The Curbsiders podcast

#421 Antiphospholipid Syndrome with Dr. Arielle Langer

January 8, 2024 | By



Transcripts available via YouTube

Conquer your fear of antiphospholipid syndrome! Dr. Arielle Langer leads us through what clinical features raise suspicion for antiphospholipid syndrome, how to interpret laboratory testing, and the nuances of antiphospholipid syndrome management.

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Show Segments

  • Intro
  • Case from Kashlak
  • What is antiphospholipid syndrome?
  • Clinical features that raise suspicion for antiphospholipid syndrome
  • Laboratory testing and diagnosis of antiphospholipid syndrome
  • Management of antiphospholipid syndrome: initial treatment
  • Management of antiphospholipid syndrome: managing recurrent thrombosis
  • Return to Case: Pregnancy in patients with a history of thrombotic APLS
  • Obstetric APLS
  • Final questions
  • Outro

Antiphospholipid Syndrome Pearls

  1. Three clinical buckets that raise suspicion for APLS include patients who are clotting through anticoagulation, patients clotting in unusual locations, or patients with a history of autoimmunity. These three buckets also help inform when to perform antiphospholipid antibody laboratory testing. 
  2. Antiphospholipid antibody laboratory testing indicates whether antibodies are present that recognize clotting proteins, not that they actually have the special property that enables them to activate the clotting cascade. Thus, false positive testing is a challenge. In particular, transient false positives are common in the setting of acute inflammation, which is why diagnostic criteria require that testing is persistently positive for at least 12 weeks. 
  3. Several trials indicate that warfarin is superior to DOACs for treatment of APLS. For patients who are experiencing breakthrough thrombosis on warfarin, some options include addition of aspirin to warfarin, switching to enoxaparin, addition of hydroxychloroquine, or addition of eculizumab.
  4. Patients may have thrombotic APLS only, obstetric APLS only, or both, depending on whether their antiphospholipid antibodies recognize clotting proteins only, placental trophoblasts only, or both.
  5. Patients with a history of thrombotic APLS should be switched from warfarin to enoxaparin for the duration of a pregnancy. Patients with a history of obstetric APLS only should be managed during a future pregnancy with aspirin +/- prophylactic-dose enoxaparin (guidelines vary).
  6. Every patient with antiphospholipid syndrome should have a hematologist!

Antiphospholipid Syndrome – Show Notes

What is antiphospholipid syndrome?

Dr. Langer typically describes antiphospholipid syndrome to patients as follows: Antiphospholipid syndrome (APLS) is an autoimmune disorder in which the body produces antibodies that recognize certain self clotting proteins. In most autoimmune conditions, antibodies cause the destruction of the self proteins they recognize. However, antiphospholipid antibodies have a special property that causes them to activate these clotting proteins, resulting in acceleration of the clotting process (Garcia et al, 2018). There is heterogeneity in how much these antiphospholipid antibodies turn on the clotting cascade from person to person, meaning there is a spectrum of how difficult it is to stop patients from clotting. There is also heterogeneity in terms of the accuracy of the testing: the laboratory testing just indicates whether antibodies are present that recognize the clotting proteins, not that they actually have the special property in which they recognize and activate these clotting proteins.

Clinical features suspicious for antiphospholipid syndrome

Dr. Langer describes three big buckets that raise her suspicion for antiphospholipid syndrome:

  1. Patients who are clotting through anticoagulation
  2. Patients that are clotting at unusual sites (ex. Arterial beds without another clear explanation such as atherosclerosis; splanchnic thrombosis; central venous sinus thrombosis)
  3. Patients with a history of autoimmunity (most commonly lupus); sometimes the autoimmune disorder is diagnosed concurrently with antiphospholipid syndrome 

Other manifestations of antiphospholipid syndrome include obstetric complications (described in more detail below), as well as rarer microvascular manifestations such as livedo racemosa and nephropathy (Garcia et al, 2018). Catastrophic APLS is a rare entity characterized by widespread microvascular and large vessel thrombosis throughout the body, causing devastating complications such as renal injury, stroke, myocardial infarction, and adrenal hemorrhage (Cervera et al, 2020; Cervera et al, 2018).

Laboratory testing and diagnosis of antiphospholipid syndrome

There are three core tests used in the diagnostic work-up of antiphospholipid syndrome: lupus anticoagulant, anti-cardiolipin IgG / IgM, and B2-glycoprotein IgG / IgM. 

