Antiphospholipid Syndrome: Definition and Treatment

Monica Galli; Tiziano Barbui

doi:10.1055/s-2003-38835

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2003; 29(2): 195-204
DOI: 10.1055/s-2003-38835

Antiphospholipid Syndrome: Definition and Treatment

Monica Galli¹ , Tiziano Barbui²

¹Assistant Professor, Department of Haematology, Ospedali Riuniti, Bergamo, Italy
²Department of Haematology, Ospedali Riuniti, Bergamo, Italy

Abstract

ABSTRACT

Antiphospholipid (aPL) antibodies (i.e., lupus anticoagulants and anticardiolipin [aCL] antibodies) are associated with obstetric complications. Recurrent spontaneous abortions and fetal death represent the obstetric criteria of the aPL syndrome. Intrauterine growth retardations, preeclampsia, and prematurity are other common clinical features not included in the syndrome. Overall, the prevalence of obstetric complications in aPL-positive women is about 15 to 20%. The presence of lupus anticoagulants carries a risk of recurrent miscarriages and fetal death ranging from and odds ratio of 3.0 to 4.8, whereas that of aCL antibodies ranges from 0.86 to 20. The mechanism(s) by which aPL antibodies causes these events still has to be defined. Thrombosis in the placental vessels, which causes placental hypoxia and eventually leads to abortion or fetal death, has been reported in aPL-positive women with obstetric complications. Impairment of embryonic implantation has also been proposed. Unfractionated or low-molecular-weight heparins, alone or in combination with low-dose aspirin, represent the current standard treatment of pregnant aPL-positive women to prevent recurrent obstetric complications. Upon treatment, the live birth rate increases from 0 to 40% to 70 to 80%. Despite these good results, heparin-treated pregnancies are still characterized by an excessive frequency of maternal and/or fetal complications, indicating the necessity of a better calibration of the dosage, duration, and timing of administration of heparin treatment.

KEYWORDS

Antiphospholipid antibody - lupus anticoagulant - anticardiolipin antibody - obstetric complications - treatment

