Bi r ds al l, M. , Zan d e ri go , A. M. , L i d de l l , H .S . & M cD ou gal l , J . ( 200 0) Do e s as pi r i n h ave a ro l e i n i mp r ov in g p re gn an c y ou tc o m e fo r w o m en w i th t he an ti p ho sp h o li p i d syn d ro m e ? A r an do m i z ed co n tr ol l e d tr ial . A me ri c an Jou rn al of Obst etr i cs an d G y ne c olo gy , 1 83 , 100 8 101 2. P e n go, V ., Tr i po d i , A ., Re b e r, G ., Ran d , J .H ., Or te l , T. L. , G al li , M. & De Gr o ot , P . G . (2 009 ) Up da te o f t he gu id e l i n es fo r l u pu s an ti c o agu lan t d e te c ti on . Su bc o m mi tt e e o n Lu p u s An ti c o agu l an t/An t ip h os p ho l i pi d An ti b od y of th e Sc i e n ti fic an d Stan d ard i s ati on C o mm i tte e o f th e I nt er n ati o nal S oc i e ty o n Th ro m bo si s an d H ae m os tasi s . Jou rn al of T hr ombo si s an d Hae mo stasi s , 7, 173 7 17 40. P e ng o, V ., Ru ffatt i, A ., L e gn ani , C ., G re s e le , P . , Barc e l l on a, D ., E r ba, N., Te sta , S. , Mar on gi u , F . , Bi so n , E . , De n as, G ., Ban zat o, A. , P ad ayatt il Jo se , S . & Il i ce t o, S. ( 201 0) C l i ni c al c ou r se of h ig h- ri s k pa ti en ts di agn o se d w i th ant ip h o sp ho l i p id syn d ro m e. Jour n al of Thr omb osi s and H ae mos tasi s, 8, 23 72 42 . P e ng o, V. , Ru ffat ti , A. , L e gn an i , C. , T e sta, S. , Fi e r ro , T. , Ma ro ng i u, F. , De M i ch e l i , V ., G r e se l e , P . , To ne l l o, M., Gh i r ard u z zi , A . , Bi so n, E ., De n as , G ., Ban z ato , A. , Pa dayat ti l Jo se , S. & Il i c e to, S . (2 011 ) In c i de n c e of a fi r st th ro m bo e mb o li c e ve n t i n as ym pt om ati c ca rr ie r s o f h i gh r is k an ti p ho sp h ol i p i d an ti bo d y p r ofi l e : a mu l ti c e n te r p ro sp e c ti ve s tu dy. Bl ood , 11 8, 4 714 47 18. P e rr y, D. J. , F i tz m aur i c e , D. A. , K i tc h e n, S. , Mac k i e , I. J. & M all e tt, S. ( 201 0) Po i n t-o f- c are te s ti ng in h aem o sta si s. B ri ti sh Jou rn al of Ha em atol og y , 1 50 , 501 5 14. P i e ran ge l i , S. S. & H arr i s, E. N. ( 20 08) A p ro to c ol for d et e rm i n ati on o f ant ic ar d i ol i p in an ti b od i e s by E LI SA . Natu re P r otoco ls , 3, 84 0 848 . Rai , R .S ., C l i ffor d , K. , C oh e n , H. & R e gan , L . (1 995 ) Hi gh p ro sp e c ti ve fe tal l o ss rate in u nt re ate d p re gn an c i e s o f wo m e n wi th r e cu r re n t m is c arr i age an d an ti ph o sp h ol i p i d a nti b o di e s . Hu man R ep rod uc ti on , 10 , 330 13 30 4. Rai , R. , Co h e n, H ., Dave , M. & Re ga n, L . (1 997 ) Ran d om i se d c on tr ol l e d tr i al o f as p i ri n an d asp i ri n pl u s he p ar i n i n p re gn an t wo m e n w i th r ec u r re n t m is c arr i age ass oc i ate d wi th ph o sp h ol i p id an ti bo d ie s (o r ant ip h os p ho l i pi d an ti bo d i es ). B MJ, 3 14, 2 53 25 7. Ran d , J. H. , W u , X. X. , An d re e , H. A ., Ro s s, J. B. , Ru si n o va, E . , G as c on - Le m a, M. G . , Cal an d ri , C . & Har pe l , P . C. ( 199 8) An ti p ho