In 1983 and during the following two years, the Lupus Research Unit at St Thomas published a number of papers showing that certain blood proteins (antiphospholipid antibodies) were associated with a syndrome of clotting (thrombosis), recurrent miscarriages and brain disease. Between 1983 and 1985, a comprehensive clinical/laboratory profile was presented showing, for the first time, a wide spectrum of clinical features including the association with artery thrombosis (including major organs such as kidney and liver), brain disease (strokes and other features), skin rashes, low platelet counts, epilepsy and migraine.
These features could and frequently did occur in the absence of lupus, leading to the term primary antiphospholipid syndrome. Laboratory assays were set up, and we instituted standardisation workshops and organised the first and second International Congresses on the subject. The seventh was held in 1996.
Diagnosing and managing Hughes' Syndrome has proved exciting and satisfying. For example, the success rate in pregnancy alone has risen from under 20% to over 70%.
The following patient's guide to Hughes' Syndrome include:
"Sticky blood" is the way Hughes' Syndrome has been described, although this is technically incorrect. Essentially patients with certain blood antibodies (antiphospholipid antibodies) have an increased risk of thrombosis - clotting - in the veins and arteries.
This tendency to blood clotting can affect individuals of any age, both male and female. It can happen quickly, for example, as a leg thrombosis (deep vein thrombosis or DVT), or chronically with a history of, for example, headaches, memory loss and fatigue going back over a number of years.
In pregnant women these antibodies are especially important: the sticky blood is sometimes unable to flow through the small and delicate blood vessels to the placenta and fetus. The placenta withers and the fetus is aborted. This syndrome has now come to be regarded as an important cause of recurrent spontaneous abortion or fetal loss.
Perhaps the simplest analogy for the syndrome is the comparison with a car engine. Too rich a mixture of petrol or gas results in a 'stuttering' of the engine and a 'chocking up' of the system, rather than improving the performance. The main features of the syndrome are listed in the following table.
1. Vein Thrombosis
Leg vein thrombosis (DVT)
Arm vein thrombosis
Thrombosis in "internal" organs
e.g. kidney, liver, lung, brain, eye
2. Artery Thrombosis
Brain - headaches, neurological features
Linb - pain and circulation problems
Heart - chest pain
Other organs, e.g. kidney, adrenal
3. Recurrent abortion or miscarriage
Often late into the pregnancy
4. Low platelet count
"thrombocytopenia" - 5 to 10%
In some patients the only manifestation of the syndrome is recurrent miscarriage. In others, it is headaches or speech or visual/neurological disturbance. Both these aspects are discussed separately.
The most dramatic sign that the disease is present is thrombosis, for example, deep vein thrombosis (DVT), in the leg or arm. This may be a 'one off', or be recurrent, or complicated by a lung clot (pulmonary embolus). In some women, it happens soon after the start of the oral contraceptive pill. Some of the most severe 'pill-associated' blood clots we have seen have been in individuals with antiphospholipid antibodies, clearly an important medical issue.
"Internal" veins may also clot, affecting organs such as the eye, the kidney, liver and so on - a diagnosis which will impinge on almost every speciality.
By definition, artery blockage is more serious that that in the veins. Clinically, apart from the small artery disease in the brain, discussed later, major artery thrombosis seems to be less common than venous. However, in some patients, the first warning of trouble was a major acute artery thrombosis. Clearly it is the concern about this which leads to a consideration of anti-clotting (anticoagulant) treatment.
A variety of other clinical features are seen in patients with Hughes' Syndrome. A peculiar blotchiness of the skin, called livedo reticularis is prominent in some patients.
This blotchiness: blue knees, purplish vein colouration on the back of the wrists etc, was described in our original clinical reports in the 1980s and is a prominent and useful diagnostic sign in some patients.
In a small percentage of patients, the platelet numbers are affected and rarely, platelet counts may fall to dangerously low numbers. Thus, patients who have been diagnosed as having low platelet counts, thrombocytopenia, should be checked for Hughes' Syndrome.
In quite a few patients, headaches, frequently with migraine features, e.g. flashing lights, speech disturbances, are an important symptom.
