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Inherited Haemoglobin disorders Flashcards

1
Q

What is haemoglobin

A

Tetrameric complex of globin chains
Each globin chain is associated with a heme group
Each heme group contains a single atom of iron
Heme groups carry oxygen
Adults:
Main haemoglobin in HbA
HbA=alpha2beta2

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2
Q

What are the globin gene clusters

A

2 genes encode the alpha globin chain on Ch16

1 genes encodes the beta globin chain on Ch11

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3
Q

What chains are in regal haemoglobin

A

HbF

Alpha2gamma2

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4
Q

Chains in adult Hb

A 
HbA 
Alpha2 beta 2 95% 
HbA2
Alpha2delta2 3.5%
HbF 
Alpha2 gamma2 
0.5-1%
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5
Q

How are haemoglobin disorders classified

A

Qualitatively
- changes to the globin chain amino acid sequence, resulting in variant haemoglobin e.g. Sickle cell disease
Quantitative
- Complete or partial reduction of a globin chain i.e. Thalassaemia

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6
Q

Sickle cell anaemia at risk population

A

African/Caribbean heritage
Middle eastern e.g. Yemeni
South Asian e.g. Indian

Consider family origins not skin colour

Evolutionary advantage for carrier state - confers some protection against falciparum malaria

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7
Q

Genetic basis of sickle cell disease

A

A genetic polymorphism results in substitution of the amino acid valine for glutamic acid at position 6 of the beta globin chain

Autosomal recessive inheritance
- HbSS, homozygotes - sickle cell disease
Both beta globin chains are abnormal - instead of making HbA (alpha alpha beta beta) they make a variant chain haemoglobin HbS (alpha alpha SS)
- HbAS heterozygotes - sickle cell trait
Only one of the beta globin genes is abnormal
They make both HbA and HbS

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8
Q

Other sickling syndromes

A

SC
S/beta thalassaemia
Spectrum of disorders, variable genotype, phenotype, haemoglobin, clinical presentations

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9
Q

What is the sickle cell trait genetic state

A

Carrier state

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10
Q

Do you get any protection from falciparum malaria in sickle cell trait

A

Partial

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11
Q

Symptoms of sickle cell trait

A

Usually asymptomatic with normal life expectancy
Can be associated with renal disease, splenic infarction, increased risk of thromboembolism, pregnancy complications, sickling under extreme physiological stress

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12
Q

Genetics to future children

A

Risk of the disease - HbSS -consider genetic counselling

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13
Q

What is the pathophysiology of SCD

A

HbS (alphalphaSS) has a propensity to polymerise when in the deoxyhaemoglobin state
Alters the structure of the red blood cells - appear like sickles on the blood film
Reduced deformability of the red blood cells resulting in venoocclusion
Reduced life span of red cells because of haemolysis

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14
Q

As SCD is a form of haemolytic anaemia what effects can this cause

A 
Shortened life span of red cells 
- increased bilirubin
- pigment gallstones
Compensatory increase in red cell production
- reticulocytosis
- potential for folate deficiency
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15
Q

Acute presentation of SCD

A 
Painful vasocclusive crises 
Infections
- septicaemia, meningitis, UTI, osteomyelitis
- hyposplenism (functional asplenia/splenic atrophy) 
Acute chest syndrome
Stroke
Acute splenic sequestration
Acute hepatocyte sequestration
Aplastic crisis- parvovirus B19 infection
Priapism
Growth delay 
Any other illness
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16
Q

How to manage a painful crisis

A

Analgesia-
-prompt
- tailored to the patient
- e.g. Paracetamol, ibuprofen, opiates morphine, diamorojine
Early review of efficacy
Fluids- oral preferred, careful fluid balance
Oxygen - monitor sats on air as well as on O2
LMWH- increased risk of thromboembolic events
Outpatient model - hospitalisation not required for uncomplicated crisis
Drug depends how is rare - only a concern in a minority of patients

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17
Q

What are the complications of an acute crisis

A

Sepsis
- frequent precipitate of admission
- frequent cause of morbidity and mortality
- may not see all classical signs
Renal
- leading cause of morbidity and mortality
- close fluid balance, monitor renal function
VTE
Acute sickle chest syndrome

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18
Q

What is acute sickle chest syndrome

A

A form of acute lung injury distinct from pneumonia
Leading cause of death
High risk - inpatients in crisis, pregnancy, post partum
Tachypnoea, cough
Chest pain, rib pain
Hypoxia
Fever
Clinical or radiological evidence of consolidation, pulmonary infiltrates
Risk of recurrence

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19
Q

Treatment of acute chest syndrome

A

Emergency
Recognise early - significant morbidity
Urgent cross match - extended phenotyping
Urgent outreach/Critical care review
Respiratory support - O2, CPAP, ventilation
General support - fluids, physio
Transfusion - top up /exchange

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20
Q

SCD as a chronic illness - what happens in end organ damage ?

