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The Paradox of the Lupus Anticoagulant: History and Perspectives Vittorio Pengo, MD1 Elisa Bison, BSc1 Gentian Denas, MD1 Alessia Bracco, MD1 Alessandra Banzato, PhD1

Semin Thromb Hemost 2014;40:860–865.

Abstract

Keywords

► ► ► ► ► ►

lupus anticoagulant β2-glycoprotein I phospholipids syndrome thrombosis pregnancy

A unique coagulation inhibitor prolonging whole-blood clotting time was described more than 50 years ago in two patients with systemic lupus erythematosus (SLE). The immunoglobulin nature of the inhibitor and its interaction with antiphospholipid antibodies was later demonstrated and the term “lupus anticoagulant (LA)” was coined to describe this laboratory finding. It soon became apparent that LA was a misnomer as it is often found in plasma from patients with clinical conditions other than SLE and is associated with thromboembolic events that may occur in otherwise healthy individuals. Individuals with LA have circulating autoantibodies that inhibits blood coagulation. These are mostly of IgG or IgM class and mainly directed against a phospholipid (PL)-binding plasma protein, β2-glycoprotein I (β 2GPI). The presence of β2GPI-dependent LA represents a well-recognized risk factor for venous and arterial thromboembolism, as well as pregnancy loss and morbidity. β2GPI-dependent LA in the presence of documented previous thromboembolism, or history of pregnancy loss/morbidity, identifies definite anti-PL syndrome. Laboratory diagnosis of LA is thus of particular importance, as it may assign patients with a common event (thrombosis) to a group with a high risk for recurrence, which is a prerequisite for long-term oral antithrombotic treatment.

Historical Context In the 1940s a report from the University of California Medical School described a young man with a fatal condition manifesting as moderate thrombocytopenia and prolonged whole blood clotting time with a hemorrhagic diathesis and intracranial and peripheral venous thrombosis.1 Even if the prolonged clotting time was attributed to “hypothromboplastinemia” and the crude tests available did not demonstrate a coagulation inhibitor, it may be speculated that this was the first report of a lupus inhibitor. Interestingly enough, the authors described that “the same quantities of normal blood or plasma, which produced a marked reduction in the coagulation time of hemophilic blood had little effect on the coagulation time of the

published online November 11, 2014

Address for correspondence Vittorio Pengo, MD, Department of Clinical Cardiology, Thrombosis Center, Via Giustiniani 2, 35128 Padova, Italy (e-mail: [email protected]).

Issue Theme A Short History of Thrombosis and Hemostasis: Part II (40th Year Celebratory Issue); Guest Editor: Emmanuel J. Favaloro, PhD, FFSc (RCPA).

patient’s blood.” Afterward, Ley et al2 reported a critically ill young man with abnormal bleeding, arthralgia, leg vein thrombosis, with prolonged blood clotting time and prothrombin (PT) time attributed to hypoprothrombinemia. Autopsy showed signs of tissue bleeding, renal changes indicative of systemic lupus erythematosus (SLE), as well as cerebral infarcts. It was in the 1950s that growing awareness about the presence of a circulating anticoagulant factor in some patients with SLE became evident. Conley,3 of Johns Hopkins, wrote a brief report about two patients with lupus and a “peculiar hemorrhagic disorder” with prolonged blood clotting and PT times, and a clear evidence of an anticoagulant factor in plasma mixing studies. Interestingly, both patients had biological false-positive tests for syphilis.

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

DOI http://dx.doi.org/ 10.1055/s-0034-1395158. ISSN 0094-6176.

