Lecture ILO’s Flashcards
What is haemoglobin?
• Globular protein found in RBCs
• Main responsibilities - O2 and CO2 carriers
• High affinity
• Consistsof4subunits–2typesofglobinchains
• Contains 4xhemegroupwith4xirongroupboundto each one
• Differentformsofhaemoglobin
• Adult (~95%, Haemoglobin A): 2 alpha, 2 beta chains
• A2 (~1.5-3%): 2 alpha, 2 delta
• Foetal (Haemoglobin F): 2 alpha, 2 gamma. Exists when in the fetus, but can occur after delivery and is elevated in people with sickle cell and beta thalassaemia. Usually reduces at 3-6 months
RBC breakdown and haemoglobin recycling
• RBCs have a life span of 3/12
• Liver is responsible for breaking it down,has special cells called Kuppfer cells which are a type of phagocyte
• Kuppfer cells break down haemoglobin into globin and iron
containing heme groups
• Globin – most are digested by enzymes and produce amino, which are either recycled or metabolised by liver.
Some are not broken down and are released into circulation as alpha and beta chains, which are removed from circulation by the kidneys
Heme – broken down to iron and bilirubin
Iron – stored by the liver within ferritin OR transported to the bone marrow within transferrin, to produce more Hb
Thalassaemia
decreased or absence of synthesis of one of the two polypeptide chains (alpha or beta) that form the normal HbA
• Defects in the alpha globin chain – alpha thalassaemia (⍺T)
• Defects in the beta globin chain – beta thalassaemia (βT)
• Gene in question is located on an autosome - one of the paired chromosomes
• Means that it doesn’t affect a specific gender
• Recessive - 2X copies of the defected gene
are required to have the trait or disorder
• 1X copy – “carrier”
Thalassaemia epidemiology
THALASSAEMIA EPIDEMIOLOGY
• Alpha Thalassaemia
• More prevalent in Southeast Asia,
Africa and India
• ~5% of the population are carriers
• BetaThalassaemia
• More prevalent in the Mediterranean, Middle East, Central and South Asia and Southern China
• ~1.5% of the population are carriers
What is the problem with Thalassaemia causing a globin chain defect?
• When a specific globin chain has a problem, your body will naturally produce more of the ‘correct’ globin chain, thus there is an imbalance in haemoglobin synthesis
• When this occurs, there is an excess of either alpha or beta chain, resulting in RBC membrane damage or cell destruction
• These cells cannot survive and cause ineffective erythropoiesis, resulting in anaemia and compensatory erythroid hyperplasia (bone marrow ect eventually becomes ineffective)
• When RBCs breakdown, they release various molecules, specifically iron which in excess can cause various problems
Signs and symptoms of Thalassaemia
Symptoms
• Fatigue
• Pallor
• Jaundice
• Poor growth and development
Signs
• Incidental finding on FBC (microcytic anaemia)
• Hepatosplenomegaly, splenomegaly
• Bony deformities (e.g frontal bossing, prominent facial bones)
• Severe cases – murmur, heart failure (due to severe anaemia)
• Gallstones
Alpha Thalassaemia presentation
Varying disease spectrum
Silent carrier:
● Often found incidentally on FBCs
Trait
● Mild microcytic anaemia (low Hb, low MCV)
● May be tired - often given iron
supplementation which does NOT resolve symptoms
HbH
● Mild - moderately severe anaemia
● May have signs including splenomegaly,
jaundice
● Peripheral blood films may show Heinz Bodies
aT major
● Incompatible with life
● Usually lethal in utero
● Causes hydrops foetalis
Beta Thalassaemia presentation
Varying disease spectrum
Trait
● Mild microcytic anaemia (low Hb, low MCV)
● May be tired - often given iron
supplementation which does NOT resolve symptoms
Intermedia
● Microcytic anaemia
● May have signs of splenomegaly, variable bone
changes
Major
● Severe haemolytic anaemia (when RBCs are destroyed faster than production)
● Hepatosplenomegaly, jaundice
● Increased RBC production demand may produce
fevers
● Facial and skeletal abnormalities
● Infancy: failure to thrive, vomiting feeds, stunted
growth, irritability
Investigations of Thalassaemia
Bedside
● Observations (HR, RR, O2, oC, BP) – are they stable?
