Latest Advances In Connective Tissue Disorders: Antiphospholipid (Hughes) Syndrome - APS

This was posted up tonight on PubMed so for those that dont have access here is the APS section. If anyone wants any of the other sections on Sjogrens, SLE, Scleroderma and Myositis please ask and I will post those too.

Latest Advances in Connective Tissue Disorders

Simon Bowman, PhD, FRCP, Vijay Rao, MRCP

Ther Adv Musculoskel Dis. 2013;5(4):234-249.

Antiphospholipid (Hughes) Syndrome

In the antiphospholipid antibody (Hughes) syndrome (APS), antibodies directed against phospholipids lead to an increased risk of arterial and venous thrombosis, recurrent pregnancy loss or other obstetric features [Harris et al. 1986]. It can occur as a syndrome in its own right or in association with SLE. The antibodies can be detected directly in the form of antiphospholipid/anticardiolipin or anti-ß2 glycoprotein (a cofactor for phospholipids) antibodies by enzyme-linked immunosorbent assay or indirectly through the lupus anticoagulant clotting test typically using the dilute Russell viper's venom test to demonstrate an in vitro (antibody) inhibitor of the clotting system.

Treatment depends on the nature of the clinical and laboratory presentation. In patients with the antibodies but without a history of thrombosis, the risk–benefit analysis for taking low-dose aspirin is unclear [Erkan et al. 2007]. A positive lupus anticoagulant test is most closely linked with thrombosis risk and adverse obstetric outcome [Galli et al. 2003; Lockshin et al. 2012] and patients with a positive result for all three antibody tests are at greatest risk [Pengo et al. 2012]. Anecdotally, clopidogrel might be used in patients who are allergic to aspirin.

Once a patient has had a thrombosis, however, the consensus would be to anticoagulate them for life due to the high risk of further thrombosis [Khamashta et al. 1995; Crowther et al. 2003; Finazzi et al. 2005]. Current practice would distinguish between patients with a single venous thrombosis for whom an international normalized ratio (INR) of 2–3 may be sufficient and patients with an arterial thrombosis or recurrent venous thromboses for whom a higher target INR of 3–4 would be more appropriate [Ruiz-Irastorza et al. 2007].

In patients who are intolerant of, or resistant to, warfarin [Scoble et al. 2011], low molecular weight heparin (LMWH) can be used [Vargas-Hitos et al. 2011]. Long-term use of LMWH is associated with osteoporosis and thrombocytopenia.

One recent development is of new oral anticoagulants such as apixaban (a factor Xa inhibitor), dabigatran (a thrombin inhibitor) and rivaroxaban (a factor Xa inhibitor) [Garcia et al. 2010; Cohen and Machin, 2010]. They do not require time-intensive monitoring and dose adjustment but they are not easily reversible if bleeding problems arise. There is a planned clinical trial of rivaroxaban in APS funded by Arthritis Research UK that will address equivalence to warfarin in an APS population (

There is no evidence in most 'straightforward' cases of APS that immunosuppression with corticosteroids or disease-modifying drugs have any beneficial effect. Hydroxychloroquine does appear to have a beneficial effect on thrombosis risk in APS, at least in patients with SLE [Petri, 1996]. Statins also have antithrombotic effects and may be sensible adjunctive therapy [Jajoria et al. 2009].

The potential exception to this is in rare patients (about 1% of APS cases) with the catastrophic APS in which a diffuse thrombotic microvasculopathy affecting the lungs, brain, heart, kidney, skin and gastrointestinal tract is associated with a high mortality rate of 30–50%. The mortality rate has improved in recent years with the use of full anticoagulation, intravenous steroids, with or without cyclophosphamide, antibiotics for any sepsis and the use of plasma exchange and intravenous immunoglobulins (IVIGs) [Cervera et al. 2009]. Some recent papers have also described the use of rituximab with beneficial effect in resistant cases [Khattri et al. 2012] and a clinical trial is also ongoing [ identifier: NCT00537290].

Warfarin is associated with a high risk of fetal malformation in the first trimester of pregnancy and with fetal bleeding thereafter. The standard of care, therefore, for women with antiphospholipid antibodies and recurrent pregnancy loss is the combination of low-dose aspirin plus prophylactic doses of heparin (unfractionated or low molecular weight) [American College of Obstetricians and Gynaecologists Committee on Practice Bulletins – Obstetrics, 2011; Empson et al. 2005; Mak et al. 2010; Danza et al. 2012]. This has improved the rate of live births very substantially to around 75% in some of the above studies. Some studies have suggested, however, that heparin does not confer additional benefit to aspirin alone [Laskin et al. 2009], but this is not the current consensus.

The role of prednisolone in improving the outcome of obstetric APS has been controversial. Initial studies using high-dose prednisolone did not identify any benefit and an increased risk of hypertensive complications and diabetes mellitus [Laskin et al. 1997]. More recent studies of low-dose prednisolone, for example 10 mg/day during the first trimester, have suggested benefit in women with recurrent pregnancy loss in whom conventional approaches have not been effective [Bramham et al. 2011]. As a result the role of prednisolone is being reevaluated. IVIG is another therapy that can be tried, although evidence for effectiveness is limited.

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13 Replies

  • Thanks, this is great info, as usual! Mary F x

  • Yes thanks indeed.

    I was worried by the claim that long term LMWH cause osteoporosis as Prof Hughes told me the the older Heparins did but LMWH did not; now I'm worried again!

    Best wishes.

    Dave xx

  • It does not define "long term".....hopefully by the time long term kicks in the new anticoags will be approved with a reversing agent so we have no issues with bleeding. I thought the same thing as you but I have been reassured by a number of Doctors. I believe Khamashta has done a later study than the one mentioned.

  • Hi

    Yes I did some googling last night and it seems that most studies have found no risk of osteoporosis with Fragmin, as opposed to 'unfractioned Heparin' and one study found that Fragmin may guard against osteoporosis.

    Dave x

  • Thanks for this

    Scleroderma and SLE would also be useful.

  • Thank you very much for this. I would be very grateful for the Sjogrens info.

    Regarding the use of heparin I have been on it for 4 years now. I have got Osteopaenia but as I have been on steroids in one form or another since the age of 8 and also had a parathyroidectomy It is likely that I am high risk anyway.

    I am becoming increasingly uncomfortable with taking clexane however as Prof. Hunt mentioned, at the Patients Conference, that it comes from China and.I am agonizing over animal welfare issues as the Chinese are hardly known for their sensitivity in this matter.

    It is an issue I will discuss with MK at my next appointment as I am finding it increasingly difficult to use it for this reason. I am extremely keen on high animal welfare.


  • I would be very interested in what he tells you. Sue

  • I will let you know. Unfortunately my appointment has been put back to January so while to wait x

  • Thanks very useful. x

  • I believe the comment about LMWH causing osteoporosis and thrombocytopenia is an error, ie that they left out the "not." There is a much lower risk of heparin induced thrombocytopenia (HIT) with LMWH than with unfractionated heparin and most (or all) MDs who have used LMWH a lot say it does not cause osteoporosis--also unlike unfractionated heparin.

  • Thank you so much for this. Can you post the PubMed link, are are you only able to post the actual reports here? I've been diagnosed with Mixed Connective Tissue Disease and would like to be able to read all the updates.... esp. the Myositis.

    Again, many thanks!


  • Brilliant post, thanks.

  • Thank you for all the info. Really interesting to read.

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