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1 Department of Clinical Cardiology, University Hospital, Padova, Italy

Seena Padayattil Jose, MD1

These observations were complemented by a report of Frick and Weimer in the mid-1950s,4 who described three patients with convincing evidence of coagulation inhibitors, including one subject with confirmed lupus. Positive serological tests for syphilis were found in all the three individuals, while one of the individuals had associated definite hemorrhagic diathesis. The reasons for the association of lupus anticoagulant (LA) coagulopathy with an hemorrhagic syndrome were clarified later. Moreover, Frick and Weimer provided evidence for transplacental transfer of the anticoagulant factor in one subject (her baby showed the presence of the anticoagulant over a period of 7 weeks after birth) and postulated an immunologic pathogenesis. The picture of LA was slowly emerging as an immunologic condition; retrospectively, anticardiolipin antibodies (aCL) were identified through the biological falsepositive tests for syphilis in these patients. Subsequent case reports demonstrated that on serum electrophoresis the Wasserman reagent and the anticoagulant localized to the same region of gamma globulins.5 The hypothesis of Frick and Weimer that the mechanism of action was “directed against thromboplastin,” which was reasonable at that time and after all not that far from the present knowledge. Rarely, in adults or in children with or without SLE, LA has been associated with a hemorrhagic diathesis caused by factor II deficiency, the LA hypoprothrombinemia syndrome.6,7 In 1959, Loeliger described a lupus patient with circulating anticoagulant and hypoprothrombinemia; addition of normal plasma to the patient’s plasma increased the clotting time.8 This led Loeliger to speculate that PT was a cofactor for the circulating anticoagulant in lupus. In the same period, reports emerged of an increased inhibitor activity by a normally occurring plasma component, the so called “lupus cofactor.”9–11 In the 1960s it was increasingly more accepted that the in vitro anticoagulant phenomenon in SLE was more associated with thrombotic disorders rather than hemorrhagic diathesis. Bowie et al12 reported the presence of circulating anticoagulant in 8 of the 11 patients with SLE; of these, 3 suffered from deep vein thrombosis and 1 from ischemic leg ulcers and livedo reticularis. The term “LA” was coined by Feinstein and Rapaport13 only later, in 1972, to designate an inhibitor of coagulation that impairs prothrombinase activation of PT, which was found in the plasma of patients with SLE. Some findings favored the hypothesis that the inhibitor was directed against phospholipids (PLs) since preincubation with PLs reduced its activity while the inhibitory effect was more pronounced when PLs were diluted.14 It seems likely that the excess of descriptions of a hemorrhagic diathesis in the early case reports, was simply due to the presentation with bleeding as the principal symptom in these unusual cases and the lack of any reason to explore coagulation in SLE patients without such a history of bleeding. In 1975, Nilsson et al published a case report of a young woman with a recurrent history of miscarriages investigated with coagulation studies during pregnancy and found to have a circulating anticoagulant.15 Of note is description of the placenta by Nilsson et al obtained from the only successful

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pregnancy, “…The placenta was severely infarcted. It is postulated that the development of antithromboplastin during pregnancy may be a contributory cause of intrauterine death.” Subsequent case reports highlighted that the LA-associated prothrombotic condition can arise in the absence of SLE or other connective tissue disorders.16 A significant diagnostic breakthrough occurred with the development of assays for aCL that were considerably more sensitive than other assays. Harris et al in 198317 demonstrated that almost two-thirds of serum samples from a cohort of 65 patients with SLE had high levels of aCL. Moreover, over 90% of those with LA had increased aCL levels, confirming the relationship previously suggested by cases with both LA and biological false-positive tests for syphilis. Finally, there was a correlation between raised aCL titer and history of thrombosis within this patient cohort with SLE. Later, in the 1980s, an association between LA and pregnancy failure was observed in four women, only one of whom had SLE.18 Subsequent reports confirmed this finding19 while others suggested additional disease associations, for example, chorea gravidarum.20 In 1985, Gastineau et al separated the LA-associated conditions into three groups: those with SLE, those without SLE, and those with drug-induced LA.21 In 1986, Thiagarajan et al described the diluted Russell viper venom time (dRVVT) that appears to be a simple, reproducible, sensitive, and relatively specific method for the detection of LA.22 A year later, Pengo et al, from the same group, demonstrated that affinity-purified IgG aCL of patients with LA are able to prolong the dRVVT when spiked in normal plasma.23 It was in the 1980s that the nomenclature “antiphospholipid syndrome (APS)” began to be generally used,24 abbreviated as “APS” afterwards. The term primary APS was introduced to describe those cases in which there was no background disease.25,26 Cases with unusually acute and severe multiorgan vaso-occlusive episodes associated with positive tests for antiphospholipid antibodies (aPL) were also reported.27,28 In 1992, Asherson (from Cape Town, South Africa) coined the term catastrophic APS (CAPS).29 It became clear that CAPS is a rare form of microangiopathic thrombosis that shares features with thrombotic thrombocytopenic purpura, disseminated intravascular coagulation and systemic inflammatory response syndrome as seen in sepsis. Due to these similarities, there is a possibility of both underand overdiagnosis, especially in view of the lack of specificity of aPL. Multiorgan involvement is typical with a predilection for lung, brain, and kidney. It may complicate previously diagnosed more typical APS or be the presenting manifestation and there is often a trigger for the acute episode, such as infection or anticoagulant withdrawal. Most of patients with CAPS have strong LA and high titer aCL.30 LA is now considered the most important acquired risk factor for thrombosis and fetal loss. The current definition of LA is autoantibodies that in vitro inhibit PL-dependent coagulation reactions in the absence of specific coagulation factor inhibition. In 1990, three groups at the same time clearly showed that aCL are not directed against PLs but against a PLbinding protein, namely, β2-glycoprotein I (β2GPI).31–33 Takeya et al explained the mechanism of action of LA in vitro, showing that anti-β2-glycoprotein I (aβ2GPI) monoclonal Seminars in Thrombosis & Hemostasis

