Focus on University College London: research is not in vein

Published on 12 April 2012
Source: Arthritis Today

Professor Anisur RahmanAntiphospholipid syndrome, also known as sticky blood syndrome, can cause havoc to the lives of sufferers. But significant new research could change the way this common condition is treated. Jane Tadman reports.

Most people are aware that warfarin is rat poison. Probably fewer people know that one of the earliest patients to be given it was the former US President Dwight D Eisenhower.

Warfarin is an anti-coagulant drug that for many years has played a vital, often life-saving role in thinning the blood of patients with a common blood-clotting disorder of the veins and arteries that, if left unchecked, can cause deep vein thrombosis (DVT) and strokes. This disorder, antiphospholipid syndrome (APS) , is also one of the major causes of recurrent miscarriage and other pregnancy problems such as high blood pressure (pre eclampsia), small babies and early deliveries.

APS was first diagnosed in people with lupus but it was later discovered that it can exist as a primary form – in people who don’t have lupus or any other autoimmune disease.

Although many people with the condition feel well and have no symptoms, the threat of a blood clot dislodging from the leg, travelling up into the lungs and causing a potentially fatal blockage (a pulmonary embolism) is never far away.

Anisur Rahman, professor of rheumatology at University College London and a leading expert on APS, puts it like this: “In a lot of musculoskeletal conditions, people have symptoms every day. In APS many people feel pretty good most of the time, but hanging over them is the possibility that they might have a life-threatening event, so there’s a mental fear about it. And they have to take medication every day of their life to prevent something that might not happen.”

Until very recently, warfarin was that medication. However, newer oral anticoagulant drugs have recently come onto the market that are now licensed and NICE-approved to prevent DVT in people undergoing hip and knee replacements, and which may offer a more effective means of controlling the lifelong condition.

“Warfarin is saving lives and no one wants to run it down, but we want something better: we want better drugs like anti-TNF for rheumatoid arthritis,” adds Professor Rahman.

His UCL colleague, haematologist Dr Hannah Cohen, concurs: “Warfarin works, but it’s troublesome for patients. It often has an erratic anti-coagulant effect in patients with APS it can also stop normal clotting that occurs after an injury, leading to severe bleeding) and patients need to have regular – sometimes twice weekly or at least weekly - blood tests to monitor its effectiveness. It also interacts with alcohol and food and other drugs that people might be taking for their lupus.”

Dr Cohen is now setting up a new £230,000 two-year Arthritis Research UK clinical trial which will compare one of the new anti-coagulants, rivaroxaban, with warfarin.

“We think it’s as effective as warfarin but potentially safer in patients with APS, it has no interactions with food or alcohol and very few drug interactions,” she says. “Patients are given a fixed dose, which produces a predictable anticoagulant effect and there’s no need for routine monitoring, which would be more convenient for patients. It’s moving towards the Holy Grail of anticoagulants!”

If the anticoagulant effect of rivaroxaban proves to be no less effective as warfarin, the team hopes it will then become the standard therapy for APS patients.

Professor Anisur Rahman and Dr Ian Giles, University College London

One hundred and fifty-four APS patients (with or without lupus) currently being treated at University College Hospital and St Thomas’s Hospital in London who have had a DVT or pulmonary embolism and are on warfarin will take part in the trial.

Half will remain on warfarin for six months, and the other half will take rivaroxaban. Dr Cohen and her team will measure their blood coagulation and bleeding rates, whether anyone had a further DVT or pulmonary embolism while on treatment and general quality of life in both groups. Recruitment will start in June.

While Dr Cohen’s trial has the potential to vastly improve the everyday lives of APS patients, Professor Rahman is engaged in a £700,000 programme of translational research to understand more about the condition and how it develops.

The disease is caused by antiphospholipid antibodies (aPL) which are present in the blood, and act on the tissues of the body to cause clots and miscarriages.

The aim of the UCL programme is to develop new blood tests which can be used to predict more accurately whether someone with APL in their blood will have clots and/or miscarriages or will remain well and develop neither.

At the moment there are three tests used to diagnose APS but even collectively they are not definitive and leave room for prognostic doubt. “We need better tests to tell us what will happen to a patient if they have these antibodies,” says Anisur Rahman. “At the moment I don’t know what to say to a young woman of 25 when she tests positive – that she shouldn’t get pregnant because of the risks? Or should a woman who has just given birth be on warfarin forever? No currently available test will tell you that. But it’s essential to advise each aPL-positive individual on the best treatment for them.”

Professor Rahman (pictured above left) and colleagues Dr Ian Giles (pictured above right) and Dr John Ioannou are also looking at how aPL cause clots and miscarriages by taking aPL antibodies purified from the blood of patients with APS and adding them to human cells grown in the laboratory. The cells that they will use are the same types of cells that are targeted by aPL in the body to cause miscarriages and clots. By looking at the behaviour of those cells under the influence of aPL they plan to work out what is happening in the body in APS.

They are also optimistic and excited at the prospect that their research, in conjunction with a biotech company, could lead to the development of a completely novel drug treatment for APS, although that could be many years down the line.

The testing of novel therapies for patients with APS will require further welldesigned clinical trials done in collaboration with different hospitals to maximise recruitment. Therefore, following their joint work to help develop the UCL trial, a group of haematologists and rheumatologists are now starting up a group called the UK Antiphospholipid Syndrome Society (UKAPSS) to foster more collaborative work in future.

Dr Hannah CohenDr Cohen was on the team led by Professor Lesley Regan in the early 1990s, which, with Arthritis Research UK funding, established that the drug heparin significantly reduced the rate of recurrent miscarriage in women with APS, compared to then standard treatment, aspirin, completely changing the management of the condition worldwide.

 

 


CASE STUDY


Bill Garwood, now 67, had his first DVT in his mid-30s. Eventually after numerous DVTs and pulmonary embolisms and being in and out of hospital, he was forced to take early retirement at the age of 50 from the job he loved, working as a cable maintenance engineer on the London Underground.

Diagnosed with APS in 1994, he was put on warfarin permanently; something he regards as a ‘life-sentence’.

Bill’s APS is at the severe end of the spectrum, and despite being on warfarin and aspirin, he still has regular ‘events’. He has also developed pulmonary arterial hypertension and requires surgery to have his furred arteries unclogged. He has to wear support stockings as the veins in his legs have become damaged and the skin can ulcerate.

“The main symptoms are shortness of breath,” he says. “Sometimes I can hardly bend over to tie my shoelaces without panting. Old ladies get up to offer me a seat on the bus!”

Despite his condition Bill, a patient of Dr Cohen at University College London Hospital, leads an active life. He goes to the gym, has an allotment and enjoys trips abroad.

“You have a problem, you know about it, and you file it,” he says, by way of explaining how he copes with living with a life-long, life-threatening condition. “It pops up from time to time, but I just get on with things.”

ANTIPHOSPHOLIPID SYNDROME – THE FACTS

APS booklet• If you have APS your immune system produces harmful antibodies. These antiphospholipid antibodies (aPL) cause the blood to become sticky and more likely to clot inside the blood vessels.

• In pregnancy aPL can also affect the cells of the womb and the placenta, increasing the risk of miscarriage.

• Ten per cent of people with acute thrombosis have APS.

• Forty per cent of lupus patients have antibodies for APS, and 10 per cent of them will have the full syndrome.

• Up to one per cent of the population have APS, with roughly two times as many women affected as men.

• APS causes one in five of all strokes in people under the age of 50.

• Fifteen per cent of women who have recurrent miscarriage have APS.

Your can read our booklet on antiphospholipid syndrome or call 0300 790 0400 to order a hard copy.