# 12 - 369 Antiphospholipid Syndrome ### 369 Antiphospholipid Syndrome Barber MRW et al: Global epidemiology of systemic lupus erythema­ tosus. Nat Rev Rheumatol 17: 515, 2021. Fanouriakis A et al: EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis 83:15, 2024. Izmirly PM et al: Prevalence of systemic lupus erythematosus in the United States: Estimates from a meta-analysis of the centers for Disease Control and Prevention National Lupus Registries. Arthritis Rheumatol 73:991, 2021. Morand EF et al: Advances in the management of systemic lupus ery­ thematosus. BMJ 383:e073980, 2023. Petri M et al: Derivation and validation of Systemic Lupus Interna­ tional Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 64:2677, 2012. Pisetsky DS et al: A novel system to categorize the symptoms of systemic lupus erythematosus. Arthritis Care Res (Hoboken) 71:735, 2019. Shumilova A, Vital EM: Musculoskeletal manifestations of systemic lupus erythematosus. Best Pract Res Clin Rheumatol 22:101859, 2023. Vale ECSD, Garcia LC: Cutaneous lupus erythematosus: A review of etiopathogenic, clinical, diagnostic and therapeutic aspects. An Bras Dermatol 98:355, 2023. Haralampos M. Moutsopoulos, Maria G. Tektonidou Antiphospholipid Syndrome ■ ■DEFINITIONS Antiphospholipid syndrome (APS) is an autoantibody-mediated acquired thrombophilia characterized by recurrent arterial or venous thrombosis, microvascular manifestations, and/or pregnancy morbid­ ity. It affects primarily young females. APS may occur alone (primary) or in association with other autoimmune diseases, mainly systemic lupus erythematosus (SLE). Catastrophic APS (CAPS) is a rare, lifethreatening, rapidly progressive thromboembolic disease involving simultaneously three or more organs. The major autoantibodies detected in APS patients are directed against phospholipid-binding plasma proteins such as β2-glycoprotein I (β2GPI) and prothrombin. The plasma protein β2GPI is a 43-kDa plasma apolipoprotein, which consists of 326 amino acids arranged in five domains (I through V). The presence of anti–domain I IgG antibodies has been associated with increased thrombotic risk. Recent evidence from animal studies has shown that the antithrombotic func­ tion of β2GPI is dependent on its fifth domain (domain V). Another group of antibodies against phospholipid-binding proteins, termed lupus anticoagulant (LA), prolongs clotting time in vitro, which is not corrected by adding normal plasma. Anticardiolipin and anti-β2GPI IgG/IgM antibodies are measured by standardized enzyme-linked immunosorbent assays (ELISA); β2GPI in combination with cardiolipin or β2GPI in the absence of cardiolipin serve as target antigens, respectively. LA testing includes a threestep procedure: (1) screening including testing with activated partial thromboplastin time (aPTT) and dilute Russel viper venom test (DRVVT); (2) mixing study; and (3) confirmation. In patients receiv­ ing anticoagulation treatment, LA test positivity should be interpreted with caution. In patients with features highly reminiscent of APS in the absence of classical antiphospholipid antibodies (aPL), testing for antiphosphatidylserine/prothrombin antibodies may have a valuable diagnostic role. ■ ■EPIDEMIOLOGY The incidence of APS is estimated to be 1–2 cases per 100,000 persons per year. The prevalence of APS in the general population is estimated to be 40–50 per 100,000. APL antibodies occur in 1–5% of the general population. Their prevalence increases with age; however, it is ques­ tionable whether they are able to induce thrombotic events in elderly individuals. Moreover, one-third of patients with SLE (Chap. 368) pos­ sess these antibodies and 10–15% of them develop APS. CHAPTER 369 ■ ■PATHOGENESIS The initiating events for the induction of antibodies to phospholipidbinding proteins seem to be endothelial injury induced by infections, oxidative stress, and major physical stresses such as surgery or trauma in an appropriate genetic background, given the previously demonstrated associations with alleles within the human leukocyte antigen (HLA) locus. These contributors seem to induce increased apoptosis of the ves­ sel endothelial cells, autoantigen presentation, and subsequent initiation of autoimmune response. The