The revised Sapporo criteria (Miyakis et al, 2006) state that patients must meet the following clinical and laboratory criteria to be diagnosed with APLS:

  • Clinical criteria: History of vascular thrombosis (arterial or venous) or pregnancy morbidity (described in more detail below)
  • Laboratory criteria: at least one of the following positive laboratory results: positive lupus anticoagulant, positive anti-cardiolipin IgG or IgM (titer >40), or positive B2-glycoprotein (titer >40). (Titers between 20-40 can be labeled as positive or intermediate positive in some labs, which often yields confusion). Notably, at least one laboratory test must be positive around the time the event occurred as well as persistently positive at least 12 weeks later. 

The pattern of laboratory results can help in risk stratification. A higher number of positive tests and higher antibody titers are both associated with higher risk (Pengo et al, 2010; Garcia et al, 2018). Positive IgG is more of a concern than IgM (Kelchtermans et al, 2016). Positive lupus anticoagulant has classically been shown to be a stronger predictor of future clotting than anti-cardiolipin and B2-glycoprotein in patients who have not yet clotted (Galli et al, 2003) (However, Dr. Langer points out that lupus anticoagulant is unique in that it can be influenced by the presence of anticoagulation, which can complicate results). 

A major challenge in interpretation of antiphospholipid antibody laboratory results is the frequency of false positives. As described, these tests only detect the ability of antibodies to recognize clotting proteins, but don’t provide information on their ability to activate the clotting process. Indeed, based on blood donor data, there is a large segment of the population with positive antiphospholipid antibody laboratory testing who will never go on to clot (e.g. will never go on to develop antiphospholipid syndrome) (Vila et al, 1994). In particular, transient false positives are common in the setting of inflammation, especially inflammation related to blood vessels – which is often exactly the situations in which we want to send these tests. Thus, diagnostic criteria require that testing is persistently positive for at least 12 weeks  (Miyakis et al, 2006). (Notably, the half life of IgG is 3 weeks, so if the testing is falsely positive in the setting of an acute insult / acute inflammatory process, 12 weeks should provide enough time for the IgG to decay away.) 

In addition to inflammatory states, lupus anticoagulant results can also be affected by the presence of anti-coagulation as mentioned, which can cause both false positives and false negatives (Chaturvedi et al, 2017). Thus, if APLS is suspected, Dr. Langer recommends obtaining a specimen for lupus anticoagulant before starting anticoagulation if possible. If this is not done, it can create difficult situations, as the prospect of stopping anticoagulation in a patient with suspected APLS to prove the diagnosis is often unsettling (practically, Dr. Langer will usually wait and obtain testing when the patient is going for a colonoscopy or surgery in which they need to stop anticoagulants, provided they are low enough risk from an APLS perspective that holding anticoagulation is safe).

Crucially, the frequency of false positives is why considering pre-test probability of antiphospholipid syndrome is so important when deciding whether to send testing – and why Dr. Langer uses the three “buckets” suspicious for APLS to inform her choices of when to test. As detailed in the American Society of Hematology (ASH) “Choosing Wisely” guidelines (ASH Choosing Wisely), antiphospholipid antibody testing should not be sent in the setting of a clear provoked clot. Pre-test probability, combined with the pattern / degree of laboratory test positivity, is also critical in deciding what to do with positive results:

  • In a patient with a very low pre-test probability for APLS (e.g. a clearly provoked clot after a fracture) and, for instance, an isolated anti-cardiolipin of 30, APLS is very unlikely; while the patient will be anticoagulated for their acute clot, they should be done so without consideration for APLS, and they may not even warrant repeat testing. 
  • Alternatively, a patient with a very high pre-test probability for APLS and highly positive laboratory should be treated presumptively for APLS until confirmatory testing is performed at the 12-week mark. 
  • Tricky situations can arise in patients with ambiguous clots (e.g. unclear whether provoked or unprovoked) and low positive laboratory testing; in these cases, shared decision making should be used to decide whether to treat presumptively for APLS until confirmatory testing at 12 weeks. Sometimes, in ambiguous situations where patients are having difficulty making a decision, Dr. Langer will offer to do lab testing at 6 weeks if they are struggling with taking warfarin, since if the titers are already negative at 6 weeks they can stop warfarin.

What about the new ACR / EULAR guidelines for APLS diagnosis?

