Download PDF
Semin Thromb Hemost 2023; 49(08): 833-839
DOI: 10.1055/s-0042-1749590
Review Article

Antiphospholipid Syndrome in Patients with Venous Thromboembolism

Vittorio Pengo
1   Department of Cardio-Thoracic-Vascular Sciences and Public Health, Thrombosis Research Laboratory, University of Padova, Padova, Italy
2   Arianna Foundation on Anticoagulation, Bologna, Italy
,
Gentian Denas
1   Department of Cardio-Thoracic-Vascular Sciences and Public Health, Thrombosis Research Laboratory, University of Padova, Padova, Italy
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Unprovoked (or provoked by mild risk factors) venous thromboembolism (VTE) in young patients, VTE in uncommon sites, or cases of unexplained VTE recurrence may be positive for antiphospholipid antibodies (aPL) and thus may be diagnosed with antiphospholipid syndrome (APS). The evaluation of aPL is standardized using immunological tests for anticardiolipin and anti-β2-glycoprotein I. The determination of functional antibodies (lupus anticoagulant) is less standardized, especially in patients on anticoagulant treatment. Patients positive for all the three tests are at high risk of recurrence, which, in turn, might lead to chronic obstruction of pulmonary vessels (chronic thromboembolic pulmonary hypertension). Randomized clinical trials have shown that triple-positive patients should be treated with vitamin K antagonists maintaining an international normalized ratio between 2 and 3. Whether patients with VTE and incomplete aPL profile can be treated with direct oral anticoagulants should be further investigated.

Keywords -  


Publication History

Article published online:
21 June 2022

© 2022. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Miyakis S, Lockshin MD, Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4 (02) 295-306
    CrossrefPubMedGoogle Scholar
  • 2 Cervera R, Piette JC, Font J. et al; Euro-Phospholipid Project Group. Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum 2002; 46 (04) 1019-1027
    CrossrefPubMedGoogle Scholar
  • 3 Andreoli L, Chighizola CB, Banzato A, Pons-Estel GJ, Ramire de Jesus G, Erkan D. Estimated frequency of antiphospholipid antibodies in patients with pregnancy morbidity, stroke, myocardial infarction, and deep vein thrombosis: a critical review of the literature. Arthritis Care Res (Hoboken) 2013; 65 (11) 1869-1873
    CrossrefPubMedGoogle Scholar
  • 4 Kearon C, Parpia S, Spencer FA. et al. Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism. Blood 2018; 131 (19) 2151-2160
    CrossrefPubMedGoogle Scholar
  • 5 Klok FA, Ageno W, Ay C. et al. Optimal follow-up after acute pulmonary embolism: a position paper of the European Society of Cardiology Working Group on Pulmonary Circulation and Right Ventricular Function, in collaboration with the European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology, endorsed by the European Respiratory Society. Eur Heart J 2022; 43 (03) 183-189
    CrossrefPubMedGoogle Scholar
  • 6 Devreese KMJ, Ortel TL, Pengo V, de Laat B. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. Laboratory criteria for antiphospholipid syndrome: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (04) 809-813
    CrossrefPubMedGoogle Scholar
  • 7 Farmer-Boatwright MK, Roubey RA. Venous thrombosis in the antiphospholipid syndrome. Arterioscler Thromb Vasc Biol 2009; 29 (03) 321-325
    CrossrefPubMedGoogle Scholar
  • 8 Calvo-Alén J, Toloza SM, Fernández M. et al; LUMINA Study Group. Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum 2005; 52 (07) 2060-2068
    CrossrefPubMedGoogle Scholar
  • 9 Chung WS, Lin CL, Chang SN, Lu CC, Kao CH. Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study. J Thromb Haemost 2014; 12 (04) 452-458
