Diagnosis of antiphospholipid syndrome

INTRODUCTION — Antiphospholipid syndrome (APS) is a clinical and laboratory diagnosis characterized by both persistent laboratory evidence of antiphospholipid antibodies (aPL) and related complications, which may include venous thrombosis, arterial thrombosis, adverse pregnancy outcomes, and nonthrombotic manifestations (eg, heart valve thickening, livedo reticularis/racemosa). APS occurs either as a primary condition or in the setting of an underlying disease, usually systemic lupus erythematosus (SLE).

The diagnosis and classification criteria for APS are reviewed here. It is important to note that:

●There are no diagnostic criteria for APS; therefore, the clinician’s assessment and judgment are critical for management decisions.

●The 2023 American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) APS classification criteria have stringent definitions to allow more rigorous classification for research studies.

Additional topics discuss:

●Pathogenesis (see "Pathogenesis of antiphospholipid syndrome")

●Clinical manifestations (see "Clinical manifestations of antiphospholipid syndrome")

●Management (see "Management of antiphospholipid syndrome")

●Obstetric implications (see "Antiphospholipid syndrome: Obstetric implications and management in pregnancy")

●Diagnosis and treatment of catastrophic APS (see "Catastrophic antiphospholipid syndrome (CAPS)")

●The effect of aPL on coagulation tests (see "Clinical use of coagulation tests", section on 'Prolonged PT and/or aPTT without bleeding or thrombosis')

TERMINOLOGY

●Antiphospholipid syndrome – Antiphospholipid syndrome (APS) describes a clinical autoimmune syndrome characterized by one or more clinical manifestations (eg, venous thrombosis, arterial thrombosis, pregnancy morbidity, thrombocytopenia) with persistent laboratory evidence of antiphospholipid antibodies (aPL) [1].

APS can occur as a primary condition or in the setting of systemic lupus erythematosus (SLE) or another systemic autoimmune disease.

APS can be further defined according to the type of clinical manifestation (some cases overlap) in each case with persistent laboratory criteria for aPL:

•Thrombotic APS – Thrombotic APS describes APS based on venous and/or arterial thrombosis.

•Obstetric APS – Obstetric APS describes APS based on certain adverse pregnancy outcomes (eg, fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses [before 10 weeks gestation]). (See 'Classification criteria' below.)

•Microvascular APS – Microvascular APS describes small vessel involvement, such as diffuse alveolar hemorrhage or aPL nephropathy, without moderate- to large-vessel thrombosis.

•Catastrophic APS – Catastrophic APS (CAPS) is a rare, life-threatening form of APS characterized by thrombotic complications (macrovascular and microvascular) affecting multiple organs that develop simultaneously or over a short period of time. (See "Catastrophic antiphospholipid syndrome (CAPS)".)

Implications of these subgrouping for management are discussed separately. (See "Management of antiphospholipid syndrome" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy" and "Catastrophic antiphospholipid syndrome (CAPS)", section on 'Management'.)

●Antiphospholipid antibodies – aPL are a heterogenous group of antibodies (immunoglobulins [Igs]) directed against phospholipids and phospholipid-binding proteins [2]. aPL can be transient (eg, associated with an acute infection) or persistent (present on two or more occasions at least 12 weeks apart).

The commonly assayed aPL include:

•Anticardiolipin antibody (aCL; IgG or IgM), assayed by enzyme-linked immunosorbent assay (ELISA)

•Anti-beta2 glycoprotein I antibody (anti-beta2GPI; IgG or IgM), assayed by ELISA

•Lupus anticoagulant (LA), assayed in a clotting test

Although cardiolipin is a phospholipid, most of the clinically relevant antibodies detected in this assay actually bind to phospholipid-binding protein(s), frequently beta2GPI, that in turn bind to the cardiolipin.

These three tests are also the ones included in the APS classification criteria. (See 'Classification criteria' below.)

Other aPL are not routinely obtained or included in the classification criteria because of lack of standardized testing and/or uncertainty about their clinical significance (eg, IgA aCL and anti-beta2GPI or antibodies directed against prothrombin, phosphatidylserine, or phosphatidylinositol). (See 'Antiphospholipid antibody testing' below and "Pathogenesis of antiphospholipid syndrome", section on 'Role of antiphospholipid antibodies'.)

