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Tuesday 14th June 2005, 9.00-9.30pm
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Programme 3. - Thrombosis


TUESDAY 14/06/05 2100-2130











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Hello. Thromboses - blood clots that form in the circulation - are easily the biggest single killer of British men and women. Most strokes and heart attacks are caused by thromboses forming in the arteries supplying the heart or brain, blocking vital blood flow with potentially fatal consequences.

But veins can be affected too - the symptoms tend to be less dramatic, but venous thrombosis can be just as lethal, particularly when part of the clot breaks off and travels around the circulation lodging in the lungs - a complication known as pulmonary embolus or PE.

And it's these type of thromboses that we are going to be concentrating on in today's programme. Ironically, hospitals are probably the most dangerous place for venous thrombosis - 25,000 inpatients die from blood clots every year in the UK. That's more than are killed by AIDs, breast cancer and road traffic accidents combined. And although the underlying venous thromboses are relatively easy to treat, most blood clots in the lungs occur without warning and are only diagnosed at post-mortem, if at all. So what more should be done to protect people in hospital?

We'll also be exploring the link between deep vein thrombosis in the leg - DVTs - and long haul air travel. Just how big is the risk, and what, if anything, can travellers do to reduce it?

And I'll be finding out how new treatments could soon put an end to the million or so blood tests that are required every month to monitor people taking the blood thinning anticoagulant warfarin.

My guest today is Ajay Kakkar, professor of surgical sciences at Bart's and London Hospitals medical school.

Ajay, when we look at the blood clots that are occurring in the arteries we associate that mainly, don't we, with narrowing of the arteries, a disease process that's associated with things like high cholesterol, high blood pressure and smoking. But veins are quite large baggy structures, so what is the difference between a thrombosis in the arterial circulation and on the venous side?

We've known that for over a 150 years. Basically a blood clot that forms in the vein results from three things happening: the blood flow becoming stagnant, the blood clotting enzymes becoming activated in that region and damage to the lining of the blood vessel.

So how does that differ between what's happening in an artery?

In an artery tiny cells that circulate - the platelets - are activated at the site of damage to the arterial wall, that activation causes them to stick together and form a tiny blood clot, which prevents flow of blood and results in a heart attack or a stroke.

So little tiny blood clots that are occurring in the arterial side, but in the venous side we're talking about much larger and a different type of clot?


And principally they're occurring in the deep veins of the leg, aren't they, why are the leg veins a particular problem?

Well that's the region of the body most distant from the heart. So the benefit of the propulsion of blood flow caused by the beating heart is lost at that stage, when the blood is returning by the veins in the leg.

So it's a sluggish blood flow?

Exactly. But what we have is the fact that these veins flow through the muscles of the calf and every time we contract our calf muscle we squeeze the blood back towards the heart, the so-called peripheral heart. And this ensures a steady flow of blood back to the centre. The problem is when we lie in a hospital bed we're not moving our legs, the muscles are not contracting, as a result of that the blood flow stagnates in the deep veins of the legs and blood clots form.

Now those blood clots can be very, very extensive and bits can break off, travel around the circulation, and end up becoming lodged in the lungs and that's a potentially serious complication.

Yes it is because there they prevent the blood flow from the heart to the lungs, this causes great stress to the heart which can eventually lead to heart failure and death.

What about the symptoms, the classic symptoms of a deep vein thrombosis?

Well there - pain in the leg, swelling, tenderness and redness. But the most important thing to remember is that 50% of patients who get a blood clot in the leg will never know they had it because there are no symptoms at all.

And if the clot breaks off and travels around to the lungs what sort of symptoms might we expect to see then?

Well acute chest pain, breathlessness and coughing up blood are the classic symptoms of what we call a pulmonary embolism - a blood clot in the lungs.

Ajay we'll come back to some of the more common underlying causes of DVT in more detail later in the programme, but blood clots are probably best known by the general public as a potential complication of long haul air travel. There is a link, but it's not as clear cut as most people think - as Vivienne Parry discovered when she decided to find out what precautions she should take before heading off on her summer holiday.

