Antiphospholipid Syndrome: Insights Into a Life-Threatening Autoimmune Disease With Limited Awareness

Lara C. Pullen, PhD

Disclosures

January 29, 2019

Editorial Collaboration

Medscape &

Antiphospholipid syndrome (APS) is a systemic autoimmune disease in which antiphospholipid antibodies (aPL) increase the risk for thrombosis, pregnancy morbidity, and other nonthrombotic complications such as thrombocytopenia.

Doruk Erkan, MD, MPH

Thanks to the concerted efforts of a small but active community of researchers, our understanding of this rare disease has expanded, and there is increased hope that the life-threatening complications of APS can be limited with proper patient identification and management.

For the past two decades, Doruk Erkan, MD, MPH, has been a leader in the field of APS. An associate physician-scientist at the Barbara Volcker Center for Women and Rheumatic Diseases, associate attending rheumatologist at Hospital for Special Surgery, and associate professor of medicine at Weill Cornell Medicine, New York, NY, Erkan also has a mission of training physicians on how to optimally classify, diagnose, and treat this rare and challenging disease. Medscape recently spoke with him about APS and his research.

Diagnostic Challenges

Medscape: You recently coauthored an overview of APS in the New England Journal of Medicine.[1] You also participated in an APS session called "The Scary Stuff"[2] this past October at the annual scientific meeting of the American College of Rheumatology (ACR) in Chicago. When it comes to diagnosing this disease, what are the specific challenges you were hoping to bring to light? Is APS really that scary?

Erkan: The primary goal of our New England Journal of Medicine article, coauthored by Dr David Garcia from the University of Washington School of Medicine, Seattle, was to educate general physicians about APS, given the significant challenges related to APS diagnosis. During the ACR session, I also summarized these diagnostic challenges, which I sometimes find scary.

A major challenge is the limited awareness of the syndrome, which causes patient frustration, misdiagnosis, and overdiagnosis. Patients are frustrated because many times they cannot find a professional who can understand and manage their disease. This limited awareness can lead to both misdiagnosis, owing to missing the signs and symptoms, and overdiagnosis resulting from overinterpretation of aPL tests.

Just to give you an example, a young patient with deep vein thrombosis may go to the emergency department; physicians may not include APS in the differential diagnosis and thus may not order aPL tests. This is mis- (or missed) diagnosis. The other scenario is physicians ordering aPL tests in this patient, but based on slightly elevated aPL test results at one point in time, they may diagnose the patient with APS. This is overdiagnosis. I do not think there are many diseases like APS, where both misdiagnosis and overdiagnosis are challenging problems on the same level.

Medscape: Given that limited awareness, how do you recommend that physicians and rheumatologists recognize these patients? And then what is your recommendation for the correct diagnosis?

Erkan: There are some red flags when physicians should think about aPL. For instance, young patients with blood clots, unexplained mild thrombocytopenia, or patients with unexplained pregnancy losses, especially those occurring during late pregnancies, are major red flags. Activated partial thromboplastin time (aPTT) is a blood test that is routinely ordered before surgical procedures; a patient with an elevated aPTT should be further investigated for aPL. Patients who have a false-positive test for syphilis should also raise a red flag, as should patients with systemic autoimmune diseases, especially those with lupus or lupus-like diseases.

The diagnosis of APS should be considered in patients with persistent, moderate- to high-risk aPL profiles when they present with aPL-related clinical problems. In clinical practice, my definition of a moderate to high-risk aPL profile is positive lupus anticoagulant tests and/or aPL ELISA test (anticardiolipin antibody or anti beta2-glycoprotein-I antibody IgG/M) level of 40 GPL/MPL or higher.

Medscape: When it comes to properly diagnosing APS, are there any tools that can help physicians?

Erkan: Classification criteria exist for APS, but not diagnostic criteria. Classification and diagnosis should be regarded as two separate concepts. Classification criteria are formulated for research studies; if you are conducting a clinical research study, then the goal is to capture a uniform group of patients; you don't need to capture all APS patients, including those with very rare manifestations. However, if you are developing diagnostic criteria, the goal should be capturing all possible patients, including patients with rare disease manifestations.