WHEN TO SUSPECT THE DIAGNOSIS — The two clinical scenarios that should raise clinical suspicion for antiphospholipid syndrome (APS) are:

●Otherwise unexplained thrombotic events (venous or arterial) or microvascular disease, especially in young patients (see "Clinical manifestations of antiphospholipid syndrome", section on 'Clinical manifestations')

●Adverse outcomes related to pregnancy, especially associated with severe preeclampsia or placental insufficiency

If any of the above scenarios occurs in a patient who also manifests livedo reticularis/racemosa, valvular heart disease, pulmonary hemorrhage, thrombotic microangiopathy affecting the kidney, and/or neurologic findings such as cognitive deficits and white matter lesions, then the diagnostic suspicion for APS should be further increased.

The presence of a systemic autoimmune disease, especially systemic lupus erythematosus (SLE), should also increase the suspicion for APS in the setting of appropriate clinical symptoms.

Laboratory abnormalities that also raise suspicion for APS include otherwise unexplained thrombocytopenia, prolongation of the activated partial thromboplastin time (aPTT), or a history of a false-positive serologic test for syphilis (Venereal Disease Research Laboratory [VDRL] or rapid plasma reagin [RPR] tests). The VDRL and RPR tests use cardiolipin. (See "Syphilis: Screening and diagnostic testing", section on 'Positive nontreponemal/negative treponemal'.)

For patients with a low suspicion of APS, we generally do not test for antiphospholipid antibodies (aPL), such as older adults with venous thromboembolism (VTE) or stroke or individuals who have other risk factors for thromboembolism [3].

DIAGNOSTIC EVALUATION — In patients with suspected antiphospholipid syndrome (APS), we perform a thorough medical history, physical examination, and laboratory testing for antiphospholipid antibodies (aPL) [4].

History — The history should focus on:

●Nature and frequency of thrombotic events

●Outcomes of pregnancies

●Thrombocytopenia

●Other risk factors for thrombosis (eg, immobility, use of estrogen-containing medications, family history of thrombophilia)

●Risk factors for other thrombotic syndromes (eg, history of heparin exposure raises the possibility of heparin-induced thrombocytopenia)

●Use of anticoagulants, which can affect the results of lupus anticoagulant (LA) testing (see 'Patients on an anticoagulant' below)

●Symptoms associated with systemic lupus erythematosus (SLE), such as arthritis/arthralgias, photosensitivity, oral ulcers, patchy hair loss, and Raynaud phenomenon (see "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'History and physical examination')

Physical examination — There are no pathognomonic physical findings of APS; however, the examination may reveal findings related to ischemia or infarction of specific organs such as the skin or the central nervous system.

Examples of such physical findings include:

●Livedo reticularis (picture 1) and particularly livedo racemosa (picture 2)

●Digital ischemia or gangrene

●Sequelae of deep vein thrombosis (leg edema, skin changes)

●A heart murmur

●Neurologic abnormalities suggestive of a prior stroke

Clinical findings are discussed in more detail separately. (See "Clinical manifestations of antiphospholipid syndrome".)

Laboratory evaluation

Routine laboratory testing — We perform the following initial laboratory tests in all patients:

●Complete blood count – Thrombocytopenia may be observed in patients with APS. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Thrombocytopenia'.)

●Baseline coagulation testing – The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are important prior to starting anticoagulation, especially if they will be used for monitoring. Testing for lupus anticoagulant is discussed below. (See 'Specific antiphospholipid antibody tests' below.)

●Serum creatinine and urinalysis with urine sediment – A serum creatinine and urinalysis with urine sediment may help identify kidney involvement; abnormal findings may also suggest a concomitant or alternative diagnosis (eg, SLE). Patients with abnormal kidney function, microscopic hematuria, proteinuria, or an active urinary sediment will need further evaluation.