● ECG – how’s their heart doing? Any signs of the heart working too hard? Eg right heart strain
● BMs – increased risk of diabetes (excess iron deposits on pancreas)
Bloods
● FBC – evaluate anaemia (would show a microcytic anaemia, ie. low Hb, low MCV)
● Haematinics – raised iron and ferritin
● U&Es – baseline kidney function
● LFTs – hyperbilirubinemia due to increased RBC breakdown
Imaging – not often done (unless indicated)
● CXR – may show cardiomegaly, signs of heart failure
● Plain skull XR – may show expansion of marrow spaces. With thalassaemia majors, you see a ’hair on end’ appearance, maxilla overgrow, overbite, prominence of incisors and separation of orbit
● CT/MRI – often done to evaluate iron overload and its deposition
Special Tests
● Peripheral blood smear– howell jolly bodies, target cells, heinz bodies
● Haemoglobin electrophoresis – looks at different types of Hb. Typically see increased expression of A2
● DNA testing – genetic abnormality
Iron overload- complication of Thalassaemia
Occurs due to ineffective erythropoiesis, recurrent transfusions and increased absorption of iron
Excess iron can deposit in various organs, most commonly the liver, heart and endocrine glands
Increasing the risk of various conditions and causing various effects
○ Liver – cirrhosis, chronic liver disease
○ Heart – heart failure, irregular heart rhythm
○ Endocrine – hypogonadism (which can lead to low sex drive, loss of fertility, absence
of menstruation), diabetes (due to deposition at beta cells in the pancreas) ○ Joints – arthritis, joint pain, osteoporosis
General management of Thalassaemia
Carriers/Trait
▶ No treatment needed, may require monitoring (depends on symptoms) Avoid unnecessary iron supplementation
Intermedia
▶ Monitor for complications of chronic haemolytic anaemia
▶ Transfuse if any growth impairment/skeletal deformities
Major
▶ Will need regular transfusions
Lifestyle
● Education and psychological support
● Avoid food rich in iron
● Genetic counselling – all families should be
offered it
● Regular monitoring
Medical
● Desferrioxamine (SC injection)
○ Iron chelation therapy – acute excretion of iron
○ Binds to iron in circulation, excreted via the urine
○ Reduces/prevents complications associated with iron overload
● Oral iron chelation – deferasirox or deferiprone
○ For chronic iron overload, those receiving repeated
blood transfusions
○ Binds to iron in circulation, excreted via faeces
● Hydroxyurea
○ Increases expression of gamma chains (increases
HbF)
● Transfusions
Surgical
● Splenectomy – removal of spleen due to hypersplenism, increased transfusion requirements
● Stem cell transplantation – potentially curative
What is sickle cell disease?
WHAT IS IT?
Sickle cell disease encompasses a group of inherited conditions which have the inheritance of sickle haemoglobin in common.
• This includes:
• Sickle cell anaemia (HbSS) • HbS
• HbSC
And more!
With SCD, there is a specific mutation in the beta chain of haemoglobin, causing RBCs to sickle due to abnormally formed haemoglobin molecules (HbS)
Sickle cell epidemiology
Estimated to affect 1 in every 2000 live births in England
• Considered the most common genetic condition at birth
• About 350 babies born each year in England have SCD
• Further 9500 babies are found to be carrier
• Highest prevalence of SCD is amongst Black African and Black Caribbean people, but cases also occur in families originating from the Middle East, parts of India, eastern Mediterranean, South and Central America
• Due to history of malaria, migration from a malarial area
Sickle cell Pathophysiology
HbF is usually replaced by HbA 3-6/12 of age
• Patients with SCD have an abnormal variant, HbS, causing RBCs to sickle
• Sickling causes damage to cell membrane and cell’s elasticity
• Become lodged in small vessels, causing vaso-occlusion, leading to chronic vascular damage and inflammation
• Inflammation of the vessel activates cells, which recruit blood cells to the area ’to help’
• Abnormal Hb molecules form in response to stress:
• Hypoxia
• Acidaemia
• Cold
• High altitude
• Dehydration
Sickle cell presentation
Symptoms correlate with the natural reduction of HbF within the 1st year of life (typically 3-6 months), but can be longer for others
● Anaemia
● Jaundice
● Pallor
● Reduced growth rate
● Expansion of medullary cavities (exhausting haematopoeisis)
● Hepatosplenomegaly due to extramedullary
haematopoiesis
● Splenic sequestration
NICE guidelines on when to suspect sickle cell anaemia
NICE says:
Suspect sickle cell disease if a person is in a high-risk group and:
● Is a child aged 9–18 months with painful dactylitis
(painful swelling of the bones of the hands and feet). There may be chronic shortening of a digit (due to epiphyseal damage)
● Has a sudden severe infection
● Presents with features of an acute crisis, or with a
history of features consistent with an acute crisis (e.g acute pain, abdominal complications, acute SOB, acute infections, stroke, priapism etc)
● Presents with features of a chronic complication of sickle cell disease (e.g chronic pain, anaemia, breathlessness, cognitive impairment, eye problems etc)
Sickle cell investigations
NICE: SCD is always diagnosed after both an initial and confirmatory test are positive. Type of test is dependent on local guidelines and facilities
Bedside
● Observations – are they stable? Any signs of infection or sepsis?