s ph o li p i d an ti bo d i es ac c e le r ate p las m a c o agu l ati o n b y i nh i b it i ng ann e xi n - V b i nd i n g to ph o sp h ol i pi d s : a l up u s p r oc o agu l an t p he n o me n o n . B l ood , 92 , 165 2 166 0. Ran d , J. H. , Wu , X. X. , Qu i n n, A . S. , Ch e n, P . P . , Hath c o c k, J. J. & Taatj e s , D.J . (2 00 8) Hyd r ox yc hl o ro q ui n e d i re c tl y re d u c es th e b i n di n g of an ti p ho sp h ol i p i d an ti b od y- be t a2- gly co p ro te i n I c om p l ex e s to p h os ph o l ip i d bi l aye r s. B l ood , 1 12 , 168 7 169 5. Re b e r, G ., Bo e hl e n , F. & d e Moe r l oo se , P . (2 008 ) Te c h ni c al as pe c ts i n lab o rato r y te sti n g f or an ti p ho sp h ol i p i d ant i bo di e s : i s s tan d ard i z ati on an i mp o ss i bl e d r ea m? S em i na rs i n Thr omb osi s an d He mos tasi s, 3 4, 3 40 34 6. Ro be r tso n , B. & G r e ave s, M. ( 200 6) An ti p h os p ho l i pi d syn d ro me : an e vo lv i ng s tor y. B l ood Re vi e ws , 20 , 201 2 12. Ro be r tso n , L ., Wu , O. , L an gh or n e, P ., T wad d l e, S. , Cl ar k, P . , L ow e , G . D., W al ke r , I. D., Gr e ave s , M. , Bre n k el , I. , Re gan , L . & Gr e e r, I .A . (2 006 ) Th ro m bo p hi l i a i n p re gn an c y: a s yst em ati c re vi e w . B r i ti sh J our na l H ae mat olo gy , 13 2, 171 196 . Ro sb or o u gh, T. K ., Jac o bs e n , J .M . & Sh e p he r d , M . F. ( 20 10) F ac to r X an d fac tor I I ac t iv it y l e ve l s d o n o t alw ays agr e e i n w arfar i n -tr e ate d l up u s an ti c oagu l an t pa ti e nt s. B l ood Coa g ul ati on an d Fi b ri n oly s i s, 21 , 242 2 44.

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Guideline
Ro so ve , M .H . & Bre w e r, P . M. ( 19 92) A n ti ph o sp h ol i p i d th ro m bo si s : c l i ni c al c ou r se afte r th e fi r st th ro m bo ti c e v en t i n 70 p ati e n ts. An na ls of In ter n al Me di c i ne , 11 7, 3 03 308 . Ru i z -I ras to rz a, G ., H un t, B. J. & K ham as hta, M .A . ( 200 7) A s ys te mat ic r ev i ew o f s e c on d ary th ro m b op ro p hy lax i s i n pati e n ts wi th an ti p ho sp h ol i p i d an ti bo d i e s. Ar thr i ti s an d Rh eu ma ti sm , 5 7, 148 7 14 95. Sac r e , K . , Br i h aye , B. , Hyafi l , F . , S er faty, J. M. , Es c o ub e t, B. , Ze nn ar o, M. C. , Li d ov e , O. , L ai ss y, J . P . & P ap o, T. (2 010 ) A sym p tom ati c m yoc ar d i al i sc h e m i c di s e ase i n an ti p h os ph o li p i d syn d ro m e : a c o n tr ol l e d c ard i ac m agn e ti c r e so n anc e i mag in g st ud y. A rth ri ti s an d Rhe u mati s m, 6 2, 20 93 21 00. Sal m o n, J .E . & G i r ard i , G . (20 04 ) T he ro le of co m p le m e n t i n t he ant ip h o sp ho l i pi d s yn dr o me . C ur re n t D i r ec ti on s i n Au toi m mu ni ty , 7 , 133 1 48. Sam ar ko s, M. , Davi e s, K. A. , G o rd o n , C. & L o iz o u , S. (2 006 ) Cl i n i c al s ig ni fi c an c e o f IgA an ti c ar di o l i pi n an d an ti - be ta2 -G P 1 an ti bo d ie s i n p ati e n ts w i th s ys te mi c l u pu s e ryth e m ato su s