●SLE testing – Patients with clinical features suggestive of SLE should also undergo the appropriate clinical evaluation for SLE. In a cohort of 1000 individuals with APS, 36 percent had SLE, and an additional 5 percent had a lupus-like syndrome [5]. Further testing is not required unless clinical features of SLE are identified. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Laboratory testing'.)

Antiphospholipid antibody testing

Specific antiphospholipid antibody tests — Antibody testing in patients with suspected APS involves two immunoassays and a functional coagulation assay (algorithm 1) [6]:

●Anticardiolipin antibodies (aCL); IgG and IgM by enzyme-linked immunosorbent assay (ELISA).

●Anti-beta2 glycoprotein I antibodies (anti-beta2GPI); IgG and IgM by ELISA.

●LA functional coagulation assay, which is a three-step procedure:

•Demonstration of a prolonged phospholipid-dependent screening test of hemostasis. Commonly used screening tests include the dilute Russell viper venom time (dRVVT) or an aPTT that has been optimized for LA testing.

•Mixing patient plasma with normal plasma fails to correct the prolonged screening test(s). This finding documents the presence of an inhibitor, rather than a coagulation factor deficiency.

•Addition of excess phospholipid shortens or corrects the prolonged coagulation test. This finding demonstrates phospholipid dependence.

A positive LA is characterized by correction of the prolonged clotting time with added phospholipid but not with control plasma, confirming that the coagulation inhibitor is phospholipid dependent [3]. (See "Clinical use of coagulation tests", section on 'Lupus anticoagulant tests' and "Clinical use of coagulation tests", section on 'Use of mixing studies'.)

The above aPL testing is consistent with recommendations from the International Society on Thrombosis and Haemostasis for laboratory criteria in APS [7].

Clinical relevance of different antibody isotypes (IgG versus IgM versus IgA) is discussed below.

We do not routinely perform laboratory testing for other antibodies such as antibodies against antiprothrombin, annexin V, phosphatidylserine, and phosphatidylinositol, given the lack of standardized testing and uncertainty about their clinical significance [8].

In addition, we generally do not test for the IgA isotypes when evaluating for APS, and we generally do not consider these antibodies as supportive evidence for the diagnosis of APS if they are reported. In contrast to IgG and IgM isotypes of aCL and anti-beta2GPI, the association of the IgA isotypes with clinical thrombosis remains controversial [9]. Very limited data indicate that medium to high levels of IgA aCL and/or IgA anti-beta2GPI may be associated with APS, although in our experience, this is extremely rare. However, many laboratories routinely test for IgA isotype aCL and anti-beta2GPI, given that rarely patients present with persistent isolated moderate- to high-titer IgA aCL or anti-beta2GPI in the setting of aPL-related clinical events.

The Laboratory Diagnostics and Trends APS Task Force of the 14^th International Congress on aPL concluded that the evidence to include IgA isotype as part of the APS Classification Criteria is only of low quality; furthermore, since IgA aPL are usually associated with aPL of other isotypes, it can be difficult to understand the role of IgA alone [8]. Thus, the utility of testing for IgA isotype is generally restricted to those patients with a strong clinical suspicion for APS who have tested negative for other tests for aPL [10]. Additional prospective studies are needed to better understand the role of IgA aCL antibody as a risk factor for thrombosis.

The Systemic Lupus International Collaborating Clinics (SLICC) revised classification criteria for SLE (table 1) include IgA isotype of aCL and anti-beta2GPI as part of the definition of aPL positivity; IgA isotype may have implications for SLE classification given that it is more common in SLE patients compared with aPL-positive patients without other autoimmune diseases [11]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria'.)

Some clinical laboratories use automated chemiluminescence tests instead of ELISA-based assays for the detection of aCL and anti-beta2GPI. Chemiluminescence assays generally have higher analytical sensitivities (they can detect lower levels of antibodies) than ELISA assays. The units and "cut-off" values used in these chemiluminescence-based tests are not equivalent to the ELISA units and cutoff values.

Timing of testing — Initial testing is usually done shortly after a clinical event, followed by confirmatory testing at least 12 weeks later.