Full Text

References

REFERENCES

1 Tanner D, Levine R, Kittner S J. Epidemiology of antiphospholipid antibodies and vascular disease. In: Levine SR, Brey RL, eds. Clinical Approach to Antiphospholipid Antibodies Boston: Butterworth Heinemann 2000: 1-18
2 Dizon-Townson D, Branch D W. Obstetric vascular disease in antiphospholipid syndrome. In: Levine SR, Brey RL, eds. Clinical Approach to Antiphospholipid Antibodies Boston: Butterworth Heinemann 2000: 8-94
3 Godfrey T, D'Cruz D. Antiphospholipid syndrome: general features. In: Khamashta MA, ed. Hughes' Syndrome London: Springer 2000: 8-19
4 Asherson R A. A `primary' antiphospholipid syndrome?. J Rheumatol . 1988; 15 1742-1746
5 Alarcon-Segovia D, Deleze M, Oria C V. et al . Antiphospholipid antibodies and the antiphospholipid syndrome in systemic lupus erythematosus. Medicine . 1989; 68 353-365
6 Wilson W A, Gharavi A E, Koike T. et al . International consensus on preliminary classification criteria for definite antiphospholipid syndrome. Arthritis Rheum . 1999; 42 1309-1311
7 Mackie I J, Donohoe S, Machin S J. Lupus anticoagulant measurement. In: Khamashta MA, ed. Hughes' Syndrome London: Springer 2000: 214-224
8 Loizou S, McCrea J D, Rudge A C. et al . Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay: standardization and quantitation of results. Clin Exp Immunol . 1985; 62 739-744
9 Galli M, Comfurius P, Maassen C. et al . Anticardiolipin antibodies (ACA) directed not to cardiolipin but to a plasma protein cofactor. Lancet . 1990; 335 1544-1547
10 McNeil H P, Simpson R J, Chesterman C N, Krilis S A. Anti-phospholipid antibodies are directed against a complex antigen that includes a lipid-binding inhibitor of coagulation: β2-glycoprotein I (apolipoprotein H). Proc Natl Acad Sci USA . 1990; 87 4120-4124
11 Matsuura E, Igarashi Y, Fujimoto M. et al . Anticardiolipin cofactor(s) and differential diagnosis of autoimmune disease. Lancet . 1990; 335 177-178
12 Galli M, Comfurius P, Barbui T. et al . Anticoagulant activity of β2-glycoprotein I is potentiated by a distinct subgroup of anticardiolipin antibodies. Thromb Haemost . 1992; 68 297-300
13 Galli M, Beretta G, Daldossi M. et al . Different anticoagulant and immunological properties of anti-prothrombin antibodies in patients with antiphospholipid antibodies. Thromb Haemost . 1997; 77 486-491
14 Polz E, Kostner G M. The binding of β2-glycoprotein I to human serum lipoproteins. FEBS Lett . 1979; 102 183-186
15 Sheng Y, Sali A, Herzog H, Lahnstein J, Krilis S A. Site-directed mutagenesis of recombinant human β2-glycoprotein I identifies a cluster of lysine residues that are critical for phospholipid binding and anticardiolipin antibody activity. J Immunol . 1996; 157 3744-3751
16 Reddel S W, Wang Y X, Sheng Y H, Krilis S A. Epitope studies with anti-β2-glycoprotein I antibodies from autoantibody and immunized sources. J Autoimm . 2000; 15 91-96
17 Day H M, Thiagarajan P, Ahn C. et al . Autoantibodies to β2-glycoprotein I in systemic lupus erythematosus and primary antiphospholipid syndrome: clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol . 1998; 25 667-674
18 Bajaj S P, Rapaport S I, Fierer D S. et al . A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood . 1983; 61 684-692
19 Arvieux J, Darnige L, Reber G. et al . Development of an ELISA for autoantibodies to prothrombin showing their prevalence in patients with lupus anticoagulants. Thromb Haemost . 1995; 74 1120-1125
20 Rao L VM, Hoang A D, Rapaport S I. Mechanism and effects of the binding of lupus anticoagulant IgG and prothrombin to surface phospholipids. Blood . 1996; 88 4173-4182
21 Malia R G, Brooksfield C, Bulman I. et al . Prothrombin fragment 1-2: the epitope for antiphospholipid antibody expression (Abst). Thromb Haemost . 1997; 78(Suppl) 170
22 Galli M, Barbui T. Antiprothrombin antibodies: detection and clinical significance in the antiphospholipid syndrome. Blood . 1999; 93 2149-2157
23 Willems G M, Janssen M P, Pelsers M A L M. et al . Role of divalency in the high-affinity binding of anticardiolipin antibody-β2-glycoprotein I complexes to lipid membranes. Biochemistry . 1996; 35 13833-13842
24 Horbach D A, van Oort E, Derksen R W M H. et al . The contribution of anti-prothrombin antibodies to lupus anticoagulant activity: discrimination between functional and non-functional anti-prothrombin antibodies. Thromb Haemost . 1998; 79 790-795
25 Oosting J D, Derksen R W M H, Bobbink I WG. et al . Antiphospholipid antibodies directed against a combination of phospholipids with prothrombin, protein C or protein S-an explanation for their pathogenic mechanisms. Blood . 1993; 81 2618-2625
26 Matsuda J, Saitoh N, Gohchi K. et al . Anti-annexin V antibody in systemic lupus erythematosus patients with lupus anticoagulant and/or anticardiolipin antibody. Am J Hematol . 1994; 47 56-58
