Traveler's Thrombosis - April 28, 2000

Patrick Kesteven, MD, Consultant Haematologist, Freeman Hospital

DR. ERICSSON: Next, we're going to hear from Patrick Kesteven, also an M.D., Ph.D., a Consultant Hematologist and Assistant Medical Director, New Castle Pontine Hospitals, NHS Trust, England. He's a fellow of the Royal Australian College of Physicians, a fellow of the Royal College of Pathologists of Australia, a fellow of the Royal College of Physicians, London, and a fellow of the Royal College of Pathologists in London.

He's of dual Australian and British nationality, and he's published close to 40 papers on various hematological studies. And his latest publication in the press relates to the topic of which he'll present, "Traveler's Thrombosis."

DR. KESTEVEN: Right. Thank you very much. I have to say I have memberships to of all of those colleges, and when you get to my stage in the NHS, they start giving them to you. And, in fact, I only passed exams for the first half of them. And when you get to England, they say, "Oh, have some more."

[LAUGHTER]

As you've heard, I work in New Castle, which is in the top right-hand corner of England, quite close to the Scottish border. And as you'll see, it's quite useful to live up there because the population is relatively fixed. Having said that, one of the speakers from the U.K., it turns out, came from New Castle, and he's shifted out. But most of them are there and very useful for epidemiological studies.

I would also like to endorse what Jonathan said yesterday, that this is the correct spelling for traveler.

[LAUGHTER]

And it's a fight with Powerpoint every single time.

[LAUGHTER]

I'll give you the definition of what I'll be talking about this morning. DVTs and pulmonary emboli, which have produced symptoms and forced the patient to turn up to the medical system somewhere, and then had some kind of objective test, and this has all occurred within 4 to 5 weeks of some form of travel. Now, I make this the definition because these are the inclusion criteria for all of the published series on this subject in the last 10 to 15 years.

All of these studies are a little bit vague about just how much of a journey you do have to have made. The reason for 4 to 5 weeks, there are good plotting reasons for this, and as we'll see it's unduly generous.

I think I don't have to remind this audience that DVTs can be extraordinarily incapacitating. They lead to long-term sequelae in the leg, and it can also lead to pulmonary emboli. Nearly all of the information on DVTs comes from studies in postoperative cases. And I would like to show that traveler's thrombosis is not quite the same as a surgical postoperative DVT.

The theory is that the clot forms usually in the calf in postoperative cases, when the blood is sluggish, and then extends if the patient is pro-thrombotic. Nearly all of the thinking about DVTs until about 10 to 15 years ago was based on an aphorism coined by Volkov in 1850, which said that you'd get a thrombosis if there's a problem with the blood flow, with the constituents of the blood over the vessel wall. And that's now considered to be only partially correct. It looks like you need a whole series of these risks in order to get a clinical thrombosis.

Now, overall, the incidence of thrombosis is roughly one in a thousand per annum for the whole population, and that figure holds both for Europe and North America. And it's highly dependent on the age of the patient. The incidence is very, very rare in children, adolescents. It's unusual in young adults, and then it shoots off very, very steeply after the age of 50. And apart from age, there are a whole list, quite a long list, of which I'll give you some here, of other clinical associations of venous thrombosis.

The epidemiologists have done a huge amount of work, especially in Holland, where they have been able to study entire populations. And they've worked out prevalence, and risk and the influence of those two parameters on the whole population. Malignancy, surgery, immobility have been known about for a long time, anything to do with pregnancy, and anything to do with estrogen therapy.

More recently, and this has been a real boom to my profession, my field, giving us something interesting to look for, is the discovery over the last 25 years of a sequence of blood disorders which predispose people to thrombosis. The first ones that were turned up, antithrombin III deficiency—that was in 1976—gives you a very, very high risk of a thrombosis, but it's extremely rare in the population. And if you pick up 100 DVTs at random, only one to two of them will have antithrombin III deficiency. So it has very little effect on the community at large.

