18min chapter

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ACoA: Rethinking APS with the Guidance of New Classification Criteria

ACR on Air

CHAPTER

Understanding Antiphospholipid Syndrome (APS)

This chapter provides an overview of Antiphospholipid Syndrome (APS), a systemic autoimmune disease characterized by thrombotic and non-thrombotic clinical problems due to autoimmune antiphospholipid antibodies. The speakers explore the complexity of APS, discussing its manifestations in different organ systems and highlighting the importance of assessing the antiphospholipid antibody profile to determine clinical relevance.

00:00
Speaker 2
Enjoy the show. Dr. Doruk, welcome to the show.
Speaker 1
Thank you, John, for inviting me to participate in ACR on air. It's a really very exciting to be a podcast guest, especially when we talk about APS.
Speaker 2
Fantastic. What is Antiphospholipid syndrome? How do you think about it?
Speaker 1
It's a good question. I can give you a very simple answer, which is a systemic autoimmune disease with thrombotic obstetric and non-thrombotic clinical problems. And of course, developing due to autoimmune antiphospholipid antibodies. But this is really a general and classic answer. And I think I can do better and I can give you a deeper, more philosophical response. Love it. In order to do that, we should start with the definition of syndrome. The word syndrome, which comes from Greek language and it means concurrence. You can Google this definition and basically the syndrome is defined as a group of symptoms occurring together, indicated specific condition, but not necessarily related. Now, they say symptoms, but in the world of APS, we have to include APL into the equation too. And if you keep the definition of syndrome in mind while defining APS, we can speculate A, Antiphospholipid antibodies will develop as a result of these symptoms. B, Antiphospholipid antibodies will co-occur together with these symptoms with no direct cause. Or lastly, we can speculate that Antiphospholipid antibodies will cause symptoms. Now, we can come up with some examples from our daily practice to support, or I can say to illustrate these points. Let's say we have a patient with severe infection and low level antico-alopin antibodies. Here, these antibodies are just bystanders. Then let's say we have a patient with DVT, T-rypolipid antibodies positive, but the blood clot happened following a major cancer surgery. Here APL is a risk factor with a potential contributor together with other thrombosis risk factors. And then let's have another patient with unprobop DBT, APL nephropathy, diffused alveolar hemorrhage, these microvascular manifestations of APL, and triple APL positivity. Here I think we have a better confidence that Antiphospholipid antibodies cause these problems. So I know you ask a short question what APS is. I gave you a long answer, a simple definition, thrombotic obstetric, non-thrombotic clinical problems in the setting of APL. But we still need high quality research to better define APS, including pathogenic versus non-potogenic APL, different clinical phenotypes, and different sub-phenotypes.
Speaker 2
Fantastic, so it's a little bit more complicated than expected. I guess that goes for many rheumatic diseases that we care for. We often put names to syndromes that co-occur together, but may not have a full understanding about their cause or pathogenesis. But in general, I guess to have APS, we'd want to think that those naphospholipid antibodies are causing the thrombosis. Is that right? Would that be your definition? These are causative to be diagnosed?
Speaker 1
So the short answer is yes, in many situations, antifospholipid antibodies cause the clinical problems. Sometimes they contribute to the problem, and this is the example that when there are many risk factors for thrombosis, let's say, including antifospholipid antibodies. And sometimes in a clinical setting, we are not sure if antifospholipid antibodies are the cause of the problem, especially with low levels or controversial APL-related manifestations. And I think we are going to talk about the diagnosis in a second, that's why it's very important to put all these factors into the equation during diagnostic assessment of APL-positive patients.
Speaker 2
Got it. That makes a lot of sense. So when we're thinking about the thrombotic complications of APS, can you tell us a little bit more about what vascular beds can be affected by APS, and when should we start thinking about that a patient may have APS, depending on what organs or tissues are affected? Sure, definitely.
Speaker 1
In an antifospholipid antibody-positive patient, these clinical manifestations represent a wide spectrum. And I think we can even start with patients who do not have any clinical problems. These patients are generally called asymptomatic APL-positive patients, and they don't have the syndrome. Regarding thrombosis, and it's often called thrombotic APS, these patients can have arterial events, generally stroke, or venous events, generally deep vein thrombosis with or without pulmonary embolism. And these events can develop with or without other risk factors. And as we just discussed, it's important to know these additional risk factors for both diagnostic and management decisions. Another group is catastrophic APS, less than 1% of patients, multiple organ involvement, generally with micro-vascular disease, and generally with systemic thrombotic microangiopathy. And I know that Tom Ortell is speaking during the review course about thrombotic microangiopathies, and it can be also a very important podcast to listen, because whenever we manage catastrophic APS patients, systemic TMA is always part of the discussions. Now I want to create a separate group, I call it microvascular APS. I already mentioned microvascular APS is generally part of catastrophic APS, but this separate group, these are the patients that you see in your clinic, rather than cap patients seen in the intensive care unit. Other APS patients, such as