Re-wiring the brain and chronic pain

Pain is a deceptively simple experience. If you hit your thumb with a hammer you feel instant pain, which peaks rapidly and then gradually resolves over a few days as the damaged tissues repair themselves.


In theory a painful crisis is just the same; the conventional wisdom is that the flow of blood inside the blood vessels within bones is blocked by sickled red cells, the tissues downstream are starved of blood and oxygen, and the resulting tissue death leads to an acute inflammatory response and severe pain. In the normal course of events, the pain resolves over a period of a week to ten days as the damage caused by the lack of oxygen is made good.

Of course, this is a gross over-simplification in so many ways. For example, the perception of pain, what you actually feel, is altered by many different factors. The classic example is of soldiers in the midst of battle, who may suffer horrific injuries but report feeling no pain until they are well away from the scene of the fighting. The stress and excitement of battle seems to be able, temporarily, to switch off pain sensation. Many other factors act in the opposite direction and will heighten pain experiences, including sleep deprivation, depression, lack of control, fear and many others. Clearly, what goes on in the brain is able to dramatically alter how we feel and respond to pain.


Pain messages are transmitted from the damaged area to the brain via nerve fibres in the spinal cord. The brain not only modifies our perception of pain but can also block or reduce upwards transmission of pain impulses via descending, modulatory pathways in the spinal cord. This is the so called “gate mechanism”.; the brain is able to control how wide or narrow the pain gate is.

One of the important ways in which pain perception is modified is known as central sensitisation. In this condition the pain circuits in the brain are fundamentally altered, usually in response to repeated, severe, poorly controlled pain experiences. Central sensitisation affects different people in different ways, but all have in common the fact that more pain is felt over longer periods of time. The pain may be experienced more intensely (hyperalgesia) or sensations which are not normally painful may be experienced as pain (allodynia); the area over which pain is felt may expand way beyond the damaged area or painful sensations may continue long after the initial cause of the pain has resolved.

Graph illustrating the concepts of hyperalgesia and allodynia

This graph illustrates the concepts of hyperalgesia and allodynia. In the normal course of events, as the intensity of the pain stimulus increases the pain experienced also increases (blue line). No surprise there!  However, repeated painful experiences, can result in central sensitisation which shifts the graph to the left (red line). The perception of pain is heightened at all levels of pain stimulus and non-painful sensations are now experienced as pain. 

Maybe as many as a one third of patients with sickle cell disease are said to have “chronic pain”; pain is experienced on a more or less continuous basis, with little if any pain free periods. It has always been difficult to understand this in terms of the simplistic notions of a painful crisis discussed above, but it is looking increasingly likely that the explanation lies in the concept of central sensitisation. When you think about it, patients with sickle cell disease are a high risk group for this complication of pain; they experience repeated episodes of severe pain throughout life and the pain is often poorly managed and ineffectively controlled. In a proportion of patients, this results in changes in pain wiring in the brain, which alters the disease from a condition characterised by intermittent episodes of pain, with long pain free intervals in-between, to one where the experience of pain is virtually continuous.

Some of the best evidence for this view comes from patients whose sickle cell has been “cured” by a successful bone marrow transplant, or where the disease activity has been effectively suppressed by regular automated exchange transfusions. In both circumstances, patients may, paradoxically, continue to experience severe pain, often requiring treatment with powerful, opiate pain killers, a situation which can persist for several years. Re-setting of the aberrant wiring in the brain, and neutralisation of the central sensitisation, eventually leads to a gradual cessation of these pain experiences.

The importance of central sensitisation, as a process which significantly adds to the misery of life for some people with sickle cell, has been highlighted in a study from John Hopkins Medical College, which is due to be published shortly in the Journal of Pain. The researchers studied 83 adult patients with sickle cell disease, testing their responses to a standard heat pain stimulus in a variety of different contexts. The subjects were then given a variety of psychological questionnaires to complete and kept a daily pain and sleep diary for the next 18 months.

From the results of the pain experiments the researchers identified two sub-groups; one, a group of 21 individuals, who scored high for central sensitisation markers and another, of 17 individuals, who had low scores. When the two groups were compared the patients with high scores for central sensitisation experienced more frequent crises and had more pain in-between crisis days, as a result they also had more contact with hospitals and doctors. Psychologically, they had an increased tendency to catastrophise, in other words they always assumed the worst was going to happen, and they had profound disturbances of sleep.