The Factor V leyden mutation, which was mentioned by the previous speaker, much more interesting. It's extraordinarily common in Scandinavian countries and in Northern England, and wherever the population from those places has spread. So there's quite a lot of it in North America as well. But it is estimated that 5 percent of the population of Glasgow have Factor V leyden mutation, and it's quite a risky thing to have. The relative risk of a thrombosis is about eightfold.

Now, it's not at all clear what advantage this mutation infers. Presumably, it came across with the Vikings, and presumably it stopped them from bleeding to death with an ax in their head—

[LAUGHTER]

But it does give you a huge risk, and we'll see. The combinations of these risk factors do appear to add up.

And to summarize all of this, I show you this diagram, which I stole from a paper in the Lancet last year, by Rosendahl. And in this example, he's shown the risk of thrombosis on that axis, time on this one, and the risk increases with age. And this particular example is somebody who has Factor V leyden mutation, and the risk ratio of that is about eightfold, which is up here. It gives you a new line.

At this point, the young woman started taking an oral contraceptive tablet, which is a threefold risk, up to here, and at this point went skiing, broke her leg, put it in plaster and had a DVT.

And what I'd like to demonstrate with the rest of this talk is that traveler's thrombosis acts in very much the same way as the immobilization of being put in the plaster. But it's a final straw acting on a whole range of other risk factors.

And my evidence to that in this rather messy slide is the studies that I could find on a series of traveler's thrombosis, in which the other risk factors for venous thrombosis are given, and there are only a handful of them. The first two, and we'll come to them again later, both come from Honolulu. This is a London study. This one is from Nantes in France. And this is our own work. And as you can see, quite uniformly, three-quarters of the patients with traveler's thrombosis have other fairly conspicuous risk factors for venous thrombosis.

With the exception of this study here, none of them included thrombophilia work; in other words, blood samples looking for those risk factors which predispose to thrombosis. In ours, we've got a slightly high figure. If we use the same parameters as the earlier studies, our figure here is 72 percent. We've added another risk factor, which is a recent flight. Sequential flights do seem to be more dangerous.

Now how big of a problem is this? And we're trying to answer the same question that Lennart addressed in the previous talk. And what I have here is another sequence of case reports in which the data is given of how many of the—all of the venous thromboses seen by that unit were traveler's thromboses. And you can see they fall into two groups. This one here is from Perth in Western Australia. It's the acute unit. And they estimated that 3 percent of all their venous thromboses had travel as an ecological factor.

Our own work at 4 percent. This is from London, also—just under 5 percent.

These are the two studies from Honolulu and a rather larger percentage. And I suspect the difference between these two numbers is a function of the traveling habits of the population studied.

Now, the first effort to work out the incidence of this problem are multiplied together. The figures for the incidence of VT in the whole population, venous thrombosis, in the whole population is roughly 1 in 1,000 per annum, with the two extremes from that previous slide. And that produces a figure of somewhere between half and three per 10,000 of the whole population per annum. Now, I stress that this is of the whole population, and presumably for frequent travelers, that figure will be slightly higher. But that particular work has not been done.

Slightly more rigorously scientific in our own work. And these are the data from the 12 months of last year. We know that the population between New Castle and the Scottish border is 650,000. And as I said before, that's relatively fixed. In the 12 months of last year, there were 635 venous thromboses in that population. Now, we're confident that we've picked up nearly all of those because the anticoagulant service in that area is centralized, and I ran it. So I've got a monopoly.

[LAUGHTER]

They can't get a venous thrombosis treated in any other way.

We also cross-checked with the X-ray departments, where the diagnosis would have been made. Now, every one of those was asked if they had traveled within the previous 4 weeks. And the cut-off was a 2-hour trip by any form of transport. And we found only 26 cases. And if you do the sums, there's a 4.1 percent of all venous thromboses, which you've already seen, and that produces a figure which is roughly the same as the rough estimate I showed you on the last slide— about .4 per 10,000 of the whole population.

If you multiply that up, assuming that the population is uniform in the U.K., that's about 2,500 cases in the whole of the United Kingdom per annum. So it's not a roaring epidemic, but it's a sizable problem that needs thinking about.