Given the reasons above, the classification criteria can be used as a guide during the diagnostic considerations, but they should not be the only tool. Diagnosis of APS (or any disease in that matter) is a very complex process including interpretation of aPL tests individually and as a whole (aPL profile), as well as assessing the clinical symptoms and other risk factors, such as for thrombosis; then you come up with the diagnosis on the basis of that thinking.

The current APS classification criteria are actually 20 years old, [3] with several limitations (eg, they do not capture some of the relatively common aPL-related manifestations). Currently there is a multidisciplinary international effort (expert- and data driven) underway to develop new classification criteria for APS,[4] a project supported by the ACR and the European League Against Rheumatism (EULAR).

Management Challenges

Medscape: After patients have been diagnosed with APS, what's the recommended management strategy?

Erkan: APS has a broad spectrum of clinical manifestations. Let's say you have a patient with a persistent moderate- to high-risk aPL profile. First, this patient may have no aPL-related symptoms, and thus no APS. Second, thrombotic complications may occur ranging from macrovascular disease (eg, deep vein thrombosis) to microvascular disease (eg, diffuse alveolar hemorrhage, aPL nephropathy) to catastrophic APS (multiple organ thrombosis generally associated with thrombotic microangiopathy). Third, female patients are at risk for pregnancy-related morbidity. And last, nonthrombotic problems may develop, such as thrombocytopenia, anemia, cognitive dysfunction, or cardiac valve disease. Depending on how these patients present, a different management strategy is required.

For patients with no events, in whom you are looking for primary thrombosis prevention, the controversy is mostly around whether or not to use low-dose aspirin, which can be effective on the basis of retrospective studies, but there are no prospective data showing that it prevents the first clot.[5] I think preventing the first clot by eliminating other thrombosis and risk factors, such as birth control pills, is more important than giving aspirin if patients do not have other cardiovascular risk factors. We recently completed a review article on primary thrombosis prevention in aPL-positive patients,[6] in which we recommend low-dose aspirin only for high-cardiovascular-risk, aPL-positive patients.

With respect to the prevention of recurrent thrombosis, the controversy is whether to use international normalized ratio (INR) ranges of 2-3 versus 3-4: moderate versus high intensity. Following retrospective studies demonstrating that high intensity is more effective than moderate intensity,[7] two randomized controlled trials (RCTs) demonstrated no difference between moderate- versus high-intensity anticoagulation.[8,9] Given that approximately 75% of the patients in these RCTs had a history of venous thrombosis, physicians are generally comfortable with the use of moderate-intensity anticoagulation after the first venous thrombosis. For arterial thrombosis, some groups still push high intensity because only 25% of patients in RCTs had arterial events, and the retrospective studies show that an INR of 3-4 is more effective.[7] I personally keep patients' INR in the 2.5-3 range and add aspirin if they have additional cardiovascular risk factors. That's in line with the recommendation from a working group of the 15th International Congress on aPL (September 2016).[10]

Microthrombotic APS and catastrophic APS patients are generally difficult to manage, though they are different. Patients with catastrophic APS are usually admitted because of their multiple clots, whereas patients with microthrombotic APS can be seen in your clinic with kidney disease or pulmonary disease. These patients do not usually respond to anticoagulation, and over the years we have been trying to understand the role of immunosuppression[11,12] for these patients. Immunosuppression, better clinical trials, and a greater understanding of the underlying mechanisms are going to be crucial for improving their care.

Medscape: It seems that these patients are extremely complicated. Are they usually followed by rheumatologists? What's the best approach for coordinating their care?