None of this may seem particularly surprising but, in terms of quality of life, it indicates that central sensitisation is a very damaging condition and demonstrates, importantly, that it is a major factor driving patients to seek repeated medical help. The authors make the point that addressing the underlying problem either by preventing the development of central sensitisation in the first place, by providing effective, rapid pain relief at all times, or diagnosing and treating the established condition, should be key therapeutic aims. Short circuiting central sensitisation would go a long way to improve the quality of life of a subset of sickle cell patients and potentially save the health service significant amounts of money. A win win situation!

An evaluation of central sensitization in patients with sickle cell disease. C C Campbell, G Moscou-Jackson, P Carroll, K Kiley, C Haywood, S Lanzkrom, M Hand, R R Edwards & J A Haythornthwaite. Journal of Pain (accepted for publication) DOI: 10.1016/j.pain.2016.01.475

For more on chronic pain see:

Cannabis, sickle cell and new concepts in chronic pain: 15th October 2015

Chronic pain conference: 14th and 17th December 2014

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Pomalidomide – more action on the foetal haemoglobin front

As many of you will know hydroxycarbamide is the only drug licensed for the treatment of sickle cell disease. It’s potential benefits in sickle cell were only discovered by accident, many years ago, when patients were being treated with the drug for something else entirely and were noted to have increased amounts of foetal haemoglobin (Hb F) in their blood. In a similar fashion, researchers in the US have just reported investigations into another drug, pomalidomide, which was also found to increase Hb F, when it was being used to treat a completely different disease, in this case, multiple myeloma, a form of blood cancer.

Large amounts of Hb F, whether occurring naturally or stimulated by taking hydroxycarbamide, inhibit sickling and greatly improve patients lives. Many drugs have the potential to increase Hb F , so why is pomalidomide any different? Well, importantly it is already being used to treat patients with multiple myeloma, so we know it can be given safely to people and its effect on Hb F production appears to be very dramatic.

The researchers in the US found that in human bone marrow cells, cultured in a test tube, and in mice, genetically engineered to have sickle cell disease, pomalidomide increased Hb F production x5-6 fold, raising Hb F levels from  a baseline of 5% to a maximum of 30%. In comparison, hydroxycarbamide only achieved a modest x2 increase in Hb F. In the mice with sickle cell disease, pomalidomide also reduced the production of sickle haemoglobin (Hb S) by 40%, a very significant decrease. So, pomalidomide reduces the synthesis of Hb S, the “bad guy” and replaces it with Hb F, the “good guy”.

Pomalidomide was found to work by significantly reducing, by up to 70%, the concentration of many of the chemicals, or transcription factors, which normally silence the gamma globin genes which make Hb F. These chemicals include the weirdly named SOX6, GATA1, KLF1 and LSD1 and, most importantly, the “master regulator” of gamma globin gene silencing, BCL11A. Removing these inhibitors allowed the gamma globin genes to start working again producing Hb F. In fact, pomalidomide appeared to re-programme the haemoglobin producing cells so that they behaved more like bone marrow cells from a newborn baby, when virtually all the haemoglobin produced is Hb F, rather than bone marrow cells from an adult.

These exciting results mean that pomalidomide can now be added to the growing list of drugs which increase the production of Hb F. It remains to be seen whether, when pomalidomide is used to treat patients with sickle cell disease, increased Hb F production is translated into reduced sickling and significant clinical improvement.

Pomalidomide reverses gamma-globin silencing through the transcriptional reprogramming of adult hematopoietic progenitors Brian M. Dulmovits, Abena O. Appiah-Kubi, Julien Papoin, John Hale, Mingzhu He, Yousef Al-Abed, Sebastien Didier, Michael Gould, Sehba Husain-Krautter, Sharon A. Singh, Kyle W. H. Chan, Adrianna Vlachos, Steven L. Allen,Naomi Taylor, Philippe Marambaud, Xiuli An, Patrick G. Gallagher, Narla Mohandas, Jeffrey M. Lipton, Johnson M. Liu and Lionel Blanc. Blood (2016), volume 127, pages 1481-1492

The foetal haemoglobin story just got more complicated – 12th March 2015

More on hydroxycarbamide – 7th January 2015

Homing in on BCL11A – 26th July 2014

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Automated red cell exchange transfusion – NICE gives the OK

NICE, the National Institute for Clinical Excellence, has just published guidance on the preferred way of undertaking exchange transfusions in sickle cell disease. These recommendations have major implications for all those living with sickle cell in the UK, and will no doubt have an impact on how services are organised, in order to ensure that all patients have access to the most advances treatments. An exchange blood transfusion is an important treatment option in sickle cell and has been in use for many years. It can be used in one off emergency situations but can also be repeated, on a regular basis, to manage some of the long term complications of sickle cell.

