Guideline sources The following summarized guidelines for the evaluation and management of antiphospholipid syndrome (APS) are prepared by our editorial team based on guidelines from the European League Against Rheumatism (EULAR 2022; 2019), the European Society for Vascular Surgery (ESVS 2021), the American College of Chest Physicians (ACCP 2021), the American College of Rheumatology (ACR 2020), the International Society on Thrombosis and Haemostasis (ISTH 2020), the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE initiative 2017), the European Association for the Study of the Liver (EASL 2016), the American College of Obstetricians and Gynecologists (ACOG 2012), and the British Society for Haematology (BSH 2012). 1 2 3 4 5 6 7 8 9 10 11 12 13 13 14 14 Definition APS is a systemic autoimmune disease characterized by thrombotic or obstetrical events in the presence of antiphospholipid antibodies. 12 Epidemiology APS is caused by autoantibodies targeting phospholipid-bound proteins, mainly -2-glycoprotein I. 14 https://web.pathway.md/diseases/recoC2V41a1ihCnHc 1/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway Pathophysiology The prevalence of antiphospholipid antibodies in the general population is estimated at 1-5%. In the United States, the estimated incidence and prevalence of APS are 5 cases per 100,000 person- years and 40-50 persons per 100,000 populations, respectively. 13 Disease course The interaction of antiphopholipid autoantibodies with phospholipid-binding plasma proteins ( -2- glycoprotein I, prothrombin, thrombomodulin, kininogens, antithrombin III, annexins, protein C, and protein S) results in activation of monocytes, endothelial cells, platelets, and the complement system, inducing a prothrombotic state that leads to inflammation, vasculopathy, venous/arterial thrombosis, and obstetric complications. 14 Prognosis and risk of recurrence APS is associated with morbidity related to stroke (13%), myocardial infarction (11%), deep vein thrombosis (9.5%), and pregnancy (6%). 13 Calculator Calculator Pathway Classification criteria for antipho Classification criteria for catastr Antiphosp Investigatio Guidelines 1. Screening and diagnosis Indications for screening: as per BSH 2012 guidelines, screen women with 3 pregnancy losses before 10 weeks gestation for antiphospholipid antibodies. B Show 3 more 2. Classification and risk stratification Risk stratification: as per EULAR 2019 guidelines, stratify patients with APS into high-risk, medium-risk, and low-risk phenotypes: Situation Guidance Multiple antiphospholipid antibodies High-risk Lupus anticoagulant or persistently high antiphospholipid antibody titers History of thrombotic and/or obstetric APS https://web.pathway.md/diseases/recoC2V41a1ihCnHc 2/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway Coexistence of other systemic autoimmune diseases such as SLE And presence of traditional cardiovascular risk factors Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma present in titers > 40 IgG phospholipid units or > 40 IgM phospholipid units, or >the 99th percentile, measured by a standardised ELISA Medium-risk Anti- -2-glycoprotein I antibody of IgG and/or IgM isotype in serum or plasma in titer > the 99th percentile, measured by a standardised ELISA Isolated anticardiolipin antibody or anti- -2- glycoprotein I antibodies at low-medium titers, particularly if transiently positive. B Low-risk Classification: diagnose antiphospholipid antibody syndrome in patients meeting laboratory criteria on two or more occasions at least 12 weeks apart, in addition to either thrombotic criteria or obstetrical criteria. 3. Diagnostic investigations Initial laboratory testing: obtain lupus anticoagulant testing and testing for IgG antibodies to -2- glycoprotein I (either IgG anticardiolipin ELISA or an IgG anti- -2-glycoprotein I ELISA). An anticardiolipin ELISA may detect antibodies to other phospholipid binding proteins as well as anti- -2-glycoprotein I. B Confirmatory testing: perform a confirmatory test (e.g., using a high phospholipid concentration, platelet neutralizing reagent or a lupus-anticoagulant insensitive reagent) to definitively establish the presence of lupus anticoagulant. A Non-IgG antibodies: Avoid measuring anticardiolipin IgM antibodies in patients with thrombosis, as it does not provide additional information that will impact management. D Avoid measuring anticardiolipin IgA antibodies. D Screening for portal vein thrombosis: consider screening for extrahepatic portal vein obstruction in patients with APS. C 4. Medical management General principles: https://web.pathway.md/diseases/recoC2V41a1ihCnHc 3/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway Screen for and manage cardiovascular risk factors appropriately in patients with antiphospholipid antibodies, including smoking cessation counseling; management of hypertension, dyslipidemia and diabetes; and promotion of regular physical activity. B Screen for and manage risk factors for venous thrombosis, and use LMWH in high-risk situations such as surgery, hospitalization, prolonged immobilisation and the puerperium. B Management of arterial thrombosis: As per EULAR 2019 guidelines, administer a vitamin K antagonist, rather than low-dose aspirin only, in patients with definite APS and first arterial thrombosis. B Show 3 more Landmark trials: TRAPS In high-risk patients with thrombotic antiphospholipid syndrome, rivaroxaban was not noninferior to warfarin with respect to vascular death, thromboembolic events, or major bleeding. Pengo V et al. Blood. 