Definitions of the 2023 ACR/EULAR antiphospholipid syndrome classification criteria

• Livedo racemosa (by physical examination): Otherwise unexplained^* violaceous, "net-like," blotchy mottling of the skin. NOTE: Livedo racemosa with nonuniform, irreversible, broken, and asymmetric persistent discoloration should be scored; livedo reticularis with uniform, reversible, unbroken, and symmetric discoloration should not be scored.
• Livedoid vasculopathy lesions (by physical examination): Otherwise unexplained^* painful papules and erythematous-violaceous purpuric plaques, which may rapidly evolve into hemorrhagic vesicles or bullae. NOTE: If ruptured, can result in painful small ulcers or reticulate, confluent, geometric, and painful ulcers.
• Antiphospholipid antibody (aPL) nephropathy (by physical examination or laboratory tests): Otherwise unexplained^* persistent: a) new-onset hypertension or deterioration of previously well-controlled hypertension; b) proteinuria ≥0.5 gm in 24-hour urine specimen or protein:creatinine ratio ≥0.5 mg/mg (50 mg/mmol); c) acute kidney failure (increased serum creatinine levels above normal); or d) glomerular microscopic hematuria.
• Pulmonary hemorrhage (by clinical symptoms and imaging): Respiratory symptoms (eg, dyspnea, cough, hemoptysis) and otherwise unexplained^* pulmonary infiltrates on imaging suggestive of pulmonary hemorrhage.

Established:

• Livedoid vasculopathy (by pathology once livedoid vasculopathy lesions described above are present): Otherwise unexplained^* thrombosis of the small dermal vessels and/or endothelial proliferation.
• aPL nephropathy (by pathology once suspected aPL-nephropathy definition above is fulfilled): a) Acute renal vascular or glomerular thrombotic microangiopathy lesions, including fibrin thrombi in arterioles or glomeruli without inflammatory cells or immune complexes; and b) chronic renal vascular or glomerular lesions, described as arterial or arteriolar organized microthrombi with or without recanalization, fibrous and fibrocellular (arterial or arteriolar) occlusions, focal cortical atrophy with or without thyroidization, fibrous intimal hyperplasia, or chronic/organized glomerular thrombi. NOTE: In patients with systemic lupus erythematosus, aPL nephropathy occurs independent of lesions attributable to lupus nephritis.
• Pulmonary hemorrhage (by bronchoalveolar lavage [BAL] or pathology once suspected pulmonary hemorrhage definition above is fulfilled): Otherwise unexplained^* progressive hemorrhagic return on BAL with aliquots or hemosiderin-laden macrophages (>20%), or lung biopsy demonstrating capillaritis or microthrombosis.
• Myocardial disease (by imaging or pathology): Otherwise unexplained^* non-ST segment elevation myocardial infarction with a normal coronary angiogram (myocardial infarction with nonobstructive coronary arteries, or MINOCA) and cardiac magnetic resonance imaging (CMRI) abnormalities as per the 2018 Society for CMRI expert consensus including: a) late gadolinium enhancement either transmurally or subendocardially; b) T2 abnormalities (weighted imaging or mapping); or c) perfusion MRI abnormalities, or histologically by thrombosis of the small vessels of the heart.
• Adrenal hemorrhage or microthrombosis (by imaging or pathology): Otherwise unexplained^* computed tomography (CT) or magnetic resonance imaging (MRI) demonstrating hemorrhage, or histologically by thrombosis of the adrenal (micro)vasculature, eg, adrenal plexus, adrenal vein.

Prefetal death (preembryonic or embryonic loss): Otherwise unexplained^* pregnancy loss before 10 weeks 0 days of gestation.

Fetal death: Otherwise unexplained^* pregnancy loss between 10 weeks 0 days and 15 weeks 6 days gestation (early fetal death), or between 16 weeks 0 days and 34 weeks 0 days gestation. NOTE: If a detailed analysis of the fetal morphology or genetic constitution is not performed or unavailable, reasonable clinical judgment should be used based on careful history and review of available medical records.