●Initial aPL testing – Typically, initial aPL testing is performed at the time of the thrombosis or adverse pregnancy outcome. While we obtain all of the tests listed above (see 'Specific antiphospholipid antibody tests' above), it is worth noting that an acute thrombotic event may falsely normalize the aPTT. Thus, a normal aPTT or other LA screening test in the acute setting may be inaccurate and may need to be repeated. The immunoassays (ELISAs for aCL or beta2GPI) are not affected by acute thrombotic events or anticoagulants. (See 'Patients on an anticoagulant' below.)

●Confirmatory aPL testing – In patients with initial positive testing for aPL, testing should be repeated after ≥12 weeks to confirm persistence of the aCL, anti-beta2GPI, or LA. Transiently elevated levels of IgG or IgM aCL, as well as a positive LA test, can occur with certain infections or drug exposures. (See 'Other conditions associated with antiphospholipid antibodies' below.)

For the majority of patients who do not have laboratory evidence of APS, we do not perform additional antibody testing. However, repeat testing may be appropriate in selected cases in which the clinical suspicion for APS is especially high.

The need for confirmatory testing due to the possibility of transient aPL positivity was illustrated in a study including randomly selected blood donors who were tested for the presence of aCL and LA [12]. On initial testing, 28 of 503 (5.6 percent) were positive for IgG aCL, 38 of 457 (8.3 percent) were positive for IgM aCL, and an additional 5 (0.9 percent) were positive for both. The number who remained positive for aCL upon repeat testing declined progressively at 3, 6, 9, and 12 months; at one year, only four (0.8 percent) were positive for IgG aCL, one (0.2 percent) for IgM aCL, and none for both isotypes. There were no positive tests for LA in any patient, and none of the individuals had clinical evidence of APS.

Patients on an anticoagulant — In patients who are receiving an anticoagulant, we test for aCL and anti-beta2GPI antibodies; these results are unaffected by anticoagulation. By contrast, different anticoagulants have variable effects on laboratory tests used to identify LA, making interpretation of the results more challenging (table 2). Communication with the consulting specialist and laboratory personnel is advised prior to LA testing in a patient receiving an anticoagulant. This subject is discussed in more detail separately. (See "Clinical use of coagulation tests", section on 'Patient on anticoagulant'.)

Interpretation of positive results

Clinically relevant antiphospholipid antibody profile — Not every positive aPL test result is clinically relevant. The interpretation of "clinically relevant aPL positivity" should take into account the type of assay, isotype, titer or level, persistence, and number of positive aPL tests.

We define a clinically relevant aPL profile as the persistent presence of one or more of the following aPL on two or more occasions at least 12 weeks apart:

●Positive LA test, based on the guidelines of International Society of Thrombosis and Haemostasis [13]

●aCL IgG or IgM, with a titer >40 units

●Anti-beta2GPI IgG or IgM, with a titer >40 units

[14-16]

The clinical significance of IgA aCL and IgA anti-beta2GPI are not clear and are addressed above. (See 'Specific antiphospholipid antibody tests' above.)

Risk stratification based on antiphospholipid antibody profile — Patients with clinically relevant aPL profiles may be further stratified into high-, moderate-, and low-risk profiles:

●High-risk profile – A persistently positive LA with or without persistently positive moderate- to high-titer aCL and/or anti-beta2GPI IgG or IgM (moderate titer 40 to 79 units, high titer ≥80 units). (See 'Clinically relevant antiphospholipid antibody profile' above.)

Some experts consider triple-positive results (LA, aCL, and anti-beta2GPI) to be associated with the highest risk for clinical complications.

Implications of high-risk aPL profiles are discussed separately. (See "Management of antiphospholipid syndrome", section on 'Risk of a first thrombosis with aPL'.)

●Moderate-risk profile – A negative LA test with persistently positive moderate- to high-titer aCL and/or anti-beta2GPI IgG or IgM (moderate titer 40 to 79 units, high titer ≥80 units).

The IgG isotype of aCL and anti-beta2GPI has a stronger association with aPL-related clinical events compared with IgM isotypes [14-16].

●Low-risk profile – A negative LA test with persistently positive low-titer aCL and/or anti-beta2GPI IgG or IgM (low titer 20 to 39 units).

