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Sickle Cell Disease (BSH 2015, bsh 2018, GTG 2011, BSH 2021)
The Haembase notes below are based on the references linked in the title. However, Dr Moosa Qureshi has also kindly provided his summary PDF of the 2018 UK standards of clinic care for sickle cell disease.
Intro
~15,00 people with SCD in UK (~9% on LT transfusion programme)
~300 infants born with SCD in UK each year
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
Pathophysiology
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
Analgesic use
Cardiovascular symptoms
Iron overload
Other – AVN, ulcers, osteomyelitis, disc protusions
Education, Employment and Training
Family Planning
Medication compliance – folic acid, pencillin, HU, ACEI, chelators
Bloods – FBC, U&E, LFT, Ferritin, Hep B Ab titre, Vit D
Red cell Genotyping
Echo
Ophthalmology review
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-
Offer genotyping
Blood Product Requirements
Rh and Kell matched. R0 for R0 where available (rr alternative)
Hb S negative
As of 2023, it is no longer recommended to select ‘fresh blood’ for any patient >1 year old. This change has been circulated by NHSBT. Formal addendums to the BSH guidelines will follow. (This replaces the original recommendation: Red cells should be <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.
Top-Up Transfusion
Preferred for treatment of acute severe anaemia
E.g. aplastic crisis, acute splenic or hepatic sequestration, >20g/l drop during a painful crisis
Exchange Transfusion
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.
Definite indications
Acute Stroke
Multi-Organ Failure, Mesenteric-Girdle Syndrome, Sepsis, Cholestasis
All SCD for high-risk surgery
Hydroxycarbamide (HU)
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.
Benefits
Reduces 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?
Offer to:
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
Chronic hypoxia
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
Leukaemogenesis
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
Fertility
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.
Teratogenicity
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.
Dosing
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.
Newer therapies
Casgvey (exagamglogene autotemcel, “exa-cel”) (MHRA UK approved in 2023)
Cellular therapy - Busulfan autograft protocol with gene editing of the apheresed cells prior to re-infusion
Mechanism: CRISPR-Cas9 gene editing of BCL11A in autologous stem cells —> Re-activation of HbF
CLIMB SCD-121 Trial (interim results ASH 2023)
Phase 3. 12-35 yo pts with severe SCD (2+ occlusive crises per year)
As of Feb 2023, 42 patients treated
95% free of occlusive crisis at 12 months f/up
In all patients, HbF >40% at month 6 onwards
Lyfgenia (lovotibeglogene autotemcel, “lovo-cel”) (Not yet UK approved as of 2023)
Cellular therapy - Busulfan autograft protocol with lentiviral-mediated gene addition to the cells prior to re-infusion
Mechanism: Lentiviral vector integrates a modified beta-globin gene —> an anti-sickling Hb (HbA T87Q) which is produced in addition to the original HbS.
Phase 1/2 study, NEJM 2022
Voxelotor
Oral HbS polymerisation inhibitor
HOPE 2019 - Ph3, 274 pts, Voxelotor vs Placebo. Short f/up but Hb higher in Voxelotor arm. No difference in QoL, Opioid use or Rescue transfusions.
NICE 2024 approval - for treatment of haemolytic anaemia caused by sickle cell disease only if hydroxycarbamide is ineffective as monotherapy (or patients ineligible/intolerant of HU)
Crinzalizumab (negative phase 3 trial. Future of drug uncertain)
Anti-P Selectin Antibody
Administered whilst well in combination with HU
STAND Trial (awaiting publication, 2023) - Did not meet its primary endpoint.
SUSTAIN 2017 – Phase 2. 45% fewer crises vs Control. SAE in 55/151, 5 deaths
Rivipansel (negative phase 3 trial. Future of drug uncertain)
P Selectin inhibitor --> inhibits the adhesion/activation of leukocytes
RESET 2023 - Did not meet its primary or secondary endpoints.
Others
Canakinumab, L-Glutamine, Butyrate, Gardos channel blockers, lenalidomide, azactidine
Pregnancy (BSH 2021)
Intro
~100-200 pregnancies in women with SCD in UK each year
Significant maternal sickle Hbpathies = SS, SC, SDpunjab, SE, SOarab, SLepore, S-Beta thal
Risk of adverse outcomes greater in HbSS compared to other sickle heterozygozity
Risks to mother, increased rates of:
Maternal mortality, acute crises, hypertension, pre-eclampsia, VTE, UTI, transfusion requirements, ITU admission
Risks to fetus/infant, increased rates of:
Fetal growth restriction, premature labour, stillbirth
..% of women with SCD experience … in pregnancy:
57% acute pain, 10%, acute chest crisis, 18% severe crisis, 25% post-natal crisis
Pre-Conception
The following should routinely be part of agenda for annual clinic reviews
Discuss risks to mother
Discuss risks to fetus
Screen father for Hbpathy – if HbS, B-thal, O-Arab, HbC, D-Punjab offer prenatal diagnosis
Discuss reproductive options, e.g. prenatal diagnosis, pre-implantation genetic diagnosis
Review systems – Chronic pain, HTN (>130/80), Renal function, Pul HTN, Iron Overload, Retinopathy, Stroke
Optimise meds – Folic Acid 5mg OD, Vit D, Pen V, Vaccinations
Stop hydroxycarbamide three months prior to conception
Stop ACEI before conception (In d/w Renal for potential alternatives)
Stop iron chelators
NSAIDS - caution before 12 weeks, avoid after 31 weeks
Antenatal
Consultation
MDT, Fetal Medicine Unit, Offer pre-natal diagnosis
Screen for end organ damage if not done pre-conception
Avoid dehydration, extreme temperatures & overexertion
Review pain management plan, social circumstances
Scans
Offer viability scan at 7-9 weeks
Routine 1st trimester scan at 10-14 weeks
Routine anomaly scan at 20 weeks
Additional monthly growth scans from 24 weeks
Other
BP & Urinalysis at every visit
Urine culture monthly
Extended red cell phenotyping (use CMV neg, HbS-neg, extended Rh & Kell matched blood)
Treatment
Aspirin from 12 weeks (reduces risk of pre-eclampsia)
Prophylactic LMWH during hospital admissions
?Prophylactic RBC transfusion - no clear evidence, patient-by-patient basis (TAPS-2 trial ongoing)
Intrapartum
Offer Induction of labour after 38+0 weeks (any mode of delivery)
Keep warm, adequate hydration
If known red cell antibodies, crossmatch blood for delivery in advance
Intrapartum fetal heart rate monitoring is recommended (increased risk of fetal distress)
Postpartum
Prevent dehydration, maintain O2 sats.
LMWH prophylaxis for 6 weeks post delivery
Test neonate for sickle
Offer contraceptive advice
Iron Chelation
See Iron Overload.
catheter associated thrombosis (BSH2024)
High risk of VTE in sickle cell overall
—> high rates of catheter-associated thrombosis in patients requiring indwelling CVC’s
Port-a-caths may have lower thrombotic risk than other CVC’s
Acknowledging the limited evidence base, BSH2024 recommends:
Before starting thromboprophylaxis assess SCD-specific bleeding risks (e.g. Moya Moya)
Consider primary thromboprophylaxis for all adult SCD patients with indwelling CVC
If no additional VTE risk factors, this can be short course of prophylactic dose at time of insertion (6 weeks) and intermittently to cover high risk periods (e.g. hospital admissions)
If additional risks present, consider long-term full-dose anticoagulation
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
Transplant
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.