antiprothrombin antibodies are associated with pregnancy loss in patients with the antiphospholipid...

Antiprothrombin Antibodies are Associatedwith Pregnancy Loss in Patients with theAntiphospholipid Syndrome

INTRODUCTION

The antiphospholipid syndrome (APS) is a multisys-temic disorder, characterized by thromboembolicevents, recurrent abortions, thrombocytopenia, eleva-ted titers of antiphospholipid antibodies or lupusanticoagulant (LAC) and other clinical manifestations,including cardiac, hematologic and neurologic mani-festations.1–6 In the early 1990s it was reported that

antiphospholipid antibodies do not bind to phosphol-ipids alone but to complexes of phospholipids andprotein cofactors, e.g. b2-glycoprotein I (b2-GPI)and ⁄or prothrombin.7–9 The LAC activity was alsoidentified as a binding reactivity to phospholipid–protein complexes10 especially complexes of phosphol-ipids and prothrombin.11 Meanwhile, there are reportsdescribing a subgroup of antiphospholipid anti-bodies binding to the protein cofactor without any

American Journal of Reproductive Immunology

von Landenberg P,Matthias T, Zaech J, Schultz M, Lorber M, Blank M,Shoenfeld Y. Antiprothrombin antibodies are associated with pregnancyloss in patients with the antiphospholipid syndrome. AJRI 2003; 49:51–56� Blackwell Munksgaard, 2003

OBJECTIVE: To document the clinical association between thehistory of pregnancy loss in patients with the diagnosis of primary orsecondary antiphospholipid syndrome (APS) and the presence ofdifferent antiprothrombin antibody subtypes [immunoglobulin G(IgG), IgM and IgA] in a cohort of patients with APS.METHODS: Records of 170 female patients with primary APS, orAPS secondary to systemic lupus erythematosus (SLE) or secondary toother autoimmune diseases were studied.RESULTS: In female APS patients with IgG antiprothrombinantibodies (n ¼ 105) significant associations to pregnancy loss(p < 0.0001), early pregnancy loss (p < 0.0001) and a negativeassociation to thrombocytopenia (p < 0.01) could be identified. In thegroup of patients with IgG antiprothrombin antibodies and at leastone pregnancy (n ¼ 84) a significant association with pregnancy loss(p < 0.005) and especially with early pregnancy loss (p < 0.0001) wasdemonstrated. No association with other immunoglobulin subtypes ofantiprothrombin antibodies could be documented. In the subgroup ofpatients with primary APS and at least one pregnancy in the history,pregnancy loss (p < 0.005) and early pregnancy loss (p < 0.0001)were found to be highly associated with the presence of IgGantiprothrombin antibodies. IgG antiprothrombin antibodiesrepresent the highest independent risk factor for pregnancy loss withan odds ratio of 4.5. There was no statistically significant associationwith venous or arterial thrombosis in all IgG antiprothrombinantibody positive patientsCONCLUSION: The results of this study document the association ofIgG antiprothrombin antibodies with pregnancy loss and in particularearly pregnancy loss in a large and well-characterized cohort ofpatients. We would recommend routine testing for antiprothrombinantibodies in young female patients with APS.

P. von Landenberg1, T. Matthias2,J. Zaech1, M. Schultz1, M. Lorber3,M. Blank4, and Y. Shoenfeld41Department of Internal Medicine I, University ofRegensburg, Germany; 2Aesku.lab Diagnostika,Wendelsheim, Germany; 3Clinical Immunology, RambamMedical Center, Israel; 4Department of Medicine B andCenter for Autoimmune Diseases, Sheba Medical Center,Tel Hashomer, Sackler Faculty of Medicine, Tel AvivUniversity, Israel

Key words: Antiphospholipid syndrome, antiprothrombinantibodies, autoantibodies, autoimmunity, pregnancyloss

Address reprint requests to Yehuda Shoenfeld,Head of Department of Medicine B,Sheba Medical Center,Tel Hashomer 52621, Israel.E-mail: [email protected]

Submitted February 1, 2002;revised April 23, 2002;accepted June 13, 2002.

AJRI 2003; 49: 51–56Copyright � Blackwell Munksgaard, 2003

ISSN 8755-8920

AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY VOL. 49, 2003

phospholipids.12,13 This further emphasizes the largeheterogeneity of antiphospholipid antibodies.Prothrombin was first described in 1959 by Loeliger14

as a cofactor for a circulating anticoagulant in patientswith systemic lupus erythematosus (SLE). It attractedattention again when it became apparent that pro-tein cofactors, especially b2-GPI but also prothrombin,are involved in the detection of antiphospholipidantibodies.15

The clinical relevance of the presence of antipro-thrombin antibodies is controversial in the literatureand possible associations with symptoms of the APSwere analyzed only in limited number of patients. Themajority of these reports describes the association ofantiprothrombin antibodies with venous or arterialthrombosis.16–20 However, in a large meta-analysisreport a better diagnostic prediction of the disease byincluding antiprothrombin antibodies in the diagnosticapproach of the APS was not achieved.21

We would like to describe an association of anti-prothrombin antibodies with pregnancy loss in acohort of 170 female APS patients.