The aim of most blood transfusions is to raise the patient’s haemoglobin concentration rapidly because they have become dangerously anaemic. This is sometimes necessary in sickle cell and is then often referred to as a “top-up” transfusion. The purpose of an exchange transfusion however is different; the main requirement is to reduce the number of sickle red cells in the patient’s blood stream, rather than increase the haemoglobin level. The frequency and severity of sickle cell related events are directly related to the amount of sickle haemoglobin in the blood; reduce the number of sickle red cells and the risk of a sickle cell event will also drop in proportion. This is why an exchange transfusion can be potentially lifesaving in something like the acute chest syndrome, by stopping further sickling in the lungs, and also why regular exchange transfusions, repeated every 4-6 weeks, can protect against recurrent attacks of pain, strokes or priapism, prevent deterioration in conditions like pulmonary hypertension (high blood pressure in the lungs) and heal chronic leg ulcers. All good news, but there are some significant problems with exchange transfusions.

In the past “an exchange” was always done manually; blood was removed from the patient using a large cannula and syringe and then replaced with exactly the same volume of blood from a blood donor. This cycle was repeated over and over again until the sickle cell concentration (Hb S%) had fallen to the desired level. In someone with sickle cell anaemia (Hb SS disease), who has not been recently transfused, the Hb S level will be 100%, in other words all the red cells will be sickle red cells. During a manual exchange transfusion the aim was to reduce the Hb S level to about 20%; meaning that only 1/5th of the red cells would be sickle red cells and the rest would be normal, transfused red cells containing haemoglobin (Hb A). In practice, this was often difficult to achieve and would frequently take all day, an exhausting business for the patient and the doctor or nurse doing the exchange.

In addition, as with all blood transfusions there were always concerns about transfusion reactions and the risk of inadvertently immunising the patient against blood group antigens. Both of these risks of increased concern in an exchange because of the large volume of blood which had to be used, often 10 to 12 bags per exchange. When regular manual exchange transfusions were used to manage chronic complications over a period of months or years, there was the added worry of iron overload, or the build up of iron in the body derived from the transfused blood.

The importance of the NICE guidance is that it recommends moving away from manual exchange transfusions and instead making use of technology which can automate the whole process. The automated systems remove blood from the patient, centrifuge, or spin, it to separate red cells from plasma, then mix the patient’s own plasma with donor red cells in the correct proportion before finally returning the re-constituted blood to the patient.

The Spectra Optia automated red cell exchange machine in action

The Spectra Optia (manufactured by Terumo BCT) is the automated red cell apheresis system preferred by NICE.

The big advantage of an automated red cell exchange transfusion is that it is quick, taking at the most 2-3 hours rather than a whole day. It is also much more efficient and will routinely bring the Hb S level down to 10% or even less leaving, in other words, only 1 in 10 sickle red cells behind. Since the risk of a sickle cell related event is directly related to the proportion of sickle red cells, the very low levels achieved with an automated transfusion virtually banish sickling completely. In addition, if the patient is on a regular programme, it is only necessary to repeat the procedure every 8-12 weeks rather than every 4-6 weeks, because it takes the sickle red cells a long time to recover from such low levels. Another big plus. Finally, it looks as if the automated exchange is “iron neutral”. In other words the quantity of red cells removed, together with the iron they contain, exactly balances the quantity of red cells and iron returned to the patient, preventing any build up of iron and iron overload. Not only are there many advantages for the patient but NICE also estimates that, using an automated exchange for all sickle patients in the UK on a regular transfusion programme could save the NHS in England £13 million a year.

There are downsides, of course. The machine is expensive, about £45,000 and staff have to be specially trained in it’s use the and the trouble shooting any problems. Then there is the vexed issue of vascular access. A manual exchange uses just one venous line, usually placed in a large vein in the arm. Blood is alternately taken out and put in using the same line. The automated systems need two large, venous lines, one out and the other in, which in practice is often achieved by using a double-barrelled femoral line placed in the large, femoral vein in the groin. Needless to say femoral lines are not popular with patients and insertion requires highly skilled staff. Fortunately, these access problems have to a large extent been overcome as expertise has developed and nowadays many patients have repeated automated exchanges through arm veins, with the two cannulae placed under ultrasound guidance, greatly improving the “hit rate”.

