Health inequalities: a call to action

The prompt for this blog was a couple of recent discussions I have been part of relating to upcoming red cell projects in the HaemSTAR project pipeline. They made me think about the NHSBT Blood and Transplant (NHSBT) Research and Development conference I attended in Birmingham last year, where health inequalities was high on the agenda; in fact, the overarching conference theme was ‘through the lens of health inequalities’.

As I found out from the conference sessions, and from The King’s Fund webpages we were directed to, health inequalities can be defined as avoidable, unfair and systematic differences in health between different groups of people. We can think about inequalities in terms of differences in people’s health status like life expectancy, access to healthcare, quality and experience of care, behavioural risks to health (eg. smoking, alcohol) and wider determinants of health such as housing. Differences are often considered by grouping people in terms of socio-economic factors, geographical factors, specific characteristics including protected characteristics, and socially excluded groups. A striking and often quoted example is, of people living in England, those in the most deprived areas have a life expectancy of 10 years shorter than those in the least deprived areas. This extends to an 18 year gap when considering healthy life expectancy.

A particular highlight of the NHSBT conference for me, was the plenary talk by Professor Bola Owolabi, Director of the National Healthcare Inequalities Improvement Programme at NHS England. She called for the need to move from simply describing the problem of health inequalities, to enacting change - a call to action. She explained how things need to be done at a national level and outlined NHS England’s frameworks for tackling health inequalities (the Core20PLUS5 for adults and Core20PLUS5 for children and young people), but also that change can be driven by individuals or groups at a local level. Examples would be setting up a warm space or a peer-support network, and I have subsequently found a useful toolkit for individuals on the British Medical Association website.

Professor Owolabi went on to emphasise the need for an equity drive in research. Without the right questions and patient representation we are limiting the generalisablity of our findings and ability to target interventions for improved future health equity. Things that can be done, she suggested, include having a wider geographical spread of research and development activity, thinking carefully about study exclusion criteria, and making research more accessible and inclusive for all in terms of clinical trial participation. As a start we can think about costs involved in participation, language and cultural barriers.

We have been thinking about how we incorporate this into our red cell projects and we have decided seeking some early patient involvement will help us to improve our plans. Watch this space for more information on getting involved with these projects later in the year and check out the links above for more information on health inequalities.

Reflections from the Main Stage - ASH 2023

The ISTH Legacy fund gave me the opportunity to attend the 65th ASH symposium in San Diego.  On Friday the 8th of December, around the time I was getting over jetlag at the ASH-a-palooza trainee event, the first ever commercial CRISPR Cas 9 genetic therapies were given approval by the FDA for use in Sickle cell disease.  CRISPR has revolutionised basic science research over the last decade and this approval may well represent a watershed moment that accelerates genetic therapy into mainstream practice.  There are two important points about the approval. Firstly, the FDA approved two therapies using the same technology for the same patient group simultaneously. Second, these therapies cost $2.2 and $3 million dollars, respectively.

Fast-forward to Monday afternoon at ASH and these two therapies are being presented in a single oral abstract session.  Given the excitement around the approval, this session commanded much fanfare.  There are around 25000 attendees at ASH and, to quote one of the presenters at another session, a popular abstract might make you feel a bit like Taylor Swift.

The data presented was remarkable with resolution of VOC for the vast majority of patients undergoing therapy, an absence of insertional mutagenesis, and overall very good tolerance of the conditioning.  Seeing these results for a disease that really has seen very little progress is amazing, even in its infancy with small numbers of patients.  As the floor was opened to questions, one of the moderators pointed out the elephant in the room, cost.

This was addressed head on by the presenter, “these patients are worth a whole lot more than 3 million dollars”.  In a slightly heated back and forth, there was a discussion of the potential for cure, the inevitable competition between these two newly approved therapies and comparison other options such as haploidentical transplant.  Classical haematology is now facing the similar questions to those posed in the high-cost world of oncology for several years - What is a therapy worth and what can we afford?

By comparison to our constant wrangling with NICE, in the US, decisions to pay are made by individual insurers.  There is, however, a key difference in sickle cell patients, this patient population is largely not commercially insured, relying upon state based healthcare instead. Medicaid accounts for only 20% of all US healthcare spending and with 100000 patients living with sickle disease in the US, the bill could quickly run into tens of billions.   Clearly the pharmaco-economics have been done by those far cleverer than me, it is estimated that the lifetime healthcare costs of sickle cell disease in the US are $5million, not taking into account several million of lost economic costs.  So the argument goes, we spend less money on this than we would over a patient’s life.  This disease, however, sits at the junction of social deprivation, race and disease.  There is a litany of things that investment would improve for these patients and their communities. Is $3million for gene therapy that is not definitively curative, with the risks of myeloablation, the best way to improve the lives of these patients? 

Since returning from ASH I have been asked by patients and their relatives about when these therapies will be available here.  Seeing the desperation in the patients and parents faces during another admission interrupting yet another university term or workday, I do not want to be the one to put a price on hope.  Behind the scenes negotiations may lead to NICE approval with the UK paying a substantially reduced cost.  The questions of value and alternatives, that I heard in the hall at ASH, however, will still be ringing in my ears.

It really is the biggest stage in haematology and I want to thank the ISTH and HaemSTAR once again for the opportunity.

65th ASH Annual meeting - San Diego

Through the ISTH legacy fund, I was given the opportunity to fund my attendance at the 65th ASH Annual meeting, held in San Diego.  