Now, what sort of people get these venous thromboses? I've called this the New Castle study, although none of the patients came from New Castle. We had an opportunity, as we were setting up that other study, to test the questionnaire that we used, and this was through a newspaper article in the national press. And we asked people who had had a DVT shortly after an airplane trip to contact us. And we thought we'd get a small number and be able to test the questionnaire. But, in fact, we got 110 responses in the next week. And we sent them all the questionnaire, and we got a 90-percent response, and slightly better than the figures that were given yesterday. But these are all volunteers.

So except that it's going to be a biased sample, because these are all volunteers, they're all nice people, and also it's absolutely impossible to control this particular group of patients. We did have to exclude some. We took a 5-year cut-off to exclude some of the memory biases likely to occur. And at interview, we expected the patients to be able to tell us that they'd had an objective test, followed by Heparin, followed by oral anticoagulation. And we accepted that as pretty good evidence that they had had a DVT or a pulmonary embolus.

Now, we asked a whole sequence of questions. This is quite a long questionnaire. And because of the lack of controls, a lot of the data is very difficult to interpret, and I won't present it. But we asked about alcohol consumption during flight, what time of day the plane took off, and where they sat in the plane. And roughly a third sat by the window, a third in the aisle, and a third in the middle.

[LAUGHTER]

We also asked where, which class they were in. And I was interested in the figures that Lennart gave us. Fifteen percent of this group had flown business class. So I stress, I'm not saying that 15 percent of all traveler's DVTs are business class, but it obviously can happen.

Now, the age of this group is more or less the same age range that you'd expect from any venous thrombosis, with the exception that there is a bias towards the younger age group. There is a younger cohort here, and 22 percent of this group are age less than 50.

The BMI—I don't know if you use BMI in this country, Body Mass Index. We hypothesized if being cramped was important to traveler's thrombosis, then large people should be over represented, and, in fact, it's quite clear that's not the case. The average BMI in the United Kingdom is 25.

A lot of people ask how much of a flight do you need to get a venous thrombosis? And it's generally assumed that the longer the flight the higher the risk, and we could not show that. Without controls, we can't say too much about these figures other than quite clearly it does happen after relatively short trips. This was interesting to us because this does differ from the existing literature. We asked when did the symptoms develop? When were they first aware that there was something going wrong? And this is timed from getting on the airplane. And 56 percent of this group had developed their symptoms either during the trip or within hours of getting off the airplane, and over 90 percent had their symptoms within 3 days.

Put this into see whether the health system was actually working well in picking up these patients. And, again, nearly all of the patients had managed to get themselves diagnosed within 4 days, which is pretty good. It's not a function of knowledge because one of these was one of the senior anesthetists at my hospital, who had come back from a conference in this country, and had developed symptoms during the flight. He'd had some leg cramps, and he had then become increasingly short of breath. And he thought it was his asthma playing up. And he spent a whole fortnight huffing and puffing around the wards and sucking away on his Ventolin inhaler before one of his colleagues put the connection to him and suggested he have a lung scan.

Now, then, does traveler's thrombosis behave in the same way as postoperative thrombosis? And the answer is, no, not really. There is this younger cohort that I mentioned earlier. And of our group, almost 50 percent actually presented with chest symptoms. And that seems to be much, much higher than the incidence of postoperative cases, which is closer to 10 percent.

And there appear to be more risk factors for venous thrombosis in these cases. Now, that may be a function of the way we perform the study. But I suspect number one and number three are picking up the same thing, and Rosendahl's diagram of multiple risks with a final straw firing off the thrombosis. And I think these people are prothrombotic and just waiting to have a thrombosis. And travel just happens to be the precipitating event.

Is flying more dangerous than other forms of transport in this regard? Now, again, it's another series of case reports of traveler's thrombosis. These two I've mentioned before are from Honolulu, and all of their patients have developed their thrombosis after flying. But the authors themselves point out that it's pretty difficult to get to Honolulu any other way.

