27th November 2018, Dr Chee L Khoo
I recently saw a young lady whose mother had anti-phospholipid syndrome (APL) . She is now worried whether she has the same problem and request some blood tests. She is otherwise fit and healthy. Sure, among other things, I ordered APL antibodies hoping that the pathologist will know what I was looking for. Pretty straight forward so far until the results of her tests came back. What does it all mean? I mean, I know something about APL syndrome. Interpreting the results is something else. How am I going to advise the young healthy lady? Should she be worried? Should I be worried? Is there “treatment” for it?
APL syndrome is a systemic autoimmune disease defined by thrombotic or obstetrical events that occur in patients with persistent antiphospholipid antibodies. The thrombotic events can either be venous, arterial or microvascular thrombosis which can be challenging when it comes to treating them. The obstetrics complication is characterised by foetal loss after 10 weeks. There are also non-thrombotic and non-obstetric features which include valvular heart disease, livedo, anti-phospholipid antibody–related nephropathy, thrombocytopenia, haemolytic anaemia, and cognitive dysfunction. It can be associated with other auto-immune diseases such as SLE although it often occurs without other auto-immune diseases.
Not everyone with APL antibody positivity has APL syndrome. Not everyone with positive APL antibodies will remain positive.
Pathogenesis
The major target of the APL antibodies is β2 glycoprotein I (β2GPI) which is a plasma protein which binds avidly onto phospholipid surfaces especially when it binds to the antibodies. When β2GPI binds to the APL antibodies, a series of processes are triggered ultimately leading to activation of inflammatory and endothelial cells, promotion of coagulation and interference with trophoblasts and decidual cells (placenta). Some of those processes include activation of endothelial-cell, complement, platelet, neutrophil and monocytes and decreased protein C activity and decreased fibrinolysis. Thus, through a whole array of mechanisms, APL antibodies results in:
- Inflammation
- Vasculopathy
- Thrombosis and
- Pregnancy complications.
Prevalence
It’s hard to know the true prevalence of APL antibody positivity in the general population. Ten percent of healthy blood donors are positive for anticardiolipin antibodies, and 1% are positive for lupus anticoagulant. However, after 1 year, less than 1% are still positive for these tests. 20% and 30% of patients with SLE have persistent moderate-to-high-risk antiphospholipid-antibody profiles that are associated with an increased risk of clinical sequelae. Among patients without autoimmune disease, the prevalence of antiphospholipid-antibody positivity is 6% among women with pregnancy complications, 10% among patients with venous thrombosis, 11% among patients with myocardial infarction and 17% among patients with stroke who are younger than 50 years of age.
Clinical presentation
Usually, patients are identified during investigations of systemic autoimmune diseases, early miscarriages, an elevated activated partial-thromboplastin time (aPTT) or a false positive result of a syphilis test. Not all patients with SLE are positive for APL antibodies. Among patients with SLE, the prevalence of thrombosis, pregnancy complications, valve disease, pulmonary hypertension, livedo reticularis, thrombocytopenia, haemolytic anaemia, acute or chronic renal vascular lesions, and moderate or severe cognitive impairment is higher among patients with antiphospholipid antibodies than among patients who are negative for such antibodies.
Otherwise, they may present with thrombotic or obstetric complications. Stroke and transient ischemic attack are the most common arterial events in patients with the antiphospholipid syndrome. Patients with venous thromboembolism most commonly present with lower-extremity deep-vein thrombosis, pulmonary embolism or both.
Interpreting the antibody tests
APL antibodies should be tested for in young patients with thrombosis, thrombosis in unusual site or recurrent thrombosis, early or severe pre-eclampsia or in HELLP syndrome. APL antibodies test is not just one test. We look at 3 different tests:
The lupus antibody (LA) test correlates better with clinical events than do anti-cardiolipin (aCL) antibodies and anti-β2GPI tests. False positive LA results may occur in patients treated with warfarin, heparin, or direct oral anticoagulants.
The aCL and anti-β2GPI antibodies
Moderate to high titres correlate better with APL-related clinical events than do lower titres; IgG is more strongly associated with clinical events than is IgM.
- A high-risk profile is defined as a positive LA test with or without a moderate to high titre of aCL or anti-β2GPI IgG or IgM.
