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Dr Kate RyanDr Kate Ryan
October 2014October 2014
HaemoglobinopathiesHaemoglobinopathies (Sickle Cell and (Sickle Cell and Thalassaemia) are the commonest genetic Thalassaemia) are the commonest genetic disorders in the UKdisorders in the UK
Increasing prevalence:Increasing prevalence:Babies identified though newborn screeningBabies identified though newborn screeningImmigration into UKImmigration into UKImproved survival with medical treatmentImproved survival with medical treatment
National antenatal and newborn screening National antenatal and newborn screening programmes are in place.programmes are in place.
Abnormal haemoglobin polymerises at low oxygen tension
Red cells become rigid
Haemolysis Vaso-occlusion
National Standards and Guidelines in Sickle Cell Disease
Sickle cell disease: clinical problemsSickle cell disease: clinical problems
Anaemia Anaemia
HbHb 77--9g/dl 9g/dl
InfectionsInfections
Painful crisesPainful crises
StrokeStroke
Leg ulcersLeg ulcers
PriapismPriapism
Visual lossVisual loss
Chronic organ damageChronic organ damage
Kidneys, lungs, joints, heartKidneys, lungs, joints, heart
SS Sb0 SC Sb+
Painful Episodes 80 100 4 4Acute Chest Syndrome
12.8 9.4 5.2 3.9
Stroke 0.6 0.1 0.2 0.1
ComplicationBeta Globin Genotype
All rates expressed per 100 patient-years.
Acute complications: how common?Acute complications: how common?Data from the Cooperative Study of Sickle Cell Disease (CSSCD)
TCD Velocity (cm/ s) Interpretat ion Yearly Risk of St roke
< 170 Normal ~1%
170 and < 200 Conditional intermediate
200 Abnormal ~10%
The role of blood transfusion in secondary stroke The role of blood transfusion in secondary stroke prevention is standard care prevention is standard care
All patients with abnormal All patients with abnormal TranscranialTranscranial Doppler scan Doppler scan should be offered prophylactic blood transfusion (STOPI should be offered prophylactic blood transfusion (STOPI and STOPII)and STOPII)
Improved outcomes with transfusion for silent cerebral Improved outcomes with transfusion for silent cerebral Infarcts (SITT Trial 2014)Infarcts (SITT Trial 2014)
HydroxycarbamideHydroxycarbamide? Not shown to prevent stroke ? Not shown to prevent stroke (TWITCH and SWITCH studies)(TWITCH and SWITCH studies)
Purpose:Purpose:
To treat anaemia and improve oxygen carrying To treat anaemia and improve oxygen carrying capacity of bloodcapacity of blood
Prevent or reduce painful/Prevent or reduce painful/vasovaso--occlusive or occlusive or sequestration complications by lowering sequestration complications by lowering proportion of proportion of HbHb S relative to S relative to HbHb A (aim < 30% A (aim < 30% acute or < 50% in some chronic situations)acute or < 50% in some chronic situations)
AlloimmunisationAlloimmunisation::
Incidence prior to Incidence prior to RhRh and K matching up to 36% and K matching up to 36% (USA) but some become undetectable(USA) but some become undetectable
Lower in UKLower in UK
Usually antiUsually anti-- C E and K C E and K All patients should have full red cell All patients should have full red cell phenotype/ genotype phenotype/ genotype
Choose blood matched for Choose blood matched for RhRh genotype and genotype and KellKell
Haemolytic transfusion reactionsHaemolytic transfusion reactionsClassical 7Classical 7--10 days10 days
HyperhaemolysisHyperhaemolysisdestruction of donor and recipient cells.destruction of donor and recipient cells.