Interestingly, in many patients the headaches predate the clotting problem by many years. For example, a 25 year old woman with recurrent miscarriages due to Hughes' Syndrome gives a history of troublesome teenage migraine, possibly suggesting that the antibodies had been there for at least a decade before.
For reasons not completely understood, the brain appears particularly sensitive to the clotting effects of antiphospholipid antibodies. The brain only has a limited number of ways of complaining at any disturbances in its supply of blood. The patient may develop transient memory loss, or slight speech disturbance, suggestive of a mini-stroke.
In others, the effect may be more insidious, with a gradually failing ability to put words, sentences, lists and so on, together.One of the gratifying experiences is to see improved performance in brain function in a patient where the diagnosis of Hughes' Syndrome has been made and appropriate anti-coagulation treatment started. The memory improvement, the confidence, the speech improvement and the whole life style seem to start coming together again.
The onset can be very dramatic. In one of my patients, a woman who was her local village darts champion, the first sign of the problem was an inability to recognise and hit the "20". In another, a successful sculptress, there was difficulty in recognising three-dimensional shapes. In another, a 29 year old labourer, the first frightening sign occurred when standing on the station when "my speech became drunk ... my friends didn't know what I was saying."
Transient loss of blood supply to the brain (transient ischaemic attacks or TIAs) are capable of causing an infinitesimal variety of symptoms. Other forms of brain abnormality include movement disorders such as chorea (St Vitus Dance) and, more commonly, fits. Epilepsy, in all its forms from petit mal (absences) through to grand mal (fits), is an important feature of Hughes' Syndrome.
One of the most interesting aspects of the syndrome is to see epilepsy, present in a patient for several years, apparently improve or even stop once proper anticoagulation treatment is started.
The blood supply to the fetus in the womb is complicated - and delicate. In pregnancy, the physiology of the body changes considerably and one of these changes is a slight increase in the blood viscosity ("stickiness"). It is no surprise, therefore, that in some pregnant women with antiphospholipid antibodies, clotting occurs in the placenta, leading to a cut off ("infarction") in areas of the placenta.
It is thought that this gradual withering of the placenta and strangulation of the fetus' blood supply is an insidious process starting in earliest pregnancy.The result is abortion, or fetal loss (the definition depending on when during pregnancy the loss happens).
It should be stressed that in many women with antiphospholipid antibody and recurrent fetal loss, there has been absolutely no past indication of trouble and (though only time will tell) many may never develop any medical problem outside of pregnancy.
The history therefore is one of fetal loss - as many as 14 in some of the saddest cases. Conversely, treating some of these women successfully through to a live birth is one of the most satisfying experiences in medicine and has changed the practice of obstetrics.
The traditional advice is to test for antiphospholipid antibodies in women who had had 2 or more spontaneous pregnancy losses. The reason is that spontaneous abortion is common and there are many causes.
To me, this advice is wrong. Yes, there are many causes of spontaneous abortion. But pregnancy loss is an extremely traumatic experience and here is a potentially treatable cause. For a few pounds or dollars, a simple blood test can screen for the syndrome. It could be argued that an antiphospholipid blood test should be a routine part of all antenatal checks.
Certainly the test should be carried out in any woman with one or more pregnancy losses (especially if the loss occurred in mid pregnancy). It should also be a routine test in women with lupus and in pregnant women who have had a previous thrombosis.
Our first studies of this syndrome were in lupus. This disease, which affects many thousands, particularly women, is a disorder of the immune system. There is a tendency for the over production of antibodies and the result is a complex illness which includes fatigue, rashes, joint pains, and in some patients potentially life-threatening kidney and brain disease.
Lupus patients produce many blood antibodies such as anti-DNA antibodies. They may also produce antiphospholipid antibodies and it was in this group of lupus patients (10% - 20% perhaps) where we showed the strong link between anticardiolipin antibodies and thrombosis.
As time has gone by, it has become obvious that those patients with Hughes' Syndrome without lupus probably outnumber those with lupus.
Obviously the two conditions are related. In both, there is an overproduction of antibodies. Surprisingly, in the 15 to 20 years we have been following these patients, very few patients presenting with the primary antiphospholipid (Hughes') syndrome go on to develop generalised lupus. This is an important clinical and prognostic point.