There's a whole rack of travel goods here, about six shelves full of flight socks, and we've been joined here by the pharmacist. Tell me what should we be looking for? I mean there's a very confusing array - some of them are obviously of different sizes, what should I be looking for?

It's actually quite simple, it's based on your shoe size and it's a below the knee sock which helps to improve circulation and keep the blood flowing up throughout the leg. Any journey where I'm likely to be immobile for longer than a couple of hours I would recommend wearing them but then I am predisposed to the condition now.

And how did you know that?

I suffered a DVT after a long haul flight to Bangkok and I had no previous history, no medical conditions, it was completely out of the blue, I was walking around the cabin, drinking lots of water, however, I still suffered a DVT. So it can happen to anybody.

So does this mean that there's something unique to air travel that causes the problem, like pressurised cabins? I asked Ian Perry, a consultant in occupational health, specialising in aviation medicine.


To our knowledge there is no scientific evidence to prove that point. Most of the stories you hear are anecdotal stories and are not in fact scientific proof that deep vein thrombosis is caused by difference in pressure, lower oxygen, lower humidity or anything to do with the aircraft cabin whatsoever.


It seems that immobility is the problem, not the means of transport. I talked to John Scurr, a consultant vascular surgeon and asked him how common DVT was.


Blood clots following any form of immobility - sitting down - is much more common than originally thought. We did a study in 2000 where we found that 10% of people travelling for more than eight hours actually got small blood clots in the calf, now none of those people knew anything about it and it was only the fact we were using these ultra-sensitive scanning techniques that we were able to demonstrate the clots. Fortunately most of the clots dissolve and go away, so you might get a small clot, you won't know anything about it, it goes, no problem, it's only the clots that get bigger and bigger that will cause you problems. We know that somewhere between two and three in a hundred passengers will get a deep vein thrombosis and there have been other studies that show that. Some passengers, of course, are at greater risk than others.


So say that I haven't got any of the risk factors, nobody in my family with thrombosis, I've not had surgery, not on the pill, should I take special precautions when I'm getting on a long haul flight?


I think the simple answer to that is yes. The risk to you is very low indeed but there is a small risk. The risk increases if you do more flights and so if you're a businessman travelling regularly, getting off a flight, on to another flight the risk starts to go up. I think the simple thing to do is to identify those people who are at high risk and give them special precautions. For low risk people, like yourself, then I would strongly recommend that you take exercise before you get on the aeroplane, you can buy a pair of compression stockings, wear them for the flight, take them off when you get to the other end, take exercise the other end, avoid drinking too much alcohol.


Okay so I'm convinced - I need a pair of flight socks. All I have to know is my shoe size. But something's worrying me. As it happens, my husband and I share the same 7 ½ shoe size, but whilst he's got big muscly calves, my legs are like little pipe cleaners. What would fit him, would fall off me. I asked John Scurr how to ensure that I got the correct stockings.


You can't just go in to a shop and buy them. The reason for that is that people have different size legs and to get the most effective stocking they need to be the right size, so they must be measured.


So not just your foot size?


No, it's very important before we fit you with any form of elastic stocking that we actually measure the ankle circumference.


My point precisely. So in a trice he was at my feet with a tape measure. My ankle measurement was eight inches, if I'd chosen a stocking based on my shoe size of 7½ rather than that of my finely turned ankle it wouldn't have fitted, as John Scurr showed me.

If I was just demonstrate on you.

Yes, they'd be very loose indeed, well they'd fall off practically.

I mean it would be a complete total waste of time.

Okay so now I have this rather glamorous item in black, let me try this on.

You need to make sure that you place the sort of fabric evenly over the leg, what you don't want to do is to get the sort of band at the top right behind the knee because it digs in, and you can just take the little wrinkles out. You can wear them home now, when you sit for hours on the tube.

Many people think that they will be protected from DVT if they pop an aspirin before a flight, but is that true? Ian Perry again.

