Tektonidou MG, Andreoli L, Limper M. EULAR recommendations for the management of antiphospholipid syndrome in adults. Ann Rheum Dis. 2019 Oct;78(10):1296-1304. doi: 10.1136/annrheumdis-2019-215213. Epub 2019 May 15. PMID: 31092409.
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 Jun 7. doi: 10.1111/jth.14192. [Epub ahead of print] PubMed PMID: 29978552.
Ruiz-Irastorza G, Cuadrado MJ, Ruiz-Arruza I, et al. Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies. Lupus. 2011 Feb;20(2):206-18. doi: 10.1177/0961203310395803. PubMed PMID: 21303837.
Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic antiphospholipid syndrome. Curr Rheumatol Rep. 2010 Feb;12(1):70-6. doi: 10.1007/s11926-009-0073-6. Review. PubMed PMID: 20425537.
Cohen D, Berger SP, Steup-Beekman GM, Bloemenkamp KW, Bajema IM. Diagnosis and management of the antiphospholipid syndrome. BMJ. 2010 May 14;340:c2541. doi: 10.1136/bmj.c2541. Review. PubMed PMID: 20472677.
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. PubMed PMID: 16420554.
Definition, Etiology, PathogenesisTop
Antiphospholipid syndrome (APS) is a disease proposed to be caused by autoantibodies directed against protein-phospholipid complexes. It manifests as venous thrombosis, arterial thrombosis, and/or pregnancy morbidity. The etiology is unknown. Complications are attributed to procoagulant effects of antiphospholipid antibodies (APLAs): lupus anticoagulant (LA), anticardiolipin (aCL) antibodies, and anti–beta2-glycoprotein (GP) I antibodies. APS may be either primary (not related to any other disorder) or secondary (associated with another autoimmune disease, which in 30%-50% of cases is systemic lupus erythematosus [SLE]). Seronegative APS with clinical features of APS but no detectable serum antibodies has also been described.
Clinical Features and Natural HistoryTop
Clinical manifestations depend on the vascular bed affected by thrombosis. Two-thirds of symptomatic patients have venous thrombosis.
1. Arterial or venous extremity thrombosis: Deep vein thrombosis (DVT) constitutes a large majority of thrombotic events, although otherwise unprecipitated arterial thrombosis is also well described; arterial thrombosis can present with acute limb ischemia or with a chronic arterial insufficiency pattern.
2. Vascular thrombosis of visceral organs may or may not be symptomatic and can affect any internal organ:
1) Pulmonary involvement: Typically manifests as pulmonary embolism, or rarely as pulmonary hypertension of thrombotic etiology or as diffuse alveolar hemorrhage secondary to small vessel capillaritis.
2) Cardiac involvement: The heart can be affected by thickening of the valve leaflets and impairment of the valvular function (mainly affecting the mitral valve, less commonly the aortic valve), small valvular vegetations (due to noninfective endocarditis, a risk factor for cerebrovascular accidents), diffuse myocardial injury, or acute coronary artery thrombosis.
3) Renal involvement: >30% of patients develop renal thrombotic microangiopathy associated with hypertension, proteinuria of varying severity, microscopic hematuria, and mildly elevated serum creatinine levels. Symptomatic renal artery or vein thrombosis and renal infarcts are rare (<3% of patients).
4) Involvement of other abdominal organs is rare and may result in esophageal or intestinal ischemia or infarcts of the liver, spleen, pancreas, or adrenal glands, causing Addison disease; Addison disease should be considered in all patients with a history of aggressive APS. Hepatic thrombosis may also occur.
3. Vascular thrombosis of the central nervous system (~20% of patients) may cause ischemic stroke or transient ischemic attacks and is a leading cause of stroke in young patients. Recurrent strokes (including mild or asymptomatic microinfarcts manifesting as diffuse “white matter disease” on magnetic resonance imaging [MRI]) may lead to cognitive impairment or neuropsychiatric manifestations.
4. Thrombosis of the ocular vessels: Retinal artery or central retinal vein thrombosis can lead to transient loss of vision (amaurosis fugax) or optic neuritis.
5. Cutaneous manifestations: The most typical feature is livedo reticularis; less frequently observed manifestations are ischemic ulcers and cutaneous necrosis.
6. Musculoskeletal manifestations: About 40% of patients exhibit arthralgia; inflammatory arthritis is rare in the absence of SLE. Aseptic bone necrosis is rare.
7. Obstetric and fetal manifestations: Possible manifestations include fetal loss, premature birth, preeclampsia, placental insufficiency, and fetal growth retardation (Table 18.4-1).
