MACS Study - Microparticles and Coagulation in Sickle Cell Disease
MACS Study - Microparticles and Coagulation in Sickle Cell Disease
Sickle cell disease (SCD) is an inherited disorder of the red blood cell. It is now the
 commonest genetic disorder in the UK and of childhood stroke, with up to 40% of children
 having a stroke (clinical or picked up on a scan) by school age. Patients are prone to
 develop acute crises necessitating hospital admission and resulting in long-term
 complications. Such events result in considerable morbidity, disability and mortality with
 its consequent burden on patients, families, the health service and society as a whole.
 Doctors have very little ability to predict who will get ill and when and so it is very
 difficult to known when and how to administer treatments. Furthermore there is very little in
 the way of treatments available and the mainstay of prevention is a chronic blood transfusion
 programme which is expensive, requires time off work and school and can be fraught with
 complications. This, in a population who is frequently educationally and socially
 disadvantaged at the outset. Recent evidence in sickle cell disease and other diseases that
 have similar underlying processes, points towards the importance of microparticles
 (circulating broken pieces of cells) and the coagulation system as being important. By
 comparing levels of these particles and molecules in patients with those found in healthy
 volunteers and with other measures known to be important, this study hopes to identify their
 role so as to improve the management of these patients and potentially to lead the way for
 new therapies. Participants will be required to donate a small amount of blood (1 teaspoon in
 the very young, two in older children and adults). The investigators aim to take this sample
 where possible when people are having a blood test in any case.
Purpose and design

 -  Why is it needed? The purpose of this study is to try and identify a measurable
 parameter to act as a disease indicator in sickle cell disease. The reason such a
 parameter is needed is that although patients seem to have the same genetic defect, they
 can have enormously different outcomes ranging from mild illness to stroke, catastrophic
 chest disease, kidney failure and death. Currently we have no real tools to properly
 prognosticate. This means it is difficult to know when to intervene in an illness and
 when to scale down and stop treatment. The repercussions of not intervening in a timely
 manner can be catastrophic and it is known that children who develop stroke have future
 ongoing and progressive intellectual deficits. The identification of a disease indicator
 could have potential for therapeutic innovation in the future. This is important as much
 of the current treatments are blunt, expensive and not always effective. In addition
 there is a paucity of treatment options for the clinician and those that are available
 e.g. blood transfusion are expensive socially and financially, have medical
 complications and are realistically not available for the majority of people who have
 sickle cell disease.

 -  Why microparticles and coagulation markers? An excellent candidate for the role of
 disease prognosticator is coagulation markers and microparticles. Microparticles and
 coagulation markers have been shown by members of this investigative group to be
 elevated in sickle cell disease and in other paediatric vascular diseases. There has
 been a lot of interest in the haematology world of late in these particles with papers
 and presentations and all the international conferences - EHA (European Haematology
 Association), BSH (British Society of Haematology) and ASH (American Society of
 Hematology), though these have been performed on small selected groups, frequently on
 adults only and only rarely with any sort of controls. What has not been done so far is
 to compare these levels to ethnically matched people or to measure these in children
 with sickle cell disease. This is remiss as it is known that the vascular changes occur
 right from the beginning of life with children have symptoms and signs of vasculopathy
 often by 6 months of age and with up to 40% having had some sort of stroke by school
 entry. What also has been omitted is performing these tests in a larger cohort and
 comparing with the variety of current measures of disease severity and measure of
 vasculopathy. It is only with this kind of information can we make proper inferences
 about the importance of these measures and go on to develop studies where these are used
 as disease prognosticators and one day even as a target for therapeutic intervention.

 -  Why here and now? Here and now presents a perfect opportunity for this study. Dr
 Trompeter is the author of the study and will be coordinating the study. She is
 currently a locum Consultant Haematologist at UCLH and a Specialist Registrar in
 Haemoglobinopathies at Guy's and St Thomas' and has been looking after the in- and
 out-patients with sickle cell disease at these sites. She has also been involved in
 ongoing studies in sickle cell disease at these sites as an investigator. Furthermore
 she has worked in a similar clinical capacity at both UCLH and The Whittington Hospital
 and has built up a good rapport and working relationship with staff, patients and their
 families at these sites. She is registered for a PhD at UCL and has already performed
 these assays as part of the original ongoing study in adults with sickle cell disease,
 which has papers published and soon to be submitted. These sites in combination
 represent one of the largest cohort of sickle cell patients in the country. The centres
 have been externally audited as part of the sickle peer review and have had their
 considerable qualities assessed and lauded. They have the capacity, ability and habit of
 measuring all the other parameters of interest in this study as a matter of routine
 clinical care. The clinicians have enormous experience and rapport with their patients
 but also have a considerable research repertoire. The Professors and scientists in this
 study have all demonstrated their immense knowledge and expertise in the fields of
 sickle cell disease and vasculopathy and are internationally renown, leading many
 important related studies. They have provided much of the support and scientific
 rationale to the designing of this study. The investigators are well known to the sickle
 community and its representatives and the author has spoken with patients groups who
 persistently express a desire for medical advancement and showed a real interest and
 support for this study. This conglomeration of sites, clinicians, experts and patients
 represents the most exciting opportunity for advancing the understanding of sickle cell
 disease.

 Recruitment

 -  Participants will be identified by the Investigator (who is part of their normal care
 team) from the in- or out-patient setting as having met the inclusion criteria. Patients
 with sickle cell disease attend dedicated clinics and are well known to the
 investigators. The consent procedures are described below. There will be no payment.

 -  In the case of the patients, they will then progress to have their scheduled blood test
 as part of their normal clinic care, onto which a further blood sample (1 teaspoon in
 the case of small children, 2 teaspoons in the case of older children and adults) will
 be obtained for the purpose of this study.

 -  There are two groups of healthy volunteers - adults and children. They should be
 ethnically matched. The majority of the adults can be identified from the sickle clinic
 setting as family members attending with their patient relative. These people have the
 additional advantage of knowing their sickle status. There are also many ethnically
 matched members of staff or other people attending the hospital that may want to be
 involved in the study. Some adult volunteers will have a blood sample for the purpose of
 the study only, others will be having blood tests in any case and the study sample being
 taken in addition, if they do not know their sickle status they will be tested. They
 will consent separately for this and the information given back to them regarding this
 second test. Separate consent will also be taken for reporting to them and their G.P.
 also. Ethnically matched children healthy volunteers will be identified from the in and
 outpatient setting. They are extremely likely to know their sickle status in any case
 because of the national screening programme. Children will only participate in the study
 if they are having a blood tests in any case.
Inclusion Criteria:

 -  Subject Inclusion Criteria:

 Patient (or parent if child) able to give informed consent Compound heterozygote or
 homozygote for a sickling disorder (i.e. has sickle cell disease) Having a blood test in
 any case

 -  Healthy volunteer Inclusion Criteria:

 Person (or parent if child) able to give informed consent If a child, having a blood test
 or cannula inserted in any case Ethnically matched - of African origin Must know their
 sickle cell status or have it tested as part of the study and agree to have this result
 given to them and their G.P.

 Exclusion Criteria:

 -  Subject Exclusion Criteria:

 Inability to meet all inclusion criteria

 -  Healthy Volunteer Exclusion Criteria:

 Compound heterozygote or homozygote for a sickling disorder (i.e. has sickle cell disease)
 Inability to meet all inclusion criteria Ongoing
 cancerous/inflammatory/haematological/infective illness (the levels of microparticles and
 coagulation parameters have been shown to be elevated in these disorders and so would not
 be appropriate to be included in a control group)