diffused alveolar hemorrhage, such as liver-doid vasculopathy-related skin ulcers, such as APL nephropathy. I can give more examples. But this is really a distinct subset from a mechanistic point of view, pathologic point of view, and treatment perspectives, such as these patients do not respond to anticoagulation. Then we can create another group, obstetric APS, major clinical problem in APS. However, this is also a heterogeneous group where patients may have early pregnancy ulcers, late pregnancy ulcers, placental vascular problems resulting in preeclampsia or growth restriction. And these different manifestations are not the same with respect to diagnostic assessment of these patients. And then lastly, I think we can create another group, and we can call it non-thrombotic problems related to antifossolephid antibodies, such as autoimmune thrombocytopenia, autoimmune hemolytic anemia, valve disease, including thickening and vegetations. So as you can see, it's really a systemic disease with many different organ involvement.
Speaker 2
Very interesting, and I love how you defined the various different areas that can be affected, because often, sort of my reflex is, oh, you know, antifossyphylipid syndrome is venous thromboembolism. But that's one part. You mention arterial thrombosis, including stroke. You mention microvascular disease like lividoid vasculopathy, pulmonary hemorrhage, APL nephropathy, these are things I don't often think about that could be related to APS. And then certainly the obstetric complications, the hemologic manifestations like thrombocytopenia, and even the cardiac valve manifestations. So it's great that you put it all out there, and, you know, we as rheumatologists should think about evaluating for APS in patients with any of these manifestations. Why do we think about the blood work in testing for antifossifalipids in, you know, either in the acute setting where somebody's having one of these things, or maybe somebody that has a history of DBT, and we're wondering whether they could have
Speaker 1
APS? This is actually such a broad topic, and you can have another podcast for your show just on antifossifalipid antibodies. It's tricky, it's complicated, but let me just give you a couple of points that I believe important while assessing antifossifalipid antibodies. The first thing I want to say is the assessment of APL positivity is not as simple as, yes, this is positive, no, this is negative. We need to assess the APL profile, and we need to accept the fact that not every positive antifossifalipid antibody test is clinically relevant. This is a major point that I want to make, and this is a point that we teach residents and fellows all the time, that presenting a patient, saying that this patient is antifossifalipid antibody positive, doesn't help us in any way. We need to know the type of the antibody, the isotype, the level, is it persistent or not? Is it in combination with other tests? What is the most recent test? Along the same lines, if somebody tells me that this patient has liposanticoagulant positivity, that doesn't help. I need to know all the details, including where it was tested, did they follow the guidelines? Was the patient guidelines meaning ISTH, International Society of Trombosis and Hemostasis? Did they follow these guidelines? Was the patient an anticoagulation when tested? What's the correction ratio? Do we have a history of elevated PTT, false positive syphilis test that can help with the accurate assessment of LA? So yes, this may sound like a very complicated assessment, but really we need to get into the details of APL assessment to understand if they are clinically relevant or not. At the end, there is a spectrum from low level anticoagulopin IgM levels to triple antifossifalipid antibody positivity with high levels of anticoagulopin antibody and antibiotic T2GP1 IgG isotype. And you can think of any other combinations in between. So clearly we need to check antifossifalipid antibodies in patients with unusual thrombosis, young age thrombosis, systemic autoimmune diseases in patients, blood clot, plus some of the clinical problems that we just discussed, such as thrombocytopenia. And then if you get a positive test, you shouldn't really stop there and look at the antifossifalipid antibody profile. How do I assess the profile? Let's say I have a patient in my clinic and I have antifossifalipid antibody test results on my desk. Anticoagulopin antibody is a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. It's a very high level. If I want to give you some kind of an algorithm about the confidence level regarding the clinical relevance of these antibodies, I'm not really talking about diagnosis now, just looking at the antibodies' clinical relevance. I guess on the top, you can have this triple-APL positivity and also lupus anticoagulopin positivity alone, and I'm talking about persistent results. Lupus anticoagulopin is a very important test, but it's a tricky test. It can be inaccurate when patients are on anticoagulation. But if it is done in the right lab, it is really important. Regarding this confidence level of the clinical relevance of APL, if you go one level down, we have lupus anticoagulopin negative patients with moderate to high level of anticoagulopin or Antibitatine to GP1 antibodies. Here, I want to differentiate between IgG and IgM because we are still questioning. We are still studying trombogenic potential of IgM. We need to be very careful from a diagnostic point of view when we have IgM, ACL, and or Antibitatine to GP1 only patients. Level 3 on the bottom, I would put patients, again, LA negative very low levels of ACL or Antibitatine to GP1. And generally, we define moderate high levels above 40 ELISA units and low like 20 to 40 ELISA units. So again, I think I gave you a long answer, but what we need to know about APL is that the correct interpretation of these results is critical. And I'm going to underline this critical while assessing the APL profile.

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