2018 Sep 27. As per BSH 2012 guidelines, administer antithrombotic therapy consisting of either antiplatelet therapy or warfarin in patients with APS and ischemic stroke with a single positive antiphospholipid antibody test result. B Show 2 more Management of venous thromboembolism: As per ESVS 2021 guidelines, do not use direct OACs in patients with deep vein thrombosis and APS who are triple positive or have a history of arterial or small vessel thrombosis. D As per EULAR 2019 guidelines, initiate a vitamin K antagonist with a target INR 2-3 in patients with definite APS and first venous thrombosis. B Show 2 more Landmark trials: TRAPS In high-risk patients with thrombotic antiphospholipid syndrome, rivaroxaban was not noninferior to warfarin with respect to vascular death, thromboembolic events, or major bleeding. Pengo V et al. Blood. 2018 Sep 27. Duration of treatment for venous thrombosis: As per EULAR 2019 guidelines, aim for long-term anticoagulation in patients with definite APS and first venous thrombosis, and in patients with unprovoked first venous thrombosis. B Show 2 more https://web.pathway.md/diseases/recoC2V41a1ihCnHc 4/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway As per BSH 2012 guidelines: Consider long-term anticoagulation in patients with unprovoked venous thrombosis. Complete a finite duration of treatment for patients with venous thrombosis in the presence of a transient risk factor. Adjustment of vitamin K antagonists: As per ACCP 2021 guidelines, consider adjusting the dose of vitamin K antagonists (target INR 2.5) over initiating direct OAC therapy during the treatment phase in patients with confirmed APS. C As per ESVS 2021 guidelines, consider titrating vitamin K antagonists to maintain a target INR of 2-3 in patients with deep vein thrombosis and triple-positive APS. C As per EULAR 2019 guidelines, target an INR of 2-3 or 3-4 taking into account the patient's risks of bleeding and recurrent thrombosis. B As per BSH 2012 guidelines, target an INR of 2-3 in patients with APS on vitamin K antagonist therapy. A Show 2 more Management of recurrent thrombosis: as per EULAR 2019 guidelines, consider one of the following options in patients with recurrent arterial thrombosis despite adequate treatment with vitamin K antagonist, after evaluating for other potential cause: targeting an INR 3-4 adding low-dose aspirin to current therapy switching to LMWH. C Direct oral anticoagulants: As per ISTH 2020 guidelines, initiate vitamin K antagonists instead of direct OACs for the treatment of thrombotic APS in patients with any of the following (high-risk patients): triple positivity arterial thrombosis small vessel thrombosis or organ involvement heart valve disease according to Sydney criteria. E Show 4 more As per EULAR 2019 guidelines: Do not use direct OACs in patients with definite APS and arterial events due to the high risk of recurrent thrombosis. D Consider initiating direct OACs in patients not able to achieve target INRs despite good adherence to vitamin K antagonists or patients with contraindications to vitamin K antagonists (allergy or intolerance to vitamin K antagonists). C 5. Specific circumstances Considerations for contraception: https://web.pathway.md/diseases/recoC2V41a1ihCnHc 5/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway As per ACR 2020 guidelines: Do not use combined estrogen-progestin contraceptives in women with positive antiphospholipid antibodies because estrogen increases the risk of thromboembolism. D Offer intrauterine devices (levonorgestrel or copper) or progestin-only pills in patients with positive antiphospholipid antibodies. A As per ACOG 2012 guidelines, do not use estrogen-containing contraceptives in patients with APS. D Considerations for hormone replacement therapy: offer HRT, if desired and in the absence of contraindications, in postmenopausal patients with positive antiphospholipid antibodies with severe vasomotor symptoms. A Show 4 more Patients undergoing ART procedures: consider administering empiric prophylactic anticoagulation in antiphospholipid antibody-positive patients undergoing IVF because of the concern regarding further increased risk of potentially life-threatening thrombosis from elevated estrogen levels during ovarian stimulation. E Show 3 more Pregnant patients: As per ACR 2020 guidelines, do not initiate prophylactic therapy for the prevention of pregnancy loss in asymptomatic