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antiphospholipid syndrome (APS); Hughes syndrome

Etiology: 1) lupus anticoagulant (54%) 2) anticardiolipin antibodies (88%) Epidemiology: 1) 82% of patients are female [4] 2) mean age 42 years [4] 3) 2-3% of venous thrombosis 4) 41% of patients with systemic lupus erythematosus (SLE) [4] 5) < 50% of patients with APS have SLE 6) 30% of women with idiopathic recurrent miscarriages Pathology: 1) arterial & venous thrombosis 2) non-bacterial thrombotic endocarditis 3) fetal wastage (9%) 4) autoimmune thrombocytopenia 5) vasculitis (maybe not) [20] 6) microangiopathic renal insufficiency [3,10] 7) antibodies may be directed at apolipoprotein H (beta-2 glycoprotein-1) 8) skin biopsy: non-vasculitic small vessel vasculopathy with microthrombi [20] Clinical manifestations: 1) symptoms of transient ischemic attacks 2) ischemic stroke* (13%) 3) history of miscarriages 4) deep vein thrombosis (DVT) 32% - pulmonary emboli (PE) (9%) - renal vein thrombosis [3] - antiphospholipd antibody increases risk of recurrent DVT 8.2% vs 4.5% 5) superficial thrombophlebitis (9%) 6) cutaneous manifestations: a) livedo reticularis (20%) b) livedoid vasculitis c) chronic edema & erythema of the lower leg & ankle secondary to DVT d) digital gangrene e) superficial cutaneous necrosis - possibly associated with warfarin f) skin rash the peels over & turns black 7) Raynaud's phenomenon 8) renal infarcts, renal insufficiency [3] 9) non-bacterial thrombotic endocarditis 10) chorea [22] Diagnosis: 1) vascular thrombosis, thromboembolism (one or more episodes) - venous thromboembolism &/or arterial thromboembolism 2) pregnancy complications a) unexplained fetal deaths < 34 weeks b) > 2 spontaneous abortions before 10th week of gestation c) one or more premature birth (< 34 weeks) due to - preeclampsia, eclampsia or placental insufficiency (maybe not) [3] 3) antiphospholipid antibody presence on 2 or more occasions 12 weeks apart a) lupus anticoagulant b) anti-cardiolipin Ab in serum in moderate-high titer - anti-cardiolipin antibody IgG &/or - anti-cardiolipin antibody IgM c) beta-2 glycoprotein-1 Ab in serum - beta-2 glycoprotein-1 IgG in serum &/or beta-2 glycoprotein-1 IgM in serum [3] Laboratory: 1) prolonged aPTT - corrects when excess phospholipid is added to the patient's plasma [21] 2) normal clotting time 3) platelet count a) generally normal, but may be diminished b) thrombocytopenia (22%) - predictor of thromboses in patients with systemic lupus erythematosus (SLE) 4) phospholipid antibody in serum - medium to high titers from >= 2 measurements >= 12 weeks apart - anti-cardiolipin antibody IgG &/or IgM (88%) - beta-2 glycoprotein-1 Ab in serum - beta-2 glycoprotein-1 IgG in serum &/or beta-2 glycoprotein-1 IgM in serum - lupus anticoagulant (54%) - mixing & neutralization studies are needed to distinguish antiphospholipid antibodies from clotting factor deficiencies & other coagulation inhibitors 7) false-positive VDRL 8) modified Russell's viper venom time 9) kaolin (recalcified) clotting time 10) hexagonal phospholipid neutralization test 11) renal function tests - serum creatinine elevated 12) serum C-reactive protein & erythrocyte sedimentation rate may be modestly elevated 13) see ARUP consult [7] Differential diagnosis: - calciphylaxis: chronic renal failure, calcium * phosphate product very high - polyarteritis nodosa: no history of miscarriages, inflammatory markers high - rheumatoid arthritis: not associated with hypercoagulability - factor V Leiden: not associated with microthromi Management: 1) deep venous thrombosis & pulmonary embolism - LMW heparin, then long-term anticoagulation (indefinitely) [3] - warfarin preferred over direct oral anticoagulation during treatment phase [3,18] (weak recommendation, low quality evidence) - rivaroxaban non-inferior to wafarin for venous thromboembolism 2) arterial thrombosis, including coronary artery thrombosis - LMW heparin, then long-term anticoagulation - warfarin with lower rate of arterial thrombosis & major hemorrhage than rivaroxaban [16,17] - triple positive patients (anti-cardiolipin antibody, beta-2 glycoprotein-1 Ab & lupus anticoagulant) have increased risk for thrombosis with rivaroxaban vs warfarin [3] 3) therapeutic INR is 2.0-3.0 [3,5] 4) duration of therapy: indefinite 5) retinal or intracranial thrombosis - low dose warfarin & aspirin or heparin (SC) 6) pregnancy: - therapeutic unfractionated heparin or LMW heparin throughout pregnancy [15] - low-dose aspirin + heparin often used [19] 7) antiphospholipid antibodies without thrombosis - no therapy 8) contraception a) avoid any form of estrogen-containing contraceptive due to high risk of thrombosis b) use barrier method, IUD (progestin-containing IUD ok) 9) catastrophic antiphospholipid syndrome a) intravenous cyclophosphamide b) plasmapheresis c) intravenous immune globulin d) glucocorticoids + plasmapheresis or intravenous immune globulin [20] e) anticoagulation * Low titers of antiphospholipid antibodies do not predict risk of recurrent ischemic stroke [6]