Hopefully, the NICE guidance will prompt a move towards the more widespread use of automated exchange transfusion technology in sickle cell, opening the way for many more patients to benefit from this innovative treatment. NICE has also called for clinicians to work together to define how regular automated red cell exchange transfusions can benefit patients with different sorts of complications. So, expect to see a burst of research activity in the near future which will define the role of this intervention in sickle cell disease more precisely.

Read the guidance from NICE:

Curtis explains the problems:

For background information on blood transfusion:

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Screening for sickle cell – it’s not just about numbers

Two recent publications have looked at the frequency and distribution of sickle cell in two widely different countries, Uganda and Jamaica. At it’s simplest screening is just about numbers, how many individuals are there with sickle cell in a given population but, with the right resources and motivation, it is also about knowledge and empowerment for both governments and people.

The Uganda study was a joint investigation between Cincinnati Children’s Hospital in the USA and Makerere Hospital in Kampala. Another example of a successful collaboration between hospitals across the developed / developing world, which are becoming a distinct feature of sickle cell research. The investigators screened nearly 100,000 young children, aged between 2 to 12 months, from all over Uganda, allowing them to build up a “frequency map” for sickle cell covering the whole country.

They found that overall 13.3% of children had sickle cell trait, although the frequency varied widely across the country, with as few as 4.6% in the south-west to nearly 20% in the east-central areas.

Map showing the frequency of sickle cell trait across Uganda, with highest frequencies in the east-central regions. Pale blue - Lake Victoria to the bottom right and Lakes Albert and Edward along the western border.

Map showing the frequency of sickle cell trait across Uganda, with highest frequencies = darker colours in the east-central regions and lowest frequencies in the south-west. Pale blue = Lake Victoria in the bottom right and Lakes Albert and Edward along the western border.

The areas with the highest frequency were also those which had the greatest burden of malaria. Further evidence for the role of sickle cell trait in helping to protect young children against the most severe effects of malaria. The presence of malaria positively selects for the survival of children with sickle cell trait, so that, over time, the frequency of individuals with sickle cell trait gradually increases in those populations chronically exposed to malaria.

Frequency distribution of sickle cell trait (on left) and malaria (on right). Darker colours indicate areas with highest frequencies.

Frequency distribution of sickle cell trait (on left) and malaria (on right). Darker colours indicate areas with highest frequencies. The frequency of malaria and sickle cell trait almost exactly match each other.

For sickle cell disease, as opposed to sickle cell trait, the average frequency was 0.8%, varying between 0.5 and 1.5%. The latter figure is remarkable implying that 1 to 2 children in every 100 will have sickle cell disease in east-central Uganda. Interestingly, the frequency of sickle cell disease in all areas of the country was lower in the older age groups, confirming that young babies with sickle cell disease have a very high early mortality.

Using their data the investigators calculated that approximately 15,000 babies are born every year with sickle cell disease in Uganda, with the birth rate varying in different parts of the country. This is very basic information, but for governments attempting to develop policies to address the specific health needs of their population, it is absolutely essential.

Burden of sickle cell trait and disease in the Uganda Sickle Surveillance Study (US3): a cross-sectional study. Grace Ndeezi, Charles Kiyaga, Arielle G Hernandez, Deogratias Munube, Thad A Howard, Isaac Ssewanyana, Jesca Nsungwa, Sarah Kiguli, Christopher M Ndugwa, Russell E Ware, Jane R Aceng. Lancet Global Health (2016); volume 4, pages e195-200. S2214-109X(15)00288-0

Screening for sickle cell has a long history on the island of Jamaica. It was a screening programme of over 100,000 consecutive deliveries in Kingston, between 1973 and 1981, that identified the Jamaican Cohort, a group of children with sickle cell disease, who have been followed throughout their lives. Much has been learnt from the cohort about the natural history of sickle cell disease and about how to intervene effectively to keep people well and healthy.

The latest screening exercise was carried out in the Parish of Manchester and was a response to a demand from college students to be told their sickle cell type.


Manchester Parish is on the south coast of Jamaica between St Elizabeth and Clarendon. Main town Mandeville.