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antibodies with LA activity enhance β2GPI binding to PLs thus reducing the assembly and activation of coagulation factors.34 A few years later, de Laat et al showed that β2GPI-dependent LA correlates with thrombosis35 and aβ2GPI antibodies with LA activity are directed against the domain I of this protein.36 Important milestones in the study of LA, and the elucidation of mechanisms involved it this LA activity, are summarized in ►Table 1.

Nature and Detection of Lupus Anticoagulant LA comprises at least two main categories of inhibitors, that is, those depending and those not depending on the presence of circulating aβ2GPI antibodies. The former shows a high association with thromboembolic events35 while data on the latter are sparse and not conclusive. The autoantibodies are of the IgG or IgM isotype, and are mainly directed against a PL-binding plasma protein, β2 GPI.37 β2GPI is a 326-amino-acid PL-binding protein with a molecular weight of 50 kDa belonging to the complement control protein superfamily. Its plasma concentration is approximately 200 μg/mL, and as 40% is bound to lipoproteins it is also termed “apolipoprotein H.” Composed of five homologous “sushi” domains of about 60 amino

acids and binding to aPL with its fifth positively charged domain, it may have a role in the elimination of apoptotic cells from circulation. β2GPI is a much conserved protein among species and bovine and human β2GPI cannot be distinguished from an antigenic point of view. The β2GPI-dependent LA is related to the presence of autoantibodies of IgG or IgM isotypes directed against β2GPI. This has been demonstrated by testing the anticoagulant properties of affinity-purified antibodies (aβ2GPI) on normal plasma.38 By prolonging PL-dependent coagulation tests (in particular dRVVT), the action of these antibodies is inhibited by an excess of PL. It has been proposed that molecular mimicry between infectious agents and the β2GPI molecule might be the basis for the generation of antibodies against β2GPI.39 Moreover, a strong homology exists between β2GPI-related peptides (target epitopes for antibodies against β2GPI) and different common pathogens. Moreover, β2GPI polymorphism (in particular the Val 247 allele) has recently been associated with both a high frequency of antibodies against β2GPI and stronger antibody reactivity than the Leu247 β2GPI allele.40 It is possible that this type of polymorphism may favor the occurrence of molecular mimicry. How these immunoglobulins determine thromboembolic events or obstetric complications is still subject to debate; possible explanations have been

Table 1 Milestones in the study of lupus anticoagulant Reference (y)

Milestone

Aggeler et al (1946)

1

First description of a coagulation inhibitor

Ley et al (1951)2 Conley (1952) Frick (1955)