Anybody taking aspirin without medical advice prior to flying is asking for a lot of trouble because we do see a lot of gastric bleeding, you should only ever take aspirin on medical advice and people who take aspirin will tell you they get a lot of indigestion, now that is something you don't need when you're flying anyway, apart from the possibility of having a gastric bleed.

It was really because of that we started looking at alternatives to aspirin.

John Scurr has been trialling Zinapin, which doesn't appear to carry the same risks of gastric bleeding. It's based on an extract of French Maritime pine bark and ginger.


Maritime pine bark is quite an effective agent and of course there's a lot of work that's been done but now we've had all those studies repeated, we've actually just finished a clinical study where we've been giving it to people who are travelling and it certainly reduces the risk of developing the superficial clots - these are the less important ones - and we've not seen anybody with a deep vein clot. So we think there is some very good evidence that it is effective.

Finally there are exercises - the best sort, of course, is walking. Apparently waggling your feet about while you're in your seat won't do and John Scurr suggests pressing your feet against an air filled device.

It's a cushion that you blow up and you put your feet on it and you can squeeze the air backwards and forward, well in fact it was invented by a British Airways pilot who said he designed it to stop clots moving around the aircraft cabin - it was to stop people getting out of their seats and walking around. But the real message here is that it's the sitting around and of course we're talking about travel today, but it could be people sitting in front of their computers for 12-14 hours, it can be sitting in a bus for 12-14 hours, it's immobility that's the key factor here.

Vivienne Parry getting some advice from John Scurr.

Immobility Ajay - presumably that's one reason why thrombosis is such a huge problem in hospital patients?

It is, and it's an important problem. But we know that the reasons why people go into hospital also drive their risk of developing a blood clot. For instance, having major surgery, an operation on the abdomen for instance, operations for cancer or hip and knee replacements will be associated with a lot of trauma.

And what sort of risk are we talking about - if you're going in for a - say you're going in for a hip or knee operation, what are your risks of having a deep vein thrombosis?

Well if you look at thrombosis that can be screened, non-clinical thrombosis, about half the patients will develop some form of blood clot without a preventive measure.

And many of those won't know about it.

They won't - the majority won't know about it.

We talk about preventative measures - what can we do to protect our patients that are going into hospital then?

Well the most effective measures are the so-called forms of pharmacological prevention and that's usually heparin or low-molecular-weight heparin, given as an injection around the time of surgery and after operation to prevent blood clots.

So this prevents blood clots but what happens if the surgeon's then going to operate on you - how does that affect the bleeding that might happen during the operation?

Well there is a small risk of bleeding associated with using these agents but when you look at the benefit of risk against the benefits of preventing thrombosis it always come out in all the clinical trials in favour of preventing the blood clots.

And what about non-surgical patients?

Well they're also at very high risk and we should be providing them with low dose or low-molecular-weight heparin to prevent thrombosis when they're immobilised in hospital beds.

What about stockings - we use those in patients?

Yes, we use those in combination usually with the pharmacological methods like heparin but they can be used alone in certain lower risk populations.

Let's move on from prevention to treatment. First of all, we've got to diagnose them, how are we confirming that somebody's got a DVT?

Well simply by doing a scan of the leg which will show us the clot and some routine blood tests that demonstrate the presence of a clot.

And how are we treating thromboses?

There are two stages to treating blood clot. The first is heparin, which is given usually as low-molecular-weight heparin by injection and that is to provide us with initial treatment. And thereafter we give a drug known as warfarin, which prevents recurrent blood clots, which occur frequently unless we provide some form to prevent them.

Now there are some half a million, three quarters of a million people taking warfarin in the UK, most of them for the prevention or treatment of thromboses, it's not easy to take necessarily is it?

No, it's associated with great difficulty, it requires a lot of monitoring because it doesn't behave in the same fashion in all patients, we have to change its dose regularly to ensure we're in a safe window, both for preventing recurrent blood clots and to ensure we're not going to cause bleeding. And their interactions with foods and other drugs.