an d p ri m ary an ti p ho sp h o li p i d s yn dr o me . Cl i n ic al Rh eu m atol og y , 25 , 19 92 04. Sc h j e tl e in , R. , S le tn e s , K .E . & W i sl o ff, F . ( 19 93) A q uan ti ta ti ve , se m i -au to ma te d and c o m pu te r as si st ed te s t for lu p u s an ti c oa gul an t. Th rom bosi s Re se ar ch , 69 , 239 25 0. Sc h u lm an , S. , Sve n u n gss on , E. & G r an qvi s t, S . ( 199 8) An ti c ar di o l ip i n an ti bo d i e s p re d i c t e ar ly r ec u r re n c e o f t hr o mb o em b ol i sm an d d eat h am on g p ati e nt s w i th v e no u s th ro mb o e mb ol i s m fo ll o wi n g an ti co agu l an t th e r apy. D ur ati o n of A nti c o agu l ati on S tu dy G r ou p . Am er i ca n Jo ur na l of Me d i ci n e, 1 04 , 332 33 8. Sh am on k i , J. M. , Sal mo n , J. E ., Hyj e k, E . & Bae r ge n , R. N. ( 200 7) E xc e ss i ve c om p l em e n t ac ti vat io n i s as so c iat e d w i th pl ac e n tal i nj u r y in p ati e n ts w i th an ti ph o sp h ol i p i d an ti bo d ie s . Am e ri ca n Jou rn al of Ob ste tri c s an d G y n ec ol og y , 1 96 , 1 67 e 16 11 65. Si m i on i , P . , S ans o n, B. , Pr an d on i , P ., To rm e n e , D. , Fr i e de r i c h, P ., G i r ol am i , B. , G avass o, S. , Hu i sm an , M. , Bu ll e r , H. , Wo u te r te n C ate , J. , G i ro l ami , A . & P r i n s, M. (1 999 ) In c i de n c e o f v e no u s th ro m bo e mb o li s m i n fam i l i e s wi th i nh e r it e d th ro m bo ph i l i a. T hr ombo si s an d Ha em osta si s, 81 , 19 82 02. Sl e tn e s, K . E ., G r ave m , K . & W i sl o ff, F. (1 992 ) P re p ara ti on of pl as ma fo r th e d e te c ti on of lu p u s an ti c oagu l an ts an d an ti ph o sp h ol i p id a nti b o di e s . Th rom bosi s Re se arc h, 6 6,435 3. Ste gn ar , M. , Boz i c , B. , Pe t er n e l , P . , K ve de r , T. , Ve n e , N. & R oz m an , B. (1 991 ) P re val e n c e o f an ti p ho sp h o li p i d an ti bo d ie s i n d e e p ve i n th ro mb o si s an d th e i r r e lat io n sh i p to bl oo d c o agu l ati on an d fi br i n ol ys i s. T hr ombos i s Res ea rc h, 63, 433 44 3. Ste p h e ns o n, M. D., Bal l em , P .J ., Tsa ng, P . , P u rk i ss , S. , E ns w or th , S. , Ho u li h an , E . & E ns o m, M .H . (2 004 ) Tr eat me n t of ant ip h o sp ho l i pi d an ti b od y syn d ro m e ( AP S ) i n pr e gn an c y: a r an do m i z e d p il o t tri al c om p ari n g lo w m o l ec u l ar w e i gh t h e p ari n to u n frac t io n ate d h e p ari n . J our na l of Obst etr i cs an d Gy n ae c olo gy Ca na da, 2 6, 7 29 73 4. Sw ad z ba, J ., Iw an ie c , T., P ul k a, M. , De Laat , B. , De G ro ot, P . G. & Mu si al , J . ( 201 1) Lu p us an ti c oag ul an t: pe r fo rm an c e o f th e te sts as r ec o m m en d e d b y th e l ate s t I STH gu i d e li n e s. Jou rn al of Th rom bosi s an d Hae mos tasi s , 9, 17 76 178 3. Th om , J. , I ve y, L . & E i ke l b oo m, J. ( 200 3) N or mal p las m a m i xi n g stu d i e s i n th e lab o rato r y d i agn o si s o f lu p u s ant i co agu l an t. Jo ur na l of Thr omb osi s an d Hae mos tasi s , 1, 