Rare Thrombotic Diseases Consortium

Antiphospholipid Antibody Syndromes (APS)

The antiphospholipid antibody syndrome (APS) is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that recognize phospholipids or phospholipid-binding cofactors (1). This disorder is classified as primary APS when it occurs in the absence of another autoimmune disorder and is classified as secondary APS if it is diagnosed in the presence of another autoimmune disorder, such as lupus, rheumatoid arthritis, or Sjögren's syndrome. Specific criteria have been developed to define the APS syndrome, known as the Sapporo criteria, which are described below.

Pathophysiology

Antiphospholipid antibodies are associated with increased thrombosis in animal models (2). Several mechanisms whereby these antibodies may result in a prothrombotic state have been proposed, including activation of endothelial cells (3), disruption of natural anticoagulant pathways (4), and enhancement of the tissue factor pathway (5). The thrombotic complications in APS have been compared to the clinical manifestations encountered in patients with heparin-induced thrombocytopenia, another antibody-mediated thrombotic disorder (6).

Epidemiology

Antiphospholipid antibodies are detected in 1% to 5% of normal, healthy individuals, but persistently elevated antibody levels appear to be much less frequent (7). Among patients with lupus, the prevalence of antiphospholipid antibodies ranges from ~15% to 35% (8), and patients with lupus and antiphospholipid antibodies have an increased incidence of thrombosis (1,9). In a prospective, nonrandomized cohort study, the incidence of thrombotic events was 2.5% per patient-year (10). Risk factors associated with an increased risk for thrombosis included a prior thrombotic event and an anticardiolipin IgG antibody titer above 40 units (10). The prevalence of antiphospholipid antibodies in patients presenting with a new venous thrombotic event has been reported to range from 8% to 14% (11,12).

Sapporo Criteria for the classification of the antiphospholipid syndrome (Wilson et al., 1999)

Clinical Criteria

1. Vascular thrombosis

One or more clinical episodes of arterial, venous, or small vessel thrombosis, in any tissue or organ. Thrombosis must be confirmed by imaging or Doppler studies or histopathology, with the exception of superficial venous thrombosis. For histopathologic confirmation, thrombosis should be present without significant evidence of inflammation in the vessel wall.

2. Pregnancy morbidity

One or more unexplained deaths of a morphologically normal fetus at or beyond the 10 th week of gestation, with normal fetus morphology documented by ultrasound or by direct examination of the fetus, or
One of more premature births of a morphologically normal neonate at or before the 34 th week of gestation because of severe preeclampsia, or eclampsia, or severe placental insufficiency, or
Three or more unexplained consecutive spontaneous abortions before the 10 th week of gestation, with maternal anatomic or hormonal abnormalities and paternal and maternal chromosomal causes excluded.

In studies of populations of patients who have more than 1 type of pregnancy morbidity, investigators are strongly encouraged to stratify groups of subjects according to a, b or c above.

Laboratory criteria

Anticardiolipin antibody of IgG and/or IgM isotype in blood, present in medium or high titer, or on 2 or more occasions, at least 6 weeks apart, measured by a standardized enzyme-linked immunosorbent assay for β 2-glycoprotein I-dependent anticardiolipin antibodies.
Lupus anticoagulant present in plasma, on 2 or more occasions at least 6 week apart, detected according to the guidelines of the International Society on Thrombosis and Hemostasis (Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies), in the following steps:
1. Prolonged phospholipid-dependent coagulation demonstrated on a screening test, e.g. activated partial thromboplastin time, kaolin clotting time, dilute Russell’s viper venom time, dilute prothrombin time, Textarin time.
2. Failure to correct the prolonged coagulation time on the screening test by mixing with normal platelet-poor plasma.
3. Shortening or correction of the prolonged coagulation time on the screening test by the addition of excess phospholipid.
4. Exclusion of other coagulopathies, e.g. factor VIII inhibitor or heparin, as appropriate.

Definite antiphospholipid antibody syndrome is considered to be present if at least 1 of the clinical criteria and 1 of the laboratory criteria are met.

Clinical Management

Decisions concerning the clinical management of patients with antiphospholipid antibodies include the following:

Thromboprophylaxis for the asymptomatic patient with elevated antiphospholipid antibody levels. Although aspirin therapy has appeared to decrease thrombosis risks in certain patient populations (15), it was not effective in other settings (16). For patients with lupus and secondary APS, hydroxychloroquine may provide protection against thrombosis (17). If possible, acquired prothrombotic risk factors should be avoided, or thromboprophylactic measures should be considered.
Treatment after a thrombotic event. Long-term anticoagulant therapy is indicated in patients with APS who have sustained an arterial or venous thromboembolic event (18,19). Initial retrospective studies suggested that a higher target INR may be necessary to prevent recurrent thromboembolism in patients with APS (20), but a recent prospective, randomized trial found that high-intensity warfarin (target INR 3.0-4.0) was not superior to standard-intensity warfarin (target INR 2.0-3.0) (21). This study did not include many patients with arterial thromboembolic events, however, and some investigators would still recommend a higher target INR for these patients. It is also important to recognize that the lupus anticoagulant can affect the prothrombin time in a subset of patients with APS, and oral anticoagulant therapy in these patients needs to be monitored using a reagent that is not affected by the presence of a lupus anticoagulant, or with an alternative assay (22,23).
Treatment for patients with poor pregnancy outcome and no history of thrombosis. For women who have sustained recurrent fetal loss, several clinical trials have documented that aspirin with heparin therapy during the pregnancy will result in an improved pregnancy outcome (24,25). Although never directly compared in a randomized clinical trial, it is felt that low molecular weight heparin is likely to be as efficacious as unfractionated heparin for these patients (26). For women with antiphospholipid antibodies and no prior history of venous thrombosis or pregnancy loss, current options include close clinical surveillance, low-dose aspirin, heparin, or low-molecular-weight heparin(27).
Treatment of patients with catastrophic antiphospholipid syndrome . The treatment of this clinical manifestation of APS is discussed in the section on catastrophic APS below.