PATIENTS AND METHODS

Records of 170 female patients with primary APS,according to the Sapporo criteria22 or APS secondary toSLE or secondary to other autoimmune diseases werestudied retrospectively for clinical and laboratory asso-ciationswith thepresenceof antiprothrombinantibodies.

Antiprothrombin ELISASera were tested for reactivity against prothrombinusing a commercially available enzyme-linked immu-nosorbent assay (ELISA) (Aesku.lab Diagnostik,Wendelsheim,Germany). Human prothrombin was puri-fied, using amodifiedmethod as described elsewhere23,24

and coated on irradiated plates. Results are expressedin units ⁄mL in a range from 0 to 300 U ⁄mL. Cut-offvalues were determined with 80 sera of healthy blooddonors. ELISA tests for determination of immunoglob-ulinG (IgG), IgM, and IgA antiprothrombin antibodieshave identical experimental settings and cut-off valuesgreater than 15 U ⁄mL indicate a positive reactivity.

DefinitionsEarly pregnancy loss in this cohort of patients meansabortion in the first trimester of pregnancy, latepregnancy loss was defined as abortion in the thirdtrimester of pregnancy.

Statistical AnalysisStatistical analysis was performed employing theSPSS 10.0 program. Conventional chi-squared test

and Fishers exact test were used to analyze qualitativedifferences in univariate analysis. P-values less than0.05 were taken to indicate statistical significance.Regarding live birth and pregnancy loss, some of thepatients had more than one event. Each live birth andpregnancy loss was taken into account separately,resulting in a higher number of these events than thenumber of patients.As an approximate of the relative risk, the odds ratio

(OR), were calculated for several putative risk factorsby multivariate logistic regression analysis. The vari-ables that achieved statistical significance in the firstanalysis were tested in a second analysis by multi-variate logistic regression analysis. An OR was con-sidered statistically significant when the lower limit ofthe 95% confidence interval (CI) was >1.0. In themultivariate logistic regression analysis, a P-value lessthan 0.05 was considered statistically significant for arisk factor.

RESULTS

Prevalence of Antiprothrombin AntibodiesA total of 170 female APS patients were studied. Mostpatients had primary APS (n ¼ 97, 57.1%), and APSwas secondary to SLE in 56 (32.9%) patients. Theremaining 17 (10.0%) patients were diagnosed as APSsecondary to other autoimmune diseases.A total of 105 (61.7%) of the patients were positive

for IgG antiprothrombin antibodies, 98 (57.6%) hadIgM antiprothrombin antibodies and 12 (7.0%) hadIgA antiprothrombin antibodies.

Association of IgG Antiprothrombin Antibodieswith Clinical and Laboratory FindingsThe IgG antiprothrombin positive population (n ¼105) demonstrated a significant association with preg-nancy loss (n ¼ 71, p < 0.001) and especially withearly pregnancy loss during the first trimester (n ¼ 64,p < 0.0001) (Table I). The association with late preg-nancy loss did not reach a statistically significant level.Furthermore, a significant negative association withthrombocytopenia (n ¼ 19, p < 0.01) was observed.No statistically significant association with any of theanalyzed laboratory parameters was identified.

Association of IgM Antiprothrombin Antibodieswith Clinical and Laboratory FindingsImmunoglobulin M antiprothrombin (positive popu-lation n ¼ 98) was significantly associated only withIgG antiprothrombin antibodies (n ¼ 74, p < 0.0001)and with IgG anticardiolipin antibodies (n ¼ 79,p < 0.05). No associations with any clinical manifes-tation could be demonstrated.

52 / VON LANDENBERG ET AL.

� BLACKWELL MUNKSGAARD, 2003

Association of IgA Antiprothrombin Antibodieswith Clinical and Laboratory FindingsImmunoglobulin A antiprothrombin (positive popula-tion n ¼ 12) was significantly associated with inferiordeep vein thrombosis (n ¼ 8, p < 0.05), pulmonaryembolism and infarction (n ¼ 5, p < 0.s01) and leuco-penia (n ¼ 4, p < 0.05) (Table II). IgA antiprothrom-bin was also associated with LAC (n ¼ 10, p < 0.01),antinuclear antibodies (ANA) (n ¼ 8, p < 0.05) andanti-Ro ⁄SS-A antibodies (n ¼ 4, p < 0.05).