8. Catastrophic APS (CAPS): A subset of APS affecting <1% of individuals. CAPS is characterized by thrombosis in ≥3 organ systems occurring simultaneously or within a span of 1 week. The most common organ systems involved are kidneys, although involvement of virtually every organ system has been described. CAPS may be triggered by infections, surgical procedures, discontinuation of antithrombotic agents, subtherapeutic international normalized ratio (INR) levels on vitamin K antagonist (VKA) treatment, drugs, trauma, and stress. Symptoms depend on the site of thrombosis and include fever, dyspnea, abdominal pain, peripheral edema, cutaneous manifestations (purpura, livedo reticularis, necrosis), and altered mental status. Multisystem organ failure can ensue. Hematologic abnormalities can include thrombocytopenia, hemolytic anemia, and features of activation of the coagulation cascade. Mortality rates are as high as 50%. CAPS may be due to a combination of autoimmune APS in a patient with an underlying, usually genetic, complement regulation disorder. It may be the first clinical presentation of APS.
See Table 18.4-1.
1. Laboratory tests: LA should be identified based on the International Society on Thrombosis and Haemostasis (ISTH) recommendations. Details: see Table 18.4-1; see www.onlinelibrary.wiley.com; see www.ard.bmj.com. In addition, LA can cause prolongation of the activated partial thromboplastin time (aPTT) in some assays; however, given the insensitivity, a prolonged aPTT is not diagnostic for the presence of LA. Positive antinuclear antibodies are found in 45% of patients with primary APS. Mild thrombocytopenia (usually >50×109/L) is observed in ~30% of patients. Hemolytic anemia can occur. Anticardiolipin and beta2-GP I testing are plagued by a high frequency of clinically unimportant low-titer antibodies and lack of laboratory-to-laboratory agreement.
2. Imaging studies: Results depend on the vascular bed affected by thrombosis.
1. Congenital and acquired thrombophilias, other acute hypercoagulable states (particularly atypical hemolytic-uremic syndrome [HUS]) (see Hypercoagulable States).
2. Arterial thrombosis: Complications of atherosclerosis, vasculitis.
3. In case of prominent hematologic abnormalities: Thrombotic thrombocytopenic purpura (TTP), typical or atypical HUS, “HELLP syndrome” (hemolysis, elevated liver enzymes, low platelet complicating pregnancy), sepsis, and disseminated intravascular coagulation (DIC).
1. Acute thrombotic events: Treatment is the same as in patients without APS (CAPS: see below).
2. Primary prevention in patients with an APLA profile suggesting a high risk of thrombosis: Address cardiovascular risk factors; acetylsalicylic acid (ASA) may also be used, particularly in patients with SLE.Evidence 1Weak recommendation (benefits likely outweigh downsides, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision. Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody–positive individuals. Arthritis Rheum 2007;56(7):2382–91. Tektonidou MG, Laskari K, Panagiotakos DB, Moutsopoulos HM. Risk factors for thrombosis and primary thrombosis prevention in patients with systemic lupus erythematosus with or without antiphospholipid antibodies. Arthritis Rheum. 2009 Jan 15;61(1):29-36. doi: 10.1002/art.24232. PubMed PMID: 19116963. Hereng T, Lambert M, Hachulla E, et al. Influence of aspirin on the clinical outcomes of 103 anti-phospholipid antibodies-positive patients. Lupus. 2008 Jan;17(1):11-5. PubMed PMID: 18089677. Ginsburg KS, Liang MH, Newcomer L, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Med. 1992 Dec 15;117(12):997-1002. PubMed PMID: 1443986. In patients with SLE and APLA, hydroxychloroquine is also recommended.Evidence 2Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients) Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to methodologic limitations. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010 Jan;69(1):20-8. doi: 10.1136/ard.2008.101766. Epub. Review. PubMed PMID: 19103632. In patients with APLA and an increased risk of thrombosis (eg, surgery, immobility, puerperium), appropriate venous thromboembolism prophylaxis should be used.
3. Secondary prevention:
1) Patients with APLA (but without confirmed APS, for instance, low-titer positive aCL antibodies or lack of a second positive confirmatory antibody after 12 weeks) who present with a first episode of arterial or venous thrombosis should be treated as patients without APS.
2) Patients with a confirmed diagnosis of APS:
a) Venous thrombosis: After initial treatment with heparin, start long-term (usually lifelong) treatment with a VKA. The target INR is 2.0 to 3.0.Evidence 3Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). High Quality of Evidence (high confidence that we know true effects of the intervention). 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 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. PubMed PMID: 13679527. 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 May;3(5):848-53. PubMed PMID: 15869575.
b) Isolated venous thromboembolism in the setting of a known transient precipitating risk factor and with a low-risk APLA profile (ie, negative LA, low-titer aCL, or antibodies to beta2-GP I only): Start anticoagulation with a VKA at a target INR of 2.0 to 3.0. A duration of treatment of 3 to 6 months only could be considered in this scenario.
c) With a history of arterial thrombosis: Start long-term treatment. Depending on the individual risk of thrombosis, its complications (eg, APLA profile, additional cardiovascular risk factors, the first or subsequent thrombotic episode, risk of organ failure), and bleeding, you may consider: ASA + VKA (INR, 2.0-3.0) or a VKA with a target INR 2.0 to 3.0.
