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. Vascular thrombosis of the extremities is frequently bilateral, recurrent, and most commonly includes deep vein thrombosis (DVT). It can also involve vessels of the head and neck. Arterial thrombosis of the upper or lower extremities is rare; it causes symptoms of acute limb ischemia.
2. Vascular thrombosis of visceral organs may or may not be symptomatic and can affect any internal organ:
1) Pulmonary involvement: This manifests typically 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), or 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 (<1% of patients) and may result in esophageal or intestinal ischemia or infarcts of the spleen, pancreas, or adrenal glands (causing Addison disease). Hepatic thrombosis may 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 14.4-1).
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, though 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%.
Classification criteria: Table 14.4-1.
1. Laboratory tests: APLAs are observed in >90% of patients (Table 14.4-1). Lupus anticoagulant 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 lupus anticoagulant. Positive antinuclear antibodies are found in 45% of patients with primary APS. Mild thrombocytopenia (usually >50,000/microL) is observed in ~30% of patients. Hemolytic anemia can occur.
2. Imaging studies: Results depend on the vascular bed affected by thrombosis.
1. Congenital and acquired thrombophilias (see Hypercoagulable States).
2. Arterial thrombosis: Complications of atherosclerosis, vasculitis.
3. In case of prominent hematologic abnormalities: Thrombotic thrombocytopenic purpura (TTP), typical or atypical hemolytic-uremic syndrome (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 (Table 14.4-2): 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. For more information, see Appendix 1. 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. For more information, see Appendix 2. 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). For more information, see Appendix 3.
b) Isolated venous thromboembolism in the setting of a known transient precipitating risk factor and with a low-risk APLA profile (ie, negative lupus anticoagulant, low-titer aCL, or antibodies to beta2-GP I only): Start anticoagulation with 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). If true failure has been confirmed, increase the intensity of the VKA therapy (target INR, 3.0-4.0) or switch to low-molecular-weight heparin (LMWH); in the case of arterial thrombosis, add ASA. The efficacy of anti-Xa or IIA inhibitors in prevention of recurrent thrombosis in APS is unknown at the present time. The efficacy of direct oral anticoagulants (DOACs) remains unclear in APS, but it may be associated with increased harm compared with warfarin.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. For more information, see Appendix 4.
5. Thrombocytopenia: No treatment is indicated for mild thrombocytopenia without evidence of bleeding (platelet count, >50,000/microL). For symptomatic patients or patients with extreme thrombocytopenia (<20,000/microL), consider treatment as in 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. For more information, see Appendix 5.
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 thrombosis.Evidence 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. For more information, see Appendix 6. (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. Lupus anticoagulant 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.
– Lupus anticoagulant
– Lupus anticoagulant + anticardiolipin antibodies + anti–beta2-GPI antibodies
– Isolated positive anticardiolipin antibodies at medium-high titersa
a Only studied in patients with concomitant systemic lupus erythematosus.
Adapted from Lupus. 2011;20(2):206-18.
anti–beta2-GPI, anti–beta2-glycoprotein I.
There has been one randomized controlled trial (RCT) comparing ASA 81 mg daily to placebo in the primary prevention of thrombosis in patients with positive APLAs, most of whom also had a concomitant autoimmune disease such as SLE. Forty-eight patients were randomized to ASA and 50 patients to placebo. Over 2.3 years of follow-up on average, there were no events in the placebo group, and only 2.75 events per 100 patient-years; the low event rate in this study meant that the relative benefit or harm of ASA was unable to be determined. A concomitant prospective observational study of 73 patients, 61 of whom were treated with ASA, and 13 of whom were not, again suffered from a low event rate over an average follow-up of 2.47 years, with no events occurring in the placebo group.1 A retrospective study performed by Tektonidou et al. analyzed a cohort of 144 APLA-positive patients with SLE. The rate of thrombosis was 20.1% over 5 years. Multivariable analyses revealed that the duration of low-dose ASA treatment was associated with a reduction in the risk of thrombosis, with a hazard ratio of 0.98/month of ASA use (P = 0.05).2 Similarly, Hereng et al. retrospectively studied thrombosis in SLE patients with APLA. There were thrombotic events in 3/27 patients taking ASA and in 4/10 patients not taking ASA (P = 0.03).3 A nested case-control study using Physicians’ Health Study data, where patients were randomized to the use of low-dose ASA or placebo, revealed that in adult male patients without a history of SLE, anticardiolipin titers were higher in patients with DVT and/or pulmonary embolism than in matched controls, but low-dose ASA use was not protective against DVT or pulmonary embolism.4 The guidelines set out by the Task Force at the 13th International Conference on Antiphospholipid Antibodies have made a recommendation to use low-dose ASA as primary prophylaxis against thrombosis in patients with lupus and antiphospholipid antibodies. A recommendation was also made for the use of ASA in patients without SLE with a high-risk APLA profile (Table 14.4-2), though this is a recommendation based predominantly on expert opinion, and universal thromboprophylaxis for all patients with positive APLAs was not recommended.