binding of aPL to the disrupted endothe­ lial cells leads to a proinflammatory and prothrombotic state involving monocytes and platelets activation, adhesion molecules and proinflam­ matory cytokines production, complement and neutrophil activation, neutrophil extracellular trap (NET) formation, and thrombus formation. Recently, type I interferon pathway activation and an imbalance between type I and III interferons have been proposed as potential mechanisms of thrombotic events and APS-related obstetric complications. Antiphospholipid Syndrome ■ ■CLINICAL MANIFESTATIONS AND LABORATORY FINDINGS Clinical manifestations include venous or arterial thrombosis, micro­ vascular events, and/or pregnancy morbidity (Table 369-1). Deep venous thrombosis occurs primarily in the lower extremities and often causes pulmonary emboli. Thrombosis of the pulmonary arteries leads to pulmonary hypertension and thrombosis of hepatic veins to BuddChiari syndrome. Cerebral venous thrombosis presents with signs and symptoms of intracranial hypertension and focal neurologic deficits. Other venous thrombosis manifestations include retinal vein throm­ bosis and renal, mesenteric, or splanchnic vein thrombosis. Arterial thrombosis affects more commonly the arteries of the brain and is manifested as transient ischemic attack, stroke, migraines, or cognitive dysfunction. Peripheral artery thrombosis presents with acute limb ischemia, ischemic leg ulcers, or digital gangrene. Thrombosis of other arteries leads to myocardial infarction, retinal artery occlusion, renal artery stenosis, and infarcts of spleen, liver, and adrenals. Microvascular manifestations include livedo reticularis, which con­ sists of a mottled reticular vascular pattern that appears as a lace-like, purplish discoloration of the skin; livedo racemosa, characterized by a broken, irregular, and asymmetric pattern; and livedoid vasculopathy, which presents with painful papules or lower limb ulcers. Another microvascular feature of APS is the so-called aPL-nephropathy, mani­ fested with hypertension, proteinuria (mild to nephrotic range), hematuria, and mild renal insufficiency. Histologically, the acute phase is characterized by thrombotic microangiopathy lesions in the glomerular capillaries and/or arterioles. In a chronic phase, fibrous intima hyperplasia, fibrous and/or fibrocellular arteriolar occlusions, and focal cortical atrophy are present (Table 369-1). Additional rare microvascular manifestations are pulmonary hemorrhage, myocardial disease confirmed by magnetic resonance imaging or histologically, and adrenal hemorrhage. Pregnancy morbidity manifests with prefetal (<10 weeks of gesta­ tion) or fetal death, preeclampsia, eclampsia, and placental insuffi­ ciency with intrauterine fetal growth restriction, abnormal umbilical arterial Doppler, and/or infarctions of the placenta Cardiac valve manifestations include valve thickening or veg­ etations. Libman-Sacks endocarditis consists of small (usually <1 cm) valve vegetations, histologically characterized by organized plateletfibrin microthrombi surrounded by growing fibroblasts and mac­ rophages. Premature atherosclerosis has been also recognized as a feature of APS. Thrombocytopenia and autoimmune hemolytic anemia are the main hematologic manifestations of APS. Musculoskeletal TABLE 369-1  Clinical Features of Antiphospholipid Syndrome MANIFESTATION % Venous Thrombosis and Skin Manifestations Deep-vein thrombosis Livedo reticularis Pulmonary embolism Superficial thrombophlebitis Thrombosis in various other sites PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders Arterial Thrombosis and Cardiac Manifestations Stroke Cardiac valve thickening/dysfunction and/or Libman-Sacks vegetations Transient ischemic attack Myocardial ischemia (infarction or angina) and coronary bypass graft thrombosis Leg ulcers and/or digital gangrene Arterial thrombosis in the extremities Retinal artery thrombosis/amaurosis fugax Ischemia of visceral organs or avascular necrosis of bone Multi-infarct dementia Neurologic Manifestations of Uncertain Etiology Migraine Epilepsy Chorea Cerebellar ataxia Transverse myelopathy 0.5 Renal Manifestations Due to Various Reasons (Renal Artery/Renal Vein/Glomerular Thrombosis, Fibrous