INTRODUCTION — Antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis and/or an adverse pregnancy outcome in the presence of persistent laboratory evidence of antiphospholipid antibodies (aPL). APS occurs either as a primary condition or in the setting of an underlying disease, usually systemic lupus erythematosus (SLE).
The diagnosis of APS will be reviewed here. Pathogenesis, clinical manifestations, and treatment are presented separately. (See "Pathogenesis of antiphospholipid syndrome" and "Clinical manifestations of antiphospholipid syndrome" and "Management of antiphospholipid syndrome" and "Antiphospholipid syndrome: Obstetric implications and management in pregnancy".)
Additional topics discuss:
●Diagnosis and treatment of catastrophic APS (CAPS). (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 venous or arterial thrombosis and/or pregnancy morbidity in the presence of 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 classified according to the type of clinical manifestation (thrombotic or obstetric; in some cases, both may be present) and whether there is life-threatening multiorgan involvement:
•Thrombotic APS – Thrombotic APS is used to describe patients diagnosed with APS based on venous or arterial thrombosis and persistent laboratory criteria for aPL.
•Obstetric APS – Obstetric APS is used to describe patients diagnosed with APS based on an APS-defining pregnancy morbidity (including fetal death after 10 weeks gestation, premature birth due to severe preeclampsia or placental insufficiency, or multiple embryonic losses [before 10 weeks gestation]) and persistent laboratory criteria for aPL. (See 'Classification criteria' below.)
Individuals with both an APS-defining pregnancy morbidity and thromboembolic complications are referred to as having both thrombotic and obstetric APS.
•Catastrophic APS – Catastrophic APS (CAPS) is a rare, severe (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 subclassifications 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 laboratory finding that can be transient (eg, associated with an acute infection) or persistent (present on two or more occasions at least 12 weeks apart).
aPL are a heterogeneous group of antibodies directed against phospholipid-binding proteins [2]. The aPL detection tests included in APS classification criteria are anticardiolipin antibody (aCL; immunoglobulin [Ig] G or IgM) enzyme-linked immunosorbent assay (ELISA), anti-beta2 glycoprotein I (anti-beta2GPI) antibody (IgG or IgM) ELISA, and lupus anticoagulant (LA) assay. Although cardiolipin is a phospholipid, most of the clinically relevant antibodies detected in this assay are actually binding to phospholipid-binding protein(s), frequently beta2GPI, that bind to the cardiolipin in the assay. There are other aPL that are not included in APS classification criteria (eg, antibodies directed against prothrombin, phosphatidylserine, or phosphatidylinositol), which are not routinely obtained because of lack of standardized testing and uncertainty about their clinical significance. (See 'Antiphospholipid antibody testing' below.)
WHEN TO SUSPECT THE DIAGNOSIS — The two clinical scenarios that should raise clinical suspicion for antiphospholipid syndrome (APS) are the following:
●One or more otherwise unexplained venous or arterial thrombotic events, especially in young patients. (See "Clinical manifestations of antiphospholipid syndrome", section on 'Clinical manifestations'.)
●One or more specific adverse outcomes related to pregnancy, including multiple embryonic losses <10 weeks gestation, fetal death after 10 weeks gestation, or premature birth due to severe preeclampsia or placental insufficiency.
If either of the above scenarios occurs in a patient who also manifests livedo, valvular heart disease, 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.
In addition, other laboratory abnormalities that also raise the potential diagnostic significance of the above scenarios (ie, thrombosis or specific adverse pregnancy outcome) include an otherwise unexplained mild 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'.)
We generally do not test for antiphospholipid antibodies (aPL) in patients at low risk of APS, such as older adult patients who present with venous thromboembolism or stroke and/or individuals who have other risk factors for thromboembolism [3].
DIAGNOSTIC EVALUATION — In patients suspected of having 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 the nature and frequency of thrombotic events, the outcomes of pregnancies in females, thrombocytopenia, and other risk factors for thrombosis, which may include immobility, use of estrogen-containing medications, and/or family history of thrombophilia. A history of heparin exposure may be relevant in patients with possible heparin-induced thrombocytopenia (HIT). The history should also include inquiries about symptoms associated with systemic lupus erythematosus (SLE) such as 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, abnormal features that may be found on examination are 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 (CBC) – 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. The aPTT is used for lupus anticoagulant (LA) testing.
●Serum creatinine level and urinalysis with urine sediment – A serum creatinine and urinalysis with urine sediment may help identify kidney involvement in APS; 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.
Patients with other 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]. Antinuclear antibody (ANA) 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 (anti-beta2GPI) antibodies; 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 that an inhibitor is present, rather than a coagulation factor deficiency.
•Addition of excess phospholipid shortens or corrects the prolonged coagulation test (demonstration of phospholipid dependence).
An 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 revised Sapporo classification criteria described below. (See 'Classification criteria' below.)
In contrast to IgG and IgM isotypes of aCL and anti-beta2GPI, the association of the IgA isotypes with clinical thrombosis remains controversial [7]. 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. However, many laboratories routinely test for IgA isotypes, 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 14th 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 isolates, 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 [9]. 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 [10]. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults", section on 'Classification criteria'.)
We do not routinely perform laboratory testing for other antibodies such as antiprothrombin antibodies, anti-annexin V, antiphosphatidylserine, and antiphosphatidylinositol antibodies, given the lack of standardized testing and uncertainty about their clinical significance [8].
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.)
Positive results from aPL testing on 2 tests ≥12 weeks apart satisfies the laboratory classification criteria for APS (see 'Classification criteria' 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 aCL and LA [11]. 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. Some anticoagulants can prolong the aPTT and make interpretation of the aPTT or other LA screening tests 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, isotype, titer, persistency, 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:
●A positive LA test, based on the guidelines of International Society of Thrombosis and Haemostasis [12]
●aCL IgG or IgM, with a titer >40 units
●Anti-beta2GPI IgG or IgM, with a titer >40 units
This approach is mostly consistent with the laboratory criteria described in the revised Sapporo APS Classification Criteria. (See 'Classification criteria' below.)