Erkan: I agree. Some patients are extremely complicated, but not all of them. Patients with single thrombotic events or pregnancy morbidity can be easily managed by their hematologists or obstetricians, respectively. Almost half of these patients have lupus or another systemic autoimmune disease; those patients are usually managed by rheumatologists. Given that the Hospital for Special Surgery is a major referral center for APS, we generally receive referrals for all kinds of aPL-positive patients, including those with difficult-to-manage aPL manifestations, such as those with recurrent thrombosis or pregnancy losses, microthrombotic manifestations, and/or nonthrombotic manifestations.

Communication is very important for coordinating care in any disease but for APS in particular. For example, I always tell my patients that if they are going to have surgery, which increases the risk for thrombosis further—and many of them are on warfarin—then they need to let me know that I can talk to their physicians to discuss the perioperative plan. Planning for surgical procedures, before and after, is key.[13] Another example is the management of catastrophic APS patients. Inpatient consult teams should be in continuous communication via emails, phone calls, and in-person meetings, because a patient's condition can change by the minute, and difficult decisions (such as continuation of anticoagulation despite bleeding) may be needed in a multidisciplinary fashion.

Collaborating to Address APS

Medscape: You're the founding member and co-chair of APS ACTION.[11] Can you tell me about this group?

Erkan: APS ACTION (APS Alliance for Clinical Trials and International Networking) was formed in 2000 with the primary goal of designing and conducting large-scale, multicenter research and clinical trials in persistently aPL-positive patients.[14] Through the dedication and hard work of 57 APS ACTION members from 33 international centers, we have several important ongoing research activities, including (1) a multicenter Web-based clinical database and repository ("registry") of aPL-positive patients (currently 800 patients included); (2) conducting observational research based on the registry data to further our understanding of the disease; (3) standardization of aPL testing through the use of APS ACTION core laboratories worldwide; (4) identification of the limitations in the existing aPL/APS literature; and (5) young scholar exchange programs, just to mention some of them. Also, APS ACTION is involved in APS clinical trials, sometimes in collaboration with other organizations; our involvement can vary between designing, conducting, endorsing, or participating in these projects.

Medscape: What has the registry told you about the natural history of disease? Have you learned something from being able to pull all of these patients together?

Erkan: One of our first registry-related studies[15] is about the impact of concomitant lupus diagnosis in aPL-positive patients. We generally discuss how aPL positivity changes the presentation in lupus patients. In this study, we asked the opposite question: how the concomitant diagnosis of lupus will change the presentation of an aPL-positive patient. We hypothesized that aPL-positive patients with lupus would have a higher risk for thrombosis, and interestingly, it was not true. The frequency of thrombosis was equally distributed among aPL-positive patients with or without lupus, as were pregnancy problems. However, the diagnosis of lupus in patients with persistently positive aPL was associated with an increased frequency of thrombocytopenia, hemolytic anemia, low complement levels, and positive IgA anti-beta2-glycoprotein-I antibodies.

Also, I should mention that the APS ACTION registry includes both the clinical database and the repository, in which we collect clinical data and blood from patients on an annual basis. The clinical repository, as a reliable and useful research resource for APS, is open to internal and external research applications. I say that it is a reliable source because our most recent paper, based on a study led by Dr Savino Sciascia from the University of Turin (Turin, Italy) and Dr Maria Laura Bertolaccini from St Thomas Hospital (London, United Kingdom), demonstrated that the results of aPL ELISA tests used for recruitment into the registry were in good agreement to the results obtained by the APS ACTION core laboratories.[16]

Medscape: Do you have any parting statement for our readers?

Erkan: We are working together with the patient organizations to increase the awareness of this potentially life-threatening disease. For instance, APS ACTION, in collaboration with APS Foundation of America, APS Foundation of Australia, and APS Support UK, jointly supported 2018 World Thrombosis Day (October 13). The primary goal was to increase APS awareness in the thrombosis community and beyond.

We are also focusing on physician education. For instance, based on a collaboration between Hospital for Special Surgery and University of Lorraine School of Medicine (Nancy, France), a free-to-download APS iBook was recently developed, which offers the key points (both in English and French) in the diagnosis and management of APS patients.

In summary, APS is complicated, though we are trying to help APS patients as much as we can.

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