antiphospholipid antibody-positive patients (without pregnancy complications or history of thrombosis). D Show 10 more As per EULAR 2019 guidelines, consider low-dose aspirin in pregnant women with a high-risk antiphospholipid antibodies profile but no history of thrombosis or pregnancy complications. C Show 5 more As per BSH 2012 guidelines, initiate low-dose aspirin and heparin at prophylactic dosages throughout pregnancy in women with recurrent pregnancy loss ( 3). B Show 2 more Pediatric patients (evaluation): Obtain the following tests in pediatric patients with suspected APS: lupus anticoagulant anticardiolipin IgG and IgM anti- -2-glycoprotein-I IgG and IgM. B Show 3 more Pediatric patients (management): consider initiating antiplatelet agents in addition to hydroxychloroquine for primary prevention of thrombosis in patients with childhood-onset SLE and antiphospholipid antibodies. C Show 5 more Patients with catastrophic antiphospholipid syndrome: https://web.pathway.md/diseases/recoC2V41a1ihCnHc 6/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway As per EULAR 2019 guidelines, initiate antimicrobial therapy promptly in all antiphospholipid antibodies-positive individuals with infection, in order to decrease the risk of catastrophic APS. B Show 3 more As per BSH 2012 guidelines, insufficient evidence to make a recommendation for the treatment of catastrophic APS. A combination of treatments including anticoagulation with heparin/warfarin and immunomodulatory therapies, including plasmapheresis, IVIGs, corticosteroids, and rituximab, have been used. 6. Patient education General counseling: counsel patients on treatment adherence, INR monitoring in patients treated with vitamin K antagonist, use of perioperative bridging therapy with LMWH in patients on OACs, oral contraceptive use, pregnancy and postpartum considerations, postmenopausal hormone therapy, and general lifestyle recommendations. B 7. Preventative measures Primary thromboprophylaxis: As per EULAR 2022 guidelines: Initiate prophylactic treatment with low-dose aspirin (75-100 mg daily) in asymptomatic antiphospholipid antibody carriers with a high-risk profile with or without traditional risk factors. B Initiate prophylactic treatment with low-dose aspirin in patients with SLE with a high-risk antiphospholipid antibody profile and no history of thrombosis or pregnancy complications. B Consider initiating low-dose aspirin in patients with a low-risk antiphospholipid antibody profile. B As per EULAR 2019 guidelines, initiate prophylactic treatment with low-dose aspirin in asymptomatic antiphospholipid antibodies carriers not fulfilling any vascular or obstetric classification criteria, with a high-risk antiphospholipid antibodies profile with or without traditional risk factors. B Show 3 more As per BSH 2012 guidelines, avoid primary thromboprophylaxis in patients incidentally found to have antiphospholipid antibodies. D References 1. Committee on Practice Bulletins Obstetrics, American College of Obstetricians and Gynecologists. Practice Bulletin No. 132 Antiphospholipid syndrome. Obstet Gynecol. 2012 Dec;120 6 1514 21. Open https://web.pathway.md/diseases/recoC2V41a1ihCnHc 7/9 6/23/23, 2:39 AM Antiphospholipid syndrome Pathway 2. Stavros K Kakkos, Manjit Gohel, Niels Baekgaard et al. Editor's Choice European Society for Vascular Surgery ESVS 2021 Clinical Practice Guidelines on the Management of Venous Thrombosis. Eur J Vasc Endovasc Surg. 2021 Jan;61 1 9 82. Open 3. Lisa R Sammaritano, Bonnie L Bermas, Eliza E Chakravarty et al. 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases. Arthritis Care Res Hoboken). 2020 Apr;72 4 461 488. Open 4. Tektonidou MG, Andreoli L, Limper M et al. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019 May 15. Open 5. Keeling D, Mackie I, Moore GW et al. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012 Apr;157 1 47 58. Open 6. 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 Feb;4 2 295 306. Open 7. 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Scott M Stevens, Scott C Woller, Lisa Baumann Kreuziger et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021 Dec;160 6):e545-e608. Open 12. David Garcia, Doruk Erkan. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med. 2018 May 24;378 21 2010 2021. Open 13. Ricard Cervera. Antiphospholipid syndrome. 2017 Mar;151 Suppl 1 S43 S47.2017 Mar;151 Suppl 1 S43 S47. Open 14. Negrini S, Pappalardo F, Murdaca G et al. The antiphospholipid syndrome: from pathophysiology to treatment. Clin Exp Med. 2017 Aug;17 3 257 267. Open 15. Lisa R Sammaritano. Antiphospholipid syndrome. Best Pract Res Clin Rheumatol. 2020 Feb;34 1 101463. Open 16. Joz lio Freire de Carvalho, Sandra Gofinet Pasoto, Simone Appenzeller. Seizures in primary antiphospholipid syndrome: the relevance of smoking to stroke. Clin Dev Immunol. 2012;2012 981519. Open 17. Cervera R. Antiphospholipid syndrome. Thromb Res. 2017 Mar;151 Suppl 1 S43 S47. 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