1 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.
2 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.
3 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.
4 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.
A systematic review by Ruiz-Irastorza et al. summarized the results of 8 observational studies reporting the effect of hydroxychloroquine on thrombosis in patients with SLE, with or without APLAs. They described moderate-quality evidence of benefit in prevention of thrombosis. There were insufficient data for venous and arterial events to be considered separately.1 Data for patients with APLAs and SLE were not analyzed independently from patients with SLE without APLAs. One retrospective observational study performed by Tektonidou et al. did address the subgroup of SLE patients with APLAs and observed that the duration of hydroxychloroquine use was associated with a significant reduction in the risk of thrombosis (relative risk of 0.99/month of hydroxychloroquine use, P = 0.04). There is thus some evidence that hydroxychloroquine reduces the risk of thrombosis in patients with SLE and APLAs. Moreover, there have been many documented benefits of hydroxychloroquine in patients with SLE in terms of lowering the risk of flare, damage accrual, and mortality, among other potential benefits,1 leading to a strong recommendation for use in patients with SLE and APLAs despite the lack of high-quality evidence in this particular subset of patients.
1 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 2003, Crowther et al. performed an RCT to compare high-intensity warfarin (targeted to an INR of 3.0-4.0) to moderate-intensity warfarin (targeted to an INR of 2.0-3.0) in patients with APS with previous venous or arterial thrombosis. High-intensity warfarin was not superior to moderate-intensity warfarin in this analysis.1 Thus, VKA targeted to an INR of 2.0 to 3.0 appears to be appropriate therapy for patients with APS. Finazzi et al. subsequently published a study with similar findings.2
1 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.
2 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.
The role of DOACs in prevention of thromboembolic events in APS is still unclear. However, there are grounds for caution with consideration of use in the APS population based on recent studies. Pengo et al. compared rivaroxaban with warfarin in an RCT of high-risk patients with APS (triple positive for LA, aCL, and beta2-GP I antibodies); however, the study was terminated early because of an increased rate of thromboembolic events in the rivaroxaban group compared with the warfarin group.1 In contrast, Cohen et al. performed an RCT of rivaroxaban versus warfarin in APS patients using predominantly laboratory markers of anticoagulation intensity. While they did not reach the primary noninferiority outcome for rivaroxaban, they did not demonstrate an increased thrombotic risk for patients on rivaroxaban compared with warfarin and concluded that it could be a safe and effective alternative for APS patients.2 Notably, however, this study was short term (<1 year) and was not powered for clinical events. While it remains plausible that rivaroxaban may be a reasonable option for low-risk APS patients, this requires further study, and in light of the risk of increased events demonstrated in high-risk patients in the Pengo study, DOACs should be considered only with caution. Warfarin remains the standard of care for this patient population.
1 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.
2 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.
There is a clinical practice guideline for diagnosis and management of CAPS.1 The evidence is largely derived from the CAPS Registry, which is an ongoing international patient registry with >500 patients enrolled to date. For first-line treatment of patients with CAPS, the guideline panel suggested combination therapy with glucocorticoid, heparin, and plasmapheresis or IVIG over single agents or other combinations of therapies. The meta-analysis of data for this question revealed lower mortality in the group receiving this combination compared with those receiving other treatments (odds ratio, 0.51; 95% CI, 0.27-0.95).
1 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.
A cohort study has shown a significant association between oral contraceptive use in patients with APLAs and the risk of thrombosis.1 A meta-analysis in patients with SLE did not show an association between oral contraceptive use and thrombosis, however notably in most of these studies, patients with APLAs were excluded.2
This evidence was graded as low-quality given the observational nature, and thus the authors offer a weak recommendation to avoid estrogen-containing contraceptives in patients with SLE and APLAs.
1 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.
2 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.