Well David Keeling is a consultant haematologist as the Oxford Radcliffe Hospitals.


Warfarin can be a very dangerous drug. If you don't give enough the patient can have another thrombosis and if you give too much the patient is at risk of bleeding. And the difference between the dose that's too much and the dose that's too little is very small for warfarin, it's what we call a narrow therapeutic index. And so you've got to get the dose just right and that requires, unfortunately, quite frequent blood tests in many patients.

We do them at our surgery, we have perhaps 15 or 20 people we have to ring up at the end of evening surgery to tell them what dose of warfarin to carry on taking. In a well controlled patient how often would they need to be tested?

I think at our anticoagulant practice the average is about three weeks although we'd like it to be longer, some patients on long term warfarin are very stable and are only tested very 6-8 weeks but unfortunately some patients end up being tested every 1-2 weeks, which is obviously quite disruptive to their lives.

I had a DVT in my left calf. It was just a sore calf, that I thought was a muscle pull and unlike other muscle pulls it wouldn't go away and I thought well I'd get this checked out and luckily I did actually. And also the x-ray showed that I had pulmonary embolism - a blood clot on the lung. I was in hospital for 10 days, I had heparin injections every day to thin the blood and then a course of warfarin, so rat poison for six months for me.

This is what we call the anticoagulation clinic, where we're monitoring people who are on oral anticoagulants, predominantly warfarin, and we open the clinic three days a week and on average we're usually seeing about a hundred people a day.

Nicholas Kelaher is an anticoagulant nurse specialist at the Royal Free Hospital.

Patients essentially are coming for a blood test which we need the result of to then advise them about their warfarin dosage.

Now you were just explaining to me before that you were taking 5 milligrams each day?

I was on 4 mils a day, it's my understanding that I now need to take alternately 5 mils and 4 mils.

I'd be happy to leave you on that for two weeks. If you want to come back in a week and we can check that again.

Good. Four one day, five the next yeah.

If a person's blood results are abnormal that's something they wouldn't necessarily know, you don't feel any different when you take warfarin and you wouldn't be necessarily aware that your blood results have gone out of kilter. So once observing those results we'd ask people to come back more often. The important part of all of that of course is they're taking a medication that has a high risk component to it, which is that it increases their risk of bleeding. So importantly if they do notice things like bleeding or bruising that are spontaneous of unknown cause then they certainly would be coming back on that basis.

But a new breed of anticoagulants that have a more predictable blood thinning effect could change all that. Imagine a drug that has the convenience of a daily tablet like warfarin which can be used in the same dose in everyone without the need for regular checks to make sure the blood's not too thick or too thin. Ximelagatran is one such drug, according to Dr David Keeling.

One of the key things with this new drug is the difference between the lowest concentration and the highest concentration that's acceptable is reasonably wide, so in contrast to warfarin if there's rather a wide therapeutic index and therefore it's easier to get the dose right. So much so in fact that we can give everybody the same dose and know we're just about right.

If it's that predictable do we need to monitor patients at all?

Well that's the key thing with this new drug - I don't think we do need to monitor it, we can give a fixed dose and we know we're not giving too little, putting the patient at risk of recurrence and we're not giving too much, putting the patient at excessive risk of bleeding. There have now been, what we call, phase three clinical trials where people have literally taken a fixed dose of this drug twice a day with no monitoring whatsoever and it's prevented them from getting further deep vein thromboses.

And how long would we need to treat somebody with warfarin or perhaps with one of these new drugs for if they've just had their first deep vein thrombosis for instance?

The standard treatment now is six months. The reason we stop warfarin after six months is because by that time the risk of having another blood clot has reduced to quite low levels and we don't think it's worth the risk of keeping people on what's quite a dangerous drug, difficult to use and carries a risk of bleeding. Now when we stop warfarin all the patients who've had a DVT in the past are at risk of having another one in the future and if we had a drug that could reliably prevent clotting and didn't carry a risk of bleeding with it we might want to treat patients for a lot longer than that.