Post transfusion Post transfusion HbHb < Pre < Pre TxTx
No No HbHb A detectedA detected
ReticulocytopeniaReticulocytopenia
Acute<7days DAT Acute<7days DAT negneg, no new , no new alloallo--abab identifiedidentified
Delayed> 7 days DAT, new all0ab foundDelayed> 7 days DAT, new all0ab found
Treat with steroids and Treat with steroids and IvIgIvIg
HyperviscosityHyperviscosity
Iron OverloadIron Overload
Transfusion transmitted infectionTransfusion transmitted infection
Sickle haemoglobin has much greater viscosity especially in the Sickle haemoglobin has much greater viscosity especially in the deoxygenated statedeoxygenated state
Increasing Hb over 10g/dl carries risk of hyperviscosity symptoms in presence of large quantities of Hb S
Top up or exchange?Top up or exchange?Advantages
Top Up Exchange
Technically easier and needs fewer resources
Better control of Hb S
Less blood required Avoids hyperviscosity
Quicker Less iron accumulation
Disadvantages
Iron accumulation Needs more resources (machine, trained nurse)
Cannot achieve acute Hb S <30% without risk of hyperviscosity
Expensive
Venous access problematic
More donor exposure
Top upTop up ExchangeExchange
Severe anaemiaSevere anaemia Acute Chest SyndromeAcute Chest Syndrome
Red cell Red cell aplasiaaplasia Acute strokeAcute stroke
SplenicSplenic sequestrationsequestration Acute hepatic sequestrationAcute hepatic sequestration
Severe sepsisSevere sepsis
Acute multi organ failureAcute multi organ failure
Progressive Progressive intrahepaticintrahepatic cholestasischolestasis
Possible indications for elective blood Possible indications for elective blood transfusionstransfusions
Level A or B evidence available
Level A and B evidence unavailable
Primary stroke prevention Fetal complications in pregnancy
Secondary stroke prevention Repeated severe painful crises
Elective surgery Pulmonary hypertension
Painful crises in pregnancy Leg Ulcers
Priapism
Transfusion is not required for steady state anaemiaTransfusion in SCD should be discussed with haematologistLaboratory should be informed that blood is for a sickle cell patient so they can ensure correct blood requestedImportant to ask patient if they have had previous reactions to blood or carry a cardDo not take Hb up to >90-100g/LTransfusion is lifesaving
Thalassaemia Standards 2008Thalassaemia Standards 2008
A group of inherited disorders A group of inherited disorders resulting in reduced synthesis of resulting in reduced synthesis of one or more one or more globinglobin chains.chains.This results in an imbalance of This results in an imbalance of globinglobin chains with the excess chains with the excess chain producing the pathological chain producing the pathological effects:effects:
damage to red cell precursors damage to red cell precursors ineffective ineffective erythropoeisiserythropoeisis
damage to mature red cells damage to mature red cells haemolytic anaemiahaemolytic anaemia
Thalassaemia MajorThalassaemia MajorTransfusion dependentTransfusion dependent
Thalassaemia Thalassaemia IntermediaIntermediaLess severe anaemia and can survive without regular Less severe anaemia and can survive without regular blood transfusionsblood transfusions
Thalassaemia Minor (trait, carrier)Thalassaemia Minor (trait, carrier)Asymptomatic carrierAsymptomatic carrier
Failure to thriveFailure to thriveFatigueFatiguePoor feedingPoor feedingDevelopmental delayDevelopmental delayPoor growthPoor growthSplenomegalySplenomegalyFacial appearance etcFacial appearance etc
Requires careful monitoring (monthly from Requires careful monitoring (monthly from diagnosis)diagnosis)
When to start transfusions?When to start transfusions?Good clinical judgement cannot be replaced by any kind of clear Good clinical judgement cannot be replaced by any kind of clear instructions instructions
regarding decisions whether to transfuse a patientregarding decisions whether to transfuse a patient [[LoukopoulosLoukopoulos, Palermo , Palermo Conference]Conference]
GenotypeGenotype
Growth / thrivingGrowth / thriving
HbHb levels as welllevels as well
Earlier:
Before any problems / spleen enlarges etc
Later:
Parents accept child needs
Child may prove not to need[best taken at Centre]
Haemoglobin levels should be maintained above 9.5-10g/dl.
Cannulation will be undertaken by an experienced nurse or doctor.
Pre-arranged transfusions should be started promptly.
Good transfusion practice must be observed
Transfusions will be given on each occasion in a designated area with suitable facilities, experienced regular named nurses and familiar supervising medical team.