There are insufficient data regarding the clinical significance of aCL or anti-beta2GPI IgG or IgM titers that are above the upper limit of the reference range for the test but <40 units.

Transient or persistent aPL may also be present in other settings besides APS and is discussed further below. (See 'Other conditions associated with antiphospholipid antibodies' below.)

DIAGNOSIS — The diagnosis of antiphospholipid syndrome (APS) is based on the presence of at least one clinical manifestation (venous thrombosis, arterial thrombosis, pregnancy morbidity) in the setting of persistently positive antiphospholipid antibodies (aPL) (algorithm 1). Laboratory testing must be positive on two separate occasions at least 12 weeks apart to confirm persistence. (See 'Antiphospholipid antibody testing' above.)

Although the diagnosis of APS is based on a combination of clinical features and positive aPL, three major factors that should be carefully assessed for APS diagnosis are:

●The strength of the association between the clinical event and aPL

●Other risk factors associated with the clinical event

●The aPL profile

In patients with thrombosis and/or pregnancy morbidity (especially in those with late fetal loss because of eclampsia, preeclampsia, or placental insufficiency), the confidence in the diagnosis of APS increases when any of the following apply:

●Two or more clinically relevant and persistent aPL laboratory results are present. (See 'Clinically relevant antiphospholipid antibody profile' above.)

●The anticardiolipin antibodies (aCL) and/or anti-beta2 glycoprotein I (anti-beta2GPI) are IgG rather than isolated IgM.

●Additional aPL-related manifestations are present, such as otherwise unexplained thrombocytopenia, heart valve disease, or thrombotic microangiopathy affecting the kidney (aPL nephropathy) [17]. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Kidney disease'.)

●Alternative explanations for the thrombosis or pregnancy morbidity are lacking.

When needed, consultation with an APS expert is advised.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of antiphospholipid syndrome (APS) is broad and includes other causes of arterial and venous thrombosis and recurrent pregnancy loss. It is also important to note that antiphospholipid antibodies (aPL) may overlap with other conditions that can cause thrombosis or pregnancy morbidity.

Other causes of thrombosis — Other causes of thrombosis include inherited and acquired thrombophilias, anatomic vascular obstruction, paroxysmal nocturnal hemoglobinuria, heparin-induced thrombocytopenia, and myeloproliferative neoplasms (MPNs). Vaccine-induced immune thrombotic thrombocytopenia (VITT) is an exceedingly rare condition seen following vaccination with an adenoviral vector-based coronavirus disease 2019 (COVID-19) vaccine. (See "Overview of the causes of venous thrombosis" and "Clinical manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria" and "Clinical presentation and diagnosis of heparin-induced thrombocytopenia" and "Overview of the myeloproliferative neoplasms" and "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

Like APS, these conditions may be associated with arterial or venous thromboembolism, with or without cytopenias. Unlike APS, these conditions are not associated with laboratory evidence of persistent aPL.

Patients with APS may also have coexisting risk factors for thrombotic events, including immobility, use of estrogen-containing medications, and/or cardiovascular risk factors. (See "Overview of established risk factors for cardiovascular disease".)

Other causes of pregnancy morbidity — Other causes of recurrent pregnancy loss include chromosomal abnormalities, anatomical abnormalities of the uterus, and endocrine disorders such as hypothyroidism. (See "Recurrent pregnancy loss: Evaluation".)

Like APS, individuals with these abnormalities may have early or late pregnancy loss. Unlike APS, these conditions generally are not associated with an increased risk of thromboembolism or the presence of aPL.

Positive antiphospholipid antibodies without antiphospholipid syndrome

Transient antiphospholipid antibodies — The incidence and clinical significance of transient aPL in the absence of clinical thrombosis or other features of APS is unclear. For selected individuals who have incidentally identified aPL without APS, follow-up testing to assess the persistence of an aPL may be helpful.

The clinical impact of repeat testing in asymptomatic individuals with aPL depends on how the results will be incorporated into patient management. For patients with multiple strongly positive tests, repeat testing provides information about potential risk assessment; by contrast, for patients with a single borderline positive test, repeat testing can be used to confirm that the result is likely to be clinically irrelevant.