You say that this particular new drug is still in the trial phase, how likely is it that it's going to become available, is it looking promising?

If you'd ask me that question 18 months ago I'd have thought we might actually have it by now. There has been a little glitch in the system. In the clinical trials they've done 6-10% of patients taking this drug had abnormal liver function tests and so that's now got to be investigated to make sure it's not an important side effect. I'm hopeful it won't be and we will get the drug. But I think I'm still quite optimistic that even if this particular drug turns out to have a problem there are lots of other similar drugs on the way and I think within the next 5-10 years we'll now have a lot of alternatives to warfarin.

Of course one of the big problems of any new drug is that they tend to be very expensive and warfarin really is dirt cheap. We'd have to offset presumably some of the added benefit from the fact we wouldn't have to monitor these patients if they were on the new drugs, there's a huge saving to be had there.

Oh that's absolutely right but it's going to be a very complicated issue isn't it. As you say there may be a drug which the tablet costs quite a lot but doesn't require any monitoring and that's got to be compared with a drug that costs only a few pence but there's a whole infrastructure to take blood tests to make sure that the patients are properly controlled. It will only be cost neutral if we can dismantle our anticoagulant clinics but of course life may not be as simple as that.

Dr David Keeling.

Ajay, we've talked about immobility and hospitalisation being key factors in deep vein thrombosis clots in the leg, what else might put someone at risk?

Well we know that pregnancy, for instance, is associated with a risk of thrombosis in certain individuals. We know that major surgery is important. We also recognise that a strong family history is an important issue when identifying patients who might be at risk for developing blood clots. And of course there's the problem of blood clots in patients with cancer.

Why is it such a problem in patients with cancer - is there something - what's the cancer doing that's affecting the blood clotting?

Well I think we know now that tumours very early on are able to activate the blood clotting system and the reason for that wasn't clear, but it appears now that not only does it result in blood clots which can be diagnosed in these patients, and can be potentially fatal in them, but also the activated blood clotting system has the ability to change characteristics in the cancer and make the cancer more aggressive. As a result, recent studies have shown that cancer patients who've received heparin like drugs, the low-molecular-weight heparins, to treat their thrombosis actually have an improved survival from the point of view of their cancer. These are very early data but very exciting data because they suggest additional benefits of providing anti-clotting drugs to cancer patients in that they may be able to change the characteristics of the tumour and therefore improve outcome for these patients.

You mentioned earlier a family history of clotting, there are a group of disorders aren't there, the thrombophilias, where people are particularly prone to excessive clotting, what's going on there?

Well over the last 15-20 years a number of genetic mutations have been identified in the blood clotting system that predispose to a heightened risk for developing blood clots, either spontaneously or under certain circumstances such as pregnancy, these mutations together are known as thrombophilias, they're not very common. The most common is something known as activated protein C resistance and that occurs in about 5% of the population. The others occur much less frequently.

Well one of the most common types of those rarer thrombophilias in the UK is Antiphospholipid Syndrome, or Hughes Syndrome as it has become known, after the man who first described the condition in the early '80s, Dr Graham Hughes from St Thomas' Hospital.

I noticed a group of patients attending our autoimmune clinic for diseases such as lupus, who got thrombosis, they got DVTs or pulmonary emboli but they got more - they had a collection of things and it was different from other clotting disorders in that it affected arteries as well as veins. And so there are much more serious potential things such as migraine, strokes and in pregnancy clotting of the placenta led to miscarriages. The theory, and I think it's probably true, is that some of these women get clots in the placenta and the baby doesn't get the oxygen and miscarries. And some of these women have 10, 12 recurrent miscarriages.

What's going wrong in the blood that's making it clot?

It's a disease in which the immune system is overactive, the body's immunity attacks itself and the buzz word is autoimmune disease for that. And in this disease a particular antibody which we've identified is directed against a chemical called phospholipid and that's the sort of sausage skin that surrounds all cells, platelets, for instance and lining of the blood vessels. And we figure that these antibodies in some way messed up, if you like, platelets and their interaction with blood vessels.