The investigators screened 16,636 students aged between 15 and 19 years over a 6 year period (2007-2013). The students gave informed consent, completed a short health questionnaire and then gave a blood sample. After the analysis of their blood was complete each student was given a laminated card specifying their haemoglobin type. Those with sickle cell trait, or any other haemoglobinopathy, were given appropriate counselling, information and support. The aim was to identify all those with sickle cell trait, haemoglobin C trait and beta thalassaemia trait, as well as any more unusual types of haemoglobin. At the end of the study the take up rate was 92%, a reflection of the motivation and enthusiasm of the students.

The frequency figures were broadly similar to the results of previous surveys. Sickle cell trait occurred in 9.6% of teenagers, Hb C trait in 3.5% and beta thalassaemia trait in 0.9%. The frequency of sickle cell disease was as predicted, with a birth rate for Hb SS disease of 1 in every 300 births and for Hb SC disease 1 in every 500 births.

More important than the figures however, was the fact that the study was driven by the demand of young people to know their sickle cell status and that the massive logistical problems of screening and counselling such large numbers were successfully overcome. The key question is one of empowerment; now that they have this information will this alter the young peoples choice of life partners, reducing the birth rate of babies with sickle cell disease? The investigators plan to start a long term screening programme of all births in the same locality to answer this question in the future.

It is often claimed that these sorts of screening programmes are too difficult and costly to undertake, the reason why they have never been implemented in areas of the USA and UK where there are many people with sickle cell trait. This study shows, on the contrary, that such programmes are feasible and, by providing the right information at the right time, allows individuals to make informed reproductive choices.

Haemoglobin variant screening in Jamaica: meeting student’s request. Karlene Mason, Felicea Gibson, Douglas Higgs, Chris Fisher, Swee L Thein, Barnaby Clark, Andreas Kulozik, Margit Happich, Beryl Serjeant and Graham Serjeant. British Journal of Haematology (2016); volume 172, pages 634-635.   doi:10.1111/bjh.13531

For a discussion by Professor Graham Serjeant about the background to the project see:

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The TWiTCH trial – a major improvement in the care of children at risk of stroke

The results of the long awaited TWiTCH trial have just been published in the Lancet.

What is TWiTCH? Well it stands for TCD With Transfusions Changing to Hydroxycarbamide, and it was a large, multi-centre clinical trial involving 26 paediatric sickle cell centres in the USA and Canada, co-ordinated by Professor Russell Ware from the Children’s Hospital in Cincinnati. The trial was designed to find out whether hydroxycarbamide could be used instead of blood transfusions to prevent strokes in high risk children with sickle cell disease.

Background: Stroke is a common and devastating complication affecting children with sickle cell anaemia. Without treatment stroke will affect between 10% to 13% of all children, usually before the age of 10 years. Children at high risk of a stroke can be identified by transcranial doppler (TCD); high TCD measurements identify a sub-population of high risk children who have a 40% risk of stroke over the next 3 years.

Transcranial doppler measurements are simple and pain free. The ultrasound probe is applied to the side of the head and records the rate of blood flow in the large arteries supplying the brain. The faster the rate of flow, the narrower the artery and the greater the risk of stroke.

Transcranial doppler is simple and pain free. The ultrasound probe is applied to the side of the head and records the rate of blood flow in the large arteries supplying the brain. The faster the rate of flow, the narrower the artery and the greater the risk of stroke.

The relatvley thin bone over the temporal region allows the ultrasound probe to assess blood flow in the large arteries at the base of the brain.

The relatively thin bone over the temporal region allows the ultrasound probe to assess blood flow in the large arteries at the base of the brain. This is a picture looking down at the base of the skull; the large oval, black hole is where the spinal cord leaves the brain, the eye sockets are at the top and the blood vessels are coloured in red.

It was the STOP trial in 1998 which first showed that if high risk children are put on a regular programme of blood transfusions to maintain their sickle cell level (Hb S) at less than 30% then their risk of a stroke is reduced by a massive 90%. As a result of this trial all children with sickle cell anaemia are now screened regularly by TCD and those at high risk (blood flow velocities >200cm/sec) are offered a regular transfusion programme. The same investigators followed this up with the STOP 2 trial (2005) which asked the question “Is it safe to stop regular blood transfusions after a minimum of 30 months treatment?” Unfortunately, they found that the answer was no. If transfusions were stopped then blood flow velocities began to increase again and with that so did the risk of a stroke.