2689 26 91. Ti e tj e n , G .E . , Day , M. , No r ri s, L ., Au ro r a, S. , Hal vo rs e n, A . , Sc h u ltz , L . R. & Le vi n e , S .R . (1 998 ) Ro l e o f an ti c ar di o l i pi n an ti bo di e s i n you n g p er so n s wi th m i gr ai ne an d t ran si e n t foc al n e u ro l og ic e v en ts : a pr o sp e c ti ve stu d y. Ne ur ol og y , 50 , 143 3 144 0. Ti n c an i, A. , A ll e gr i , F. , Bal e st ri e r i, G ., R e be r , G . , San m arc o , M ., Me ro n i, P . & Boffa, M. C. (2 004 ) Mi n i mal re q ui r e me n ts fo r an ti ph o sp h ol i p id an ti bo d ie s E L IS As p ro p os e d by th e E u ro pe an Fo r um o n an ti p ho s ph o li p i d an ti bo d i e s. Th rom bosi s Re se ar ch , 11 4, 55 35 58. To pp i n g, J. , Qu e n by, S ., F arq u ha rs on , R. , Mal i a, R. & G r e ave s, M. ( 19 99) Mark e d var i ati o n i n ant i ph o sp h ol i p id an ti b od i e s d ur i n g pr e gn an c y: r e la ti on s hi p s t o p re g nan c y o u tc om e . Hu man Re prod u cti on , 14 , 224 2 28. Tri p o di , A. , Ch an tar ang ku l , V . , C le r i c i , M. , Ne gri , B., G al li , M. & Man n uc c i , P .M . ( 20 01) L abo rator y c o n tro l o f o ral an ti c o agu lan t tre at me n t b y th e I NR s yst em i n p ati e nt s w i th the an ti p h os p ho l i pi d syn d ro me an d l u pu s an ti c o agu lan t. Re su l ts o f a c o ll ab or ati ve st ud y i nv ol vi n g n in e c om m e rc i al th ro m bo pl as ti n s. B ri ti sh Jou rn al Hae ma tol og y , 11 5, 67 2 678 . Tu lp p al a, M. , M artt un e n , M. , So de r st ro m- A nt ti la, V. , Fo u di l a, T., Ai l u s, K ., P alo s uo , T. & Yl i ko rkal a, O. (1 997 ) Lo w -d o se as pi r i n i n pr e ve n ti on of m i sc ar ri age i n wo m e n w i th un e xp l ai ne d o r aut oi m m un e re l ate d r e cu r re n t mi s c arr i age : e ffe c t on p ro st ac yc li n an d t hr om b ox an e A 2 p ro d u cti on . Hu ma n Re pro du cti on , 12 , 15 67 157 2. Urb an us , R .T. , S i e ge ri n k, B., Ro e st, M ., Ro se n d aal, F. R. , d e G r oo t, P .G . & Al gr a, A . ( 200 9) A nt i ph o sp h ol i p id an ti b od i e s and r i sk of myo c ar di al i nfar c ti o n an d i sc h ae mi c st ro ke i n you n g wo m e n in th e RA TIO stu d y: a c ase - c on tr ol stu d y. L an ce t Ne u rol og y , 8, 9 98 10 05. Vi l a, P ., He r n an de z , M. C. , Lo p e z -F e rn an de z , M. F. & Batl l e , J. (1 994 ) P re val e n c e , fol l ow - up and c li n i c al s i gn ifi c an c e of th e an ti c ar di o l i pi n ant i bo d ie s in n or m al s u bj e c ts. Thr omb osi s an d Ha e most asi s, 7 2, 2 09 213 . Zo ghl am i -R i nt e le n , C ., V or m i ttag, R ., Sa il e r , T ., Le h r , S. , Qu e he n b e rge r , P . , Ru mp o ld , H. , M ale , C. & P ab in ge r , I . (2 00 5) Th e pr e se n c e o f IgG ant i bo di e s ag ain s t b e ta2- gl yc o pr o te i n I pr e d ic t s th e ri s k of th ro mb o si s i n p ati e nt s wi th t he lu p u s ant i co agu l an t. Jou rn al o f Thr omb osi s an d Hae mos tasi s , 3, 11 60 11 65.

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