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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

B-thal pathophys.png


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:

 

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

CLIMB THAL-111 2022

  • 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

catheter associated thrombosis (BSH2024)

High risk of VTE in thalassaemia 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:

  • Consider primary thromboprophylaxis for all adult Thal patients with indwelling CVC

  • If no additional VTE risk factors, this can be prophylactic dose

  • If additional risks present, consider long-term full-dose anticoagulation

  • (Thal-specific additional risks include: splenectomy, iron overload, age >35, long-term anaemia)

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