Interactions

disease interactions

Related

anti-cardiolipin antibody anti-phospholipid antibody beta-2-glycoprotein 1; APC inhibitor; activated protein C-binding protein; anticardiolipin cofactor; apolipoprotein H; apo-H; beta-2-glycoprotein I; B2GPI; beta(2)GPI (APOH, B2G1) deep vein thrombosis (DVT) hexagonal phospholipid neutralization test ischemic stroke livedo reticularis; livedoid vasculopathy; mottled skin; cutis marmorata livedoid vasculitis lupus anticoagulant phospholipid IgA in serum phospholipid IgA/IgG/IgM panel phospholipid IgG in serum phospholipid IgM in serum pulmonary embolism (PE) Seddons's syndrome transient ischemic attack (TIA) VDRL reagin slide (VDRL)

General

autoimmune disease genetic disease of the immune system hypercoagulability

Database Correlations

OMIM 107320

References

  1. Contributions from Linda Kuribayashi MD, Dept of Medicine, UCSF Fresno
  2. Mayo Internal Medicine Board Review, 1998-99, Prakash UBS (ed) Lippincott-Raven, Philadelphia, 1998, pg 788
  3. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  4. Journal Watch 22(10):79, 2002 Cervera R, Piette JC, Font J et al Antiphospholipid syndrome: clinical and immunologic manifestations and patterns of disease expression in a cohort of 1,000 patients. Arthritis Rheum. 2002 Apr;46(4):1019-27. PMID: 11953980
  5. Journal Watch 23(21):170, 2003 Crowther MA 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 349:1133, 2003 PMID: 13679527 Lochshin MD & Erkan D, N Engl J Med 349:1177, 2003
  6. Journal Watch 24(5):39, 2004 Levine ST for the APASS Investigators. Antiphospholipid antibodies and subsequent thrombo-occlusive events in patients with ischemic stroke. JAMA 291:576, 2004 PMID: 14762036
  7. ARUP Consult: Antiphospholipid Syndrome - APS The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/antiphospholipid-syndrome - ARUP Consult: Antiphospholipid Syndrome Testing Algorithm https://arupconsult.com/algorithm/antiphospholipid-syndrome-testing-algorithm
  8. Baker WF Jr, Bick RL The clinical spectrum of antiphospholipid syndrome. Hematol Oncol Clin North Am. 2008 Feb;22(1):33-52 PMID: 18207064
  9. Bick RL, Baker WF. Treatment options for patients who have antiphospholipid syndromes. Hematol Oncol Clin North Am. 2008 Feb;22(1):145-53 PMID: 18207072
  10. Palomo I, Segovia F, Ortega C, Pierangeli S. Antiphospholipid syndrome: a comprehensive review of a complex and multisystemic disease. Clin Exp Rheumatol. 2009 Jul-Aug;27(4):668-77. PMID: 19772805
  11. Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med. 2013 Mar 14;368(11):1033-44 PMID: 23484830
  12. 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. PMID: 16420554
  13. Gupta A, Johnson DH, Nagalla S. Antiphospholipid Antibodies JAMA. 2017;318(10):959-960 PMID: 28898362 http://jamanetwork.com/journals/jama/article-abstract/2653717
  14. Kearon C, Parpia S, Spencer FA, et al. Antiphospholipid antibodies and recurrent thrombosis after a first unprovoked venous thromboembolism. Blood 2018 Feb 28 PMID: 29490924 http://www.bloodjournal.org/content/early/2018/02/27/blood-2017-09-805689
  15. Garcia D, Erkan D. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med 2018; 378:2010-2021. May 24, 2018 PMID: 29791828 https://www.nejm.org/doi/full/10.1056/NEJMra1705454 - Rothaus C The Antiphospholipid Syndrome. NEJM Resident 360. May 23, 2018 https://resident360.nejm.org/content_items/the-antiphospholipid-syndrome
  16. Pengo V, Denas G, Zoppellaro G et al. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood 2018 Jul 12; PMID: 30002145 http://www.bloodjournal.org/content/early/2018/07/12/blood-2018-04-848333
  17. Ordi-Ros J, Saez-Comet L, Perez-Conesa M et al Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial. Ann Intern Med. 2019. Oct 15. PMID: 31610549 https://annals.org/aim/article-abstract/2753019/rivaroxaban-versus-vitamin-k-antagonist-antiphospholipid-syndrome-randomized-noninferiority-trial - Wahl D, Dufrost V et al Direct Oral Anticoagulants in Antiphospholipid Syndrome: Too Early or Too Late? Ann Intern Med. 2019. Oct 15. PMID: 31610546 https://annals.org/aim/article-abstract/2753020/direct-oral-anticoagulants-antiphospholipid-syndrome-too-early-too-late
  18. Stevens SM, Woller SC, Kreuziger LB et al Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest 2021 Dec;160(6):e545-e608 PMID: 34352278
  19. Rai R, Cohen H, Dave M, Regan L Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ. 1997 Jan 25;314(7076):253-7. PMID: 9022487 PMCID: PMC2125731 Free PMC article
  20. NEJM Knowledge+ Rheumatology
  21. NEJM Knowledge+ Hematology
  22. Hu S, Zhou Y, Li M, Zeng X, Zhao J. Dancing with disorder: chorea - an unusual and neglected manifestation of antiphospholipid syndrome. Lupus Sci Med. 2024 Oct 1;11(2):e001332. PMID: 39353714 PMCID: PMC11448224 Free PMC article. https://lupus.bmj.com/content/11/2/e001332