Basically the plates are a fundamental of the clot, so if they're sticky and the lining of the blood vessels is sticky you're asking for trouble.


Do we know why they have the antibodies?

It's probably slightly genetic. If you look at large families of patients with this you'll find thyroid disease, rheumatism, arthritis lupus in a slightly increased number of the family. So it's probably genetic, can lie dormant and then be triggered by another event.


Looking at the deep vein thrombosis side of it, it's a very important cause of deep vein thrombosis isn't it, probably the most common.

It's the most common, it's still under-recognised, I know I'm speaking a bit passionately but a large study from Newcastle, from France, from Italy have all shown a one in five ...

Of all deep vein thrombosis?

Of all deep vein thrombosis. And there are clues as to who gets the syndrome, very common is a history of migraine, you ask the patient when you were a teenager did you get migraine - yes doctor, severe. And that's often a clue or of course miscarriage.

Are these deep vein thrombosis coming out of the blue or are they occurring in circumstances that we might expect them, for instance someone who's had an operation or broken their leg?

Yes definitely, additive factors - commoner in smokers, common when you go on the pill. We've seen a number of our patients on long haul flights who've got DVTs and I personally feel that the poor old airlines get all the flak for this but there are some patients who are more predisposed to it than others. Susan's a case in point, she's a patient of mine, coming up for an outpatient visit who I think presented fairly dramatically with a clot, probably starting in the legs but spreading to the lung, so-called pulmonary embolus.

How did you know you had a problem Susan, what was the first thing?

I actually had a pulmonary embolus after a long flight in 2000 ...

You got off the plane and everything was fine, did you?

Got off the plane and had a very high heart rate and my legs were quite swollen. I went to see a GP there, I think because I'd had a long flight he obviously did a few tests and things were a bit suspicious and realised it was a pulmonary embolus. But then while I was in hospital getting treatment for that they started to wonder what was going on because there was something a bit unusual about my blood and they couldn't make it thin enough and it was actually a medical student on the ward who'd just read something about Hughes Syndrome who suggested it and that's what it was found to be.

Graham was there anything in Susan's past history that was suggestive of Hughes, rather than a DVT for other reasons?

Yes, Susan got quite a few characteristics of the syndrome, not, it must be said, recurrent pregnancy loss but others, notably headaches and visual disturbances - migraine like - and I think you, Susan, had had headaches before hadn't you?

I hadn't actually had headaches as such but I had really very disturbed vision and getting to the point where they were happening several times a day and then after being diagnosed with Hughes Syndrome and started taking warfarin they stopped completely and I didn't get them at all again.

Are we now routinely screening everybody who's had a factor that was suggestive of it?

The obstetric world has taken the lead here I think because it's such a major treatable cause of recurrent miscarriage. It's only a routine test if you've had two or more miscarriages.

But at 1 in 500 it's very unlikely that we're ever going to be looking at screening the general population for this.

That's true. So I think we've devised things that we always ask about and they are headaches, I've mentioned before, migraine, family history of autoimmune things - thyroid, rheumatism ...

Family history of DVT as well?

Yes indeed, definitely.

Dr Graham Hughes.

Ajay do you think we're doing enough to identify people who are at particular risk of a deep vein thrombosis before they go into hospital?

Well one of the recommendations of the recent health select committee inquiry into thrombosis blood clots was that patients coming into hospital should be risk assessed. But the risk assessment is based upon the conditions that bring them into hospital and the procedures they're going to have, rather than blood testing. It is very important we do this because we have such a volume of evidence that provides us with confidence about providing methods to prevent blood clots, such as the heparins and low-molecular-weight heparins, that it's a tragedy if patients who are at risk are not provided with the benefit.

Professor Ajay Kakkar, that's all we have time for, thank you very much.

Next week's programme is for all you parents and grandparents and will be coming from the Alder Hey Children's Hospital in Liverpool.


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