First description in a SLE patient with hypoprothrombinemia

3

Anticoagulant in mixing studies and false-positive test for syphilis

4

Postulated an “immunologic” pathogenesis

Laurell, Nilsson (1957)5 Loeliger (1959)

Possible link with false-positive tests for syphilis

8

Description of the “lupus cofactor” phenomenon

Bowie et al (1963)

12

Corrigan et al (1970)

Associated with a thrombotic rather than a hemorrhagic diathesis 6

Description of lupus anticoagulant hypoprothrombinemia syndrome

Feinstein, Rapaport (1972)13 Nilsson et al (1975)

Coined the term “lupus anticoagulant”

15

Case report of recurrent pregnancy loss and circulating anticoagulant

Manoharan et al (1977)

16

LA and thrombosis in the absence of SLE

Firkin et al (1980)18 Harris et al (1983)

Association between lupus anticoagulant and pregnancy failure

17

Gastineau et al (1985)

Development of assays for anticardiolipin antibodies 21

Bingley, Hoffbrand (1987)

Description of lupus anticoagulant -associated conditions 24

Denomination of antiphospholipid antibody syndrome

Thiagarajan et al (1986)22 Pengo et al (1987)

Description of dRVVT to detect lupus anticoagulant

23

Affinity purified IgG anticardiolipin possess lupus anticoagulant activity

Three groups: Galli et al, McNeil et al, and Matsuura et al (1990)31–33

Anticardiolipin antibodies are directed toward β2-glycoprotein I

Takeya et al (1997)34

Mechanism of action of lupus anticoagulant in vitro

de Laat et al (2004)

35

β2-glycoprotein I-dependent lupus anticoagulant correlates with thrombosis

de Laat et al (2005)

36

Antibodies directed to domain I of β2-glycoprotein I cause lupus anticoagulant

Abbreviations: dRVVT, diluted Russell viper venom time; SLE, systemic lupus erythematosus. Seminars in Thrombosis & Hemostasis

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• High: Unprovoked venous thromboembolism (VTE) and (unexplained) arterial thromboembolism (ATE) in young patients (< 50 years of age), thrombosis at unusual sites, late pregnancy loss, any thrombosis, or pregnancy morbidity in patients with autoimmune diseases (SLE, rheumatoid arthritis, autoimmune thrombocytopenia, autoimmune hemolytic anemia). • Moderate: Accidentally found prolonged aPTT in asymptomatic subjects, recurrent spontaneous early pregnancy loss, provoked VTE in young patients. • Low: VTE or ATE in elderly patients. Calculations of cutoff values for each diagnostic step are also clearly stated in the revised guidelines.43 To avoid misinterpretation, it is recommended to perform laboratory procedures 1 to 2 weeks after discontinuation of warfarin treatment or when the international normalized ratio is less than 1.5. Bridging with low-molecular-weight heparin (LMWH) in case of oral anticoagulant discontinuation is recommended with the last dose of LMWH administered more than 12 hours before the blood is drawn for LA testing. LA results should always be considered in the context of a full laboratory aPL profile comprising aCL and aβ2GPI enzyme-linked immunosorbent assays. The presence of medium-high titers aCL and aβ 2GPI of the same isotype (most often IgG) is in agreement with a positive LA and identifies patients at high risk for thrombosis and fetal losses.44 Diagnostic steps are confirmed to be those of previous guidelines, namely, (1) screening step; (2) mixing test; and (3) confirmatory test. Results of screening tests are potentially suggestive of LA when their clotting times are longer than the local cutoff value. Results should be expressed as follows:

where PNP is pooled normal plasma.

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Perform testing on patient plasmas mixed with PNP at 1:1 proportion and express results as follows:

Confirmatory test: Results are confirmatory of LA if the percentage correction of patient’s plasma at low (screen) and high (confirm) PL concentration is above the local cutoff value. Sensitive aPTT: Same procedure as dRVVT should be used. A final paragraph reports the interpretation of the results in general and in particular situations. The performance of laboratories across the world to detect LA is a matter of concern. Misclassification of positive or negative LA plasma samples is commonly encountered in external surveys. Recently, in a survey of centralized LA diagnosis, we reported that approximately 33% of plasma samples collected by thrombosis centers and labeled locally as LA positive were reported as LA negative in a central laboratory.45 As far as the standardization of laboratory tests for the diagnosis of APS is concerned, there is a tremendous need for reference material. Monoclonal antibodies to domain I with LA activity might be a solution. In the meantime, the establishment of a reference laboratory should be considered for multicenter studies to enroll a homogenous population of patients with APS.

