12,500 SCD in UK (9% on LT transfusion programme)
Caused by inheritance of the sickle mutation on the HBB gene (Glu6Val, bs)
Sickle Cell Trait = HbAS
Sickle Cell Anaemia = HbSS
Sickle Cell Disease = HbSS or sickling compound heterozygotes = HbSC, HbS/b0, HbS/b+, HbSC, HbSOArab
In West Africa, SCD responsible for 16% of all deaths in <5 year olds
In Jamaica, 10% of SCD infants die between 6-12 months of age
In the UK, 99% survival to age of 16 years
In hypoxic states, erythrocytes become rapidly, but reversibly, deformed.
Intracellular polymerization of the abnormal HbS molecule stretches cell into rigid sickle form
Sickled cells cause vaso-occlusion, along with many other cellular and plasma factor interactions
--> Cycle of repeated ischaemia and inflammation
Re-oxygenation restores the normal red cell shape. Cells cycle in and out of this state until forced into intravascular haemolysis or extravascular removal by the reticendothelial system.
HbS is a low oxygen affinity haemoglobin --> right shift on the oxygen dissociation curve --> partly explains the chronic anaemia in SCD (which is not all due to haemolysis)
Annual Review Clinic
Height, weight, BP, O2 Sats
No. & severity of crises in the last year
Other – AVN, ulcers, osteomyelitis, disc protusions
Education, Employment and Training
Medication compliance – folic acid, pencillin, HU, ACEI, chelators
Bloods – FBC, U&E, LFT, Ferritin, Hep B Ab titre, Vit D
Red cell Genotyping
Vaccinations – 5 yearly pneumococcus, seasonal ‘flu, Hep B
A&E Management plan
Transfusion (see here for more)
Extended phenotype at baseline
Rh, Kell, Jk, Fy & Ss
Check U if S-, s-
Blood Product Requirements
Rh and Kell matched. R0 for R0 where available (rr alternative)
Hb S negative
RBC <10 days old for top-up, <7 days for Exchange
TAPS Trial (Transfusion Alternatives Preoperatively in Sickle Cell Disease)
Pre-Op transfusion if Hb <90 reduces risk of acute chest crisis post-op
Trial stopped early due to clear benefit in favour of pre-op transfusion.
Preferred for treatment of acute severe anaemia
E.g. aplastic crisis, acute splenic or hepatic sequestration, >20g/l drop during a painful crisis
Preferred for immediate or sustained reduction in complications of SCD
Bonus: Achieves neutral or negative iron balance
Manual exchange: Aim to exchange 30% of blood volume – 4 units out, 3 + saline in.
Multi-Organ Failure, Mesenteric-Girdle Syndrome, Sepsis, Cholestasis
All SCD for high-risk surgery
Mechanism of Action
HU is a ribonucleotide reductase inhibitor --> depletes intracellular deoxynucleotide pools required for DNA synthesis and repair --> cytostatic effect.
This alteration to the cell cycle kinetics, along with effects on guanylyl cyclase and SAR1, increases HbF production.
HbF inhibits intracellular HbS polymerization, and higher HbF% associated with reduced morbidity and mortality.
17 years of observational follow-up from the Multicentre Study of Hydroxyurea (MSH) found hydroxycarbamide use was associated with a 40% reduction in adult mortality.
Reduces Acute Pain and Chest Crises
MSH 1995 - double-blind, placebo controlled trial of hydroxycarbamide --> 40% reduction in median number of painful crises over two years (4.5 vs 2.5), median time to first crisis doubled and incidence of ACS reduced.
Reduces hospitalisations and pain in the community
Shown in repeated observational studies
Prevents first stroke?
HU has not been formally assessed as first line therapy for children with raised transcranial Doppler velocities (TCD).
A switch to HU after a minimum of one year of initial transfusion has been shown to be non-inferior to ongoing transfusion, provided that there is no MRI evidence of vasculopathy (TWiTCH 2016)
Prevents organ damage
Evidence is not entirely clear or in agreement but there may be beneficial effects of HU on preserving splenic function, improving renal dysfunction, improving oxygen saturation, preventing priaprism and improving pain in avascular necrosis.
There is no evidence at present to suggest HU is beneficial in preventing pulmonary hypertension.
Which HbSS and HbS/BetaO patients should be on HU?
Infants aged 9-42 months regardless of clinical severity to reduce sickle complications
Children aged >42 months, teenagers and adults to reduce mortality
Children on a regular transfusion schedule for primary prevention of stroke, after 1 year of transfusion and provided there is no MRI evidence of vasculopathy
Recommend to adults and children who have:
3+ mod-severe pain crises in a 12 month period
Sickle pain that interferes with daily activities
A history of severe and/or recurrent ACS
Chronic anaemia that interferes with daily activities
Also give consideration to potential benefits listed above regarding prevention of organ damage and discuss these issues with patients.
Concerns about HU
Short term Side Effects
Transient, reversible myelosuppression
Mild GI symptoms
Skin and nail hyperpigmentation, hair thinning
Skin ulcers are reported but are not any more frequent that in those not on HU
There is no risk of leukaemogenesis when HU is used for the treatment of haemoglobinopathies
Growth and Development
There is no evidence to show growth or development is impaired by HU
There is no evidence that HU affects fertility.
However, there is some suggestion of an effect of HU on male spermatogenesis in laboratory studies. It is recommended that post-pubertal male patients who are due to start HU for the first time should be offered sperm cryopreservation.
There is laboratory evidence of teratogenicity at suprapharmacological doses.
