Thalassaemia (UKTS 2016)
With thanks to Moosa Qureshi for these notes (PDF version)
N.B. Limited text functions on this site make this page a challenge, so all Greek characters have been swapped into the Latin.
N.B. Screening and diagnostic tests are covered here
b-thal Definitions
b-Thal Major – More than 7 transfusion episodes per year
b-Thal Intermedia – 7 or fewer transfusion episodes per year
b-Thal Carrier – do not require transfusion
B-thal pathophysiology
Networks for care and commissioning
Every patient should have a key contact health professional and Local Haemoglobinopathy Team (LHT)
Role of Specialist Haemoglobinopathy Centres (SHC)
Acting in a hub and spoke model with other linked providers
Annual comprehensive review
Specialist advice and transfer of complex care
Systems for information sharing, clinical governance, accountability and staff development
National Haemoglobinopathy Registry (NHR)
Captures information on AEs, transfusion, medication, iron overload
Provides information for future planning of service delivery
Participation is voluntary —> requires informed consent
Integrated care, audit, clinical guidelines, clinical pathways
Peer Support groups
Annual review
New symptoms
Events over preceding 12 months
Transfusion management
Iron status
Iron chelation and concordance
Prophylaxis for splenectomised patients: vaccination (Hib, meningitis, pneumococcal) and antibiotics (Pen V or erythromycin)
Specialist referrals, eg cardiac, hepatology, endocrine, transplant
Growth (for children)
Clinical exam: cardiac, liver, pubertal status
Fertility, conception, partner testing
Psychosocial evaluation
Education, lifestyle —> influence concordance with treatment
Quality Assessment
Independent external peer review of thalassaemia services every 2 to 3 years —> Report to NHSE
Each SHC should be responsible for a defined geographical area
SHC should monitor annual patient data from their network: number of thalassaemia patients under active care, number having annual review, AEs in thalassaemia patients
Robust fail-safe mechanisms for appropriate clinical care pathways for babies identified by new-born screening programme
Psychosocial care
Challenges: transition to adulthood/independence, poor self-esteem, low mood, health anxieties, needle phobia, treatment compliance, school and work difficulties, relationship problems, cultural issues
Milestones: Initial diagnosis, first transfusion, start of chelation, puberty, transition, pregnancy, other major life events
Core staffing of SHC to include a clinical psychologist with special interest in thalassaemia —> They should be an embedded member of the MDT
Offer peer support groups
Empower patients, eg involve them in monitoring their own progress such as ferritin results
The newly diagnosed infant
Neonatal heel prick test is a screening test, not a diagnostic test
Diagnosis of a serious thalassaemia needs to be timely and accurate —> include globin genotype
FBC, blood film, Hb electrophoresis or HPLC, b and a globin genotype, Xmn1 polymorphism (see below)
Test parents —> Genetic counselling regarding future pregnancies, other family members
Clinical phenotype cannot be predicted accurately in early stages —> Close monitoring of child to determine clinical course
Family’s importance as the central care-givers —> Inform them
National Haemoglobinopathy Registry
Transfusion
Monitor infants with b-thalassaemia carefully for transfusion indications:
Severe anaemia (Hb <70 on two occasions)
Failure to thrive
Thalassaemic bone deformity
Cardiac failure
Consider other causes such as IDA or G6PD
Extended red cell phenotype and genotype before starting transfusions
Investigations
Serial Hb measurements; G6PD screen and assay if low
Full red cell extended phenotype and genotype (C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis)
LFT and baseline ferritin assay
Hepatitis B surface antigen; Hepatitis C antibody; HIV antibody
Safe transfusion
Start (and ideally complete) course of hepatitis B vaccinations before first transfusion
Maintain Hb at trough 90 to 105 g/L
ABO compatible, fully matched for all Rh antigens and K, and antigen-negative for any clinically significant (historic or current) antibodies
RBC units should be <2 weeks old
Good transfusion practice
Clinical review of patient before transfusion by HCP
Review of transfusion-dependent patients by designated clinician every 3 months, in addition to annual review
Iron overload
SHC/LHT information sharing
Inform patients about benefits and possible AEs of each treatment option
Support concordance with chelation:
MDT approach - doctors, nurse specialists, clinical psychologists, play therapists for children
Peer support
Use annual transfusion requirement to estimate iron stores
Indications for iron chelation:
Serum ferritin >1000 ug/L on two occasions + 10-12 transfusions + Age >2yrs
Alternatively TSAT >90% and/or when 1000g pure red cells transfused
Ferriscan (R2 MRI) to evaluate Liver Iron Concentration: Normal LIC is 0.2-1.8 mg/g dry weight, but aim for 3-7 mg/g dw (to avoid chelator toxicity). Levels above 15 mg/g dw have been associated with increased morbidity/mortality.