Transfusion therapy and monitoring iron loading in Transfusion therapy and monitoring iron loading in thalassaemiathalassaemia
1 blood unit contains 200 mg iron 1 blood unit contains 200 mg iron
A 60 kg thalassaemia patient A 60 kg thalassaemia patient receiving 45 units of blood receiving 45 units of blood annually has annually has transfusionaltransfusional iron iron intake of 9 g iron/yearintake of 9 g iron/year
0.4 mg iron/kg body wt/day0.4 mg iron/kg body wt/day
In addition, up to 4 mg/day may In addition, up to 4 mg/day may be absorbed from the gutbe absorbed from the gut
Up to 1.5 g iron/yearUp to 1.5 g iron/year
Porter JB. Br J Haematol 2001;115:239 252
200 250 mg iron:Whole blood: 0.47 mg iron/mLPure red cells: 1.16 mg iron/mL
Organ systems susceptible to iron overloadOrgan systems susceptible to iron overload
Clinical Clinical sequelaesequelae of iron overloadof iron overload
PituitaryPituitary Impaired growth, infertilityImpaired growth, infertility
HeartHeart CardiomyopathyCardiomyopathy, cardiac , cardiac
failurefailure
LiverLiver Hepatic cirrhosisHepatic cirrhosis
PancreasPancreas Diabetes mellitusDiabetes mellitus
GonadsGonads HypogonadismHypogonadism
Repeated transfusions lead to Repeated transfusions lead to iron overloadiron overload
0
10
20
5
15
25
30
0 20 40 60 80 100 140120 160
Iro
n (
mg
/g d
ry w
eig
ht)
Transfusion duration (months)
R=0.795
Harmatz P et al. Blood 2000;96:76 79, American Society Hematology, with permission
Significant correlation between transfusion duration and liver iSignificant correlation between transfusion duration and liver iron ron on biopsyon biopsy
Borgna-Pignatti C et al. Haematologica 2004; 89(10): 1187-93
NN %% NN %%
Heart failureHeart failure 133133 60.260.2 3131 50.850.8
InfectionInfection 1515 6.86.8 99 14.814.8
ArrhythmiaArrhythmia 1515 6.86.8 44 6.66.6
Myocardial infarctionMyocardial infarction 44 1.81.8
CirrhosisCirrhosis 99 4.14.1
ThrombosisThrombosis 99 4.14.1
MalignancyMalignancy 88 3.63.6 22 3.33.3
DiabetesDiabetes 77 3.23.2 22 3.33.3
AccidentAccident 44 1.81.8 11 1.61.6
Renal failureRenal failure 33 1.41.4
HIV / AIDSHIV / AIDS 33 1.41.4 22 3.33.3
Familial autoimmune disorderFamilial autoimmune disorder 22 0.90.9 11 1.61.6
AnorexiaAnorexia 11 0.50.5 11 1.61.6
Haemolytic anaemiaHaemolytic anaemia 11 0.50.5 11 1.61.6
ThrombocytopeniaThrombocytopenia 11 0.50.5
UnknownUnknown 66 2.72.7 55 8.28.2
TotalTotal 221221 6161
All patients (N=1073) All patients born after 1970* (N=720)
Causes of death in Thalassaemia
Serum ferritinSerum ferritin reflect current iron stores.reflect current iron stores.
Liver biopsyLiver biopsy gold standardgold standard Invasive Invasive
MRI techniquesMRI techniques Standard of careStandard of care
End organ functionEnd organ function Too lateToo late
DiseaseDisease--free survival related to body iron levels free survival related to body iron levels assessed by serum ferritinassessed by serum ferritin
Chelation therapy (years)
0.00
0.50
0.25
0.75
1.00
0 2 4 6 8 10 1412 16
Pro
po
rtio
n w
ith
ou
t ca
rdia
c d
isea
se
<33% ferritin measures>2500 ng/mL
33 67% ferritin measures>2500 ng/mL
>67% ferritin measures>2500 ng/mL
Cardiac disease-free survivalin patients with:
Olivieri N et al. N Eng J Med 1994;331:574 578. Massachusetts Medical Society, with permission
Olivieri NF & Brittenham GM. Blood 1997;89:739 761
Liver iron and risk from iron overload
50403020100
50
100
150
200
250
Age (years)
Hep
atic
iro
n (
µmo
L/g
wet
wei
gh
t)
50
40
30
20
10
0
Hep
atic iron
(mg
/g d
ry weig
ht)
Increased risk of complications
Normal
Thalassemia major
Threshold for cardiac disease and early death
Optimal level in thalassaemia
T2* MRI: emerging new standard for cardiac iron
Anderson LJ et al. Eur Heart J 2001;22:2171 2179, Oxford University Press, with permission
Lef
t ve
ntr
icu
lar
ejec
tio
n f
ract
ion
(%
)
0
50
70
40
30
20
10
60
80
90
0 20 40 60 9080 10010 30 50 70
Heart T2* (ms)
Cardiac T2* value of 37 in a normal heart
Cardiac T2* value of 4 in a significantly iron overloadedheart
Relationship between myocardial T2* values and left ventricular ejection fraction. Below a myocardial T2* of 20 ms, there was a progressive and significant decline in left ventricular ejection fraction (R=0·61, P<0·0001)
Goals of Goals of chelationchelation therapytherapy
What is What is chelationchelation therapy?therapy?