As my first ASH conference, the experience did not disappoint. The day before the conference officially started, I attended the TMA Workshop, hosted by the USTMA and UK TTP Registry. It turned out to be one of my favourite events where I felt the semi-informal atmosphere was key to encouraging lively discussion between world experts in TMAs and without falling into cliches, watching them debate the nuances of diseases that I hadn’t appreciated previously was inspirational. It was also enlightening to learn about the contribution of organisational barriers or health policy to the differences in clinical practice. There were also case presentations by US and UK trainees & newly qualified consultants; and this was a great opportunity to meet others with a similar level of experience with whom I shared common interests.  

Another highlight of the conference was attending the Ham-Wasserman lecture, where the speaker is an individual from outside of the US, who has made a major contribution to the understanding of an area of haematology. The lecture was presented by Professor Andreas Greinacher on thrombotic diseases caused by platelet-activating IgG antibodies against PF4. Professor Greinacher wove a compelling narrative, incorporating both basic science and clinical cases, beginning with the familiar heparin-induced thrombocytopenia (HIT) before moving onto the much-publicised vaccine-induced immune thrombotic thrombocytopenia (VITT) and finally, highlighting the existence of VITT-like disorders identified in patients with severe acute thrombosis and thrombocytopenia, without prior heparin or vaccine exposure, but associated with infection in many cases. His lecture just preceded the timely update of the BSH guideline on the diagnosis and management of HIT at the end of December. 

The scale of ASH is immense: although, I initially had harboured some reservations that there would be sufficient non-malignant sessions across all days of the conference, I was mistaken as every day there were multiple sessions covering the gamut of non-malignant haematology and occasionally, I had to choose between sessions. I also had the excellent (yet nerve-wracking!) opportunity to present at the Thrombotic Microangiopathies oral session and to discuss my findings with others after the session.  

Apart from the clinical and science sessions, there were also sessions aimed at career development for trainees by subspecialty and despite admittedly having a US bent to them, they still provided general advice that was helpful and were also an interesting insight to their training pathway. In addition, there were a number of networking events that one could attend; one for Women in Haematology and one for the Haemostasis and Thrombosis Community in particular caught my eye.  

Overall, you are spoilt for choice at ASH, and I could not attend everything that I was interested in! I had an incredible time there and I would highly recommend that all haematology trainees should experience it at least once so I’m very grateful to HaemSTAR for supporting my trip. 

HaemSTAR Chair's New Year Message

Writes Richard Buka, HaemSTAR Chair

It’s been a whirlwind six months since taking over as Chair from Pip Nicolson. Leading a fluid, dynamic organisation like HaemSTAR is both a challenge and an opportunity and I’m really looking forward to 2024 and beyond.

In 2023, we added some great talent to our committee, including Olga Tsiamita, Stephen Hibbs, and Lottie Hickman. These additions make a real difference and each committee member is now driving important projects.

ISTH Legacy Funds

My highlight of 2023 has to be the awarding of nearly £30,000 from the ISTH London 2022 Legacy Fund. We’re putting this to great use with £20,000 allocated to travel grants and £10,000 for funding a HaemSTAR fellowship in collaboration with the Nigerian Society for Haematology and Blood Transfusion (NSHBT). This project is driven by Stephen Hibbs, with help from Imelda Bates, and we will be appointing two Nigerian haematology trainees as fellows in the first part of 2024 with the intention of facilitating research projects in Nigeria. We’ve also been able to invite Omalade Awodu, President of NSHBT to BSH to speak in the UK-TReN – HaemSTAR session.

Education

We’ve also introduced some educational offerings and have now hosted three webinars in collaboration with the limbic. So far, over 250 people have attended the webinars and in 2024 we will welcome talks from Suthesh Sivapalaratnam (Friday 19th January, 0830), Bernard Lämmle, Tom Bullock, Simon Stanworth and more to be confirmed. Previous talks are available on demand. Pip and I have also been recording a podcast focusing on advancements and critical appraisal in non-malignant haematology with the first episode to launch on 8th January.

Projects

Despite all these exciting projects, research and audit are our raison d’être, and we have ploughed ahead with several. The highest profile has been RAPIDO, a national audit of reversal agents for DOAC-associated bleeding. The project has over 300 collaborators entering data and has collected data on around 2,500 patient episodes including about 300 where andexanet alfa was given. Data collection closes on 5th January. We will spend a few months analysing the data and writing up with the intention of submitting an abstract to ASH 2024 with a manuscript to be submitted by the end of the summer.

Upcoming projects

I’m particularly excited about the projects coming down the pipeline. Lorna Cain, Christina Crossette-Thambiah, and Stephen Hibbs have been leading a haemoglobinopathy group that is working on, among others, a project looking at the problem of vascular access in sickle cell disease. Eman Hassan has been working on the use of tranexamic acid in anticoagulant-associated heavy menstrual bleeding, with a clinician survey recently completed and gathering 102 responses. Giulia Simini, Sajida Kazi, and Gill Swallow have been developing a project to look at the management of maternal pulmonary embolism including the use of thrombolysis and catheter-directed thrombolysis. This will start with a survey of centres to assess access to catheter-directed thrombolysis, and we will collaborate internationally with groups in Italy and the USA. This survey will come out in January 2024. Olga Tsiamita and Nick Fordham are working on an audit of neonatal thrombocytopaenia management with a data collection form now completed and ready to launch. Phil Weir and Marquita Camilleri are planning a project to look at the use of apixaban in thromboprophylaxis in myeloma. Again, this is in the later stages of planning and the team are looking for funding. Finally, we will be supporting Rupen Hargreaves with his exciting project investigating the occurrence and type of thrombosis in MPN.

Careful management of the HaemSTAR resource

I’m acutely aware that HaemSTAR collaborators are a finite resource. We cannot simply stack-up project after project, expecting people to contribute. This is why we are carefully optimising our workflow and crafting a package of projects that will appeal to different people. That said, we will always look to support creative, enthusiastic clinicians (juniors and consultants) to develop and deliver their projects. However, we are dedicated to ensuring fair recognition for each and every person who contributes to a project with a commitment to collaborative authorship.