    CrossrefPubMedGoogle Scholar
  • 10 Ruffatti A, De Silvestro G, Marson P. et al. Catastrophic antiphospholipid syndrome: Lessons from 14 cases successfully treated in a single center. A narrative report. J Autoimmun 2018; 93: 124-130
    CrossrefPubMedGoogle Scholar
  • 11 Anderson M, Belmont HM. Severe thrombotic events associated with pre-procedural interruption of anticoagulation in systemic lupus erythematosus with secondary antiphospholipid syndrome: Cases and literature review. Lupus 2022; 31 (02) 261-267
    CrossrefPubMedGoogle Scholar
  • 12 Hoxha A, Banzato A, Ruffatti A, Pengo V. Detection of lupus anticoagulant in the era of direct oral anticoagulants. Autoimmun Rev 2017; 16 (02) 173-178
    CrossrefPubMedGoogle Scholar
  • 13 van Os GM, de Laat B, Kamphuisen PW, Meijers JC, de Groot PG. Detection of lupus anticoagulant in the presence of rivaroxaban using Taipan snake venom time. J Thromb Haemost 2011; 9 (08) 1657-1659
    CrossrefPubMedGoogle Scholar
  • 14 Tripodi A, Scalambrino E, Chantarangkul V. et al. Impact of a commercially available DOAC absorbent on two integrated procedures for lupus anticoagulant detection. Thromb Res 2021; 204: 32-39
    CrossrefPubMedGoogle Scholar
  • 15 Tektonidou MG, Andreoli L, Limper M, Tincani A, Ward MM. Management of thrombotic and obstetric antiphospholipid syndrome: a systematic literature review informing the EULAR recommendations for the management of antiphospholipid syndrome in adults. RMD Open 2019; 5 (01) e000924
    CrossrefPubMedGoogle Scholar
  • 16 Pengo V. Additional laboratory tests to improve on the diagnosis of antiphospholipid syndrome: Response from Pengo. J Thromb Haemost 2020; 18 (11) 3118-3119
    CrossrefPubMedGoogle Scholar
  • 17 Pengo V, Ruffatti A, Legnani C. et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost 2010; 8 (02) 237-242
    CrossrefPubMedGoogle Scholar
  • 18 Pengo V, Ruffatti A, Legnani C. et al. Incidence of a first thromboembolic event in asymptomatic carriers of high-risk antiphospholipid antibody profile: a multicenter prospective study. Blood 2011; 118 (17) 4714-4718
    CrossrefPubMedGoogle Scholar
  • 19 Ruffatti A, Tonello M, Del Ross T. et al. Antibody profile and clinical course in primary antiphospholipid syndrome with pregnancy morbidity. Thromb Haemost 2006; 96 (03) 337-341
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Pengo V, Ruffatti A, Del Ross T. et al. Confirmation of initial antiphospholipid antibody positivity depends on the antiphospholipid antibody profile. J Thromb Haemost 2013; 11 (08) 1527-1531
    CrossrefPubMedGoogle Scholar
  • 21 Rampazzo P, Biasiolo A, Garin J. et al. Some patients with antiphospholipid syndrome express hitherto undescribed antibodies to cardiolipin-binding proteins. Thromb Haemost 2001; 85 (01) 57-62
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Pengo V, Ruffatti A, Tonello M. et al. Antibodies to Domain 4/5 (Dm4/5) of β2-Glycoprotein 1 (β2GP1) in different antiphospholipid (aPL) antibody profiles. Thromb Res 2015; 136 (01) 161-163
    CrossrefPubMedGoogle Scholar
  • 23 Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood 2003; 101 (05) 1827-1832
    CrossrefPubMedGoogle Scholar
  • 24 de Laat B, Derksen RH, Urbanus RT, de Groot PG. IgG antibodies that recognize epitope Gly40-Arg43 in domain I of beta 2-glycoprotein I cause LAC, and their presence correlates strongly with thrombosis. Blood 2005; 105 (04) 1540-1545
    CrossrefPubMedGoogle Scholar
  • 25 Pengo V, Testa S, Martinelli I. et al. Incidence of a first thromboembolic event in carriers of isolated lupus anticoagulant. Thromb Res 2015; 135 (01) 46-49
    CrossrefPubMedGoogle Scholar