Persistent lupus anticoagulant or medium-/high-titer anticardiolipin antibody/anti-beta2 glycoprotein I IgG/IgM — Occasionally, individuals are identified who have a high- or moderate-risk aPL profile but no clinical manifestations of APS. (See 'Risk stratification based on antiphospholipid antibody profile' above.)

The two most common scenarios in which this occurs are patients with systemic lupus erythematosus (SLE) who are routinely screened for aPL and patients undergoing coagulation screening for an unrelated indication who are found to have a lupus anticoagulant (LA).

While these patients do not have APS by classification or diagnostic criteria, they are at risk for aPL-related clinical manifestations as noted above.

It is reasonable to assume that all patients with APS were, for some period of time in the past, asymptomatic individuals with significant levels of aPL. The level of risk and the role of prophylaxis in such patients is controversial and discussed elsewhere. (See "Management of antiphospholipid syndrome", section on 'Primary thrombosis prevention'.)

Other conditions associated with antiphospholipid antibodies — In addition to their occurrence in primary APS, aPL may be present in some people who are otherwise healthy, have an autoimmune or rheumatic disease, and/or have been exposed to certain drugs or infectious agents.

The presence of aPL alone, in the absence of a thrombotic event or pregnancy morbidity, is insufficient for diagnosis of the clinical syndrome of APS. (See 'Diagnosis' above.)

The evaluation of a patient with a positive aPL for autoimmune and infectious conditions depends on the presentation and clinical setting. In general, we limit our evaluation to a thorough history and physical examination and testing appropriate to evaluate clinical findings. We do not perform antinuclear antibody (ANA) testing or other studies to evaluate for these conditions in the absence of other clinical findings suggestive of an autoimmune or infectious disorder. (See 'Diagnostic evaluation' above.)

●Autoimmune and rheumatic diseases – The most frequent rheumatic disease associated with aPL is SLE. A clinically significant aPL profile in the absence of APS has been detected in approximately 30 percent of patients with SLE [18]:

•Approximately 31 percent of patients have LA [19]

•23 to 47 percent have an anticardiolipin antibody (aCL) [9,19,20]

•20 percent have antibodies to beta2 glycoprotein I (beta2GPI) [9]

Conversely, in a cohort of 1000 APS patients, APS was associated with SLE in 36 percent of patients and with a lupus-like syndrome in an additional 5 percent [5].

Both LA and aCL have also been found in patients with a variety of other autoimmune and rheumatic diseases (eg, scleroderma, psoriatic arthritis), but in the absence of clinical events associated with the APS, their significance is not clear [21,22].

●Infections – aPL have also been noted in patients with infections. These are usually low-level IgM aCL, which may rarely result in thrombotic events [21,23]. Furthermore, these antibodies usually are not beta2GPI dependent; thus, patients with infections usually do not express antibodies to beta2GPI [24,25].

Infections that have been associated with aPL include [22,24-32]:

•Bacterial – Bacterial sepsis, leptospirosis, syphilis, Lyme disease (borreliosis), tuberculosis, leprosy, infective endocarditis, post-streptococcal rheumatic fever, and Klebsiella infections.

•Viral – Hepatitis A and B; mumps; human immunodeficiency virus (HIV); human T-lymphotropic virus type 1 (HTLV-I); cytomegalovirus; varicella-zoster; Epstein-Barr virus (EBV); adenovirus; parvovirus; rubella; and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19.

Additional information regarding COVID-19 and the presence of aPL can be found elsewhere. (See "Pathogenesis of antiphospholipid syndrome", section on 'COVID-19 and antiphospholipid antibodies'.)

•Parasitic – Malaria, Pneumocystis jirovecii, and visceral leishmaniasis (also known as kala-azar).

●Medications – A number of medications have been associated with aPL. These include phenothiazines (chlorpromazine), phenytoin, hydralazine, procainamide, quinidine, quinine, ethosuximide, alpha interferon, amoxicillin, chlorothiazide, oral contraceptives, and propranolol [22,23,33,34].

The aPL are usually transient, often of the IgM isotype, and rarely associated with thrombosis. The mechanism of drug-induced aPL is not known.