HaemSTAR Annual Meeting – 5th February 2024

2024 is going to be a huge year for HaemSTAR and I am grateful for all your enduring support. If you are able to, please come to the HaemSTAR Annual Meeting in Birmingham on Monday 5th February 2024. Attendance is free and importantly, the meeting is tagged onto the ASH/ISTH non-malignant headlines meeting on the following day at the same venue. Whilst most delegates have to pay for this, non-consultant clinicians attending the HaemSTAR day can attend this for free by emailing sophie@hartleytaylor.co.uk once you have signed up for our day.

Blood sucking demon foetuses: women's health, evolution, and iron deficiency

Writes Dr Richard Buka,

Dr Angela Weyand is a plenary speaker for the HaemSTAR annual meeting - Feb 2024

Women’s health is going to form the focus of much of what HaemSTAR do in the coming years. For our HaemSTAR Update Day in Birmingham on 5th February 2024, we’re going to be welcoming Dr Angela Weyand as a plenary speaker - her work is discussed below.

We’re also doing some exciting projects. The first centres on the idea of giving tranexamic acid to women who are starting anticoagulation for VTE with the idea of reducing menstrual blood loss, and improving quality of life. We’re starting this with a survey.

The second project is called MaTrOn. The Maternal Audit on ThRombolysis Outcome and DecisioN will look at the use of thrombolysis for pregnant women with venous thromboembolism. Again, this will start with a survey and then we will be gathering retrospective observational data on a national scale.

Anyway, on with the blog.

Eve: How 200 years of evolution shaped the female body. Cat Bohannon

This month, I’ve been listening to a brand new audiobook that gives a unique take on human evolution. Cat Bohannon’s ‘Eve, How The Female Body Drove 200 Million Years of Human Evolution’, is a fascinating exploration of mammalian development that puts women at its centre.

It’s full of those “Oh wow!” moments and really changes your perspective. It begins with explaining how medical research is dominated by experimentation on males - male rodents are used as controlling for menstrual cycles is difficult, and makes science more expensive. She goes on to talk about the evolution of milk - did you know that egg laying mammals like the platypus don’t have nipples, with milk instead just sort of oozing from the torso. Nipples make feeding a lot more efficient.

Perhaps the most powerful idea is pinning the success of hominin species on the practice of gynaecology. She includes a whole range of practices under the gynaecology umbrella - from peer-assisted birth, to how primates seek out plants to consume that reduce fertility or induce miscarriage.

The high prevalence of iron deficiency

A renewed focus on women’s health that transcends medicine is long overdue and this is certainly true in haematology. Take iron and anaemia for example, women and girls are much more likely to suffer iron deficiency, which is poorly treated and impacts quality of life. Writing in JAMA earlier this year, Angela Weyand and colleagues found the overall prevalence of iron deficiency (ferritin <25 ng/mL) in American women and girls from age 12 to 21, was 39% and, 17% (ferritin <15 ng/mL) and 78% (ferritin <50 ng/mL. The overall prevalence of iron deficiency anaemia was 6.3% (Hb <12g/L). Iron deficiency, even without anaemia, can cause symptoms including tiredness and poor quality of life.

This got me thinking. What’s the evolutionary perspective on this? Has nature selected for iron deficiency - is this such a difficult problem to tackle?

Tonsillitis

My wife recently had a bout of tonsillitis. It left her in bed for three days with fever and horrible pain. Curiously, she’s not supposed to have any tonsils as they were removed when she was a kid. Nevertheless, when she was seen by the emergency out of hours service, strep throat was diagnosed and she was given some antibiotics. I’ve no doubt that these were necessary, and she quickly recovered.

This came out of the blue and I started thinking about how this came about. We had spent the preceding Sunday at a kids’ party in a soft-play – well known melting pots of disease. She’s otherwise a healthy 30-something, just a touch iron deficient probably because a) she’s a woman, and b) she’s had two children in the last three years and is breastfeeding the youngest. She started taking oral iron supplements again a couple of weeks before this came on.

Rates of iron deficiency around the world can be even higher than in the JAMA paper. Globally, anaemia affects 30% of women, and 40% of children rising to 60% in Africa. The vast majority of this is caused by iron deficiency. If you’re interested, there are loads of statistics on the WHO website.

Is this all nutritional? This is certainly a major causative factor. But even so, humans have evolved to thrive with scarcity of resources. It doesn’t make sense that iron deficiency should be so common unless it exerts a survival advantage in certain conditions.

Evolution and menstruation

We have evolved curious traits that, if we just think of iron deficiency as being bad, make no sense. For example, the volume of blood lost in menstruation varies widely among different species. Humans lose a lot of blood- an average about 80 ml.

This is really rare in mammals - only a handful lose this amount of blood. Most mammals simply reabsorb the material. There are a few possible explanations for this trait.

One, which has been discredited, is that this is a mechanism of cleansing the reproductive tract but there’s no evidence that more pathogens are present before or after menstruation. Another crap theory is that women synchronise periods so that all the men can get busy doing “other stuff” for that week.

“Bloodsucking demon foetuses”

In Eve, Cat Bohannon suggests that periods are a survival mechanism. Pregnancy is a stalemate between the foetus trying to hoover up as much nutrition as possible against the uterus trying to protect the mother. Building up the endometrium prior to a fertilised egg being known about is rare but evolved three times - in higher primates, elephant shrew, and some bats. The book states that “human women menstruate because it’s part of how we survive our bloodsucking demon foetuses.” By building up the endometrium prior to an egg being fertilised means that uterine defences can be dug early.