Significance of Positive Lupus Anticoagulant LA is an important test in vascular medicine, since its detection on two occasions 12 weeks apart in a patient with venous or arterial thromboembolism is a first step toward the diagnosis of APS, and this in turn determines a different approach to secondary prevention and treatment. As thrombosis is a common event, laboratory diagnosis of LA becomes crucial in identifying patients with APS. When LA and medium-high titers of aβ2GPI and aCL are present in the plasma of patients with clinical features of APS, APS diagnosis is more likely. Due to laboratory pitfalls in detecting LA, isolated LA positivity is of uncertain diagnostic value in patients with thrombosis and pregnancy loss or in carriers (those with positive laboratory profile but without overt disease). Isolated LA positivity might be present in other pathologic conditions such as cancer46 and infections or chronic illness.47 We have recently shown that as opposed to carriers of a full laboratory profile, carriers of isolated LA positivity are at low risk of thromboembolic events.48 Moreover, if antihuman PT antibodies are responsible for LA, they are poorly associated with thromboembolic events.49 Therefore, the development of simple coagulation tests improving the clinical significance of positive LA is important.50,51 In clinical practice, when LA is the only positive test, the following considerations should be made: (1) LA may be a false positive, in particular when it is weak or borderline or when the sample contains heparin, or the patient is on one of the newer direct oral anticoagulant drugs (thrombin time should be always performed; anti-Xa assay could also be considered)45; (2) sole LA positivity is often not confirmed after 12 weeks52; (3) carriers of isolated LA positivity do not carry a high risk for thrombosis. According to the available Seminars in Thrombosis & Hemostasis

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put forward but none is considered very resounding. One possibility is that antibodies responsible for LA in vitro also interfere with the in vivo function of PL-dependent anticoagulant pathways. In fact, PL-dependent inactivation of factors Va/VIIIa by the thrombomodulin–protein C–protein S system or by PL-dependent tissue factor inhibition by tissue factor pathway inhibitor may be impaired in the presence of LA.41 Previous criteria for the diagnosis of LA were those proposed by Brandt et al42: prolongation in at least one PLdependent coagulation test out of two or more screening assays (activated partial thromboplastin time [aPTT], kaolin clotting time [KCT], dRVVT, diluted PT time). Recent guidelines43 gave particular emphasis to patient selection, and aimed to minimize inappropriate requests for LA testing. Modalities for blood collection and processing were fully delineated and the choice of tests was limited to dRVVT43 and a sensitive aPTT. Appropriateness to search for LA can be graded according to clinical characteristics into low, moderate, and high.

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data, LA prevalence in the normal population is 3.6% when using KCT as the screening test, but it may be much less. The prevalence of LA in the SLE population is between 10 and 50%, depending on the test used.53

15 Nilsson IM, Astedt B, Hedner U, Berezin D. Intrauterine death and

Conclusion

17

LA represents an immunoglobulin IgG or IgM directed in most cases against a plasma protein (β2GPI) whose physiological role is still unclear. As a result, the pathogenesis of thromboembolic phenomena associated with LA remains uncertain. The coagulation tests used to identify LA suffer from problems of standardization and there is a lack of reference material. Despite this, positivity for LA, together with that for aCL and anti-β2GPI (triple positivity) is able to identify patients at high risk for thrombosis and pregnancy loss. The introduction of new immunological tests that identify specific subgroups of LA will probably improve the identification of high-risk patients in the future.

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The paradox of the lupus anticoagulant: history and perspectives.

A unique coagulation inhibitor prolonging whole-blood clotting time was described more than 50 years ago in two patients with systemic lupus erythemat...
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