Antiphospholipid syndrome (APS) is an autoimmune disorder typically characterized by blood clots and pregnancy complications. However, the spectrum of APS-related clinical symptoms is much broader (see below). APS can develop alone or in association with other autoimmune conditions such as lupus. (Learn more about antiphospholipid syndrome terminology.)
|Selected Antiphospholipid Syndrome-related Clinical Problems
|Stroke, transient ischemic attacks1, memory problems
|High blood pressure, chronic kidney disease, protein in the urine
|Myocardial infarctions, vegetations2 on valves, thickened and leaky valves
|Anemia, low platelet counts
|Livedo3, skin ulcerations
|Deep venous thrombosis4 (DVT)
|Pulmonary embolism5, pulmonary hypertension6
|Miscarriages, premature births, fetal growth restriction
Classification criteria are intended to be used in a medical research setting. Diagnostic criteria are used in a clinical setting for the purpose of managing diseases in patients. The two sets of criteria may have overlapping elements, but they have separate goals.
The goal of classification criteria is to ensure that patients with common characteristics, thought to be specific for a certain disease, are included in appropriate research studies. This helps ensure the integrity of the research data during the analysis of the study. Classification criteria do not necessarily encapsulate all of the clinical or laboratory features of that particular disease. Rather, the goal is to capture a uniform group of patients with a similar clinical presentation for medical research purposes only.
The goal of diagnostic criteria is to identify, as accurately as possible, whether patients have that particular disease. While some of the diagnostic criteria may overlap with the classification criteria, many of the uncommon signs and symptoms of a disease are not included in the classification criteria. However, this does not mean they are not a feature of that disease. Diagnostic criteria aim to maximize the number of patients that can be identified as having a particular disease. This is in contrast to classification criteria, which are more stringent in order to identify a more specific cohort of patients.
Yes, the revised Sapporo APS Classification Criteria have been used for classifying APS patients. Published in 1999 and updated in 2006, these criteria allowed researchers to determine who can be identified as an APS patient to participate in laboratory or clinical research. A simplified version of the APS classification criteria is shown below. Based on these classification criteria, patients who have at least one positive clinical and one positive laboratory criteria are considered to have a diagnosis of APS suitable for research purposes.
However, some of the limitations of the revised Sapporo APS Classification Criteria included:
Thus, an international group of APS clinicians and/or researchers, supported by American College of Rheumatology (ACR) and European Alliance of Associations of Rheumatology (EULAR) (co principal investigators Dr. Doruk Erkan [New York, NY] and Dr. Stephane Zuily [Nancy, France]), developed and recently published a more comprehensive classification criteria (also known as 2023 ACR/EULAR APS Classification Criteria).
New APS classification criteria are based on a weighted point system of symptoms, physical examination findings, and laboratory results. These are calculated across eight domains, divided into two types: (1) clinical domains and (2) laboratory domains. Please refer to the original publication or the classification criteria calculator for details.
The new classification criteria include an entry criterion followed by additive weighted criteria (score range 1 to 7 points each) clustered into six clinical and two laboratory domains. Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS for research purposes.
At least one clinical criterion listed below (domains 1 to 6) plus positive antiphospholipid antibody (aPL) test (lupus anticoagulant test, or moderate-to-high titers of anticardiolipin or anti-Beta-2-glycoprotein-I (aβ2GPI) antibodies [IgG or IgM]) within three years of the clinical criterion.