Patients on HU should use contraception
Women who become pregnant whilst taking HU require careful review of the risks of stopping HU (i.e. increased risk of sickle-related pregnancy complications) as this may outweigh the possible risk of teratogenicity.
Adults: Start at 15mg/kg/day (rounded up to nearest 500mg)
Children: Start at 20mg/kg/day (rounded up to nearest 500mg)
Increase dose by 5mg/kg/day every 8-12 weeks aiming for a neutrophil count of 2-3.
Stop if the neutrophil count falls below 1.
This is the maximum tolerated dose.
Aim to deliver the maximum tolerated dose as evidence to suggest best outcomes with this approach.
Adjust dose for renal impairment.
Continue for minimum of six months before assessing response to therapy.
Failure to respond should be assessed by a lack of clinical response and not by laboratory values.
Treatment should be continued during hospital admissions, unless for febrile neutropenia.
P Selectin inhibitor --> inhibits the adhesion/activation of leukocytes
Anti-P Selectin Antibody
Administered whilst well in combination with HU
SUSTAIN Trial – Phase 2. 45% fewer crises vs Control. SAE in 55/151, 5 deaths
Canakinumab, Voxelotor, L-Glutamine, Butyrate, Gardos channel blockers, lenalidomide, azactidine
Discuss risks to mother– perinatal mortality, acute crises
Discuss risks to fetus - fetal growth restriction, premature labour
Screen father for Hbpathy – if HbS, B-thal, O-Arab, HbC, D-Punjab offer prenatal diagnosis
Review systems – Pul HTN, Iron Overload, Retinopathy, HTN, Renal function
Optimise meds – Pen V, Folic Acid, Vaccinations
Stop HU three months prior to conception
Stop ACEI before conception
MDT, Fetal Medicine Unit
Screen for end organ damage if not done pre-conception
Avoid dehydration, extreme temperatures & overexertion
Offer viability scan at 7-9 weeks
Routine 1st trimester scan at 11-14 weeks
Routine anomaly scan at 20 weeks
Additional monthly growth scans from 24 weeks
BP & Urinalysis at every visit
Urine culture monthly
Aspirin from 12 weeks (reduces risk of pre-eclampsia)
Prophylactic LMWH during hospital admissions
?Prophylactic RBC transfusion - no clear evidence, patient-by-patient basis
Offer Induction of labour after 38+0 weeks (any mode of delivery)
If known red cell antibodies, crossmatch blood for delivery in advance
Intrapartum fetal heart rate monitoring is recommended (increased risk of fetal distress)
Prevent dehydration, maintain O2 sats.
LMWH prophylaxis 7 days post NVD, 6 weeks post C-Section
Test neonate for sickle
1 unit RBC = 200-250mg iron
Context (2016 NHS England policy document):
12,500 SCD in UK, 80% living in London, 9% on long-term transfusion programme
40% of the 9% are on chelation —> Approx 450 people
1,500 thal pts in UK, 50% transfusion dependent
60% on chelation (this more than the 50% on transfusion due to non-transfusion dependent Thal (NTDT) patients still prone to iron overload.
Both figures will increase in future with birth rate and increased survival
Prevent harmful effects of free iron
Prevent or reverse organ damage
Maximise quality of life
When to start?
After first 10-20 units RBC
Or when ferritin >1000 ng/ml
Or MRI Liver demonstrates >7mg/gram of dry weight iron loading
Desferrioxamine (Desferol) DFO
SC/IV injection or continuous infusion. Only works whilst infusing
20-60mg /kg / day
Ideally given as portable SC infusion for 8-12 hours daily (longer if tolerated)
Hearing / Visual impairment (3 monthly screening mandated)
Yersinia infection (mimic appendicitis)
Arthralgia / Myalgia
SE are reducing by maintaining ratio of Mean Daily Dose (mg/kg) / ferritin below 0.025
Deferiprone (Ferriprox) DFP
2nd line license – as monotherapy if Desferol contraindicated or inadequate
Superior improvement in cardiac function than desferrioxamine
Small joint arthritis
Agranulocytosis – weekly FBC for neutrophils. Re-challenge not recommended
Deferasirox (Exjade, Jadenu) DFX
Exjade - Oral dispersible tablet, OD, 10-40mg/kg/day
Jadenu – Coated tablet, 1/3 the dose of Exjade, usually better tolerated (fewer GI SE)
Better tolerated but slower change in free iron levels
GI disturbance / ulcers
Stroke Prevention in Children
Before introduction of TCD, 5-15% of children suffered acute stroke
STOP 1998 – 1o prevention - TCD >200cm/s --> regular transfusion prevents stroke (92% RR)
STOP2 2005 – 1o prevention - ?Can you stop transfusing --> No, the stop arm had new strokes
SWiTCH – 2o prevention - ?Can you switch from transfusion to HU after 30 months --> No.
TWiTCH 2016 – 1o prevention - ?Transfusion + HU & eventually stop transfusion --> Yes
Only curative procedure
Very difficult to choose right patient at the right time
Best outcomes if proceed prior to organ damage, but want to select only severely affected patients due to the morbidity and mortality associated with HSCT (including infertility).
Most success so far in matched sibling, bone marrow harvest, myeloablative HSCT in children.
Effective in preventing future clinical complications of SCD.
In adults, 87% EFS reported with matching sibling RIC allografts.
Unrelated transplant currently appears unsafe for widespread use. Higher mortality and GVHD.
Gene Therapy Autografts?
Stem cell collection --> Ex vivo gene therapy to add HbA gene --> myeloablative conditioning and re-infusion of modified autologous stem cells