Cardiac T2* MRI is expressed in milliseconds – the higher the reading, the lower the cardiac iron. Aim for >20 ms (low risk). 10-20 ms is mild/moderate risk, <10 ms is high risk of cardiac failure.
Pregnancy:
If planned, then prior intensive chelation to reduce SF, LIC and myocardial iron
Stop all chelators as soon as pregnancy diagnosed
DFO can be considered from 20/40 gestation if iron load is high, to prevent cardiac complications. DFX should be avoided and DFP is contraindicated.
Iron Chelators:
See iron overload page
Referral for Blood and Bone marrow transplantation
Offer to parents when child is 1-2 years of age
Growth, Development and Endocrine Function
Iron toxicity —> pituitary damage —> hypogonadotrophic hypogonadism, short stature, delayed puberty
Further pituitary failure can lead to secondary hypothyroidism and adrenal failure
Ideally joint clinic with experts in bone metabolism and endocrine
Regularly monitor growth and development of children
Minimum annual review for disturbance of hypothalamo-pituitary axis, calcium and bone homeostasis
Ask about menstrual history and impotence
Can give GH (to children), oestrogen, testosterone, cortisol, etc
Transition from Paediatric to adult services
Transition with named key worker should commence from 13 years age
Support and education for transition for taking responsibility for own health and choices
Close monitoring of adherence to iron chelation
Note that many toxic effects of iron accumulation can present at this age range
Fertility and management of pregnancy
Factors affecting fertility:
Hypogonadotrophic hypogonadism
Diabetes
Hypothyroidism
BM transplant
Paediatric endocrinologist: Closely monitor pubertal development, growth, endocrine function in boys and girls
For males:
HCG injections can help with spermatogenesis.
Stop DFP/DFX 3/12 before conception, switch to DFO
For females:
Joint management of pregnancy and increased risks: cardiomyopathy, osteoporosis, haemosiderosis off-chelation, diabetes (risk for foetus), osteoporosis, infection
Review by cardiologist at 28/40 gestation
Can re-start DFO from second trimester and continue through breast-feeding (not DFP or DFX)
See also: thalassaemia pregnancy management plan.
Management of acute complications
Discuss with SHC as soon as possible, and consider transfer
Enter serious acute complications on the NHR
Cardiac: High risk if MRI T2* <10 ms (see below)
Sepsis:
Consider as immunocompromised.
Consider line-related infections, Klebiella, Yersinia, malaria.
Acute back pain/spinal cord compression:
Osteoporotic fracture
Extramedullary haematopoiesis should be treated with hyper-transfusion (aim for Hb 120 g/L) +/- hydroxycarbamide, but give radiotherapy if there is spinal cord compression. Surgical decompression is rarely an option.
Endocrine: Diabetes, hypocalcemia, hypothyroidism
Gallstones and renal stones/hydronephrosis
Liver
Anaemia
Cardiovascular management
Access to cardiology service with experience in management of cardiac consequences of thalassaemia
Age 7 to 10 years: first cardiac evaluation, including clinical, ECG, echo and MR T2* (see above)
High risk is age 16 to 25 —> require annual assessments as a minimum
Myocardial iron and LV impairment require urgent review by SHC team —> inpatient intensive chelation
Note that chronic anaemia leads to hyperdynamic circulation and cardiac chamber dilatation: lower limit of normal EF is 63%
Address lifestyle factors
Full anticoagulation if indwelling venous lines or AF
Acute decompensated heart failure:
IV DFO, oral DFP, adrenocorticoid therapy, thiamine, potassium and magnesium replacement
Inotropic support should be used cautiously
Pulmonary HTN:
More common in untransfused patients
Treatment includes intensive transfusion, life-long anticoagulation
Refer to national pulmonary HTN centre for consideration of sildenafil.
Pregnancy: Should have T2* >20 ms and EF >65% before conception
Glucose Tolerance and Diabetes Mellitus
Annual check for impaired glucose regulation and diabetes from puberty, or from age 10 years if family history.
