Preface
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:
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Definition
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Clinical Features
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The Brain
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Pregnancy
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Who should be tested?
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Relationship to lupus
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What are the tests?
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Treatment
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How big is the problem?
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Future Research
1. Definition
"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.
"STICKY BLOOD"
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.
AN IMPORTANT CAUSE OF ABORTION
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.
2. Main Clinical Features
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1. Vein Thrombosis
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Leg vein thrombosis (DVT)
Arm vein thrombosis
Thrombosis in "internal" organs
e.g. kidney, liver, lung, brain, eye
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2. Artery Thrombosis
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Brain - headaches, neurological features
Linb - pain and circulation problems
Heart - chest pain
Other organs, e.g. kidney, adrenal
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3. Recurrent abortion or miscarriage
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Often late into the pregnancy
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4. Low platelet count
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"thrombocytopenia" - 5 to 10%
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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.
DEEP VEIN THROMBOSIS
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.
ARTERIES CAN ALSO CLOT
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.
BLOTCY SKIN
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.
HEADACHES AND MIGRAINE
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.
MEMORY LOSS ...
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.
...CAN IMPROVE
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."
TALKIG NONESENSE
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.
ODD MOVEMENTS
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.
THE BABY'S LIFELINE
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.
RECURRENT MISCARRI AGE CAN BE TREATED
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.
TESTING IS CHEAP AND EASY
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.
SOME PATIENTS ALSO HAVE LUPUS...
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.
...BUT VERY FEW
Most laboratories and clinics use two main tests:
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the antiphospholipid antibodies measures the actual antibody levels
(most labs use anticardiolipin antibodies, ACA, on the standardised
blood screen);
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the confusingly named lupus anticoagulant is a more complicated
clotting test, far less reliable and more subject to laboratory
variables.
ASK FOR AN ACA TEST
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.
STICKY BLOOD NEEDS THINNING
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.
BABY ASPIRIN
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%.
PREGNANCY SUCCESS RATE IMPROVES
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.
KEEP THE BLOOD THINNER
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.
ANTICOAGULANTS WORK!
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.
ONE OF OUR MAJOR DISEASES?
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).
CHILDREN TOO
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.
MISCARRIAGE? CHECK THE BLOOD TEST
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).
ADDED PROBLEMS: SMOKING AND THE PILL
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.
RESEARCH
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.
... MAY HELP ARTERY DISEASE
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.
History of the Syndrome
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.
BRAIN AND THROMBOSIS
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.
SOME LUPUS PATIENTS HAVE THROMBOSIS
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.
NEW SYNDROME
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.
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The tendency for both artery and vein thrombosis.
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The association with strokes and neurological features.
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The strong association with recurrent fetal loss.
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The tendency to low platelet count.
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The fact that the syndrome could exist "outside" lupus.
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The description and standardisation of laboratory assays to measure the
antibodies.
BLOOD TESTS
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.
RESEARCH CONFERENCES
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.
THROMBOSIS MECHANISM CLEARER
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.
Pagina principale
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