The conclusion from the two STOP trials was that regular transfusions successfully protected high risk children from a stroke, but once they had been started they needed to continue indefinitely. This is an enormous burden for children and their families to live with and repeated blood transfusions also carry the risk of serious complications such as iron overload, viral transmission and allo-immunisation.

The Bottom Line: What has proved to be so important about the TWiTCH trial was that the investigators were able to show that after 12 months you can safely switch a child from regular transfusions to taking hydroxycarbamide instead. Hydroxycarbamide maintains blood flow velocities at low, stable levels, there is no increase in the risk of stroke and it also avoids the monthly admissions to hospital for a blood transfusion with all the problems that involves.

What They Did: The TWiTCH trial was a classic clinical trial. The investigators identified 121 children aged 4-16 years at high risk of stroke (TCD >200cm/sec) who were already on a regular transfusion programme. 61 children continued on standard, monthly blood transfusion treatment, which maintained their Hb S at <30%, either by simple top-up transfusions or by manual or automated exchange transfusions. The other 60 patients were changed to hydroxycarbamide, initially at a dose of 20mg/kg/day, which was gradually increased, over a period of about 6 months to an individualised maximum tolerated dose. Over the same time period blood transfusions were gradually weaned off and eventually stopped. Each patient was then followed up for 2 years.

What They Found: At the end of the study period the two groups were remarkably similar. TCD’s remained low and were about the same in each group; 143cm/sec in the transfused children and 138cm/sec in the hydroxycarbamide children. No strokes occurred in either group; 6 children did have “mini-strokes” (transient ischaemic attacks or TIA’s), but they were equally divided, with 3 in each treatment group. The children taking hydroxycarbamide did have more episodes of vaso-occlusive pain but apart from that there was no difference in side effects or adverse events in each treatment arm. The TWiTCH trial therefore provides convincing evidence that high risk children with sickle cell can be safely changed from regular monthly transfusions to daily medication with hydroxycarbamide and still keep their low risk of stroke.

An accompanying editorial in the Lancet also makes clear, that the trial opens up important treatment options for children in the developing world. About 90% of the 300,000 children born each year with sickle cell live in sub-Saharan Africa. Treatment with regular blood transfusions, even for one year, is simply not an option for the vast majority of these children because of the cost and safety concerns around the transmission of viral infections by contaminated blood. Hydroxycarbamide, on the other hand, is cheap and requires relatively little laboratory monitoring. A clinical trail is currently underway in Nigeria comparing fixed low dose (10mg/kg/day) and fixed high dose (20mg/kg/day) hydroxycarbamide started as soon as a high risk child is identified by TCD. This trial will hopefully determine whether immediate treatment with hydroxycarbamide can remove the need for an initial period of blood transfusion and whether a more simple, fixed dosing regime is effective.

A word of Warning: We know that patients can find it very difficult to take tablets on a regular daily basis. It is clear from the data in the paper that the children in the hydroxycarbamide treatment arm were very good at taking their hydroxycarbamide and were no doubt encouraged to do so by the trial investigators;. Their MCV (mean cell volume – the size of their red blood cells) increased from 86fl to 107fl and their Hb F (foetal haemoglobin) went up from 8.8% to a very impressive 24.4%. Clearly for the hydroxycarbamide to work it has to be taken regularly every day and it will be interesting to see whether these excellent results in the environment of a clinical trial can be replicated in the real world.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia- TCD With Transfusions Changing to Hydroxycarbamide (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Russell E Ware and 44 others. The Lancet, 2016, volume 387, pages 661-670

For more information about strokes and silent cerebral infarcts in sickle cell you might like to have a look at another blog – “Stroke in children with sickle cell disease” published on 09/01/2015. Other relevant blogs include: “More on hydroxycarbamide” – posted on 07/01/2015 and “Blood transfusion” – posted on 19/06/2015.



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Red cell dehydration

We generally understand the term “dehydration” to mean that our body is short of water. It is a potentially dangerous condition, particularly in sickle cell, and normally the amount of water in the body is very carefully controlled and regulated.  The body’s natural fluid balance is determined by how much fluid you drink and how much fluid you lose, mainly through passing urine and sweating. If you are becoming dehydrated you will feel thirsty, prompting you to drink more, and your kidneys will reduce the amount of urine they produce, helping to conserve the body’s water stocks.