A further theory, not discussed in Eve is to do with a possible evolutionary benefit for iron deficiency. Excessive menstrual blood loss could be an adaptation to enable iron loss and maintain a state of iron deficiency, thus protection against infection.

Being able to better survive infection is often a strong driver of evolution. Many bacteria thrive on iron and the body can respond by reducing available iron which, in extended infections or inflammatory diseases leads to anaemia (anaemia of inflammation). This theory is discussed in detail in an intriguing review: Nutritional iron deficiency: an evolutionary perspective.

A good example of this is the link between intravenous iron and infection. A recent analysis showed that the number needed to treat for IV iron to lead to a 2 g/L rise in haemoglobin is 5 and to prevent transfusion was 36. Conversely, the number needed to harm – to cause infection was 62.

Plague

The drug desferrioxamine which is used as an iron chelator in people with iron overload comes from the bacterium streptomyces pilosus. The bacterium uses it to hoover up iron in its vicinity. A well known side effect of desferrioxamine treatment is sepsis caused by Yersinia enterocolitica. If you’re thinking that this infection sounds familiar, it should be - Yersinia enterocolitica is related to Yersinia pestis – the plague bacterium (and Alexandre Yersin is my favourite scientist of all time).

Yersinia enterocolitica can’t produce its own siderophore, molecules that help bacteria sequester iron. In the gut, it is able to use other bacteria’s siderophores and can cause enterocolitis. It rarely causes septicaemia except in the case of people taking desferrioxamine – as it can take-up iron bound to this in the blood stream.

A reminder of the close link between iron regulation and immunity is the HFE gene. This gene codes for a protein that influences iron absorption by modulating the expression of hepcidin. It is located on chromosome 6, close to the major histocompatibility complex (MHC) genes. Mutations in this gene cause haemochromatosis when inherited in a homozygous manner but the benefit to being a heterozygote is unclear. One might imagine that it would provide some advantage by boosting iron levels and therefore protecting against anaemia, especially in populations where dietary iron was scarce. Although this is a compelling argument, there is not much actual evidence for this; C282Y heterozygotes don’t have improved iron absorption. Another possibility is that the mutation may have in fact offered some protection against diseases including malaria through a variety of mechanisms.

Conclusion

Away from my digression into plague and haemochromatosis, I’ll come back to the main point of this piece: women’s health. We just have to accept that the way that women and girls experience and perceive the world is different to that of males. This is especially pertinent in healthcare where the experience of illness and pain is poorly studied in women. All of this needs to be viewed in the context of sexism and misogyny, both for patients and those of us that work in healthcare systems. The more we become aware of how important gender is on the way that we perceive the world, the more we can understand it, empathise, and improve lives for the better.

If you want to read more from Rich, follow his blog, Classical Compass or check out his podcast, ‘Don’t Just Read the Guidelines’ on all major platforms.

Rapido and the art of remaining vigilant

According to the Medicines and Healthcare products Regulatory Agency (MHRA) pharmacovigilance is summarised in three main steps: monitoring the use of medicines in everyday practice to identify previously unrecognised adverse effects, re-assessing the risks and benefits of medicines and information sharing with healthcare professionals and patients to improve safety.

Despite the existing regulatory scrutiny before a drug receives its marketing authorisation for a specific indication, history has shown that both healthcare professionals and patients should remain vigilant and report (yellow card scheme) any suspected adverse reactions as our way of contributing to the establishment of pharmacovigilance.

But what does that really mean and what is the relevance with DOAC reversal agents and the ongoing RAPIDO audit?

The clinical evidence for the NICE approval of andexanet alfa (for major GI haemorrhage only), came from ANNEXA-4, a single-arm trial of andexanet alfa in people taking a direct factor Xa inhibitor who had an acute major bleed. The two primary outcomes in the trial were not clinical outcomes - they were 1) the change in anti-factor Xa activity and 2) haemostatic efficacy, a measure of whether bleeding had stopped which has complex definitions depending on the site of bleeding. Of course, NICE must make judgements on the cost-efficacy of new therapies and for this need data pertaining to clinical outcomes particularly survival. A propensity-matched comparison of outcomes between patients treated with andexanet alfa in ANNEXA-4 and prothrombin complex concentrate in the UK observational ORANGE registry study suggested a benefit. Further, patients with GI haemorrhage in ANNEXA-4 were reported to have better outcomes than their Rockall scores would have predicted. Nevertheless, these non-randomised comparisons are at high risk of bias.

The ANNEXA-I study which has compared andexanet alfa against standard of care for intracranial haemorrhage will report very soon and will provide evidence as to the best approach. Nevertheless, the aim of RAPIDO is to provide real-world data on the use and outcomes of patients who received adnexanet, idarucizumab or PCC when emergency anticoagulation reversal is required. Primarily, the intention is to check that these agents are being appropriately used - in patients with major, life-threatening bleeding. This real world data will provide patient demographics, timings, dosages and adverse events recorded from several hospitals throughout the UK. Although RAPIDO is not designed to recapitulate a randomised controlled trial, there are elements of natural experiment which will make drawing causal inference from these observational data less prone to bias than indirect comparisons. This is particularly important for patients who have bleeding at sites that are not intracranial and those who are older, more comorbid, and sicker, who would not have been included in the prospective trials. Our data should tell us how representative the trials are of the patients who are receiving these therapies which is valuable information.

Most importantly, by involving us, the (not so junior) junior doctors in the data collection process, RAPIDO is a call for everyone to remain vigilant in the storm of clinical trial data, information overload and NHS crises that we currently experience.

And if medicine is an art, it could be the art of remaining vigilant.