Prevalence of Antiprothrombin Antibodies in APSPatients with At Least One PregnancyA total of 126 (74.1%) of the 170 patients, had at leastone pregnancy (Table III). IgG antiprothrombin anti-bodies were detected in 84 patients (66.7%), IgM in 77patients (61.1%), and eight (6.3%) patients had IgAantiprothrombin antibodies.

In this population of 126 female patients, pregnancylosses occurred in 96 (76.2%) and 80 (63.4%) of thosewere characterized as an early pregnancy loss duringthe first trimester. Live births were recorded in 63(50.0%) cases.In patients with IgG antiprothrombin antibodies

(n ¼ 84), 71 (84.5%) had pregnancy loss (p < 0.005),and 64 (76.1%) of those were identified as havingearly pregnancy loss (p < 0.0001). Live births wererecorded in 34 (40.4%) (p < 0.005). Regarding thelaboratory findings in this population of patients wefound a significant association of IgG antiprothrom-bin antibodies with IgG anticardiolipin antibodies(n ¼ 73, 86.9%, p < 0.05) and IgM antipro-thrombin antibodies (n ¼ 59, 70.2% p < 0.005). Anegative association of IgG antiprothrombin anti-bodies with ANA (n ¼ 26, 30.9%, p < 0.005) wasidentified.

TABLE II. Frequency of Clinical

Symptoms in Relation to IgA Antipro-

thrombin Antibodies in Female

Patients with the APS (n = 170)

IgA positive

(n = 12) (%)

IgA negative

(n = 158) (%) Significance

APS findings

Inferior deep vein thrombosis 8 (66.6) 55 (34.8) p < 0.05

Pulmonary embolism and infarction 5 (38.4) 17 (10.7) p < 0.01

Leucopenia 4 (33.3) 13 (8.2) p < 0.05

Laboratory findings

Lupus anticoagulant 10 (83.3) 69 (43.6) p < 0.01

Antinuclear antibodies 8 (66.6) 58 (36.7) p < 0.05

Anti-Ro ⁄SS-A antibodies 4 (33.3) 15 (9.4) p < 0.05

TABLE III. Frequency of Clinical

Symptoms and Laboratory Findings in

Relation to IgG Antiprothrombin Anti-

bodies in Patients with the APS and

with At Least One Pregnancy

(n = 126)

IgG positive

(n = 84) (%)

IgG negative


APS findings

Pregnancy loss 71 (84.5) 25 (59.5) p < 0.005

Early pregnancy loss 64 (76.1) 16 (38.0) p < 0.0001

Live birth 34 (40.4) 29 (69.0) p < 0.005

Laboratory findings

IgG anticardiolipin antibodies 73 (86.9) 30 (71.4) p < 0.05


IgM antiprothrombin antibodies 59 (70.2) 18 (42.8) p < 0.005

TABLE I. Frequency of Clinical

Symptoms in Relation to IgG Anti-

prothrombin Antibodies in Female

Patients with the APS (n = 170)

APS findings

IgG positive

(n = 105) (%)

IgG negative


Pregnancy loss 71 (67.6) 25 (38.5) p < 0.0001


Thrombocytopenia 19 (18.1) 24 (36.9) p < 0.01

ANTIPROTHROMBIN ANTIBODIES IN APS / 53


Prevalence of Antiprothrombin Antibodiesin a Female Population with Primary APSand At Least One PregnancyIn the subgroup of 126 APS with at least onepregnancy, 85 patients (67.5%) had the diagnosis ofprimary APS and 31 (24.6%) patients had APSsecondary to SLE. Fifty-nine patients with primaryAPS (69.4%) had IgG antiprothrombin antibodies(Table IV). Fifty-two (88.1%) cases with pregnancyloss and with antiprothrombin IgG antibodies(p < 0.005) were identified, and 46 (77.9%) of thosepatients were characterized with early pregnancy loss(p < 0.0001). Twenty-two (37.2%) cases of live birthswere documented (p < 0.005). We found a significantassociation of IgG antiprothrombin antibodies withIgM antiprothrombin antibodies (n ¼ 40, 67.8%,p < 0.05). A negative association with the presenceof IgG antiprothrombin antibodies and ANA (n ¼ 11,18.6%, p < 0.005) was achieved.

Multivariate AnalysisImmunoglobulin G anticardiolipin, IgG anti-b2-GPIand IgG antiprothrombin antibodies were analyzed aspossible risk factors for early pregnancy loss in amultivariate logistic regression analysis.Immunoglobulin G antiprothrombin antibodies

turned out to be the most significant risk parameterfor early pregnancy loss with an OR of 4.5 (95% CI2.2–9.6). IgG anticardiolipin antibodies were deter-mined as a minor risk parameter with an OR of 3.4(95% CI 1.4–8.4), while anti-b2-GPI-antibodies turnedout not to be a statistically relevant risk parameter forpregnancy loss.