Most laboratories and clinics use two main tests:
In many ways, it would be attractive to get rid of the older lupus anticoagulant test in favour of anticardiolipin. Unfortunately, there are slight differences between the two tests; some patients may show positive on one and not the other. The usual advice is to measure both.
Anticardiolipin levels are generally expressed as low, medium or high. Statistically, the higher the level, the more risk of thrombosis or miscarriage. However, in medicine and real life, this is not necessarily the case; some individuals with high levels are without a medical problem, whilst some patients with low to medium positive levels have full blown Hughes' Syndrome! As usual, treatment decisions are based both on laboratory and clinical criteria.
The discovery of the syndrome, especially for those patients with lupus who also have it, has made treatment decisions much more precise. Previously, lupus patients with neurological diseases were generally put on high dose steroids. Now we know that many organs can be affected by Hughes' Syndrome, simple blood testing can point to much more appropriate treatment with anticoagulants where this syndrome is felt to be the cause.
The three drugs most commonly used are aspirin, Warfarin (Coumadin) and Heparin. Aspirin, used in small doses such as 75 to 100mgs daily (or 150mgs), which is equivalent to a quarter or half an asprin or one "baby asprin", is known to make the blood platelets less "sticky" and help prevent a thrombosis. Lose dose aspirin is now used throughout the world for patients who have suffered heart attacks or strokes. For those with major thrombosis, especially strokes, the anticoagulation should be with an INR of 3. This means that the blood should be three times "as thin" as normal blood. For these patients, anticoagulation should be probably lifelong.
In patients with Hughes' Syndrome, asiprin is clearly beneficial in milder cases (comparative trials are still continuing). In recurrent miscarriage, the addition of asprin alone has improved the success rate dramatically.In the lupus pregnancy clinic run by Drs Khamashta, Bewley and Hunt at St Thomas' Hospital, London, for example, the success rate for pregnancy in patients with the syndrome has risen over the past five years from a dreadful 19% to over 70%.
Whilst there are certainly many factors in this success (earlier delivery, use of heparin etc), the addition of aspirin to the equation has been crucial.
In those patients with a large thrombosis, stronger measures are required. Warfarin (Coumadin) is an anticoagulant drug used worldwide as a blood-thinning agent. For example, most patients who have suffered a leg vein thrombosis are put on Warfarin (Coumadin) for six months. In those with recurrent thrombosis (including some patients with Hughes' Syndrome), the treatment is life-long. Anticoagulants are surprisingly safe. The blood thickness (ideally like skimmed milk, one third of normal, or with an INR ratio of 3) is monitored in hospital amticoagulant clinics and the dosage changed accordingly.
Heparin is less widely used, being administered by injection. It does have two potential advantages over Warfarin: its anticoagulant effects can be easily reversed. This it is useful around the time of an operation, or pregnancy delivery; it can be used throughout pregnancy. Warfarin (Coumadin) can affect the developing fetus and is almost always avoided in much of the pregnancy.
Choice and timing are specialist matters. Getting anticoagulant treatment correct is rewarding for both patient and physician.
Just to give an example, a number of my patients who have had brain clotting problems know precisely when their anticoagulant treatment is inadequate; the headaches and slurred speech return!
In 1990, an American medical journal (World Neurology) estimated that there were 100,000 individuals in the USA with one form or another of the antiphospholipid syndrome. According to the Leader in this journal, the cost to the US Government was over 100 million dollars per annum.
Every clinic in the world dealing with clots, strokes, heart problems and vascular disease sees a proportion of patients with Hughes' Syndrome. Studies therefore of "prevalence" are now being busily carried out in most countries. All age groups can be affected. I recently saw a six year old child from Italy who had been diagnosed as having Hughes' Syndrome following investigation for an aggressive behavioural disorder! Brain scan (MRI) revealed the presence of a small number of ischaemic areas (blood clots).
At the present time, the most consistently diagnosed group, for obvious reasons, are women with recurrent pregnancy loss. There are, clearly, many reasons for an unsuccessful pregnancy. To date, estimates of the contribution of Hughes' Syndrome to recurrent abortion varies from 5% to 25%. My own feeling is that the true figure is nearer to 5%. Whatever the percentage, this group is important as treatment has a high chance of success.