Recently, the American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) published a new set of guidelines for APLS diagnosis (Barbhaiya et al, 2023). These guidelines provide a detailed, complex algorithm that incorporate components such as nonthrombotic clinical manifestations (like thrombocytopenia or valvular vegetations), risk stratification by traditional thrombosis risk factors, risk stratification by antiphospholipid antibody profile, etc. Dr. Langer emphasizes that these guidelines were primarily developed to refine the population designated as having APLS for research purposes to capture patients that truly have the condition, and thus intentionally has increased specificity and lower sensitivity. Dr. Langer believes these new guidelines are a brilliant research tool, mirror what hematologists think about in the office, and can help teach younger hematologists how to think about these concepts. However, she thinks that for the general internist, these guidelines are likely too complicated and the Sapporo criteria are a better, simpler tool for general internists to use in routine practice to screen patients who should see a hematologist to further adjudicate the diagnosis.

Management of antiphospholipid syndrome

Initial treatment of APLS

Patients with APLS need to be on anticoagulation for life. Multiple studies have indicated that warfarin is superior to direct-oral anticoagulants (DOACs) in APLS:

  • A study of rivaroxaban vs. warfarin for patients with triple positive APLS was stopped early due to much higher breakthrough thrombosis rates in the rivaroxaban arm (Pengo et al, 2018)
  • A study of apixaban vs. warfarin in patients was conducted in a more heterogeneous population (patients could be single, double, or triple positive, and could have historically reported labs.) The study initially used a prophylactic dose of apixaban, and later modified this to a therapeutic dose of apixaban. The study observed higher breakthrough thrombosis in the apixaban arm at both dosage levels for single, double, and triple positive patients (Woller et al, 2022).

Dr. Langer notes that the majority of events in these studies were strokes. Thus, patients with a history of stroke are those in whom she is most diligent about using warfarin. In patients who are single-positive  and had a non-stroke thrombosis, she will still recommend warfarin, though will walk through the data with the patient and engage in shared decision making.

Enoxaparin is another option but usually isn’t used upfront since many people don’t like long-term self-injection, and long-term use of enoxaparin can be detrimental to bone density (Gajic-Veljanoski et al, 2016).

Addition of aspirin to warfarin is not typically recommended upfront after a stroke due to increased bleeding risk . However, addition of aspirin is an option in patients with breakthrough thrombosis (see “Management of patients with breakthrough thrombosis” below).

Normal or higher intensity INR goal? Several small studies showed that using a higher INR goal had similar thrombotic outcomes to the normal INR goal of 2-3 in patients with APLS (Crowther et al, 2003; Finazzi et al, 2005). These studies did not document a substantially higher bleeding risk, though this is likely due to small sample size and/or limited follow-up time given that we know from other research that a higher intensity INR goal is associated with higher bleeding risk. Thus, there is no indication to use a higher intensity INR goal in APLS due to lack of evidence for a benefit (unless there is another indication such as a mechanical mitral valve).

Management of patients with breakthrough thrombosis?

For patients with breakthrough thrombosis on warfarin, several options are available:

  • Addition of aspirin to warfarin can be considered in patients who develop a breakthrough thrombosis in the arterial bed (many hematologists will also add aspirin for breakthrough thrombosis in the venous bed given the low safety risk, though this is not data-driven).
  • Switch from enoxaparin to warfarin (this can be done either if the patient is clotting at a goal INR, or if they are clotting because they can’t sustain a goal INR) (Dentali et al, 2005)
  • Addition of hydroxychloroquine

For patients with catastrophic APLS in the hospital, high-dose glucocorticoids and plasma exchange or IVIG is typically recommended; addition of complement inhibition with agents like eculizumab may be warranted (López-Benjume, 2022).

Patients with APLS on warfarin going for a surgery or colonoscopy

For higher-risk patients with APLS, sometimes endoscopists will be willing to perform screening colonoscopies with the patient continuing on anticoagulation; some advanced endoscopists will be comfortable doing smaller polypectomies on anticoagulation. However, if anticoagulation needs to be stopped, for instance for a major surgery, it can be done with meticulous bridging. Typically, the patient’s warfarin is stopped ~1 week in advance, and when the INR drops low enough, they will be transitioned to enoxaparin, which can be held right before surgery to minimize the time off anticoagulation. The patient can then be bridged back on warfarin afterwards . The patient’s hematologist should always be involved in this process. 

What about aspirin for primary prevention of thrombotic APLS?

For patients with persistent positive antiphospholipid antibody laboratory testing but without a history of thrombosis, the question of aspirin use for primary prevention is not backed with clear-cut data (Garcia et al, 2018; Arnaud et al, 2014). Dr. Langer will be more likely to suggest aspirin for primary prevention of thrombotic APLS in patients with prior obstetric APLS, patients with positive lupus anticoagulant, or patients who are triple positive (especially with high antibody titers). Additionally, if you are on the fence about whether to start a patient on aspirin for another reason (for instance, atherosclerotic risk), the presence of persistent positive antiphospholipid antibody testing may help tip you over the edge.