27 Berard M, Sugi T, McIntyre J A. et al . Prevalence and kininogen-dependence of antiphosphatidylethanolamine antibodies. Nouv Rev Franc Hematol . 1995; 37(Suppl II) S69-S72
28 Jones D W, Mackie I J, Gallimore M J, Winter M. Antibodies to factor XII and recurrent fetal loss in patients with the anti-phospholipid syndrome. Br J Haematol . 2001; 113 550-552
29 Cugno M, Dominguez M, Cabibbe M. et al . Antibodies to tissue-type plasminogen activator in plasma from patients with primary antiphospholipid syndrome. Br J Haematol . 2000; 108 871-875
30 Smirnov M D, Triplett D A, Comp P C. et al . On the role of phosphatidylethanolamine in the inhibition of activated protein C activity by antiphospholipid antibodies. J Clin Invest . 1995; 95 309-316
31 Marciniak E, Romond E H. Impaired catalytic function of activated protein C: a new in vitro manifestation of lupus anticoagulant. Blood . 1989; 74 2426-2432
32 Galli M, Ruggeri L, Barbui T. Differential effects of anti-β2-glycoprotein I antibodies on the anticoagulant activity of activated protein C. Blood . 1998; 91 1999-2004
33 Salemink I, Blezer R, Willems G M. et al . Antibodies to β2-glycoprotein I associated with antiphospholipid syndrome suppress the inhibitory activity of tissue factor pathway inhibitor. Thromb Haemost . 2000; 84 653-656
34 Dobado-Berrios P M, Lopez-Pedrera C, Velasco E. et al . Increased levels of tissue factors mRNA in mononuclear blood cells of patients with primary antiphospholipid syndrome. Thromb Haemost . 1999; 82 1578-1582
35 Galli M, Finazzi G, Duca F, Norbis F, Moia M. The G1691A mutation of factor V, but not the G20210A mutation of factor II or the C677T mutation of methylenetetrahydrofolate reductase genes, is associated with venous thrombosis in patients with lupus anticoagulants. Br J Haematol . 2000; 108 865-870
36 Loizou S, McCrea J D, Rudge A C. et al . Measurement of anticardiolipin antibodies by an enzyme-linked immunosorbent assay: standardization and quantitation of results. Clin Exp Immunol . 1985; 62 739-744
37 Harris E N, Gharavi A E, Patel S, Hughes G RV. Evaluation of the anti-cardiolipin antibody test: report of an international workshop held April 4 1986. Clin Exp Immunol . 1987; 68 215-222
38 Harris E N. The second international anticardiolipin standardization wet workshop/the Kingston Antiphospholipid Antibody study (KAPS) group. Am J Clin Pathol . 1990; 94 476-484
39 Harris E N, Pierangeli S, Birch D. Anticardiolipin wet workshop report: Vth International Symposium on Antiphospholipid Antibodies. Am J Clin Pathol . 1994; 101 616-624
40 Pierangeli S S, Stewart M, Silva L K, Harris E N. Report on anticardiolipin wet workshop during the VIIth International Symposium on antiphospholipid antibodies. J Rheumatol . 1998; 25 156-162
41 Giordano P, Galli M, Del Vecchio G. et al . Lupus anticoagulant, anticardiolipin antibodies and hepatitis C virus infection in thalassemia. Br J Haematol . 1998; 102 903-906
42 Green D, Hougie C, Kazmier F J. Report on the working party on acquired inhibitors of coagulation: studies on the lupus anticoagulant. Thromb Haemost . 1982; 49 144-147
43 Brandt J T, Triplett D A, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulant: an update. Thromb Haemost . 1995; 74 1185-1190
44 Arnout J. Antiphospholipid syndrome: diagnostic aspects of lupus anticoagulants. Thromb Haemost . 2001; 86 83-91
45 Lockshin M D. Pregnancy loss and antiphopsholipid antibodies. Lupus . 1998; 7 S86-S89
46 Lynch A, Marlar R, Murphy J. et al . Antiphospholipid antibodies in predicting adverse pregnancy outcome. A prospective study. Ann Intern Med . 1994; 120 470-475
47 Barbui T, Cortelazzo S, Galli M, et a l, Antiphospholipid antibodies in early repeated abortions: a case-controlled study. Fertil Steril . 1988; 50 589-592
48 Infante-Rivard C, David M, Gauthier R, Rivard G-E. Lupus anticoagulant, anticardiolipin antibodies, and fetal loss. N Engl J Med . 1991; 325 1063-1066
49 Ginsberg J S, Brill-Edwards P, Johnston M. et al . Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus: a cross-sectional study. Blood . 1992; 80 975-980
50 Gris J C, Quéré I, Sanmarco M. et al . Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nimes Obstetricians and Haematologists Study-NOHA. Thromb Haemost . 2000; 84 228-236
51 Balash J, Reverter J C, Creus M. et al . Human reproductive failure is not a clinical feature associated with β2-glycoprotein I antibodies in anticardiolipin and lupus anticoagulant seronegative patients (the antiphospholipid/cofactor syndrome). Hum Reprod . 1999; 14 1956-1959
52 Franklin R D, Hollier N, Kutteh W H. et al . β2-glycoprotein I as a marker of antiphospholipid syndrome in women with recurrent pregnancy loss. Fertil Steril . 2000; 73 531-535