●Malignancy – aPL have been detected in patients with solid tumors (lung, colon, cervix, prostate, kidney, ovary, breast, and bone); Hodgkin disease and non-Hodgkin lymphoma; MPNs (primary myelofibrosis, polycythemia vera); and myeloid and lymphocytic leukemias [22,35].

CLASSIFICATION CRITERIA — Classification criteria for antiphospholipid syndrome (APS) were developed to define a patient population for clinical and laboratory research studies [36,37]. Consequently, these criteria emphasize specificity over sensitivity, meaning that some patients may have a clinical diagnosis of APS without meeting classification criteria. As an example, a patient who meets laboratory criteria and has a venous thromboembolism (VTE) or macrovascular arterial thrombosis would not meet classification criteria for APS if they have a high-risk profile for VTE or cardiovascular disease. Similarly, patients who meet clinical criteria but who only have anticardiolipin antibody (aCL) or anti-beta2 glycoprotein I (beta2GPI) IgM without IgG or lupus anticoagulant (LA) would not meet classification criteria. Thus, while the underlying principles of the classification criteria can be useful to guide diagnosis and document key disease features, use of these criteria should not substitute for clinical judgment when diagnosing APS [38,39]. (See 'Diagnosis' above.)

The American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) released updated classification criteria in 2023 [40]; they include definitions of clinical and laboratory criteria (table 3), definitions of high-risk profiles for VTE and cardiovascular disease (table 4), and a graphic describing a scoring system (figure 1). Patients who fulfill entry criteria and who have at least three weighted criteria in both the clinical and laboratory domains meet the classification criteria for APS:

●Entry criteria – Patients must fulfill at least one documented clinical criterion below and have a positive antiphospholipid antibody (aPL) test within three years of the clinical criterion (defined as a positive LA or a moderate to high titer of IgG or IgM aCL or anti-beta2GPI).

●Clinical criteria – Patients must meet three or more weighted criteria, with possible clinical manifestations including the following (figure 1):

•Macrovascular venous thromboembolism – An otherwise unexplained VTE including but not limited to pulmonary embolism, deep vein thrombosis of the arms or legs, and thrombosis of the splanchnic veinous system, renal vein, cerebral venous system, or retinal vein. VTE must be confirmed by appropriate testing (eg, imaging or pathology). Superficial venous thrombosis does not satisfy this criterion. Criterion weighting depends on whether patients have a high-risk profile for VTE (eg, active malignancy, recent surgery, or major trauma) (table 4).

•Macrovascular arterial thrombosis – An otherwise unexplained arterial thrombosis including but not limited to myocardial infarction, stroke, thromboses of the peripheral, splanchnic, or retinal arteries, and organ infarcts without visualized thrombus (eg, kidney, liver, spleen). Arterial thrombosis or organ infarct must be confirmed by appropriate testing (eg, imaging or pathology). Weighting depends on whether patients have a high-risk profile for cardiovascular disease (eg, hypertension, hyperlipidemia) (table 4).

•Microvascular manifestations – These include suspected or established livedo racemosa or livedoid vasculopathy, aPL nephropathy, pulmonary or adrenal hemorrhage, and myocardial disease. Weighting depends on whether diagnosis is suspected or established (eg, examination versus pathology for livedoid vasculopathy).

•Pregnancy morbidity – These include three or more consecutive pre-fetal (<10 weeks gestation) or early fetal (10 to 15 weeks gestation) deaths, fetal death (16 to 33 weeks gestation) in the absence of severe preeclampsia or placental insufficiency, and severe preeclampsia or/or placental insufficiency before 34 weeks gestation with or without fetal death.

•Cardiac valve abnormalities – These include types of valve thickening and vegetations as outlined in the table (table 3).

•Hematologic abnormalities – This includes thrombocytopenia (20 to 130 x 10⁹/L) confirmed on peripheral smear and repeat testing.

●Laboratory criteria – Patients must meet three or more weighted laboratory criteria. Persistence (two positive tests at least 12 weeks apart) is required for aCL and anti-beta2GPI, and part of the weighting for LA. Laboratory criteria include the following:

•LA detected according to published guidelines [3,41].