Intima Hyperplasia) Musculoskeletal Manifestations Arthralgias Arthritis Obstetric Manifestations (Referred to the Number of Pregnancies) Preeclampsia Eclampsia Fetal Manifestations (Referred to the Number of Pregnancies) Early fetal loss (<10 weeks) Late fetal loss (≥10 weeks) Premature birth among the live births Hematologic Manifestations Thrombocytopenia Autoimmune hemolytic anemia Source: Adapted from R Cervera et al: Arthritis Rheum 46:1019, 2002. manifestations may also occur in APS including arthralgias/arthritis, avascular bone necrosis, bone marrow necrosis, nontraumatic frac­ tures, and osteoporosis. ■ ■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The diagnosis of APS should be seriously considered in cases of throm­ bosis, cerebral vascular accidents in individuals <55 years of age, or pregnancy morbidity, in the presence of livedo reticularis or thrombo­ cytopenia. In these cases, aPL antibodies should be measured. Accord­ ing to the 2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria for APS, the presence of at least 3 points from clinical domains and 3 points from laboratory domains is required to classify APS. Clinical manifestations with other equally or more likely explanations than APS will not be counted. Clinical domains include (1) venous throm­ boembolism; (2) arterial thrombosis; (3) microvascular events; (4) obstetric complications; (5) cardiac valve disease; and (6) hematologic manifestations, as shown in Table 369-2. Laboratory domains include (1) LA, (2) anticardiolipin (aCL), and/or (3) anti-β2GPI antibodies, at moderate (40-79 units) or high titers (≥ 80 units) on two occasions 12 weeks apart. Differential diagnosis is based on the exclusion of other inherited or acquired causes of thrombophilia (Chap. 121), Coombs-positive hemolytic anemia (Chap. 105), and thrombocytopenia (Chap. 120). Livedo reticularis with or without a painful ulceration on the lower extremities may be also a manifestation of disorders affecting (1) the vascular wall, such as atherosclerosis, polyarteritis nodosa, SLE, cryoglobulinemia, and lymphomas; or (2) the vascular lumen, such as TABLE 369-2  2023 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) Classification Criteria for Antiphospholipid Syndrome Clinical Domains  DOMAINS/CRITERIA POINTS Venous thromboembolism (VTE) • With high-risk VTE profile • Without a high-risk VTE profile Microvascular events Suspected (any of below) • Livedo racemosa (exam) • Livedoid vasculopathy lesions (exam) • Acute/chronic aPL-nephropathy (exam or lab) • Pulmonary hemorrhage (symptoms and imaging)  Established (any of below) • Livedoid vasculopathy (pathology) • Acute/chronic aPL-nephropathy (pathology) • Pulmonary hemorrhage (BAL or pathology) • Myocardial disease (imaging or pathology) • Adrenal hemorrhage (imaging or pathology) Cardiac valve disease • Thickening • Vegetation Arterial thrombosis • With high-risk CVD profile • Without high-risk CVD profile Obstetric complications • >3 consecutive prefetal (<10 w) and/or early fetal deaths (10w0d–15w6d) • Fetal death (16w0d–33w6d) in the absence of preeclampsia (PEC) with severe features or placental insufficiency (PI) with severe features • PEC with severe features (<34w0d) or PI with severe features (<34w0d) with/without fetal death • PEC with severe features (<34w0d) and PI with severe features (<34w0d) with/without fetal death Hematologic manifestations • Thrombocytopenia (otherwise unexplained lowest platelet count ever between 20 and 130 × 109/L) Laboratory Domains (aPL) DOMAINS/CRITERIA POINTS Lupus anticoagulant (LA) test • One time positive • Persistent Anticardiolipin (aCL) and/or anti-β2GPI antibodies (persistent) • Moderate (40–79 units) or high (≥80 units) IgM aCL and/or   anti-β2GPI • Moderate (40–79 units) IgG aCL and/or anti-β2GPI • High (≥80 units) positive IgG aCL or anti-β2GPI • High (≥80 units) IgG aCL and anti-β2GPI Abbreviations: aPL, antiphospholipid antibody; anti-β2GPI, anti-β2-glycoprotein I; BAL, bronchoalveolar lavage; CVD, cardiovascular disease; Exam, physical examination; Lab, laboratory tests. Source: Modified with permission from R Zuo et al: The 2023 ACR/EULAR Antiphospholipid Syndrome Classification Criteria. Arthritis Rheumatol 75:1687, 2023.