53 Nilsson I M, Astedt B, Hedner U, Berezin D. Intrauterine death and circulating anticoagulant (`antithromboplastin'). Acta Med Scand . 1975; 197 153-159
54 De Wolf F, Carreras L O, Moerman P. et al . Decidual vasculopathy and extensive placental infarction in a patient with repeated thromboembolic accidents, recurrent fetal loss, and a lupus anticoagulant. Am J Obstet Gynecol . 1982; 142 829-834
55 Out H J, Kooijman C D, Bruinse H W, Derksen R H. Histopathological findings in placentae from patients with intra-uterine fetal death and anti-phospholipid antibodies. Eur J Obstet Gynecol Reprod Biol . 1991; 41 179-186
56 Blank M, Cohen J, Toder V, Shoenfeld Y. Induction of anti-phospholipid syndrome in naive mice with mouse lupus monoclonal and human polyclonal anti-cardiolipin antibodies. Proc Natl Acad Sci USA . 1991; 88 3069-3073
57 Bakimer R, Fishman P, Blank M. et al . Induction of primary antiphospholipid syndrome in mice by immunization with a human monoclonal anticardiolipin antibody (H-3). J Clin Invest . 1992; 89 1558-1563
58 Di Simone N, Meroni P L, Del Papa N. et al . Antiphospholipid antibodies affect trophoblast gonadotropin secretion and invasiveness by binding directly and through adhered β2-glycoprotein I. Arthritis Rheum . 2000; 43 140-150
59 Di Simone N, Caliandro D, Castellani R. et al . Low-molecular weight heparin restores in-vitro trophoblast invasiveness and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome. Human Reprod . 1999; 14 489-495
60 Di Simone N, Caliandro D, Castellani R. et al . Interleukin-3 and human trophoblast: in vitro explanations for the effect of interleukin in patients with antiphospholipid syndrome. Fertil Steril . 2000; 73 1194-2000
61 Rai R S, Clifford K, Cohen H, Regan L. High prospective fetal loss rate in untreated pregnancies of women with recurrent miscarriage and antiphospholipid antibodies. Hum Reprod . 1995; 10 3301-3304
62 Kutteh W H. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol . 1996; 174 1584-1589
63 Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriages associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J . 1997; 314 253-257
64 Backos M, Rai R, Baxter N. et al . Pregnancy complications in women with recurrent miscarriage associated with antiphospholipid antibodies treated with low dose heparin and aspirin. Br J Obstet Gynaecol . 1999; 106 102-107
65 Backos M, Rai R, Thomas E. et al . Bone density changes in pregnant women treated with heparin: a prospective, longitudinal study. Hum Reprod . 1999; 14 2876-2880
66 Ruffatti A, Orsini A, Di Leonardo L. et al . A prospective study of fifty-three consecutive calcium heparin treated pregnancies in patients with antiphospholipid antibody-related fetal loss. Clin Exp Rheum . 1997; 15 499-504
67 Ruffatti A, Dalla Barba B, Del Ross T. et al . Outcome of fifty-five newborns of antiphospholipid-positive mothers treated with calcium heparin during pregnancy. Clin Exp Rheum . 1998; 16 605-610
68 Rai R. Obstetric management of antiphospholipid syndrome. J Autoimm . 2000; 15 203-207
69 Lubbe W F, Butler W S, Palmer S J, Liggins G C. Fetal survival after prednisone suppression of maternal lupus-anticoagulant. Lancet . 1983; 1 1361-1363
70 Cowchock F S, Reece E A, Balaban D. et al . Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am J Obstet Gynecol . 1992; 166 1318-1323
71 Silver R K, McGregor S N, Sholl J S. et al . Comparative trial of prednisone plus aspirin versus aspirin alone in the treatment of anticardiolipin-positive obstetric patients. Am J Obstet Gynecol . 1993; 169 1411-1417
72 Lockshin M D, Druzin M l, Qamar T. Prednisone does not prevent recurrent fetal death in women with antiphospholipid antibody. Am J Obstet Gyncol . 1989; 160 439-443
73 Laskin C A, Bombardier C, Hannah M E. et al . Prednisone and aspirin in women with autoantibodies and unexplained recurrent fetal loss. N Engl J Med . 1997; 337 148-153
74 Branch D W, Peaceman A M, Druzin M. et al . A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. Am J Obstet Gynecol . 2000; 182 122-127
75 Daya S, Gunby J, Porter F. et al . Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage. Hum Reprod Update . 1999; 5 475-482
76 Udoff L C, Branch D W. Management of patients with antiphospholipid antibodies undergoing in vitro fertilization. J Autoimm . 2000; 15 209-211
77 Homstein M D, Davis O K, Massey J B. et al . Antiphospholipid antibodies and in vitro fertilization success: a meta-analysis. Fertil Steril . 2000; 73 330-333
78 Petri M, Robinson C. Oral contraceptives and systemic lupus erythematosus. Arthritis Rheum . 1997; 40 797-803
79 Arden N K, Lloyd M E, Spector T D, Hughes G RV. Safety of hormone replacment therapy (HRT) in systemic lupus erythematosus. Lupus . 1994; 3 11-13