DISCUSSION

The presence of antiprothrombin antibodies in 170patients with known APS was studied and the clinicalmanifestations and laboratory parameters of thesepatients were analyzed. We employed a commerciallyavailable antiprothrombin assay to identify subgroups

of patients with APS having these antibodies. A totalof 105 IgG, 98 IgM, and 12 IgA antiprothrombinpositive patients were identified. The most prominentresult was the significant association of the presence ofIgG antiprothrombin antibodies with pregnancy loss(p < 0.001). Especially, early pregnancy loss seems tobe closely related to these antibodies (p < 0.0001).Analysing only patients with at least one completedpregnancy, the high prevalence of IgG antiprothrom-bin antibodies in patients with pregnancy loss,especially early pregnancy loss, was confirmed. Theclosest association between IgG antiprothrombinantibodies and early pregnancy loss was found inpatients with the primary APS. In the subgroup withthe IgA antiprothrombin antibody a statisticallysignificant association with inferior deep vein throm-bosis was observed. In all other subgroups of patientsno statistical association of antiprothrombin antibo-dies with arterial or venous thrombosis was observed.In a recent meta-analysis, Galli et al.21 reviewed thecurrent literature regarding antiprothrombin antibod-ies as a diagnostic criterion for arterial and venousthrombosis in the APS. Testing for antiprothrombinantibodies instead of or in addition to routinelyanalyzed anticardiolipin and anti-b2-GPI antibodiesoffered no advantage for the diagnosis of thromboem-bolic events in patients with APS. Our results supportthis conclusion, showing that the association withinferior deep vein thrombosis in our population isstatistically significant, only with IgA antiprothrombinantibodies in a small subgroup of patients and not withIgG or IgM antiprothrombin antibodies. However, wefound a high prevalence of IgG antiprothrombinantibodies in patients with early pregnancy loss.Furthermore, this association was more evident inpatients with the primary APS. In a recent publicationof Tsutsumi et al.25 the investigators could not identifyantibodies to the phosphatidylserine–prothrombincomplex in a population of patients with unexplainedmiscarriages. In contrast to their study we used anassay coated only with pure prothrombin without anycofactor (as per the manufacturer’s information).

IgG positive

(n = 59) (%)

IgG negative


APS findings

Pregnancy loss 52 (88.1) 15 (57.6) p < 0.005


Live birth 22 (37.2) 19 (73.0) p < 0.005

Laboratory findings


IgM antiprothrombin antibodies 40 (67.8) 12 (46.2) p < 0.05

TABLE IV. Frequency of Clinical

Symptoms and Laboratory Findings in

Relation to IgG Antiprothrombin Anti-

bodies in Patients with the Primary

APS and with At Least One Preg-

nancy (n ¼ 85)



There are different studies demonstrating the closerelation between the presence of IgM anti-b2-GPIantibodies and LAC.26–28 Moreover, Balasch et al.29

described that in patients without LAC, IgM anti-b2-GPI antibodies could not characterize patients withpregnancy loss, indicating that a single laboratoryparameter is not sufficient to identify patients withpregnancy loss. There are few studies using antipro-thrombin antibodies to address this question. Forasti-ero et al.17 evaluated the presence of antiprothrombinand anti-b2-GPI antibodies showing an association ofpregnancy loss only with anti-b2-GPI antibodies andnot with antiprothrombin antibodies. In another studyof Donohoe et al.18 IgG antiprothrombin antibodieswere not associated with thrombosis or pregnancy loss,however, IgM antiprothrombin antibodies were linkedto both.In a recent evaluation Zangari et al.30 reported an

increased level of prothrombin activation fragments1 + 2 in pregnant patients with antiphospholipidantibodies. This indicates a possible pathogenic roleof an activated coagulation system in the pathogenesisof the APS and its symptoms impairing pregnancies. Itmight as well explain the occurrence of antiprothrom-bin antibodies in these patients.Regarding the pathophysiological implications of

our results, recent studies31,32 with prothrombin defi-cient mice showed that prothrombin deficiency inthese models lead to partial embryonic fatality as aresult of bleeding in the yolk sac cavity and tissuenecrosis of the embryos. Prothrombin seems to beimportant in the development of the embryos andespecially for the vascular integrity. It might bespeculated that the decrease of prothrombin causedby antiprothrombin antibodies in patients with theAPS might lead to the same fatal changes in thedevelopment of the fetal life.There is a need for further prospective studies to

confirm the association between antiprothrombinantibodies and pregnancy loss. Nevertheless, basedon our data we believe that it is justified to screenroutinely in young female APS patients also forantiprothrombin antibodies in order to apply optimalanticoagulant therapy in case of a pregnancy. Inaddition antiprothrombin antibodies should be addedas a screening of infertile couples.

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