•Positive IgM aCL and/or anti-beta2GPI in moderate or high titer (moderate titer 40 to 79 units, high titer ≥80 units measured by a standardized enzyme-linked immunosorbent assay [ELISA] according to recommended procedures) [6,42].

•Positive IgG aCL and/or anti-beta2GPI in moderate or high titer (moderate titer 40 to 79 units, high titer ≥80 units measured by a standardized ELISA according to recommended procedures) [6,42]. Weighting depends on whether it is moderate or high titer and whether one or both antibodies are present.

Prior classification criteria for APS include the revised Sapporo APS classification criteria (also called the Sydney criteria) (table 5) [36]. When compared with these criteria, the 2023 ACR/EULAR criteria have higher specificity and lower sensitivity (specificity 99 percent versus 86 percent, sensitivity of 84 percent versus 99 percent) [40].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Antiphospholipid syndrome".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Antiphospholipid syndrome (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Clinical presentation – Clinical suspicion for antiphospholipid syndrome (APS) should be raised in either of the following settings (see 'When to suspect the diagnosis' above and "Clinical manifestations of antiphospholipid syndrome"):

•Thrombotic events – One or more otherwise unexplained venous or arterial thromboses/thromboemboli, especially in young patients.

•Adverse pregnancy outcomes – One or more specific adverse pregnancy outcomes, including multiple embryonic losses <10 weeks gestation, fetal death after 10 weeks gestation, or premature birth due to severe preeclampsia or placental insufficiency.

Clinical suspicion is further increased if either of these occur in a patient with livedo reticularis/racemosa; valvular heart disease; neurologic findings (eg, cognitive deficits and white matter lesions); or a systemic autoimmune disease, especially systemic lupus erythematosus (SLE).

Laboratory abnormalities suggestive of APS include unexplained mild thrombocytopenia, increased activated partial thromboplastin time (aPTT), or false-positive serologic test for syphilis.

●Laboratory testing – In patients with suspected APS, we perform a thorough medical history, physical examination, complete blood count, and testing for antiphospholipid antibodies (aPL). (See 'Diagnostic evaluation' above.)

We generally perform initial testing around the time of a clinical event, followed by confirmatory testing ≥12 weeks later (see 'Timing of testing' above). We test for three aPL (see 'Specific antiphospholipid antibody tests' above):

•aCL – Anticardiolipin antibodies (aCL); IgG and IgM, by enzyme-linked immunosorbent assay (ELISA)

•Anti-beta2GPI – Anti-beta2 glycoprotein I (anti-beta2GPI) antibodies; IgG and IgM, by ELISA

•LA – Lupus anticoagulant (LA), using a functional clotting assay (see "Clinical use of coagulation tests", section on 'Lupus anticoagulant tests')

It may be appropriate to pursue additional laboratory testing or to evaluate patients for other possible causes of thromboembolism and/or adverse pregnancy outcomes.

●Diagnosis – The diagnosis of APS is based on a combination of clinical features (venous or arterial thromboembolism or certain pregnancy morbidities) and the aPL profile (persistently positive clinically relevant aPL) (algorithm 1). Risk factors for thrombosis other than APS should also be evaluated during the diagnostic assessment. (See 'Diagnosis' above.)

●Differential diagnosis – The differential diagnosis of APS includes other causes of arterial and venous thrombosis and recurrent pregnancy loss. aPL may also be present in other conditions (autoimmune or rheumatic disease, malignancy, infection, medications). In some individuals with aPL, an associated condition is not identified. (See 'Other causes of thrombosis' above and 'Other causes of pregnancy morbidity' above and 'Other conditions associated with antiphospholipid antibodies' above.)

●Classification criteria – APS classification criteria (table 3 and table 4 and figure 1) were designed for research purposes and can be useful to help guide clinical diagnosis, but they should not substitute for clinical judgment when diagnosing APS. Specifically, classification criteria alone should not be used to exclude the diagnosis of APS in patients with clinical manifestations and laboratory findings consistent with the APS diagnosis. (See 'Classification criteria' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Peter Schur, MD, and Bonnie Bermas, MD, who contributed to earlier versions of this topic review.