A 
Renal - concentration defect, CKD
Lungs- chronic sickle lung 
Strokes - infarct or haemorrhage 
Cardiac - cardiomegaly, right heart failure, pulmonary hypertension 
Eyes - retinopathy
Hepatobiliary - gallstones
Leg ulcers - int/ext malleoli 
Avascular necrosis at femoral heads 
Erectile dysfunction secondary to priapism
21
Q

General principles of SCD management-acute

A

Early recognition and prompt expert management

22
Q

General principles of SCD management- chronic

A

Education
PSychological support
Primary / secondary prevention
Screening
- children - transcranial dopplers to assess risk of stroke
- adults - echocardiography to pulmonary hypertension
Management of established complications

23
Q

What specific interventions are included in patient SCD management

A 
Folic acid
Analgesia
Infection
- penicillin prophylaxis 
- vaccination - pneumococcal, HIb, meningococcal, flu
- early recognition of symptoms 
- self referral, direct access
- empowerment to ask for expertise 
Blood transfusion 
- top up exchange 
- exchange transfusion
- regular transfusion programmes e.g. To prevent stroke in children with high risk Dopplers
Hydroxycarbamide 
- patients with severe recurrent painful crises or episodes of acute chest syndrome
24
Q

Risks of blood transfusions

A 
Alloimmunisation
Haemolytic transfusion reactions 
Transfusion associated infections
Iron overload with chronic transfusion
Hyperviscosity