Letting Go

It was with mixed emotions that I handed over the HaemSTAR chair role June 2023. After the initial discussions with Cheng-Hock Toh, Dan Hart and Mike Desborough that led to the formation of HaemSTAR in 2017, the network has become something for which I feel an over-exaggerated sense of responsibility, a bit like it was one of my children. HaemSTAR has been steadily growing up and maturing and I've been gradually devolving responsibility for its various aspects to others over the years. Looking back, I do sometimes wonder if I was trying to find excuses to stay being a registrar, just so I could get HaemSTAR to the point where it would no longer require my parental support. But my 10 year tenure as a registrar finally came to an end this year and I realise that HaemSTAR has come-of-age to a point where it can manage perfectly well without me (thank you very much).

Hence the trepidation I feel about finally letting go. But I have a lot of reassurance in knowing that it is being run by such a fantastic committee and that it will be safe with Richard Buka at the helm. I've known him since 2018 and he is a great guy. Among his many qualities, he brings a refreshing naivety and energy with him (which is why I sometimes describe collaborating with him as akin to trying to direct an over-excited puppy). He has already indelibly stamped HaemSTAR with his entrepreneurial spirit and has rightly identified some further opportunities to provide research training and so it is very exciting to see the plans for the educational webinars and podcasts coming together so quickly.

HaemTRIAL

Having said all that, I'm not completely ready to sever all ties with my offspring. With the help of Andy Doyle at GSTT, I aim to address two of HaemSTAR's limitations; firstly is the question of what happens when our study leads and regional representatives when they complete their registrar training and are no longer 'eiligible' for HaemSTAR membership; and secondly is the recurring criticism of HaemSTAR that the truly self-led projects have all been retrospective. HaemSTAR has been able to collect vast amounts of data in short periods of time, but any retrospective data is subject to bias that is impossible to eliminate. This will ultimately limit the research's applicability. And whilst HaemSTAR has undoubtedly enthused a generation of trainees and involved them in research studies, have any of the HaemSTAR projects thus far made a real difference to patient care? These limitations of retrospective studies are why the gold standard medical evidence for anything is the prospective randomised controlled trial (RCT). As a collaborative of registrars who have a time-limited engagement with the network, HaemSTAR has been unable to run any prospective studies. This is mainly because of the time commitment involved and the need to have a permanent contract in order to be considered as a chief investigator. Hence the development of an aligned network for senior registrars and consultants with an interest in running clinical trials that aim to answer important questions in non-malignant haematology.

 Our vision is that HaemSTAR will continue to provide training and networking for haematology registrars through collaborative retrospective studies. This educates and up-skills trainees but also generates hypothesis generating and produces baseline data which can be used to develop prospective clinical trials through the new sister network; Haematology Trials, Research, Innovation and Learning (HaemTRIAL).

 An example of how HaemSTAR and HaemTRIAL can complement each other:

There is little evidence to support venesection in secondary polycythaemia. There is robust data that aggressive venesection of patients with primary polycythaemia reduces thrombosis and mortality (Marchioli et al., New Eng J Med. 2013). There is good evidence that polycythaemia, regardless of cause and independent of confounders such as obesity and smoking, is associated with a modest increase in thrombosis and mortality (Wouters et al., Blood Advances 2020). But the only evidence of the benefit of venesection in secondary polycythaemia comes from small physiological studies done between the 1960s and 80s which show transient benefit in symptoms and small improvements in physiological markers such as pulmonary blood flow (Wade et al., Brit J Med. 1981, Weisse et al., Am J Med. 1975, Segel & Bishop. J Clin Inv. 1966). There is no evidence that venesection for any secondary polycythaemia improves mortality, thrombosis, or even HRQoL let alone anything that defines a target haematocrit. This has led to guidelines that say 'consider' venesection in this patient group (McMullin et al. Brit J Haematol. 2018) and a resultant wide variation in practice and patient experience. It would be great to run an RCT of venesection vs observation for patients with secondary polycythaemia. I feel there is a win-win here that either justifies and refines our current practice or allows us to discharge these patients from secondary care. But we lack justification for a clinical trial because this variation in practice is not well documented and we do not know whether clinicians would be willing to randomise their patients into such a study. I was also amazed to find that we do not know the annual thrombosis rate for patients with secondary polycythaemia, whether venesected or not. This makes it challenging to design an adequately powered study. HaemSTAR can solve all these problems; an audit of current practice combined with a clinician survey would overcome all of the barriers to setting up a clinical trial that could then be run by HaemTRIAL.

Like HaemSTAR, clearly the HaemTRIAL model will evolve with time and experience but we felt it was time to share our vision. Thank you to all of you who have been involved in the HaemSTAR network these past six years. What has been achieved would have been impossible without you.

Pip Nicolson

If you would like to contact me about HaemSTAR or HaemTRIAL - please email me: pnicolson@nhs.net

Tales from the 2023 International Society of Thrombosis and Haemostasis meeting in Montreal

As a core medical trainee aspiring to secure a spot in Haematology training, one of the things I had eagerly anticipated was the opportunity to attend international conferences and connect with haematologists from all around the world.

Becoming a specialty registrar amid the COVID-19 pandemic meant no face-to-face meetings or international conferences during the initial part of my specialty training. While online meetings became the new norm and reshaped the way we work and communicate, I welcomed the return to in-person meetings with immense relief.

I am still filled with gratitude for being able to see people face-to-face, stroll amongst posters, and present my research in person, rather than through a screen. This overwhelming sentiment animated me during ISTH 2023 this year.

My excitement was palpable as I boarded my 7-hour flight to Montreal, and I had already marked on my calendar all the lectures I wanted to attend, focusing heavily on gene therapy and obstetric haematology.

