Editorials

Antiphospholipid (Hughes') syndrome

The antiphospholipid syndrome, first described in 1983,¹ is now recognised as an important prothrombotic disorder associated with a specific group of antibodies. Its main clinical feature is thrombosis, both venous and arterial (especially recurrent cerebral ischaemic attacks). Other features include mild thrombocytopenia, chorea, heart valve disease, livedo reticularis, and, most commonly, recurrent pregnancy loss.² The importance of the syndrome in general medicine, especially in vascular and neurological disease, is now acknowledged.

The syndrome has had various names. Hughes originally studied it in patients with systemic lupus erythematosus but recognised that most patients "had atypical lupus, or no lupus at all"–hence the concept of "primary" antiphospholipid syndrome.³ In the early 1990s it was found that a phospholipid binding protein, ß2 glycoprotein I, was required for the binding of antibodies to phospholipids. More recently, other such proteins have been shown to be involved.⁴ The complex and possibly indirect links between antiphospholipid antibodies and thrombosis led to the suggestion that the name of the syndrome be changed to "Hughes' syndrome."⁵

One of the major features of the syndrome in women is pregnancy loss, most typically in the second trimester. Some women suffer six or more miscarriages before the diagnosis is made. Even worse, in others the diagnosis remains "infertility." Even in patients with systemic lupus erythematosus it is now recognised that most of the excess fetal loss occurs in association with antiphospholipid antibodies.⁶

Recurrent pregnancy loss, defined as three or more spontaneous consecutive miscarriages, affects 1-2% of women. There are many known causes. What proportion of this major problem does antiphospholipid syndrome represent? The published studies suggest a figure between 7% and 25%. Even if the lower percentage is true (and our own bias is towards the lower end of the range) the annual incidence of pregnancy loss among women in Britain alone because of this potentially treatable condition must be huge.

The causes of pregnancy failure may be numerous, but the consensus is that thrombosis leading to placental insufficiency is the central mechanism. Logically, therefore, antithrombotic treatment is preferred to corticosteroids (once widely recommended). The current choice is aspirin or heparin, or both.

The use of low dose aspirin has never been subjected to randomised clinical trial, although there are several non-randomised studies suggesting that 75 mg daily is an effective treatment.^{7 8} Furthermore, low dose aspirin has been reported to reduce pregnancy loss in experimental antiphospholipid syndrome in mice.⁹ In a recent study pregnancy outcome improved from 19% to 70% after treatment with low dose aspirin in all patients and subcutaneous heparin in those with previous thrombosis.¹⁰

Heparin does not cross the placenta and is not known to cause any adverse fetal effects. However, long term use of heparin in pregnancy has been associated with osteoporosis in the mother. Many centres are now using low molecular weight heparin, since it has increased bioavailability and a longer half life and can therefore conveniently be given once daily.¹¹ It seems to have no greater deleterious effect on bone density than occurs physiologically during pregnancy.¹² Two prospective, randomised studies have shown that heparin plus low dose aspirin provides a significantly better outcome than low dose aspirin alone.^{13 14} One, published in this week's BMJ (p 253), included a high proportion of patients who were positive for lupus anticoagulant¹³; the other, from Dallas, Texas, excluded such individuals.¹⁴ The clinical conclusions, however, are similar.

The improved outlook for successful pregnancy in patients with antiphospholipid or Hughes' syndrome is a medical achievement worth celebrating. In the immediate future better antithrombotic regimens are likely. Most importantly, there will be increased awareness of the syndrome (and its potential for treatment) by physicians, obstetricians, and general practitioners.

Munther A Khamashta, Senior lecturer,^a Charles Mackworth-Young, Consultant physician ^b

^a Lupus Unit, St Thomas's Hospital, London SE1 7EH, ^b Rheumatology Department, Charing Cross Hospital, London W6 8RF

1. Hughes GRV. Thrombosis, abortion, cerebral disease and the lupus anticoagulant. BMJ 1983;287:1088-9.
2. McNeil HP, Chesterman CN, Krilis SA. Immunology and clinical importance of antiphospholipid antibodies. Adv Immunol 1991;49:193-280.
3. Hughes GRV. The anticardiolipin syndrome. Clin Exp Rheumatol 1985;3:285-6. [Medline]
4. Roubey RAS. Autoantibodies to phospholipid-binding plasma proteins: a new view of lupus anticoagulants and other `antiphospholipid' autoantibodies. Blood 1994;84:2854-67.
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6. Lima F, Buchanan NMM, Khamashta MA, Kerslake S, Hughes GRV. Obstetric outcome in systemic lupus erythematosus. Semin Arthritis Rheum 1995;25:184-92. [Medline]
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8. Balasch J, Carmona F, Lopez-Soto A, Font J, Creus M, Fabregues F, et al. Low-dose aspirin for prevention of pregnancy losses in women with primary antiphospholipid syndrome. Hum Reprod 1993;8:2234-9. [Abstract/Free Full Text]
9. Krause I, Blank M, Gilbrut B, Shoenfeld Y. The effect of aspirin on recurrent fetal loss in experimental antiphospholipid syndrome. Am J Reprod Immunol 1993;29:155-61.
10. Lima F, Khamashta MA, Buchanan NMM, Kerslake S, Hunt BJ, Hughes GRV. A study of sixty pregnancies in patients with the antiphospholipid syndrome. Clin Exp Rheumatol 1996;14:131-6.
11. Nelson-Piercy C. Low molecular weight heparin for obstetric thromboprophylaxis. Br J Obstet Gynaecol 1994;101:6-8.
12. Shefras J, Farquharson RG. Bone density studies in pregnant women receiving heparin. Eur J Obstet Gynecol Reprod Biol 1996;65:171-4.
13. Rai R, Cohen H, Dave M, Regan L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid (or antiphospholipid antibodies). BMJ 1997;314:253-7. [Abstract/Free Full Text]
14. Kutteh WH. Antiphospholipid antibody-associated recurrent pregnancy loss: treatment with heparin and low-dose aspirin is superior to low-dose aspirin alone. Am J Obstet Gynecol 1996;174:1584-9.