Antiphospholipid antibody syndrome

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Overview

• Antiphospholipid syndrome (APS) is an acquired hypercoagulable state causing increased risk of thrombosis or pregnancy-related adverse outcomes.
• Patients who have persistently positive antiphospholipid antibodies plus a thrombotic event meet criteria for thrombotic APS (TAPS) and warrant long-term anticoagulation for secondary thrombosis prevention.

Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

• Long-term anticoagulation with vitamin K antagonists remains the mainstay of treatment of APS patients.
• Studies have shown superiority of vitamin K antagonists such as warfarin versus direct oral anticoagulants (DOACs) for secondary prevention of thrombosis in patients with high risk, triple positive APS.
• The evidence for the efficacy of DOACs in patients with single and double positive APS remains unclear and societal guidelines differ as to the use of DOACs in patients with TAPS who do not have triple positive disease.

British Society for Haemotology (BSH)

• 2020: Arachchillage et al. Addendum to British Society for Haematology Guidelines on Investigation and Management of Antiphospholipid syndrome, 2012 (Br. J. Haematol. 2012; 157: 47–58): use of direct acting oral anticoagulants PubMed

• 2012: Keeling et al. Guidelines on the investigation and management of antiphospholipid syndrome PubMed

European League Against Rheumatism (EULAR)

• 2019: Tektonidou et al. EULAR recommendations for the management of antiphospholipid syndrome in adults PubMed

International Society on Thrombosis and Haemostasis (ISTH)

• 2020: Zuily et al. Use of direct oral anticoagulants in patients with thrombotic antiphospholipid syndrome: Guidance from the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis PubMed

All lines of therapy

Aspirin & Warfarin

Regimen

Study	Evidence	Comparator	Efficacy
Okuma et al. 2009	Phase 3 (E-esc)	Aspirin	Lower cumulative incidence of ischemic stroke (primary endpoint)

Note: Small study of 20 patients. All meeting the 2006 Sydney criteria for APS in setting of an ischemic stroke.

Anticoagulation

• Warfarin (Coumadin) PO with INR goal 2 to 3.0
• Aspirin 100 mg PO once per day

Continued indefinitely

References

1. Okuma H, Kitagawa Y, Yasuda T, Tokuoka K, Takagi S. Comparison between single antiplatelet therapy and combination of antiplatelet and anticoagulation therapy for secondary prevention in ischemic stroke patients with antiphospholipid syndrome. Int J Med Sci. 2009 Dec 5;7(1):15-8. link to original article link to PMC article PubMed

Rituximab monotherapy

Regimen

Study	Evidence	Efficacy
Erkan et al. 2013 (RITAPS)	Phase 2	Some improvement in non-criteria manifestations of APS

Note: This small phase 2 study (19 patients) did not identify any significant change in the antiphospholipid antibody profiles of the enrolled patients, but it did observe some improvements in the non-criteria manifestations of APS. This included thrombocytopenia, cardiac valve disease, skin ulcer, aPL nephropathy, and cognitive dysfunction.

Immunosuppressive therapy

• Rituximab (Rituxan) 1000 mg IV once on day 1

14-day cycle for 2 cycles

References

1. RITAPS: Erkan D, Vega J, Ramon G, Kozora E, Lockshin MD. A pilot open-label phase II trial of rituximab for non-criteria manifestations of antiphospholipid syndrome. Arthritis Rheum. 2013 Feb;65(2):464-71. link to original article PubMed

Rivaroxaban monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Cohen et al. 2016 (RAPS)	Phase 2/3 (E-switch-ooc)	Warfarin	Inconclusive whether non-inferior percent change in endogenous thrombin potential (primary endpoint)
Pengo et al. 2018 (TRAPS)	Phase 3 (E-switch-ooc)	Warfarin	Higher rate of thromboembolic events, major bleeding, and vascular death (primary endpoint)

Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm. Although we include here for historical context, this regimen should not be used outside of the context of a clinical trial.

Anticoagulation

• Rivaroxaban (Xarelto) PO 20 mg PO once per day

Continued indefinitely

References

1. RAPS: Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; 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 Sep;3(9):e426-36. link to original article link to PMC article PubMed ISRCTN68222801
2. TRAPS: Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. link to original article PubMed NCT02157272

Warfarin monotherapy

Regimen

Study	Evidence	Comparator	Efficacy
Crowther et al. 2003	Phase 3 (C)	Warfarin; high-intensity (INR 3.1 to 4.0)	Did not meet primary endpoint of recurrent VTE
Finazzi et al. 2005 (WAPS)	Phase 3 (C)	Warfarin; high-intensity (INR 3 to 4.5)	Did not meet primary endpoint of recurrent symptomatic VTE
Cohen et al. 2016 (RAPS)	Phase 2/3 (C)	Rivaroxaban	Inconclusive whether non-inferior percent change in endogenous thrombin potential
Pengo et al. 2018 (TRAPS)	Phase 3 (C)	Rivaroxaban	Fewer events
Ordi-Ros et al. 2019 (SAP-02)	Phase 2/3 (C)	Rivaroxaban	Inconclusive whether non-inferior new VTE

Note: TRAPS was closed prematurely due to excess events in the rivaroxaban arm.

Anticoagulation

• Warfarin (Coumadin) PO titrated to goal INR 2 to 3.0
  • Note: some trials specify a goal INR 2.5 without a range given

Continued indefinitely

References

1. Crowther MA, Ginsberg JS, Julian J, Denburg J, Hirsh J, Douketis J, Laskin C, Fortin P, Anderson D, Kearon C, Clarke A, Geerts W, Forgie M, Green D, Costantini L, Yacura W, Wilson S, Gent M, Kovacs MJ. 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 Sep 18;349(12):1133-8. Erratum in: N Engl J Med. 2004 Jul 8;351(2):200. N Engl J Med. 2003 Dec 25;349(26):2577. link to original article PubMed
2. WAPS: Finazzi G, Marchioli R, Brancaccio V, Schinco P, Wisloff F, Musial J, Baudo F, Berrettini M, Testa S, D'Angelo A, Tognoni G, Barbui T. 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 May;3(5):848-53. link to original article PubMed
3. RAPS: Cohen H, Hunt BJ, Efthymiou M, Arachchillage DR, Mackie IJ, Clawson S, Sylvestre Y, Machin SJ, Bertolaccini ML, Ruiz-Castellano M, Muirhead N, Doré CJ, Khamashta M, Isenberg DA; 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 Sep;3(9):e426-36. link to original article link to PMC article PubMed ISRCTN68222801
4. TRAPS: Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. Epub 2018 Jul 12. link to original article PubMed NCT02157272
5. SAP-02: Ordi-Ros J, Sáez-Comet L, Pérez-Conesa M, Vidal X, Riera-Mestre A, Castro-Salomó A, Cuquet-Pedragosa J, Ortiz-Santamaria V, Mauri-Plana M, Solé C, Cortés-Hernández J. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: a randomized noninferiority trial. Ann Intern Med. 2019 Nov 19;171(10):685-694. Epub 2019 Oct 15. link to original article PubMed EudraCT 2010-019764-36