The quality and volume of research presented were jaw dropping. Some highlights from the lectures I attended include:

-The haemophilia basic science sessions on FVIII and FIX, where the German group from the University of Bonn presented intriguing research on intracellular trafficking of full-length versus B-domain deleted FVIII. Matthew Cormier's presentation on the relationship between gut microbiota and the risk of developing FVIII inhibitors in a mouse model during the second basic science session on Monday.

-I also thoroughly enjoyed the SSC women's health session, particularly Dr Rohan D'Souza's lecture on understanding the decision-making process for anticoagulation choice in pregnant patients with mechanical heart valves.

-The haemophilia gene therapy sessions for haemophilia A provided valuable updates from GENEr8-1 and SPK-8011 trials, along with an overview of the gene therapy WFH registry by Professor Barbara Konkle.

Amidst the lectures, I had the chance to network with many clinicians and scientists from around the world. During the poster session, I reconnected with a colleague from La Sapienza University in Rome, with whom I graduated in 2016. She is now a specialist in Internal Medicine with an interest in haemostasis & thrombosis. I enthusiastically shared information about HaemSTAR and my desire to collaborate internationally with Italy, and she quickly thought of also involving her colleagues from the Netherlands, where she had conducted research in the past.

Me and Rossella Talerico, from Policlinico Gemelli in Rome, remembering our university years and thinking about ways of collaborating in the future.

Another significant highlight was connecting with the Haemostasis and Thrombosis Research Society, a scientific community based in North America dedicated to research, mentoring, networking, and medical education in haemostasis and thrombosis. On a beautiful sunny Sunday, I met with Barbara Lam and Justine Ryu to discuss our shared interests in non-malignant research and how HaemSTAR and HTRS could collaborate in the future, paving the way for international trainee collaborations.

Over tasty panini (and losing track of time), we realized the immense potential of joining forces between our two networks that share similar goals and scientific/educational missions.

Later, we attended the early career mentoring session, where we met with the early career committee. Barbara and I pitched our plans to form international connections among trainees and early career researchers with great enthusiasm. It would be wonderful to have a dedicated session on trainees' networks worldwide at ISTH 2024 in Bangkok!

Crashing the HTRS meeting – that Matcha latte was amazing!

Leaving Montreal, I felt overwhelming gratitude and confidence in the future. I eagerly anticipate transforming these connections into long-lasting scientific collaborations.

I am reminded of something Professor Cuneo, head of the Haematology unit in Ferrara, wrote to me in 2017 when I was leaving Italy for the UK. With his words, I want to conclude as it perfectly summarizes my feelings post ISTH.

My Vision for HaemSTAR

It’s an immense honour to take over from Pip Nicolson as HaemSTAR chair. Pip has led us over the last six years from inception and has grown HaemSTAR into a real force to be reckoned with. Whilst we have thus far had tremendous success, it is not time to rest on our laurels. Rather, it is time to harness the energy and momentum that Pip has built up and transform HaemSTAR into something even more powerful.  

Producing Impactful Change 

Both Pip and I agree that the real point of clinical research is to produce impactful change for the better. Whilst our large-scale audits and observational studies add much value and will continue, we need to focus on how we best make use of the finite resource that is our collaborators. Thanks to our amazing collaborators – registrars, other junior doctors, and plenty of consultants – HaemSTAR can do things that very few other organisations can do. That’s why we want to harness this and lead projects that can inform better care. To this end, Pip will set up HaemTRIAL, a parallel network that will work in partnership with HaemSTAR to perform prospective studies. The HaemSTAR committee have already met to brainstorm ideas and we have three potential projects: 1) Randomised trial of venesection versus no venesection for idiopathic and secondary polycythaemia; 2) Randomised trial of blanket screening for antiphospholipid syndrome in patients with unprovoked VTE; 3) a randomised trial of tranexamic acid in heavy menstrual bleeding. These will all be fleshed out and discussed further in due course with the intention of applying for funding. 

Professionalising HaemSTAR 

HaemSTAR has grown from something that could easily be managed by a handful of people to a machine that has many moving parts and requires a good deal of management. Pip is tremendously organised – a quality that I cannot replicate. We have therefore unanimously decided to employ an administrator who will at first work four hours a week to answer emails, arrange meetings, and perform other day-to-day admin tasks. We are delighted that we have recruited Helen Apperley to this post. Helen is attentive and diligent, and will be a fantastic addition to the team. 

Widening Access to Research 

There are many ideas and many people in search of projects. HaemSTAR can help bring these together by creating a project matchmaking page on our website. Expansion of the network will continue, especially among doctors and registrars, with a focus on fostering relationships that could lead to research partnerships. We will help set up parallel networks of nurses and allied health professionals, facilitating their involvement in research projects. 

Widening Access to Research Through Education 

I am keen that we provide a small educational offering by inviting inspiring speakers to deliver talks via a free, monthly Webinar that will take place on a weekday morning 8:30 – 9:00 (not clashing with the excellent UKHCDO programme). The idea of these is to bring you really interesting speakers that will be more idea and research focussed than pure content. We have some really engaging talks lined up and this will be launched soon. 

We have also applied for funding to produce a monthly journal club podcast. More details will follow if this is awarded.  

Funding Travel and International Collaboration 

We are excited that we have been awarded $37,500 from the ISTH London 2022 legacy fund. This will go towards awarding travel grants ($25,000) and setting up international collaborations ($12,500). Information on eligibility and how to apply for this funding will be on our website shortly. 