  • 26 Pengo V, Biasiolo A, Pegoraro C, Cucchini U, Noventa F, Iliceto S. Antibody profiles for the diagnosis of antiphospholipid syndrome. Thromb Haemost 2005; 93 (06) 1147-1152
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 de Groot PG, Lutters B, Derksen RH, Lisman T, Meijers JC, Rosendaal FR. Lupus anticoagulants and the risk of a first episode of deep venous thrombosis. J Thromb Haemost 2005; 3 (09) 1993-1997
    CrossrefPubMedGoogle Scholar
  • 28 Pengo V, Biasiolo A, Gresele P. et al. A comparison of lupus anticoagulant-positive patients with clinical picture of antiphospholipid syndrome and those without. Arterioscler Thromb Vasc Biol 2007; 27 (12) e309-e310
    CrossrefPubMedGoogle Scholar
  • 29 Pengo V. Additional laboratory tests to improve on the diagnosis of antiphospholipid syndrome. J Thromb Haemost 2020; 18 (08) 1846-1848
    CrossrefPubMedGoogle Scholar
  • 30 Kaul M, Erkan D, Sammaritano L, Lockshin MD. Assessment of the 2006 revised antiphospholipid syndrome classification criteria. Ann Rheum Dis 2007; 66 (07) 927-930
    CrossrefPubMedGoogle Scholar
  • 31 Brouwer JL, Bijl M, Veeger NJ, Kluin-Nelemans HC, van der Meer J. The contribution of inherited and acquired thrombophilic defects, alone or combined with antiphospholipid antibodies, to venous and arterial thromboembolism in patients with systemic lupus erythematosus. Blood 2004; 104 (01) 143-148
    CrossrefPubMedGoogle Scholar
  • 32 Cattini MG, Bison E, Pontara E, Cheng C, Denas G, Pengo V. Tetra positive thrombotic antiphospholipid syndrome: Major contribution of anti-phosphatidyl-serine/prothrombin antibodies to lupus anticoagulant activity. J Thromb Haemost 2020; 18 (05) 1124-1132
    CrossrefPubMedGoogle Scholar
  • 33 Pengo V, Banzato A, Bison E, Zoppellaro G, Padayattil Jose S, Denas G. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome: Rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome (TRAPS) trial. Lupus 2016; 25 (03) 301-306
    CrossrefPubMedGoogle Scholar
  • 34 Pengo V, Denas G, Zoppellaro G. et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018; 132 (13) 1365-1371
    CrossrefPubMedGoogle Scholar
  • 35 Cerdà P, Becattini C, Iriarte A, Hernández JC, Corbella X, Riera-Mestre A. Direct oral anticoagulants versus vitamin K antagonists in antiphospholipid syndrome: A meta-analysis. Eur J Intern Med 2020; 79: 43-50
    CrossrefPubMedGoogle Scholar
  • 36 Cohen H, Hunt BJ, Efthymiou M. et al; RAPS trial investigators. Rivaroxaban versus warfarin to treat patients with thrombotic antiphospholipid syndrome, with or without systemic lupus erythematosus (RAPS): a randomised, controlled, open-label, phase 2/3, non-inferiority trial. Lancet Haematol 2016; 3 (09) e426-e436
    CrossrefPubMedGoogle Scholar
  • 37 Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M. et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med 2019; 171 (10) 685-694
    CrossrefPubMedGoogle Scholar
  • 38 Woller SC, Stevens SM, Kaplan D. et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv 2022; 6 (06) 1661-1670
    CrossrefPubMedGoogle Scholar
  • 39 Pengo V, Ruiz-Irastorza G, Denas G, Andreoli L, Khamashta M, Tincani A. High intensity anticoagulation in the prevention of the recurrence of arterial thrombosis in antiphospholipid syndrome: ‘PROS’ and ‘CONS’. Autoimmun Rev 2012; 11 (08) 577-580
    CrossrefPubMedGoogle Scholar
  • 40 Rosove MH, Brewer PM. Antiphospholipid thrombosis: clinical course after the first thrombotic event in 70 patients. Ann Intern Med 1992; 117 (04) 303-308
    CrossrefPubMedGoogle Scholar
  • 41 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332 (15) 993-997
    CrossrefPubMedGoogle Scholar