Just as the whole body can become dehydrated it is possible for different compartments in the body to become dehydrated at different times. One of those “compartments” are the red cells circulating in the blood, and what happens to them is of especial interest in sickle cell. The reason for this is because the rate at which sickle haemoglobin “sickles”, causing the red cell to change shape, is exquisitely dependent on the concentration of sickle haemoglobin inside the red cell. If the red cells become dehydrated, the concentration of sickle haemoglobin increases and as a result the rate of sickling increases dramatically. Sickled red cells and “dense cells”, which are those red cells permanently damaged by repeated sickling, are the cause of all the problems in sickle cell disease. Prevent sickling and the symptoms of sickle cell should be greatly reduced.

This is a blood film from someone with sickle cell anaemia. The "sickled" red cells are easy to spot - they are the darkly staining, bent, curved ones. Less easy to identify are the "dense" red cells - they are round, smaller than other red cells and again more darkly staining.

This is a blood film from someone with sickle cell anaemia. The “sickled” red cells are easy to spot – they are the darkly staining, bent, curved ones. Less easy to identify are the “dense” red cells – they are round, smaller than the other red cells and again are more darkly staining without a pale central area.

Making sure that red cells stay well hydrated should therefore be an effective way of reducing the amount of sickling which occurs. It turns out that the amount of water inside red cells is just as carefully controlled and regulated as the amount of water in the body as a whole. The red cells absorb the water they need from the bloodstream, but there are also three pathways or routes by which water and salts can be lost from the red cells. If it was possible to block or inhibit these pathways, then the hope is that water would be retained inside the red cells, keeping them maximally hydrated at all times, and minimising the symptoms of sickle cell. To this end many drugs which affect these pathways have been tried out in patients with sickle cell disease.

The three pathways by which water is lost from red cells are called: the P-sickle Pathway, the Gardos Channel  and the K-Cl Co-transport Pathway. 

The P-sickle pathway seems to be activated by the process of sickling itself and there was some hope that this pathway may be blocked by a drug called dipyridamole, which is already used in patients who have had a stroke or heart attack. Unfortunately, further investigation did not show any benefit from taking this drug.

The Gardos Channel is activated by calcium resulting in the loss of potassium and water from the red cell. In the test tube the pathway can be blocked by a group of drugs, which are also used to treat fungal infections. They include, clotrimazole and senicapoc. Despite initial high hopes neither of these have proven to be beneficial when tried out on patients.

The K-Cl Co-transporter pathway results in the loss of potassium (K) and chloride (Cl) from red cells together with water. It is the main pathway determining the hydration status of the red cell and so would be the most important one to try and block. It is inhibited by magnesium, which led doctors to test whether magnesium pidolate, given to patients might limit symptoms, but again the trials proved very disappointing.

Over the years many other drugs, whose mechanism of action is less well understood, have been tried to see whether they had any beneficial effects on red cell hydration and sickle cell symptoms. They include; piracetam, zinc sulphate, sodium chromoglycate and diltiazem. None of these have stood the test of time after testing in patients.

We are left then with a situation where we know that blocking water loss and maintaining red cell hydration is a potential way we can interfere with the sickling process, but none of the drugs yet tried have proved to be effective. Rather than wasting time and money continuing to test large numbers of different drugs, it would perhaps be more effective to try and understand how these pathways work in more detail. Then, in time, it might be possible to be more selective about the drugs used or indeed attempt to develop new drugs designed specifically to interfere with these pathways. This is precisely what a team of Australian investigators, led by Dr Fiona Brown from Monash University in Melbourne have done. They used a strain of mice, which had been genetically engineered to have sickle cell disease, to dissect the workings of the K-Cl co-transporter pathway.

They found that the K-Cl co-transporter pathway is controlled by four genes, called KCC1 to KCC4. In sickle cell disease mice the activity of the co-transporter is set at a higher level than normal actually potentiating the risk of red cell dehydration. The investigators identified a mutation in one of the genes, KCC1, which resulted in increased activity of the co-transporter. When this mutation was bred into the strain of mice with sickle cell disease the presence of the mutation resulted in a much more severe type of sickle cell, many of the affected mice having serious complications and dying at a very young age.

Dr Brown and her team clearly established that the K-Cl co-transporter was  a very important determinant of sickle cell severity. Increased activity of the pathway resulted in a significant worsening of the disease, so presumably reducing the activity of the pathway should result in a similar improvement in symptoms. What is more, the identification of the four genes controlling the co-transporter opens up a whole new area for targeted drug therapy. Variation in the activity of the co-transporter, as a result of additional genetic influences, may help to explain some of the great variability in the severity of sickle cell disease seen between different patients.