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. Similarly, there are insufficient data regarding the clinical significance of aCL or anti-beta2GPI IgA titers that are above the upper limit of the reference range.
The IgG isotype of aCL and anti-beta2GPI has a stronger association with aPL-related clinical events compared with IgM isotypes [13-15].
Risk stratification based on positive antiphospholipid antibodies — 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 (≥40 units). (See 'Clinically relevant antiphospholipid antibody profile' above.)
Some experts consider triple positive results (LA, aCL, and anti-beta2GPI) as being 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.
●Low-risk profile – A negative LA test with persistently positive low titer aCL and/or anti-beta2GPI IgG or IgM (20 to 39 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.)
CLASSIFICATION CRITERIA — Classification criteria for antiphospholipid syndrome (APS) have been developed to select patients for clinical and laboratory research purposes [16,17]. Although classification criteria should not be used for diagnostic purposes, they can be useful to guide clinicians in diagnosing patients and documenting key disease features [18,19]. However, the use of these criteria should not substitute for clinical judgment when diagnosing APS. (See 'Diagnosis' below.)
According to the revised Sapporo APS Classification Criteria (also called the Sydney criteria) (table 3), APS is present in patients who meet at least one of the following clinical criteria and at least one of the following laboratory criteria:
●Clinical criteria – One or more of the following is present:
•Vascular thrombosis – One or more episodes of venous, arterial, or small vessel thrombosis in any tissue or organ, with unequivocal imaging or histologic evidence of thrombosis. Superficial venous thrombosis does not satisfy this criterion.
•Pregnancy morbidity – One or more unexplained deaths of a morphologically normal fetus at ≥10 weeks gestation or one or more premature births of a morphologically normal neonate <34 weeks gestation because of eclampsia, preeclampsia, or placental insufficiency or three or more consecutive spontaneous pregnancy losses at <10 weeks gestation, unexplained by chromosomal abnormalities or by maternal anatomic or hormonal causes.
●Laboratory criteria – One or more of the following antiphospholipid antibodies (aPL) on two or more occasions at least 12 weeks apart:
•IgG and/or IgM anticardiolipin antibodies (aCL) in moderate or high titer (>40 GPL or MPL units, respectively, or a titer >99th percentile for the testing laboratory), measured by a standardized enzyme-linked immunosorbent assay (ELISA).
•IgG and/or IgM anti-beta2 glycoprotein I (anti-beta2GPI) >40 GPL or MPL units, respectively, or a titer >99th percentile for the testing laboratory, measured by a standardized ELISA according to recommended procedures [6,20].
•Lupus anticoagulant (LA) detected according to published guidelines [3,21,22].
The revised Sapporo criteria also indicate that the presence or absence of additional risk factors for thrombosis should be noted during research studies, if present. This information may be useful for research and for long-term management.
These criteria have also been shown to be specific but may lack sensitivity for the diagnosis of APS in children.
DIAGNOSIS — The diagnosis of antiphospholipid syndrome (APS) is based on the presence of either a venous or arterial thrombosis or a 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 of laboratory findings. (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
●The presence or absence of 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 level for a 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 IgG isotype of anticardiolipin antibodies (aCL) and/or anti-beta2 glycoprotein I (anti-beta2GPI) are present rather than an isolated IgM isotype.
●Additional aPL-related manifestations are present, such as otherwise unexplained thrombocytopenia, heart valve disease, or thrombotic microangiopathy affecting the kidney (aPL nephropathy) [23].
●No alternative explanations for the thrombosis or pregnancy morbidity are present.
When needed, consultation with a clinician with expertise in the diagnosis of APS is advised.
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of APS is broad and includes other causes of arterial and venous thrombosis and recurrent pregnancy loss.
Other causes of thrombosis — Other causes of thrombosis include inherited and acquired thrombophilias, anatomic vascular obstruction, paroxysmal nocturnal hemoglobinuria (PNH), heparin-induced thrombocytopenia (HIT), and myeloproliferative neoplasms (MPN). 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 antiphospholipid syndrome (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 antiphospholipid antibodies (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 — A minority of individuals have transient aPL without clinical thrombosis or other features of APS. The clinical significance is unclear, but follow-up testing to assess the persistence of an aPL in selected individuals 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 (possibly meeting the revised Sapporo laboratory criteria) but no clinical manifestations of APS. (See 'Risk stratification based on positive antiphospholipid antibodies' 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 [24]:
•Approximately 31 percent of patients have LA [25]
•23 to 47 percent have an anticardiolipin antibody (aCL) [7,25,26]
•20 percent have antibodies to beta2 glycoprotein I (beta2GPI) [7]
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 [27,28].
●Infections – aPL have also been noted in patients with infections. These are usually low level IgM aCL, which may rarely result in thrombotic events [27,29]. Furthermore, these antibodies usually are not beta2GPI dependent; thus, patients with infections usually do not express antibodies to beta2GPI [30,31].
Infections that have been associated with aPL include [28,30-38]:
•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 [28,29,39,40].
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; MPN (primary myelofibrosis, polycythemia vera); and myeloid and lymphocytic leukemias [28,41].
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".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
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 thrombotic events or 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 (CBC), 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 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 aPL should also be evaluated during the diagnostic assessment. (See 'Diagnosis' above.)
APS classification criteria (table 3) 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. (See 'Classification criteria' 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.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Peter Schur, MD, and Bonnie Bermas, MD, who contributed to earlier versions of this topic review.