Chelate
Chelator MetalChelator
Toxic
ExcretionMetal
Comparison of Comparison of chelatorschelators
Property DFO Deferiprone Deferasirox
Usual dose (mg/kg/day)
25 60 75 20 30
Routesc, iv
(8 12 hours, 5 days/week)
Oral
3 times daily
Oral
Once daily
Half-life 20 30 minutes 3 4 hours 12 16 hours
Excretion Urinary, faecal Urinary Faecal
Adverse effects
Local reactions, ophthalmologic, auditory, growth
retardation, allergic
Gastrointestinal disturbances,
agranulocytosis/ neutropaenia,
arthralgia
Gastrointestinal disturbances, rash, mild
non-progressive creatinine increase,
ophthalmologic, auditory
DFO therapy improves survival in regularly transfused thalassaemia patients
Gabutti V & Piga A. Acta Haematologica 1996;95:26 36. S Karger AG, Basel, with permission
Su
rviv
al %
0
60
80
50
40
30
20
10
70
90
100
0 282624222018161412108642 30 32 34 36 38 40
Years
300 365225 300150 22575 1500 75
DFO Infusions/year
Kaplan-Meier analysis of survival in 257 consecutive
thalassaemic patientsaccording to the mean
compliance with subcutaneous DFO therapy
Deferasirox effectively decreases LIC across a range of transfusion-dependent anaemias
Thalassaemia (Study 107)
Thalassaemia (Study 107)
All anaemias(Study 108)
SCD (Study 109)
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
0
Mea
n c
han
ge
in L
IC (
mg
Fe/
g d
w)
Deferasirox 30 mg/kg/day DFO > 50 mg/kg/day
Deferasirox was non-inferior to DFO at doses of >20 mg/kg/day.
Studies 107, 108, 109Cappellini MD et al. Blood 2006;107(9):3455-3462; Porter J et al. Presented at ASH 2004 [Blood 2004;104(11):abst 3193]; Vichinsky E et al. Presented at ASH 2005 [Blood 2005;106(11):abst 313]
Decision based on Decision based on
Tolerance of current treatmentTolerance of current treatment
Current iron stores as evidenced by serum Current iron stores as evidenced by serum ferritin levels and liver/ heart imaging ferritin levels and liver/ heart imaging techniquestechniques
Trends in ferritin levelsTrends in ferritin levels
Patient choicePatient choice
Liver loading appears more important than Liver loading appears more important than cardiac loadingcardiac loading
Ferritin levels unreliableFerritin levels unreliable
Liver MRI techniques now recommendedLiver MRI techniques now recommended
Many patients have significant lifetime Many patients have significant lifetime transfusion burden even if not on regular transfusion burden even if not on regular transfusionstransfusions
Optimal iron Optimal iron chelationchelation intensity unclearintensity unclear
Transfusion may be lifesaving or reduce morbidity in Transfusion may be lifesaving or reduce morbidity in Sickle Cell Disease or ThalassaemiaSickle Cell Disease or Thalassaemia
The number of patients on transfusion is likely to The number of patients on transfusion is likely to increaseincrease
National guidelines indicate which patients with SCD National guidelines indicate which patients with SCD need transfusionsneed transfusions
Iron accumulation is a significant problem for these Iron accumulation is a significant problem for these patients and patients and chelationchelation should aim to prevent should aim to prevent complications complications
Blood should be Blood should be genotypicallygenotypically matched to prevent matched to prevent alloimmunisationalloimmunisation