References

(1) Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med. 2002;346:752-763.

(2) Pierangeli SS, Liu XW, Barker JH et al. Induction of thrombosis in a mouse model by IgG, IgM and IgA immunoglobulins from patients with the antiphospholipid syndrome. Thromb Haemostas. 1995;74:1361-1367.

(3) Del Papa N, Guidali L, Sala A et al. Endothelial cells as target for antiphospholipid antibodies. Human polyclonal and monclonal anti-b2-glycoprotein I antibodies react in vitro with endothelial cells through adherent b2-glycoprotein I and induce endothelial activation. Arthritis Rheum. 1997;40:551-561.

(4) Smirnov MD, Triplett DT, Comp PC 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.

(5) Amengual O, Atsumi T, Khamashta MA, Hughes GRV. The role of the tissue factor pathway in the hypercoagulable state in patients with the antiphospholipid syndrome. Thromb Haemost. 1998;79:276-281.

(6) Arnout J. The pathogenesis of the antiphospholipid syndrome: a hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thromb Haemostas. 1996;75:536-541.

(7) Petri M. Diagnosis of Antiphospholipid Antibodies. Rheum Dis Clin North Am. 1994;20:443-469.

(8) Love PE, Santoro SA. Antiphospholipid antibodies: Anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders. Ann Intern Med. 1990;112:682-698.

(9) Wahl DG, Guillemin F, de Maistre E et al. Risk for venous thrombosis related to antiphospholipid antibodies in systemic lupus erythematosus -- a meta-analysis. Lupus. 1997;6:467-473.

(10) Finazzi G, Brancaccio V, Moia M et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four year prospective study from the Italian registry. Am J Med. 1996;100:530-536.

(11) Ginsberg JS, Wells PS, Brill-Edwards P et al. Antiphospholipid antibodies and venous thromboembolism. Blood. 1995;86:3685-3691.

(12) Simioni P, Prandoni P, Zanon E et al. Deep venous thrombosis and lupus anticoagulant. A case-control study. Thromb Haemost. 1996;76:187-189.

(13) Wilson WA, Gharavi AE, Koike T et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome: report of an international workshop. Arthritis Rheum. 1999;42:1309-1311.

(14) Brandt JT, Triplett DA, Alving B, Scharrer I. Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemostas. 1995;74:1185-1190.

(15) Erkan D, Merrill JT, Yazici Y et al. High thrombosis rate after fetal loss in antiphospholipid syndrome: effective prophylaxis with aspirin. Arthritis Rheum. 2001;44:1466-1467.

(16) Ginsburg KS, Liang MH, Newcomer L et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med. 1992;117:997-1002.

(17) Petri M. Hydroxychloroquine use in the Baltimore Lupus Cohort: effects on lipids, glucose and thrombosis. Lupus. 1996;5 (Suppl 1):S16-S22.

(18) Buller HR, Agnelli G, Hull RD et al. Antithrombotic therapy for venous thromboembolic disease. The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest. 2004;126 (Supplement):401S-428S.

(19) Schulman S, Svenungsson E, Granqvist S, et al. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104:332-338.

(20) Khamashta MA, Cuadrado MJ, Mujic F et al. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med. 1995;332:993-997.

(21) Crowther MA, Ginsberg JS, Julian J et al. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome. N Engl J Med. 2003;349:1133-1138.

(22) Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med. 1997;127:177-185.

(23) Tripodi A, Chantarangkul V, Clerici M et al. Laboratory control of oral anticoagulant treatment by the INR system in patients with antiphospholipid syndrome and lupus anticoagulant. Results of a collaborative study involving nine commercial thrombplastins. Br J Haematol. 2001;115:672-678.

(24) Rai R, Cohen H, Dave M, Regan L. Randomized controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). Br Med J. 1997;314:253-257.

(25) Kutteh WH, Ermel LD. A clinical trial for the treatment of antiphospholipid antibody-associated recurrent pregnancy loss with lower dose heparin and aspirin. Am J Reprod Immunol. 1996;35:402-407.

(26) James AH, Brancazio LR, Ortel TL. Thrombosis, thrombophilia, and thromboprophylaxis in pregnancy. Clin Adv Hematol Oncol. In press.

(27) Bates SM, Greer IA, Hirsh J, Ginsberg JS. Use of antithrombotic agents during pregnancy: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126 (Supplement):627S-644S.

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