Diabetes review:
BM control
CVS risk factors (smoking, bp, cholesterol)
Diabetic complications (retinal screening, foot)
Sexual health
Diagnosis: Oral glucose tolerance test
Monitoring: Fructosamine levels (HbA1c or glycated Hb are unreliable after transfusion and should be avoided in thalassaemia patients)
Bone problems
Focus on achieving peak bone mass
Lifestyle advice eg smoking cessation, ETOH, undertaking weight bearing exercise
Optimal transfusion during childhood to prevent irreversible bone deformities of skull and face
Avoid desferrioxamine bone toxicity (eg pseudorickets) by not exceeding recommended DFO dose
Vitamin D supplements if needed (aim for 80 nmol/L, higher than ‘normal range’ 50 nmol/L)
HRT for hypogonadism
Monitor adult patients for osteoporosis: DEXA scan, consider bisphosphonates
Liver
Monitor LFTs monthly on oral chelation and every 3 months on DFO
Ferriscan (see above)
Hepatitis A and B vaccination
Designated specialist hepatologist in cases of chronic active HBV or active HCV —> consider antiviral therapy
HCV can be treated with Harvoni (Ledipasvir–sofosbuvir) oral agent, but will require i.v. Ribavirin if there is cirrhosis
Monitor AFP and USS six-monthly in patients with cirrhosis
Prenatal diagnosis and preimplantation genetic diagnosis
Thalassaemic disorders: b-thalassaemia major/intermedia, haemoglobin E/b thalassaemia, a0 thalassaemia hydrops fetalis or severe haemoglobin H disease
All couples at risk of having children with thalassaemia disorder > Refer to specialist genetic counsellor with expertise in haemoglobin disorders
Inform of prenatal diagnosis and preimplantation genetic diagnosis as options
If prenatal diagnosis shows an unaffected fetus and the couple already have a child with thalassaemia, then perform fetal HLA typing —> Collect cord blood cells at birth if the fetus and the affected child are HLA-compatible, to provide future BM transplant option
Offer PGD if female partner is aged <50 years and there is no living unaffected child from the current relationship
See also notes on UK screening program
Previously treated outside the UK
Thorough assessment in SHC asap after arrival in UK
Focus on transfusion history, chelation, co-morbidities, medications, developmental history, splenectomy, complications of iron overload, bone problems, family history
Baseline investigations/assessments (see below)
Vaccinate and re-start transfusion without delay
Cellular Therapy
Casgvey (exagamglogene autotemcel, “exa-cel”)
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
12-35 yo pts with transfusion-dependent beta-thalassaemia (approx. 36 units in previous 2 yrs)
As of Feb 2022, 44 patients treated
42 of 44 stopped red cell transfusions
Approved by MHRA for use in UK in 2023
Management of non-transfusion-dependent thalassaemias
DNA diagnosis (b globin / a globin genotype, Xmn1 C—>T polymorphism) can help predict for a NTDT. Further detail available in the 2016 standards (link in title).
Clinical phenotype may not always be predictable from genotype —> Monitor children carefully during first 5 years of life for evidence of transfusion need
Monitor older children, adolescents and adults with NTDT regularly
Indications for transfusion:
Before splenectomy
Growth delay
Pulmonary HTN
EMH masses
Clinical phenotypes on NTDT are as follows:
Moderate/Severe (10% of b/b, majority of E/b, very small proportion of HbH) can only just about manage without transfusions, but have significant problems such as reduced exercise tolerance, hypersplenism, poor growth
Mild (small proportion of b/b, some with E/b, most patients with HbH) do not require transfusion but can experience long-term complications usually after age 30, including pulmonary HTN, gallstones, osteoporosis, VTE and iron overload
Monitoring iron overload in NTDT:
Low hepcidin levels —> increased iron absorption from GI tract and release from RES —> relatively low serum ferritin but high iron load in the liver (irrespective of RBC transfusion)
LIC is most important parameter in NTDT, Ferriscan should be repeated every 2 to 5 years from age 10
Annual SF should be correlated with LIC
Iron chelation is recommended where LIC is >5 mg/g dry weight, and DFX (not DFO) is first line for this patient group
Myocardial T2* MRI should be reserved for older patients and those who require 3 to 6 transfusions per year