Improving Engagement with Regional Representatives 

We have some wonderful regional reps but thus far have not been too good at engaging with them. In the last year, Pip and I have made a point of meeting with all new regional reps to introduce ourselves, the concept of HaemSTAR and what we would like them to do. This has helped but we also intend on having an online meeting twice a year to update on projects and promote a two-way conversation. The details for the first meeting which will take place in September will be released soon. 

HaemSTAR Prizes 

We know that some of you put in immense amounts of effort and work into the things that you do, consistently going above and beyond your day job. It is important to recognise and reward this excellence and I am pleased to announce that prizes will be awarded at our annual meeting in 2024. The exact nature of these prizes is yet to be determined but will likely include awards such as project of the year, HaemSTAR rep of the year, and non-malignant haematology educator of the year. 

Working with Industry Partners 

Working with industry can often be contentious but I feel it is both necessary and mutually beneficial to continue to develop our industry links in a way that maintains our integrity but allows us to do fantastic work. The RAPIDO project is a good example of how to work with industry. AstraZeneca have provided £90,000 funding for the project with academic control of the project remaining with us. This shows that where interests align, there are huge opportunities. Of course, we will remain vigilant to exploitation and seek advice from senior academics where appropriate. 

HaemSTAR is yours

No matter what my goals are for HaemSTAR, it remains an organisation for you. We are here to offer opportunities to get into research and to promote non-malignant / classical haematology. If you have an idea or want to find out more, just send me an email - richard.buka@nhs.net.

If you want to read more of my musings mostly about classical/non-malignant haematology, follow my blog on Substack.

The Woes and Wonder of Immunohaematology in the United Kingdom

In recent years there has been an increasing expansion of haematologists with an interest in immune-mediated disease within the classical haematology world. This has been driven by an increased knowledge of these conditions and novel targeted treatments that are now available. However, it has become apparent that an abundance for some conditions is balanced by limitations for others.

First, let us start with the wonders: thrombotic thrombocytopenic purpura (TTP) and immune thrombocytopenia (ITP). TTP is a devastating and life-threatening diagnosis albeit a rare one. In the last year, NHS England has recognised this with the development of a national TTP framework providing regional access to 24-hour plasma exchange services by experts in its diagnosis and treatment. The use of caplacizumab, a nanobody that reduces von Willebrand factor-platelet binding, has been approved with the TITAN and HERCULES studies showing improved outcomes when added to plasma exchange and immunosuppression. The use of rituximab in treating sub-clinical ‘ADAMTS13’ relapses has also become standard of care in the UK TTP Network. Results from the nationwide UK TTP registry and on-going recruitment in the UK-led ERTTP study will give clinicians further information on dosing options.

ITP is likely to be the most common condition faced by the immunohaematologist. It still lacks a specific diagnostic test but due to its higher incidence, clinicians have more experience and are comfortable in its treatment. Refractoriness or loss of response is one of the key concerns for clinicians but the arsenal of therapies available to treat the condition has increased over the last decade. The TPO receptor agonists, romiplostim, eltrombopag and avatrombopag, as well as rituximab are now being used earlier and with greater confidence. Fostamatinib, a SYK inhibitor, has recently been approved by NICE and the HaemSTAR-supported FLIGHT study gave support for the early use of mycophenolate with steroids at the time of diagnosis. A combination of better clinical data for ‘old-fashioned’ drugs and the industry development of new targeted therapies has helped to transform the list of treatment options. Excitingly, HaemSTAR is now working with industry to trial novel immunosuppressants in this space.

Let us now turn our heads to the woes: antiphospholipid syndrome (APS) and acquired haemophilia A (AHA). APS is a prothrombotic condition causing venous and arterial thromboses as well as obstetric morbidity. Its problems at present lie in several areas: 1) its multi-headed nature making clinical or surrogate end-points difficult to assess in clinical trials, 2) poor outcomes in anticoagulation studies, and 3) the lack of a clear molecular target. Assessing the surrogate markers of thrombin generation assays in the TRAPS study comparing warfarin to rivaroxaban, failed to translate into safe patient outcomes. DOACs have become the standard of care in the 2020s for treating venous thromboembolism in the UK however due to the findings from the TRAPS study, warfarin still remains the preferred anticoagulant for APS. Similarly, varying forms of immunosuppression have yet to show clear benefit. The HaemSTAR supported A2PLS audit has provided a snapshot of current practice in the UK and publication is eagerly awaited. Although there is recognition that β2-glycoprotein plays a key role in the condition, antibodies to the protein are not seen in all patients and its physiological and pathogenic role are still poorly understood. These issues remain a key barrier to the treatment of this disease.

Finally, acquired haemophilia A (AHA). Similar to TTP, this is rare but treatment options are less well tested and the field is plagued a lack of prospective data. Control of bleeding and immunosuppression are key. Rituximab has shown some benefit for AHA, similar to other immune-mediated conditions, but large multi-centre data has yet to be presented and the risk of subsequent relapse is less clear. The EACH2 Registry helped to give better understanding of the impacts of cyclophosphamide and steroid for the disease. Factor VIII bypassing agents including FEIBA and recombinant factor VIIa, are used but they are non-specific, can be problematic to administer, and there is a lack of experience in non-specialist haemostasis centres; surely, these must impact upon patient outcomes. Emicuzimab, a bivalent FVIII-mimicking monoclonal antibody, has revolutionised the bleeding experience of patients with cogenital haemophilia A with inhibitors. However, despite anecdotal evidence and case reports, industry-supported prospective studies for AHA have yet to materialise. It is only in Japan that emicizumab is licences for AHA.

Going forwards there is a clear need to better understand the underlying disease processes in these conditions in order to develop targeted therapies. Along with this, clinicians need to be able to engage with industry to improve the treatment of these rare or neglected conditions. However, it takes many years drug development to bring these therapies from bench to bedside. Developing clinical care networks to support research in immunohaematology has shown benefit in some of these diseases. Surely, this must be applicable to others on a national scale to focus clinical research questions, rationalise currently available treatments and improve patient outcomes.