[LAUGHTER]

All other series do include other forms of transport. So it's quite clear that you can get a venous thrombosis after sitting still on terrestrial transport. Only one of them is car travel more frequent than flying, and this is the one from Nantes. And it's pretty difficult to take a long-haul flight out of Nantes?.

Now, I've looked for evidence in the literature for other factors, which may be significant in precipitating a thrombosis in an airplane. In other words, are there other factors, other than sitting still, which can induce thrombosis in flight. This is only one of many papers which has shown that on long-haul flights people do tend to become moderately dehydrated.

And this was a poster presented last year in this city, a Bleeders and Clotters Jamboree, in which a bunch of Norwegian medical students were locked in a pressure chamber for a week. Now, it was apparently quite a comfortable pressure chamber. It was one designed as a whole apartment. It was used for training olympic athletes. And the pressure was then changed to 2,000 meters, equivalent to cruise on a long flight, and subsequently to 4,500 meters to duplicate mountaineering, rather dangerous mountaineering. And they were able to show there was some activation of the coagulation system only in that first pressure change, which took place over about 10 minutes. It then settled back to normal over the next hour or two and did not recur when they went up to 4,500 meters. There were no controls to this group, so it's not clear whether it was being locked in the pressure chamber, which caused the changes. And there's also a report, which wasn't on the poster itself, but which the authors told me, as well as the 12 medical students, there were two nurses locked in there as well and a lot of alcohol.

[LAUGHTER]

So I don't detract from this. There may be something there related to the pressure change. It's most unlikely to be hypoxia because that has been investigated elsewhere. People have looked for the incidence of venous thrombosis in patients with respiratory failure. And hypoxia on its own does not appear to be thrombogenic for venous thrombosis.

And I'm going to finish off with two slides. Recommendations: It's relatively easy for high-risk groups. And by high risks, I mean people who have had a previous venous thrombosis, although there is good evidence that they are going to have a thrombosis. And these patients need to be offered some form of thrombo prophylaxis.

Now, all of these three have certain risks. So there's an element of risk balancing that has to go on, and you have to judge each individual case. My own practice is to give these patients low molecular weight Heparin. This comes in preloaded syringes. And provided they can give subcutaneous injection or you can teach somebody who is very close to them to give a subcutaneous injection, they just need one on each day of travel. And "touch wood," I've not had any problems with that, either in terms of complications or recurrences.

In this country, quite a lot of thrombo prophylaxis is done with Warfarin, and that will work perfectly well. It just strikes me it's much, much harder to be accurate. And if you want to sit and straddle the fence, aspirin does provide some venous prophylaxis. It's not as strong as this, but it is better than placebo, and the side effects are slightly more predictable.

What I call low-risk group, those passengers who do not have any conspicuous risks already, what can you suggest to them? And by and large, it's what the airlines already suggest. The important thing is to avoid sitting with the knees bent. It seems to be that the problem does start in the popliteal vein, which creases up when you've been seated. So you've got to find some trick for straightening your legs. Now, the suggestion of getting up and walking around is fine for one or two cases, but you can't ask the entire jumbo load to do so. So you've got to find some trick, whether that's pay enough money to sit in first class and lie down flat or whatever.

Exercising the calf muscles is clearly going to be of assistance and improve venous flow. Dehydration does have to be an element. No doubt people do get dehydrated on airplanes, but again, it's very, very easy to combat.

I've put in surgical support stockings, with my question marks there, that some authorities do recommend this. And undoubtedly they are very helpful in postoperative cases, where people are lying flat and the blood has just gone sludgy. I suspect they would be fiercely uncomfortable, and unless they're a perfect fit, I suspect they'd be counterproductive because they'll rock up behind the knee.

And most importantly, if you've been on one flight, and you've developed odd symptoms, and quite a few of our patients in our series, people have gone away on holidays and diagnosed themselves as having strained a calf muscle, which then blew up on the return trip, but if you have developed odd symptoms, get them checked out before you get on the return trip.

At which point I'll stop, and thank you for your attention.

[APPLAUSE]

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