• Severe blood pressure elevation: Systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥110 mmHg on 2 occasions at least 4 hours apart while the patient is on bed rest (antihypertensive therapy may be initiated upon confirmation of severe hypertension, in which case severe blood pressure elevation criteria can be satisfied without waiting until 4 hours have elapsed).
• Central nervous system dysfunction: New-onset headache unresponsive to medication and not accounted for by alternative diagnosis.
• Visual disturbances.
• Pulmonary edema.
• Impaired liver function: Abnormally elevated blood concentrations of liver enzymes (more than twice the upper limit of normal concentrations), or severe persistent right upper quadrant or epigastric pain unresponsive tomedications, not accounted by alternative diagnosis.
• Kidney dysfunction: Serum creatinine concentration >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other kidney disease.
• Thrombocytopenia: Platelet count of <100 × 10⁹/L.

Placental insufficiency with severe features: Intrauterine fetal growth restriction defined as biometry indicating estimated fetal weight of less than the 10^th percentile for gestational age or postnatal birth weight less than the 10^th percentile for gestational age in the absence of fetal-neonatal syndromes or genetic conditions associated with growth restriction and 1 or more of the following "severe features":

• Abnormal or non-reassuring fetal surveillance test(s) suggestive of fetal hypoxemia, eg, a nonreactive non-stress test.
• Abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, eg, absent end-diastolic flow in the umbilical artery.
• Severe intrauterine fetal growth restriction suggested by fetal biometry indicating an estimated fetal or postnatal birth weight of <3^rd percentile for gestational age.
• Oligohydramnios, eg, an amniotic fluid index ≤5 cm, or deepest vertical pocket <2 cm.
• Maternal vascular malperfusion on placental histology suggested by placental thrombosis/infarction, inadequate remodeling of the uterine spiral arteries (decidual vasculopathy), decreased vasculosyncytial membranes, increased syncytial knots, or decidual inflammation. NOTE: Maternal vascular malperfusion on placental histology can be detected in the placentas of aPL-negative patients with intrauterine growth restriction and/or preeclampsia, and even in normal pregnancies; thus, these findings are not specific for APS.

Valve thickening (otherwise unexplained^*): Based on World Heart Federation echocardiographic criteria, mitral valve thickening is defined as >4 mm between ages 20 to 39 years and >5 mm for those older than age 40 years, and >3 mm for other valves for any age (valve thickening can be associated with valvular dysfunction [regurgitation or stenosis]).

• A 3-step procedure (screening - mixing study - confirmation) with 2 screening test systems (diluted Russell's viper venom time and a sensitive activated partial thromboplastin time [low phospholipids and silica as activator]) is necessary to confirm the presence of LAC. The LAC test should be considered positive if at least 1 of the 2 test systems yields a positive result following all 3 steps (phospholipiddependent correction of the prolonged screening tests).
• Results of LAC testing should be interpreted with caution, as false positive and negative results can occur during anticoagulation (thus, LAC testing is ideally performed in patients not receiving anticoagulants), as an acute-phase response (eg, acute thrombosis) due to acute-phase reactants (eg, Factor VIII and C-reactive protein), and in pregnancy due to increase in blood coagulation factors.
• Samples from patients receiving anticoagulants (vitamin K antagonists, heparin, direct oral anticoagulants, indirect Factor Xa inhibitor) should be marked positive or negative on the LAC assay only if reviewed/confirmed by an individual with expertise in performing/interpreting the LAC assay, eg, expert laboratory personnel.

• Correlation of the numerical values between the moderate/high thresholds of ELISA and automated platforms varies substantially. For instance, based on the ISTH Scientific and Standardization Committee (SSC) LA/aPL Subcommittee estimates from 1 study, an IgG aCL ELISA value of 40 to 79 units corresponds to a CLIA value of 200 to 400 units and MFI of 700 to 2000. While these data may provide future guidance, there is currently no direct application and therefore, more validation studies are needed.
• Recommendations to maintain homogeneity, consistency, and comparability of clinical research studies include the following: a) results of analytical platforms should not be mixed; b) pending additional studies and official guidance from the ISTH SSC LAC/aPL Subcommittee for semiquantitative comparisons on aCL/anti-beta₂GPI moderate/high thresholds of ELISA and automated platforms, we recommend delaying use of the automated platforms for APS classification; and c) if no options exist beside the use of automated platform results for APS research, researchers should direct efforts to identifying and validating moderate/high thresholds of their platform, correlating it with aCL/anti-beta₂GPI ELISA moderate/high thresholds (these measures should be discussed in their methods, and supported by official guidance).