|Domain 1. Macrovascular (Venous Thromboembolism [VTE])
|VTE with a high VTE risk profile
|VTE without a high VTE risk profile
|Domain 2. Macrovascular (Arterial Thrombosis [AT])
|AT with a high CVD risk profile
|AT without a high CVD risk profile
|Domain 3. Microvascular*
|Domain 4. Obstetric
|Three or more consecutive pre-fetal (<10w) and/or early fetal (10w 0d -15w 6d) deaths
|Fetal death (16w 0d – 33w 6d) in the absence of pre-eclampsia (PEC) with severe features or placental insufficiency (PI) with severe features
|PEC with severe features (<34w 0d) or PI with severe features (<34w 0d) with/without fetal death
|PEC with severe features (<34w 0d) and PI with severe features (<34w 0d) with/without fetal death
|Domain 5. Cardiac Valve
|Domain 6. Hematology
|Thrombocytopenia (lowest 20-130x109/L)
|Domain 7. aPL test by coagulation-based functional assay (lupus anticoagulant test [LA])
|Positive LA (single – one time)
|Positive LA (persistent)
|Domain 8. aPL test by solid phase assay (anti-cardiolipin antibody [aCL] ELISA and/or anti-Beta-2-glycoprotein-I antibody [aβ2GPI] ELISA [persistent])**
|Moderate-high positive (IgM) (aCL and/or aβ2GPI)
|Moderate positive (IgG) (aCL and/or aβ2GPI)
|High positive (IgG) (aCL or aβ2GPI)
|High positive (IgG) (aCL and aβ2GPI)
Patients accumulating at least three points each from the clinical and laboratory domains are classified as having APS.
In summary, these new ACR/EULAR APS classification criteria were developed using rigorous methodology with multidisciplinary international input. Hierarchically clustered, weighted, and risk-stratified criteria reflect the current thinking about APS, providing high specificity and a strong foundation for future APS research.
There are no diagnostic criteria for APS.
If a patient has signs and symptoms that suggest they have APS, laboratory testing to determine the presence of antiphospholipid antibody (aPL) is ordered to establish the diagnosis. However, aPL test results need to be interpreted cautiously, because not every person who has a positive aPL test result necessarily has APS or clinically relevant aPL positivity.
Our bodies may develop aPL due to conditions other than APS, such as in responses to infections. Patients who have positive initial aPL tests, but test negatively in repeated confirmatory tests after a period of time are said to have "transient aPL positivity." In other words, the aPL positivity is temporary. If their aPL results remain positive, then patients are said to have persistent aPL positivity. Some people may also have aPL levels that are frequently slightly elevated (technically a positive result) but in such low levels that these results are not considered "clinically meaningful" – meaning they do not indicate that a person has APS.
To be considered clinically meaningful, an aPL test should:
Antiphospholipid syndrome is diagnosed by your physician based on the careful assessment of:
Antiphospholipid syndrome diagnosis can be challenging due to two problems: missed diagnosis and over-diagnosis.
As discussed above, the goal of the APS classification criteria is to identify patients that have a high likelihood of having APS based on common and typical APS-related clinical manifestations. A common misconception is that the classification criteria for APS should also be used as diagnostic criteria. Although APS classification criteria may guide physicians in making a diagnosis, it should not be substituted for a doctor’s clinical judgment, which is based on a complete evaluation of the patient.
There are efforts to develop new tests to diagnose APS. Antiphosphatidylserine/prothrombin antibodies or anti-Domain-I antibodies are two tests that may be used more commonly in the future; however, more clinical studies are required to understand their potential diagnostic role.
As discussed above in question 3, the aPL laboratory profile assessment is critical. Depending on the type, subtype, level and persistence of the aPL laboratory tests, patients may or may not have a "clinically significant" aPL profile.
Even if you have a clinically significant aPL profile, it does not mean that you have APS. There are patients without any symptoms that have positive aPL. This condition is commonly referred to as "asymptomatic aPL positivity".
In summary, a full assessment should be performed by your doctor taking into account your medical history along with your aPL test results.
Not necessarily. Lupus anticoagulant is one of the tests to detect aPL. The reason why it is named "lupus anticoagulant" is because the discovery of the test was originally made in lupus patients. However, our understanding of this test has since evolved and now we know that lupus anticoagulant positivity is not exclusive to lupus patients, and does not necessarily indicate that a person has lupus.
Mert Sevgi, MD
Former Academic Visitor, Department of Rheumatology, Hospital for Special Surgery
Yasaman Ahmadzadeh, MD
Former Visiting Research Fellow, Department of Rheumatology, Hospital for Special Surgery
Stephane Zuily, MD, PhD
Attending Cardiovascular Specialist, Nancy Academic Hospital; Professor of Medicine, School of Medicine of Nancy, Lorraine University, Nancy, France