4. Treatment failure: First, verify that treatment failure occurred (therapeutic INR at the time of the event; confirm that a new event is seen on objective testing). If true failure has been confirmed, switch to therapeutic low-molecular-weight heparin (LMWH); in the case of arterial thrombosis, add ASA. Direct oral anticoagulants (DOACs) should not be used in this setting.Evidence 4Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and heterogeneity. Pengo V, Denas G, Zoppellaro G, et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12. PubMed PMID: 30002145. 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 Sep;3(9):e426-36. doi: 10.1016/S2352-3026(16)30079-5. PubMed PMID: 27570089; PubMed Central PMCID: PMC5010562.
5. Thrombocytopenia: No treatment is indicated for mild thrombocytopenia without evidence of bleeding (platelet count >50×109/L). For symptomatic patients or patients with extreme thrombocytopenia (<20×109/L), consider treatment as in immune thrombocytopenia (see Immune Thrombocytopenia). For patients with an active systemic connective tissue disease, such as SLE, treat as SLE (see Systemic Lupus Erythematosus).
6. APS in pregnancy:
1) Patients with an uncomplicated pregnancy, no history of pregnancy morbidity, and an incidental finding of APLAs: No treatment or low-dose ASA.
2) Patients with a history of pregnancy morbidity and positive APLAs: Treatment depends on the type and level of the antibodies and may include ASA and LMWH. Referral to a specialist center is recommended.
7. CAPS: Treat the underlying cause if identified. Recommended first-line therapy is the combination of anticoagulation (typically with IV heparin), glucocorticoids, plasmapheresis, and/or intravenous immunoglobulin (IVIG).Evidence 5Strong recommendation (benefits clearly outweigh downsides; right action for all or almost all patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the only observational nature of data coming from a limited number of patients. 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 Jun 7. doi: 10.1111/jth.14192. [Epub ahead of print] PubMed PMID: 29978552. Complement therapies may have a role to play, particularly in critically ill patients.
8. Women with APS/APLAs should avoid the use of estrogens (in the form of oral contraceptive agents or hormone replacement therapy), as these may increase the risk of thrombosisEvidence 6Weak recommendation (downsides likely outweigh benefits, but the balance is close or uncertain; an alternative course of action may be better for some patients). Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to observational data only. Choojitarom K, Verasertniyom O, Totemchokchyakarn K, Nantiruj K, Sumethkul V, Janwityanujit S. Lupus nephritis and Raynaud's phenomenon are significant risk factors for vascular thrombosis in SLE patients with positive antiphospholipid antibodies. Clin Rheumatol. 2008 Mar;27(3):345-51. Epub 2007 Sep 2. PubMed PMID: 17805483. Rojas-Villarraga A, Torres-Gonzalez JV, Ruiz-Sternberg ÁM. Safety of hormonal replacement therapy and oral contraceptives in systemic lupus erythematosus: a systematic review and meta-analysis. PLoS One. 2014 Aug 19;9(8):e104303. doi: 10.1371/journal.pone.0104303. eCollection 2014. Review. PubMed PMID: 25137236; PubMed Central PMCID: PMC4138076. (see Systemic Lupus Erythematosus).
The prognosis depends on the location, severity, and frequency of thrombotic episodes and their complications. CAPS is a life-threatening condition. In secondary APS, the prognosis also depends on the underlying condition.
1. Vascular thrombosis: ≥1 episode of arterial, venous (excluding superficial veins), or small-vessel thrombosis affecting any tissue or organ confirmed by imaging studies, Doppler study, or histology; histologic features should reveal thrombosis without inflammation of the vessel wall
2. Pregnancy morbidity:
1) ≥1 death of a morphologically normal fetus at ≥10 weeks’ gestation (confirmed with ultrasonography or a direct examination)
2) ≥1 preterm birth of a morphologically normal neonate before 34 weeks’ gestation because of preeclampsia, eclampsia, or severe placental insufficiency
3) ≥3 spontaneous miscarriages <10 weeks’ gestation with no anatomic or chromosomal abnormalities
1. LA detected in plasma on ≥2 occasions at a ≥12-week interval
2. IgG and/or IgM anticardiolipin antibodies present in the plasma or serum in a moderate or high titer (ie, >40 GPL or MPL units or >99th percentile) detected using a standardized ELISA method on ≥2 occasions at ≥12-week intervals
3. Anti–beta2-glycoprotein I antibodies in plasma or serum (in a titer >99th percentile) detected using a standardized ELISA method on ≥2 occasions at ≥12-week intervals
APS is diagnosed when ≥1 clinical and ≥1 laboratory criterion is fulfilled.
A high-risk APLA profile is defined as the presence of laboratory criterion 1; laboratory criteria 2 + 3; or persistently high APLA titers.
a The criteria must not be applied in patients with the onset of clinical manifestations of APS within <12 weeks or >5 years from the first detection of APLAs.
APS, antiphospholipid syndrome; APLA, antiphospholipid antibody; ELISA, enzyme-linked immunosorbent assay; LA, lupus anticoagulant.