● ECG – signs of right heart strain due to pulmonary hypertension
● Sputum sensitivity and culture – if there are signs of chest infection
Bloods
● FBC – evaluate anaemia
● LFTs – hyperbilirubinaemia
● U&Es – evaluate kidney function. May cause chronic kidney disease
Imaging
● CXR – pulmonary infiltrates may be seen if concerned about acute chest
● CT head if concerned about VTE e.g stroke
Special Tests
Peripheral blood film – presence of sickle cells, howel jolly bodies
Haemoglobin electrophoresis – needed to make diagnosis of SCD. Shows absence of HbA, increased percentage of HbS (80-95%), HbF (2- 20%)
Sickle solubility test – produces a turbid appearance in solution due to precipitation of HbS
Sickle cell management:
Lifestyle
● Patient information/education (about condition, signs of crisis)
● Specialist referral – followed up regularly
● Avoid sickle cell crisis triggers e.g dehydration, cold
● Immunisations: pneumococcal, influenza and
meningococcus for all >2 years
● Modify risk factors putting them at an increased
risk of chronic complications
Medical
● Lifelong antibiotic prophylaxis (due to splenic dysfunction, reducing ability of immune system).
○ Important that there is adherence up to 5 years of age. Should start by 3/12 of age
○ Typically penicillin (or erythromycin if pen allergic)
● Folic acid supplementation
● Transfusion
● Hydroxyurea
○ Increases HbF – doesn’t sickle, shown to reduce frequency of crisis
● L-glutamine
○ MOAunknown–decreases susceptibility of sickling to oxidative damage
Iron chelation
Surgical/more invasive interventions
● Splenectomy - hypersplenism
● Cholecystectomy – hyperbilirubinaemia
● Stem cell transplantation (if sibling has identical
HLA match)
Sickle cell trait and malaria
• SCD is common in areas with a high burden of Malaria, such as Africa, India, Middle East and the Carribean
• Having one copy of the gene ie sickle cell trait, is known to have partial protection against malaria (plasmodium falciparum)
• Believed to:
• Prevent severe form of disease
• Enhanced resistance – able to better fight off the disease
• The sickle shaped cell has a porous membrane,
leaking nutrients which the disease may need to thrive so are eliminated quite fast from circulation
• Therefore,it is a selective advantage to have the sickle cell gene in areas of malaria
Still provide malaria prophylaxis though
Types of sickle cell crisis
Types of Sickle Cell Crisis:
● Vaso-occlusion (painful crisis)
● Aplastic crisis
● Sequestering crisis
● Acute chest syndrome
Sometimes somebody’s first presentation of SCD can be a crisis!
Vaso occlusive sickle cell crisis
Vaso-occlusive/painful crisis
● Sickle shaped cells block small vessels, causing distal ischaemia
● Increased risk by exposure to cold, dehydration and fever
● Clinical features: intense pain, fever, priapism (persistent erection), VTE in larger vessels (e.g stroke symptoms)
Aplastic sickle cell crisis
Aplastic crisis
● Temporary loss of erythropoiesis, usually caused by infection (typically parvovirus B19)
● Clinical features: signs and symptoms of infection, significant anaemia (often symptomatic e.g reduced exercise tolerance, fatigue etc)
Sequestering sickle cell crisis
Sequestering crisis
● RBCs block blood flow within the spleen, causing sudden increased blood volume in the spleen
● Clinical features: acutely enlarged and painful spleen, hypovolaemic shock, severe anaemia, signs and symptoms of infection
● Recurrent sequestering crisis can cause splenic infarction, increasing susceptibility to infection
Acute chest syndrome sickle cell crisis
Acute Chest syndrome
● Infarction of the small vessels of the lungs, due to infection (e.g pneumonia, bronchiolitis) or non-infective causes (e.g pulmonary vaso- occlusion)
● Clinical features: fever, chest symptoms, new infiltrates on CXR
Management of sickle cell crisis
● EMERGENCY: A - E approach! Low threshold for admission
● If known SCD, often have a personalised management plan
● Treat any infection
● Manage pain with analgesia
● Keep warm
● Keep hydrated (IV Fluids may be needed)
● Penile aspiration in priapism
● Distraction techniques
● Avoid any other potential triggers
● Blood transfusions
Indications for urgent referral for sickle cell disease
• Severe pain that isn’t controlled by simple analgesia or low dose opioids
• Dehydration caused by severe vomiting or diarrhoea
• Signs of sepsis
• Symptoms or signs of acute chest syndrome: e.g
raised RR, hypoxia, signs of lung consolidation
• New neurological signs or symptoms
• Symptoms or signs of acute fall in haemoglobin
• Acute enlargement of spleen or liver over 24 hours
• Marked increase in jaundice
• Haematuria
• Priapism lasting more than 2 hours or worsening of recurrent episodes
Screening for Thalassaemia in pregnancy
Thalassemia
● All pregnant women are offered a test, typically at 10 weeks
● If the woman is a carrier, father will be tested
● Can have further testing if dad is a carrier e.g
chorionic villous sampling, amniocentesis to determine whether baby has thalassemia
Screening for SCD in pregnancy
Sickle Cell Disease
● Not all women are offered a test
● Those from high risk groups and in areas with a higher prevalence of haemoglobin diseases are
offered a test
● Can use family origin questionnaires if unsure whether to consider offering a test
● If the woman is a carrier, father will be tested
● Can have further testing if dad is a carrier e.g chorionic villous sampling, amniocentesis to
determine whether baby has SCD
● SCD carries increased risk of miscarriage, prematurity, pre-eclampsia, vaso-occlusion, chest crisis and anaemia
Classify the different types of anaemia and what are some of the common causes?