Three areas of research are leading the way. Firstly, epidemiology, the study of the "geography" of the disease. Careful studies in different countries may give more than just prevalence data. They may also show the importance of the addition of other risk factors (smoking and "the pill", for example).
They may even provide clues to genetic aspects of the disease - there are undoubtedly a small number of families with more than one member with Antiphospholipid Syndrome (APS).
The second area is immunology. Why do the antibodies affect clotting? To what do they bind? Would somehow removing the antibodies help?
Recent research has certainly succeeded in pinpointing the site to which the antibodies bind (a complex of protein and phospholipid) and this, in turn, may lead the way to developing methods for blocking this reaction.
The third is clinical. Old fashioned clinical observations have defined the broad limits of the antiphospholipid (Hughes' Syndrome). But new clinical discoveries are still being made. Recently, a small number of patients with the syndrome were found to have an abnormality in their arteries very like atheroma.
This observation led to the further discovery that, under certain circumstances, antiphospholipid antibodies could cross-react with oxidised low density lipoproteins - the cholesterol variants associated with atheroma. The ripples spread outwards.
It is now fifteen years since the clinical description of the syndrome. In that time, the syndrome has become an established medical condition, meriting articles, textbook chapters, research, conferences and so on.
More important, it has provided, by means of simple blood tests, a whole new
approach to treatment. In those patients in whom Hughes' Syndrome is diagnosed
and treated early, the outlook has dramatically changed for the better.
Our work leading to the detailed description of the syndrome was carried out in the lupus unit in the mid-to-late seventies. I had always been interested in the mechanisms of brain disorder in lupus and in the early seventies my group, as well as those of other colleagues, published a series of papers on antibodies reacting with the brain.
In 1975, Dr Wedell Wilson and I, studying a group of patients in Jamaica suffering from a form of paralysis called Jamaican neuropathy suggested that some of the antibodies in this disease might be directed against phospholipids - molecules important in both brain tissue and cell membranes.
As so often happens, our studies led sideways, to the finding that these antibodies, far from being associated primarily with neurological disease, were very strongly linked with clotting and thrombosis. Working in a large lupus unit, it became clear that there were a group of patients with lupus who had clotting problems, not only in veins but also in arteries. Furthermore, these problems were associated with other clinical features. This syndrome was associated with the presence of antiphospholipid antibodies.
While our earlier studies concentrated on systemic lupus, it was immediately clear that the syndrome was also found in mild lupus, in discoid (skin) lupus and, indeed, in patients with no lupus at all - the beginning of the primary antiphospholipid syndrome.
In 1982, I presented the findings to the American College of Rheumatology meeting and at the Heberden Round of the British Society for Rheumatology meeting at Hammersmith Hospital.
The following year, 1983, we published the observations and between 1983 and 1985 published a number of papers giving detailed descriptions of the syndrome with the five headline stories now widely accepted as a syndrome.
The assay work was lead by Drs Nigel Harris and Aziz Gharavi in my lab, and subsequently by Dr Munther Khamashta, colleagues who shared with me the international prize in 1993 presented to us all at the opening ceremony of the 4 yearly international (ILAR) rheumatology congress in Barcelona.
In 1984 we held our first international conference on the topic, soon to be followed by the second at St Thomas' Hospital in 1986. Since then, the story has become huge. There are now over 5,000 published articles on the syndrome and the seventh international conference on antiphospholipid syndrome held in New Orleans in 1996 attracted several hundred researchers.
In the sixth such conference at Leuven in 1994, important data was presented confirming that the mechanism for clotting was (as expected) complicated and involved proteins as well as phospholipids.
What originally started as the "anticardiolipin syndrome" (cardiolipin was the phospholipid we happened to choose for our assays) and served for a decade as the "antiphospholipid" syndrome needed an updated title. A group of colleagues at the Leuven meeting suggested renaming it Hughes' Syndrome. For me, it was an immense honour, acknowledging that my group described the full syndrome with a dozen or more features, set up assays with international standards, initiated workshops and perhaps most important, provided clinical advice and training to colleagues worldwide.
It is these colleagues to whom this book is dedicated.