Activation of the erythroid K-Cl cotransporter Kcc1 enhances sickle cell disease pathology in a humanized mouse model. Fiona C. Brown, Ashlee J. Conway, Loretta Cerruti, Janelle E. Collinge, Catriona McLean, James S. Wiley, Ben T. Kile, Stephen M. Jane and David J. Curtis. Blood, December 2015, volume 126, pages 2863-70

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Reassurance about the effects of exercise

We all know that regular exercise is “good for us” and the many health benefits of exercise were discussed in a previous blog on the 5th March 2015 – “More on the Benefits of Exercise”. There are certainly grounds to think that people with sickle cell stand to gain in many important ways from regular exercise, but there have always been those, doctors and patients, who took the view that exercising is too risky when you have sickle cell. Exercise might provoke a crisis or the acute chest syndrome, for example, and there are some theoretical grounds to support this point of view.

In many ways sickle cell can be thought of as an inflammatory condition.  Various chemicals, which can be measured in the blood and which are associated with the inflammatory response, are increased in concentration even in well patients with sickle cell disease. The levels of these chemicals increase further when patients become ill with a crisis. These blood markers include a wide range of different chemicals, some of whose names you may recognise from tests done when you go to hospital. They include: CRP (C-reactive protein), IL-6 (interleukin 6), TNF (tumour necrosis factor), fibrinogen, fibrin d-dimers and sVCAM (soluble vascular cell adhesion molecule) to name but a few. The WBC (white blood cell count) and platelet count are also generally raised in patients with sickle cell and behave in the same way as the other inflammatory markers, increasing further during a crisis.

Interestingly, these same markers are also increased in the blood of anyone who exercises. The less fit someone is the higher the baseline level of these so-called inflammatory markers and the more they go up during exercise. Regular aerobic training, when you get out of breath by running or cycling for example, results in an improvement in these markers and this may be the way that exercise helps to protect us against heart disease.

So, the argument goes, if these same chemicals are already increased in the blood of people with sickle cell, exercise will increase them further and so tend to exacerbate any ongoing inflammatory process such as a crisis, making the pain worse and causing the crisis to last for longer. If this were indeed true, it would mean that patients with sickle cell should be advised to avoid any strenuous physical activity and they would thereby be denied the all the health benefits of regular exercise.

A group of doctors from the Children’s Hospital in Chicago have tested this theory out on 60 young patients with sickle cell anaemia (average age of 15.1 years) and compared them with 30 young people without sickle cell. All of the subjects, normal and sickle cell, were maximally exercised on a static bicycle until they were too exhausted to continue and regular blood samples were collected during and after the exercise period. These test periods of maximal exertion lasted from 5-8 minutes at a time.

As you might expect, the sickle cell patients could not exercise at the same intensity or for the same length of time as the control subjects, however, they all managed to complete this fairly intense exercise regime without developing any sickle cell related complications. The baseline levels of all the inflammatory markers were raised in the sickle cell patients, even before they exercised  and, just as in people without sickle cell, the levels of the inflammatory markers rose higher during the exercise period, Subsequently, after stopping exercise, they dropped back to baseline levels again during the recovery period. What was interesting was that the the size of the increase in the concentration of the markers, as well as the time they took to return to baseline values, were very similar in both the sickle cell patients and the normal, control subjects.

These results are reassuring; although baseline inflammatory markers are raised in people with sickle cell the pattern of change seen during and after maximal exercise is very comparable in both patients and control subjects. Provided that you follow simple rules – keep warm and well hydrated, before, during and after exercise and build up exercise levels gradually – it is safe for young people with sickle cell to exercise as hard as they can. Certainly, running around the playground at school, playing football or basketball or going to the gym is something that all sickle cell patients should be able to enjoy. On the basis of this study there is no reason why patients with sickle cell should be denied the important and well described benefits of regular exercise.

The acute phase inflammatory response to maximal exercise testing in children and young adults with sickle cell anaemia. Liem RI, Onyejekwe K, Olszewski M, Nchekwube C, Zaldivar FP, Radom-Aizik S, Rodeghier MJ and Thompson AA. British Journal of Haematology, 2015, volume 171, pages 854-861

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