Diving into clinical academia: what’s holding you back?

This blog is for all those out there who feel like they don’t have their ‘foot in the door’ of clinical academia, or who are feeling the very well-known ‘imposter syndrome’ when they think about getting more involved in research.

Good news – there’s no reason why you can’t get involved in research later in your training career. From my own experience, I had not undertaken an intercalated degree nor any research whilst at university (isn’t the medical degree enough?!), and had never been in an academic training post – but, I was really interested in clinical research and what it involved, and actively sought out opportunities with my colleagues by expressing a keen interest. With the help of supportive and encouraging mentors and consultants, I was able to go out of the haematology training programme to do a PhD in April 2019, and I haven’t looked back since.

I have always believed that the more you put into any aspect of your life, the more you will get out of it, and this most definitely includes in your career. No-one can deny that those first steps into clinical academia can be daunting; it is a very steep learning curve, a whole new language and way of working – but there are plenty of us around who will happily talk about the highs and lows of our career journey so far and share in all your sentiments! I’ve had the chance to meet so many different people from across the country through the HaemSTAR network, made good friends and had so many uplifting conversations about our shared experiences.

So, if you are interested and keen in being involved in clinical research, at whatever capacity that may be, don’t be put off – don’t compare yourself to what others may have done - and do grab every opportunity that comes your way. We all have our individual strengths to bring to the table, and research really can be for everyone.

2023 HaemSTAR Meeting Highlights

Writes Dr Eman Hassan, Haematology Registrar, West Midlands

Finally, after a long four years of waiting, on Monday 6th February, HaemSTAR members had the chance to get together for a face-to-face meeting. The event in Newcastle upon Tyne was tagged to the popular ASH/ISTH non-malignant highlights day, making the journey even more worthwhile.

It was an exciting opportunity for people of different backgrounds to come together to share experiences, get the most recent updates on HaemSTAR projects, and listen to some compelling educational content delivered by experts in classical haematology. A wide variety of delegates attended including junior doctors, haematology trainees, consultants, pharmacists, clinical scientists, and industry representatives. The meeting was also streamed online for those unable to attend in person to ensure no one missed out.

The meeting started with a warm welcome from the HaemSTAR chair Pip Nicolson, and this was followed by a rich session about current and future HaemSTAR Projects. Lorna Cain presented initial results from the national Two Sample Rule survey which has been supervised by Dr Suzy Morton, Birmingham. The survey was circulated end of last year to ED doctors through HaemSTAR leads. Strikingly, results showed poor understanding of the reasons for the Two Sample Rule; two thirds had taken two samples from the same blood draw and labelled them with different times. This had a lot of interest on Twitter! Full results will be presented at the BSH ASM this year.

Following this, Christina Crossette-Thambiah, presented results from A2PLS study, which was also presented at the ASH meeting at the end of last year. This project was conceived and supervised by Dr Deepa Arachchilage. A2PLS is a national audit of antiphospholipid syndrome to assess national practice. It included 500 patients and to our knowledge is the largest cohort of APLS patients ever. It found a 40% risk of recurrent thrombosis at 10 years, higher in arterial thrombosis. Interestingly, the risk of thrombosis recurrence with lupus anticoagulant positivity was same as triple anti-phospholipid positivity. The manuscript is in preparation.

Becks Shaw then presented data from the ConNeCT study – a questionnaire-based study on long term neurological complications in TTP which is supervised by Dr Tina Dutt, Liverpool. 30% of patients recruited had moderate-severe depression. The study is still recruiting, and enthusiastic trainees were encouraged to get involved.

The final talk of the session was an update from Pip Nicolson on three randomised trials that HaemSTAR are supporting – testing the utility of Ianalumab, an anti-B cell activating factor (BAFF) monoclonal antibody. Two studies are in ITP and one in warm autoimmune haemolytic anaemia. Already, HaemSTAR members have helped set up sites.

After lunch, our educational session kicked off with haematology consultant, Noémi Roy, gave an inspirational lecture on the pain in sickle cell disease. The talk concluded with a call to action – can HaemSTAR support patient driven studies for better pain control?

Next, we welcomed Ian Roberts who ran many of the large trials on tranexamic acid including the CRASH and WOMAN trials. Ian gave an update on tranaexamic acid use in trauma, major haemorrhage, post-partum and surgery, and discussed that despite the strong evidence of benefit, tranexamic acid remains under used.

Following on from Ian’s talk, we held a discussion forum, breaking off into small groups to discuss the workings of HaemSTAR and how to make an impact. These discussions were constructive and allowed thoughts and plans to evolve.

In the final session, Vickie McDonald presented the output from the more than 5,000 patient strong UK adult ITP registry with a focus on how treatment of ITP changed during the COVID-19 pandemic. The registry has a lot of potential for answering further research questions and anyone interested in analysing data can contact Vickie.

To close the day, Richard Buka presented interim results of RAPIDO audit, our national project looking at the use of reversal agents for DOACs. This was presented in the context of a talk on the weak evidence for DOAC reversal. Thus far, RAPIDO has collected data on 837 patients, median age 81, 88% of whom received PCC. Mortality was high at 40%. Early results show heterogeneity of practice. More data will be collected in Autumn 2023.

We would like to thank all the delegates and speakers for attending what we think was a great event. We are really looking forward to seeing some of you at the BSH ASM in April in Birmingham and we plan to run this meeting annually.

If you would like to find out more about our projects, check out our Past Projects and Current Projects pages; or email haemstarnetwork@gmail.com.