Classification Versus Diagnosis of Antiphospholipid Syndrome: How Are They Different? – Top 10 Series

1. What is the definition of antiphospholipid syndrome?
2. What are the differences between disease-specific classification criteria and diagnostic criteria?
3. Are there classification criteria for antiphospholipid syndrome?
4. What is new in 2023 ACR/EULAR antiphospholipid syndrome classification criteria?
5. Are there diagnostic criteria for antiphospholipid syndrome?
6. Why is diagnosing antiphospholipid syndrome challenging?
7. Is there any role for APS classification criteria for antiphospholipid syndrome diagnosis?
8. What are the recent efforts to improve antiphospholipid syndrome diagnosis?
9. One of my antiphospholipid antibody tests came back positive, do I have antiphospholipid syndrome?
10. My lupus anticoagulant test is positive. Do I have lupus?

1. What is the definition of antiphospholipid syndrome?

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.)

Table showing different organ systems and how APS may affect them

1. Episodes of neurological problems such as speech, movement or behavior abnormalities that typically last less than an hour and resolve on their own. Their mechanism of development is similar to a stroke. It is due to blockages in blood vessels that supply the brain, but there is no permanent damage to the brain.
2. Debris of coagulated tissue that sits on heart valves which develop due to damage caused by antibodies to valves.
3. Reddish-purple discoloration of the skin in a lace-like pattern, associated with the damage to small blood vessels.
4. Blockage of veins, usually in the leg, by a blood clot due to damaged inner lining of veins and propensity to clotting. It can present with swelling, redness and pain in the leg.
5. Blockage of blood vessels within the lung. This usually develops when part of the blood clot that was in the leg breaks off and travels to the lung. It can cause shortness of breath and chest pain.
6. Increased blood pressure within the main blood vessel that start from the heart and goes to the lungs. Usually develops due to persistent clots that travel from the legs to the lungs. It can cause strain on the heart as it tries to pump against increased pressures.

2. What are the differences between disease-specific classification criteria and diagnostic criteria?

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.

Classification criteria – Medical research setting

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.

Diagnostic criteria – Clinical setting

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.

3. Are there classification criteria for antiphospholipid syndrome?

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.

Revised Sapporo Antiphospholipid Syndrome Classification Criteria (simplified) 

Clinical criteria

• Blood clots within arteries, veins, or small blood vessels.
• Adverse outcomes during pregnancies, such as three or more spontaneous abortions before 10th week of pregnancy, unexplained fetal deaths1 at or beyond 10th week of pregnancy, or premature births before 34th week of pregnancy due to severe preeclampsia2 or eclampsia3.

Laboratory criteria (antiphospholipid antibody tests)

• Positive lupus anticoagulant test.
• Positive anticardiolipin antibody (aCL) IgG or IgM.
• Positive anti-Beta-2-glycoprotein-I antibody (aβ2GPI) IgG or IgM.

1. Spontaneous death of fetus due to any cause which leads to pregnancy loss.
2. A disorder characterized by new-onset high blood pressure that develops after the 20th week of pregnancy that leads to damage in various organs, most commonly protein leakage from kidneys. Severity depends on the degree of damage to organs or level of blood pressure.
3. Development of seizures in women with preeclampsia that cannot be explained by any other cause.

However, some of the limitations of the revised Sapporo APS Classification Criteria included:

• No representation of some of the well-established clinical problems related to APS.
• No clear definition on what aPL test level indicates "positive" aPL.
• A lack of risk assessment based on the presence or absence of other risk factors.

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).

4. What is new in 2023 ACR/EULAR antiphospholipid syndrome 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.

Step 1: Entry Criteria

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.

Step 2: Clinical Domains

* Suspected: Livedo racemosa, livedoid vasculopathy lesions by exam, or acute/chronic aPL-nephropathy by physical examination and/or laboratory, or pulmonary hemorrhage by symptoms and imaging.

Established: Livedoid vasculopathy by pathology; acute/chronic aPL-nephropathy by pathology; pulmonary hemorrhage (by BAL or pathology; myocardial disease by imaging or pathology; or Adrenal hemorrhage by imaging or pathology.

Step 3: Laboratory (aPL) domains

** Moderate (40-79U) and high (>80U) level aCL/(aβ2GPI) are based on enzyme-linked immunosorbent assays (ELISA)

Step 4: Final assessment

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.

5. Are there diagnostic criteria for antiphospholipid syndrome?

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:

• Adhere to the guidelines for testing methods and use validated tests.
• Remain persistently positive on two separate time points performed at least 12 weeks apart.
• Be determined based on LA test and/or moderate-to-high anticardiolipin antibody (aCL) or anti-Beta-2-glycoprotein-I (aβ2GPI) antibody positivity (of note, low titers of aCL or aβ2GPI are not clinically meaningful).

Antiphospholipid syndrome is diagnosed by your physician based on the careful assessment of:

• Clinically meaningful aPL profile, as discussed above.
• Clinically relevant health problems (that is, health problems known to frequently occur due to aPL).
• Additional thrombosis risk factors (for instance birth control pill use or smoking) or medical problems.

6. Why is diagnosing antiphospholipid syndrome challenging?

Antiphospholipid syndrome diagnosis can be challenging due to two problems: missed diagnosis and over-diagnosis.

1. Missed diagnosis – APS is not even considered in the list of possible diagnoses to explain a patient’s medical problems.
   Example clinical scenario: A patient goes to the emergency department complaining of leg swelling and redness. She is taking birth control pills for contraception and she is a smoker. This is her first time experiencing similar symptoms; however, she has a history of recurrent second trimester miscarriages as well as slightly low platelet counts. She is diagnosed with a blood clot in association with additional thrombosis risk factors and is treated appropriately. The patient does not undergo testing for aPL; and APS is not included in the differential diagnosis, possibly because she had other risk factors (birth control pill and smoking) that could explain her tendency to develop blood clots.
2. Overdiagnosis – APS is diagnosed incorrectly, based on a single, weak positive aPL test.
   Example clinical scenario: The patient above undergoes testing for aPL; results are positive but her anticardiolipin antibody (aCL) IgG is only slightly elevated above normal antibody titers (low level aCL).

7. Is there any role for APS classification criteria for antiphospholipid syndrome 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.

8. What are the recent efforts to improve antiphospholipid syndrome diagnosis?

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.

9. One of my antiphospholipid antibody tests came back positive, do I have antiphospholipid syndrome?

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.

10. My lupus anticoagulant test is positive. Do I have lupus?

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.

Updated: 11/30/2023

Authors

References

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