  • 42 Krnic-Barrie S, O'Connor CR, Looney SW, Pierangeli SS, Harris EN. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997; 157 (18) 2101-2108
    CrossrefPubMedGoogle Scholar
  • 43 Finazzi G, Marchioli R, Brancaccio V. et al. A randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS). J Thromb Haemost 2005; 3 (05) 848-853
    CrossrefPubMedGoogle Scholar
  • 44 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 (12) 1133-1138
    CrossrefPubMedGoogle Scholar
  • 45 Tektonidou MG, Andreoli L, Limper M. et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis 2019; 78 (10) 1296-1304
    CrossrefPubMedGoogle Scholar
  • 46 Nuri E, Taraborelli M, Andreoli L. et al. Long-term use of hydroxychloroquine reduces antiphospholipid antibodies levels in patients with primary antiphospholipid syndrome. Immunol Res 2017; 65 (01) 17-24
    CrossrefPubMedGoogle Scholar
  • 47 Comarmond C, Jego P, Veyssier-Belot C. et al. Cessation of oral anticoagulants in antiphospholipid syndrome. Lupus 2017; 26 (12) 1291-1296
    CrossrefPubMedGoogle Scholar
  • 48 Asherson RA. The catastrophic antiphospholipid syndrome. J Rheumatol 1992; 19 (04) 508-512
    PubMedGoogle Scholar
  • 49 Asherson RA, Cervera R, de Groot PG. et al; Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003; 12 (07) 530-534
    CrossrefPubMedGoogle Scholar
  • 50 Pontara E, Banzato A, Bison E. et al. Thrombocytopenia in high-risk patients with antiphospholipid syndrome. J Thromb Haemost 2018; 16 (03) 529-532
    CrossrefPubMedGoogle Scholar
  • 51 Legault K, Schunemann H, Hillis C. et al. McMaster RARE-Bestpractices clinical practice guideline on diagnosis and management of the catastrophic antiphospholipid syndrome. J Thromb Haemost 2018
    PubMedGoogle Scholar
  • 52 Ruffatti A, Tarzia V, Fedrigo M. et al. Evidence of complement activation in the thrombotic small vessels of a patient with catastrophic antiphospholipid syndrome treated with eculizumab. Autoimmun Rev 2019; 18 (05) 561-563
    CrossrefPubMedGoogle Scholar
  • 53 Keogh AM, Mayer E, Benza RL. et al. Interventional and surgical modalities of treatment in pulmonary hypertension. J Am Coll Cardiol 2009; 54 (1, Suppl): S67-S77
    CrossrefPubMedGoogle Scholar
  • 54 Galiè N, Hoeper MM, Humbert M. et al; ESC Committee for Practice Guidelines (CPG). Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 2009; 30 (20) 2493-2537
    CrossrefPubMedGoogle Scholar
  • 55 Pengo V, Lensing AW, Prins MH. et al; Thromboembolic Pulmonary Hypertension Study Group. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350 (22) 2257-2264
    CrossrefPubMedGoogle Scholar
  • 56 Pepke-Zaba J, Delcroix M, Lang I. et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011; 124 (18) 1973-1981
    CrossrefPubMedGoogle Scholar
  • 57 Schulman S, Svenungsson E, Granqvist S. Duration of Anticoagulation Study Group. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998; 104 (04) 332-338
    CrossrefPubMedGoogle Scholar
  • 58 Garcia D, Akl EA, Carr R, Kearon C. Antiphospholipid antibodies and the risk of recurrence after a first episode of venous thromboembolism: a systematic review. Blood 2013; 122 (05) 817-824
    CrossrefPubMedGoogle Scholar
  • 59 Cheng CY, Zhang YX, Denas G, Du Y, Jing ZC, Pengo V. Prevalence of antiphospholipid (aPL) antibodies among patients with chronic thromboembolic pulmonary hypertension: a systematic review and meta-analysis. Intern Emerg Med 2019; 14 (04) 521-527
    CrossrefPubMedGoogle Scholar
  • 60 Jiang X, Du Y, Cheng CY. et al. Antiphospholipid syndrome in chronic thromboembolic pulmonary hypertension: a well-defined subgroup of patients. Thromb Haemost 2019; 119 (09) 1403-1408
    Article in Thieme ConnectPubMedGoogle Scholar