APLS and pregnancy

A subset of antiphospholipid antibodies can recognize placental trophoblasts during pregnancy (Alijotas-Reig, 2022). This can lead to an abnormally structured placenta, which can predispose to preeclampsia spectrum disorders and other obstetric complications (Alijotas-Reig, 2022). Notably, a patient may have anitphoshoplipid antibodies that recognize both placental trophoblasts and clotting proteins, or only one or the other. This creates a Venn Diagram of patients who have obstetric APLS only, thrombotic APLS only, or both obstetric and thrombotic APLS. Only a subset of patients with obstetric APLS only will go on to develop thrombotic APLS.

Pregnancy in patients with a history of thrombotic APLS 

Patients with a past history of thrombotic APLS are at risk of recurrent thrombosis given the added pro-thrombotic state of pregnancy; however, if they are on appropriate anticoagulation prior to pregnancy and didn’t have a history of recurrent clots previously, the risk of recurrent thrombosis during pregnancy should be relatively low. Patients with a past history of thrombotic APLS are also at increased risk of developing obstetric APLS.

Patients with a history of thrombotic APLS who become pregnant should be switched to therapeutic dose enoxaparin (Bates et al, 2012; Sammaritano et al, 2020), as warfarin is a known teratogen. Ideally, patients should be switched pre-emptively to enoxaparin when they are trying to get pregnant so that they are already on enoxaparin prior to conception. Enoxaparin is safe during pregnancy (not only is it not teratogenic, but it also doesn’t cross the placenta so the fetus is not anticoagulated). Patients with a history of thrombotic APLS  should also be put on aspirin for pre-eclampsia prevention (Bates et al, 2012; Sammaritano et al, 2020). When patients are ready post-partum, they can be switched back to warfarin.

Patients with obstetric APLS

Obstetric manifestations of APLS by the Sapporo criteria (Miyakis et al, 2006) include: 1) premature birth before 34 weeks due to preeclampsia spectrum disorder, 2) at least one unexplained loss of a morphologically normal pregnancy beyond 10 weeks, or 3) at least three consecutive pregnancy losses at < 10 weeks gestation (according to Dr. Langer, this is the least reliable criteria. Notably, these pregnancy losses must be consecutive).

In a future attempt at pregnancy, patients with a history of obstetric APLS and no history of thrombosis should be put on aspirin for pre-eclampsia prevention (Bates et al, 2012; Sammaritano et al, 2020). In addition to aspirin, some guidelines (which Dr. Langer follows) suggest that patients should be put on prophylactic dose enoxaparin from the start of pregnancy to 6 weeks postpartum, while other guidelines give an option in certain cases for only postpartum anticoagulation (Bates et al, 2012; Sammaritano et al, 2020, UpToDate). Dr. Langer leans towards using anticoagulation during pregnancy for these patients given the low bleeding risk for prophylactic dose enoxaparin.

After the postpartum period, patients with obstetric APLS only who have never clotted in maternal circulation do not need to continue on anticoagulation (Garcia et al, 2018) (the rationale for this is grounded in the Venn Diagram of antiphosholipid antibodies targeting placental trophoblasts vs. clotting proteins discussed above, such that only a subset of patients with obstetric APLS will go on to develop thrombotic APLS). As mentioned previously, there is debate over whether use of aspirin for primary prevention of thrombotic APLS is warranted in patients with obstetric APLS only.


Listeners will develop an approach to the diagnosis and management of antiphospholipid syndrome

Learning objectives

After listening to this episode listeners will…  

  1. Identify common clinical manifestations of APLS and key steps in diagnosis
  2. Describe an approach to long-term anticoagulation in patients with thrombotic APLS 
  3. Recognize the manifestations of obstetric APLS and describe considerations for anticoagulation during pregnancy in patients with obstetric APLS, as well as in patients with a history of thrombotic APLS who become pregnant


Dr. Langer reports no relevant financial disclosures. The Curbsiders report no relevant financial disclosures. 


Gandhi MM, Langer A, Williams PN, Watto MF. “#421: Antiphospholipid Syndrome with Dr. Arielle Langer”. The Curbsiders Internal Medicine Podcast. Final publishing date January 8th, 2024.

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Episode Credits

Producer, Writer, Show Notes, Infographics, and Cover Art: Malini Gandhi
Hosts: Matthew Watto MD, FACP; Paul Williams MD, FACP
Reviewer: Fatima Syed MD
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP
Technical Production: PodPaste
Guest: Arielle Langer MD

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