Microcytic anaemia:
Iron deficient anaemia
Anaemia of chronic disease
Thalassaemia
SCD
Normocytic anemia:
Folate + iron deficiency
Macrocytic anaemia:
B12 deficiency
Folate deficiency
Alcohol
Pregnancy
Chronic liver disease
Haemolytic
Bone marrow failure
Iron absorption
• Fe2+ = Ferrous State
• Fe3+ = Ferric State
• Haem= Porphyrin ring containing iron in ferrous state
• Iron is either absorbed as haem or as free iron ions
• Free iron in ferric state requires reduction to ferrous state for absorption by
– Acidic conditions of stomach acid
– Ascorbic Acid (Vitamin C) also reduces to ferrous state
– Duodenal cytochrome b ferric reductase (found on brush border of duodenal enterocytes)
• Absorbed mostly in proximal small intestine (duodenum)
What is blood made up of and how is it analysed?
Red blood cells
White blood cells
Platelets
Plasma
Centrifuge the blood:
Plasma (55% of the blood at the top)
Leukocytes and platelets (<1% in the middle)
Erythrocytes (45% at the bottom)
What happens during haematopoeisis?
Formation of blood cellular components which are all derived from haematopoietic stem cells
What is Erythropoiesis?
Erythropoiesis is the process which produces red blood cells, which is the development from erythropoietic stem cell to mature red blood cell.
Lifespan of platelets, erythrocytes and leukocytes
Platelets 9-10 days
Erythrocytes 120 days
Leukocytes a few days to a few years
Where does haematopoeisis take place in a foetus, infant and adult?
Foetus 0-2 months yolk sac
Foetus 2-7 months lover, spleen
Foetus 5-9 months bone marrow
Infant bone marrow (practically all bones)
Adults vertebrae, ribs, sternum, skull, sacrum, pelvis, proximal end of femur
Bone marrow
Located within all bones
Red marrow and yellow marrow
At birth all bone marrow is red
In adults half is red
Red marrow: haematopoietic tissue
Yellow marrow:
fat cells
Micro environment-
stormal cells - fibroblasts, fat cells, endothelial cells, macrophages Express adhesion molecules and secrete growth factors
Stromal matrix - physical support for haematopoietic cells
Erythropoiesis
Blood stem cell
Myeloid stem cell (CFU-GEMM)
Proerythroblast
Early erythroblast
Late erythroblast
Normoblast
Reticulocyte
Erythrocyte
Structure of erythrocytes
Biconcaved disk shape
Central area of pallor
Production: Erythropoiesis
Growth factor: erythropoietin
Lifespan: 120days
No organelles
Oxygen and carbon dioxide transporters
Thrombopoiesis
Blood stem cells -> Myeloid stem cell -> megakaryoblast -> promegakaryocyte -> megakaryocytes -> platelets
Monopoiesis
Blood stem cell
Myeloid stem cell
Monoblast
Promonocyte
Monocytes
Wandering macrophage (monocytes migrate to tissues and mature into macrophages)
Neutrophils
Formed from granulopoiesis
Approx 14days for myeloblasts to form mature cells which are released into peripheral blood
Most abundant white blood cell (50-70%)
1st line defence to bacteria
Average life span in circulation is 5 days and then further 1-2 days in tissues
Eosinophils
Formed from granulopoiesis
1-4% of circulating leukocytes
Provide protection against parasites
Involved in allergic responses
8-12 hours lifespan in circulation and further 8-12 days in tissue
Lymphopoiesis
Lymphocyte production
T lymphocyte
B lymphocyte
Plasma cells
Natural killer cells