- A moderate-risk profile is defined as a negative LA test with a moderate to high titre of aCL or anti-β2GPI.
- Low risk A low-risk profile is defined as a negative LA test with a low titre of aCL or anti-β2GPI IgG or IgM.
Under the Sapporo classification criteria, a positive result necessitates a repeat in 12 weeks to confirm the positivity.
Prevention & Treatment
Risk stratification
In patients without thrombosis, we need to look at the APL antibody profile, presence of autoimmune diseases and other risk factors for thrombosis. We must not forget the traditional risk factors for cardiovascular disease, such as smoking, hypertension, diabetes and dyslipidaemia which are also risk factors for thrombosis. A moderate to high risk APL profile warrants avoidance of oestrogen supplements when possible and aggressive postoperative prophylaxis against thrombosis if feasible.
Primary thrombosis prevention
The absolute risk of thrombosis in APL positive patients who do not have any other risk factors is <1% per year. For those who are APL positive and has thrombosis, they often have other causes as well. The annual risk of a first thrombosis in patients with persistently moderate-to-high-risk antiphospholipid-antibody profiles and a systemic autoimmune disease or additional thrombotic risk factors may be as high as 5%.
Use of Aspirin
The evidence for the use of aspirin in primary prevention is lacking (just like aspirin for primary prevention of CV events). There is some evidence that hydroxychloroquine may reduce the risk of thrombosis in patients with SLE but not for primary prevention.
Secondary prevention of venous thrombosis
For patients with APL syndrome defined by venous thrombosis, the usual treatment is low molecular weight (LMW) heparin followed by warfarin (aiming for INR 2-3). Higher intensity warfarin (aiming for INR 3-4) does not further reduce recurrence. For most patients with persistent APL antibodies and otherwise unprovoked venous thromboembolism, the risk of recurrent thrombosis is too high to discontinue warfarin. However, the benefit of prolonged anticoagulation is less certain in patients who are positive for antiphospholipid antibodies and in whom thrombosis was provoked — for example, by a surgical procedure — and in patients with laboratory tests for antiphospholipid antibodies that become negative over time.
Secondary prevention of arterial thrombosis
For older patients with stroke and a single test showing a low titre of acL antibodies, aspirin alone may be as effective as warfarin. However, patients with moderate-to-high-risk APL profiles are often treated with warfarin (target INR, 2 to 3), with or without low-dose aspirin.
Warfarin failure
Recurrent venous thrombosis despite warfarin use is a well-recognised complication of the antiphospholipid syndrome. There is limited evidence to support any particular treatment strategy but options include higher-intensity warfarin therapy, the addition of low-dose aspirin, hydroxychloroquine or a statin, use of a different anticoagulant, such as low-molecular-weight heparin and a combination of these approaches.
NOACs
There is insufficient evidence to determine the relative efficacy and safety of such agents in patients with venous thrombosis.
Obstetrical APL Syndrome
For women who as antiphospholipid-antibody–positive but have no history of thrombosis or pregnancy complications, the recommendation is low dose aspirin but data for this approach is lacking. These women should also receive a prophylactic dose of low-molecular weight (LMW)
heparin for at least 6 weeks post-partum, given the increased risk of thrombosis during this period. For women who has APL syndrome during pregnancy, low dose aspirin and therapeutic dose heparin should be used. Women who have a history of obstetrical APL syndrome but no other risk factors for thrombosis, do not need long term anti-thrombotic prophylaxis.
In summary, an asymptomatic patient coming in requesting an APL antibody testing, we can order anti-phospholipid antibodies and your laboratory should know what array of tests to perform. Otherwise, you could specifically request lupus anti-cardiolipin and anti-β2GPI antibodies. You might as well check for other risks for thrombosis as part of your risk stratification. If the antibody tests are positive, they need to be repeated after twelve weeks.
With the results at hand, you can then assess their APL profile to determine their risks. Whether and what treatment they require depends on the APL risk profile.
Understanding the future
Although LA, aCL, and anti-β2GPI tests are the mainstay of APL syndrome diagnosis, several additional APL tests have been developed recently; the clinical significance of other proposed tests must be established with additional outcome-based studies.
Reference
David Garcia, Doruk Erkan. Diagnosis and Management of the Antiphospholipid Syndrome. N Engl J Med 2018;378:2010-21.