When considering transfusion

  • seek expert advice
  • consider the patients steady state Hb
25
Genetic basis of alpha thalassaemia
``` Reduction of a globin chain production - lack of HbA Relative excess of beta and gamma chains , from abnormal haemoglobins Beta 4 = Hb H Gamma 4 = Hb Barts ``` Autosomal recessive inheritance, various genetic defects Pathophysiology - ineffective haemopoiesis and haemolysis due to unstable red cells cause anaemia
26
What is the regional variation in carrier type
``` Alpha 0- aa/ -- High risk haplotype SE Asia East Med Alpha + a/-a Low risk haplotyoe Africa India ```
27
What happens as the globin chains reduce
aa/aa - normal - a/-- heterozygous + low MCV /MCH - a/-a homozygous + low MCV/MCH - -/aa heterozygous 0 low MCV/MCH - -/-a heamoglobin H disease Thal intermedia - -/-- Hb Barts Hydrops
28
Genetic basis of beta thalassaemia
Reduction of beta globin chain production Beta 0 mutations - total loss of beta chain production from the gene Beta + mutations - partial reduction of beta chain production from the gene B/B normal B/B0 beta thal trait B0/B0 homozygous B0 thalassaemia - beta thalassaemia major B0/B+ compound heterozygote = beta thalassaemia intermedia
29
Pathophysiology of beta thalassaemia
Absent or severely reduced beta chain production Relative access of alpha chains Excess alpha chains are unstable and precipitate in red cell precursors, interfering with red cell maturation Ineffective erythropoiesis and haemolysis lead to anaemia
30
Presentation of beta thalassaemia major
Healthy at birth Progressive anaemia as HbF reduces Failure to thrive Cardiac failure Extramedullary haemopoiesis - liver, spleen Bony overgrowth - e.g. Skull, dental abnormalities Ideally detected as part of antenatal screening programme and monitored/ followed up for complications
31
Requirement for blood transfusion in beta thalassaemia
Starts around 6-9 months continues 2-4 weekly for life ( unless they have a bone marrow transplant ) Reverses progressive anaemia
32
What is iron overload
Major toxicity of chronic blood transfusion Contributes or growth failure Multiple endocrine dysfunctions Cardiac and hepatic toxicity
33
Endocrine dysfunction in beta thalassaemia major
Associated with high levels of iron overload Anterior pituitary iron deposition affect hypothalamus-pituitary axis - hypogonadism - delayed puberty, subfertility - hypoparathyroidism - calcium metabolism - hypothyroidism Pancreatic damage Diabetes Mellitus , increased with FH of type 2 DM
34
What is the management of diabetes
Screw with glucose tolerance test - earlier with family history Intervention - lifestyle advice, chelation Manage with help of diabetic care specialists - fructosamine monitoring (HbA1c unreliable) - long term complications
35
What happens to the bones in beta thalassaemia
Osteoporosis Short stature Bony overgrowth Calcium profile, vit D, PTH assessment and replacement if low Bone deformity - monitoring every 2 years from childhood Lifestyle intervention - smoking, alcohol, diet, exercise Sex hormone replacement
36
How is cardiac disease associated with beta thalassaemia
Associated with chronic severe iron overload Before iron chelation therapy it was universal Still remains a major chase of death - severe cardiac failure, dysrhythmia Preventable with iron chelation Assess cardiac iron using MRI T2*
37
How is liver disease associated with beta thalassaemia
Associated with chronic severe iron overload Cirrhosis Other liver diseases can increase the risk of progression - transfusion acquired hep B and C Risk of HCC
38
What drug is used in iron chelation and how is it administered
Desferrioxamine 3-5 night a week of over night subcutaneous infusions Start around 2 yo Concordance issues
39
Are there another ways to administer iron chelation
Oral forms Deferasirox - once daily solution Renal and liver toxicity require monitoring Deferiprone Thrice daily schedule Risk of neutropenia so FBC monitoring Very effective in removing cardiac iron
40
Acute presentation of thalassaemia - infections
``` Infections - splenectomy - penicillin prophylaxis, immunisations Biliary tract sepsis Unusual infections seen - yersinia Query neutropenia if on deferiprone Line related sepsis Travel history - malaria ```
41
Acute presentation of thalassaemia - cardiac
History of poor compliance , low T2* (<10mins) Dysthymia Cardiac failure Cardiology care - inotropes, ACE inhibitors, diuretics, intensive chelation- IV DFO, deferiprone Psychological support
42
Acute presentation of thalassaemia - endocrine
Diabetic Hypoadrenal crisis Hypocalcaemia
43
What is the only curative option for beta thalassaemia
``` Bone marrow transplant Risk of mortality/morbidity -death -graft - GvHD - infertility Ideally done as an infant before developing comorbidity ```
44
What are the screening programmes for beta thalassaemia
Antenatal and neonatal only Antenatal screening to identify 'at risk' pregnancy Aim to screen in the first trimester- early offers most choices Screening strategy determined by local prevalence - bham universal screening - less prevalent areas selective screening based on family origin Neonatal screening Aim to identify infants with SCD to allow early intervention I.e. Education, penicillin, vaccination Additionally it identifies carriers of other structural variants and beta thalassaemia major
45
Investigations to do in beta thalassaemia
``` FBC Hb MCV MCH RBC -blood film Ferritin Iron deficiency is differential for microcytic anaemia apparent in thalassaemia ```
46
What is part of the haemoglobinopathy screen
Sickle solubility test Screen for HbS pos if HbSA train or HbSS SCD HPLC/Hb electrophoresis Separate and quantify proportions of normal haemoglobins Identify variant haemoglobins HbA2 is raised in beta thalassaemia
47
What are the result of the blood investigation in those with the sickle cell trait
FBC normal Film usually normal Solubility test positive HPLC HbA and HbS
48
What are the result of the blood investigation in those with the sickle cell disease
``` Hb variable 60-110 g/L MCV normocytic MCH normochromic Film sickle cells target cells Solubility test positive HPLC HbS ```
49
What are the result of the blood investigation in those with the alpha mad beta thalassaemia trait
Hb low normal or reduced MCV microcytic e.g. 65fl MCH hypochromic e.g. 20p.g. RBC raised > 5 x 10^12 /L Film microcytic hypochromic, anisopoikilocyosis , target cells, tear drops, basiphikic stippling, fragements, uncleared reds HbA2 raised in beta thalsasseamia normal in alpha thal Ferritin normal unless coexisting iron deficiency

Y3 (22 decks)

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