Case 8: Haemoglobinopathy, sickle cell, thalassaemia

Question 1

Minor allergic reaction: blood transfusion

Answer 1

• Caused by foreign plasma proteins
• Features: pruritus, urticaria
• Management: stop the transfusion, antihistamine, monitor

Question 2

Blood transfusion: acute haemolytic reaction

Answer 2

• ABO incompatible blood i.e. secondary to human error
• Features: fever, abdominal pain, hypotension
• Management: stop transfusion. Confirm diagnosis (check identity on blood product, send blood for direct Coombs test, repeat typing and cross matching. Supportive care- fluid resuscitation

Question 3

Blood transfusion: Transfusion associated circulatory overload (TACO)

Answer 3

• Excessive rate of transfusion, pre-existing heart failure
• Features: pulmonary oedema, hypertension
• Management: slow or stop transfusion, consider IV loop diuretics i.e. furosemide and oxygen

Question 4

4 blood components that can be given

Answer 4

• Red cells
• Fresh frozen plasma: used to replace clotting factors
• Cryoprecipitate: concentrated fibrinogen
• Platelets: used for low platelet levels

Question 5

Platelet transfusion: thresholds

Answer 5

• Platelets mixed with plasma and platelet additive solution
• Threshold of <30 x10^9/L for non-severe bleeding
• 50x10^9/L for severe / life threatening bleeding

Question 6

Fresh frozen plasma

Answer 6

• Has to be thawed: takes 15 minutes
• Approx 250mls/unit
• Therapeutic dose: 15-25 mls/kg in adults or about 4 units (1000mls) can be issues if patient is fluid overloaded
• In bleeding patients with not enough clotting factors i.e. liver failure or prolonged bleed

Question 7

Cryoprecipitate

Answer 7

• Has to be thawed
• Should be thought of early in major haemorrhage: in big bleeds
• Rich in fibrinogen and other clotting factors: get more clotting factors with less fluid
• Usual adult dose = 2 pools (each of 5units or donors)

Question 8

Prothrombin complex concentrate (PCC)

Answer 8

• Contain the Vitamin K-dependent clotting factors (II,VII,IX,X, protein C and S)
• Main indication for use is rapid reversal of warfarin therapy
• FFP is no longer used for this indication as you’d have to give large volumes of plasma
• Need to discuss with haematologist
• Derived from plasma donations

Question 9

Anaemia management pathway for surgery

Answer 9

• Iron deficient anaemia: absolute (ferritin <30) or functional (ferritin 30-100 and transferrin saturation <20%)
• > 8 weeks before surgery (clinically non-urgent): trial of oral irone, recheck Hb in 4 weeks if anaemia persists day case admission for IV iron. Recheck Hb after 2 weeks. If Hb normalises with oral iron continue until surgery
• <8 weeks before planned surgery date i.e. clinically urgent: day case admission for IV iron- recheck HB after 2 weeks.

Question 10

Patient blood management (PBM)

Answer 10

• Optimising the care of patients who might need blood transfusions
• 1st pillar: diagnose and manage anaemia- before surgery or childbirth
• 2nd pillar: Minimise blood loss by controlling bleeding- minimally invasive surgery, avoid anticoagulants/antiplatelets before surgery, stop bleeds quickly
• 3rd pillar: avoiding unnecessary transfusions- using evidence based criteria

Question 11

PBM recommendations

Answer 11

• Tranexamic acid: given IV, especially in GI and cildbirth
• Intraoperative cell salvage- recycling blood being lost and putting it back in the patient. Blood is suctioned out and put in catheter bag with heparin to stop it clotting. Put in the cell saver where its spun and filtered and washed in saline. Red cells are re-infused in patient
• Use restrictive transfusion thresholds
• If not bleeding give one unit then re-assess
• Minimise volume of blood samples

Question 12

Haemoglobinopathies risk factors

Answer 12

• Afro-Caribbean descent
• Not uncommon in Indian, Mediterranean or middle eastern populations
• The most common newly diagnosed inherited condition in the UK
• Screened at birth

Question 13

Sickle cell disease complications

Answer 13

• Stroke
• Pregnancy loss
• Fatigue, Pain
• Priapism
• Hyposplenism
• Retinopathy
• AVN (avascular necrosis)
• Renal disease
• Lung disease
• Life expectancy in mid-60’s though increased morbidity

Question 14

Sickle cell genetics

Answer 14

• Mutation in beta chain, glutamic acid is replaced by valene
• Autosomal recessive inheritance
• 3 major genotypes: SCD-SS, SCD-SC, and SCD-S/β Thal

Question 15

Pathophysiology of sickle cell anaemia

Answer 15

• A Haemoglobinopathy: red blood cells have shortened life span. Causes mild haemolysis giving protection against malaria
• Sickle Hb is normal when carrying oxygen
• Sickle cell disease causes a single base causing HbS, this haemoglobin can polymerise when deoxygenated
• Polymerised rods of Hb molecules distort red cell shape, blocking capillaries; damage the cell membrane and cause haemolysis.

Question 16

HbS polymerisation results in

Answer 16

• Haemolytic anaemia
• Release of free Hb into the circulation and nitric oxide depletion
• Vaso-occlusion of the microcirculatory beds, causing ischemia-reperfusion injury

Question 17

Presentation of veno-occlusive crisis (sickle crisis)

Answer 17

• Precipitants: extremes of temperature, dehydration, infection, psychological stressors, alcohol, menstrual periods
• Commonly affects the extremities, back, and chest
• Associated mild fever and swelling of bones and joints
• Normally prodrome, painful episode typically lasts 2-7 days
• Normally supportive management

Question 18

Risk factors for sickling and vaso-constriction

Answer 18

• Sickling risk increases with: hypoxia, increased temperature (fever), acidosis. Typically in infection which sickle cell patients are at an increased risk of with Hyposplenism
• Vaso-constriction risk increases with: dehydration, pain and cold. This increases vaso-occlusion risk
• Sickling is associated with acute pain. Pain releases peptide sickling molecules which worsen vaso-constriction
• Vaso-occlusion: where sickle cells block the blood flow in the capillaries by getting stuck resulting in ischaemia

Question 19

Cycle of sickle cell crisis

Answer 19

• Sickling causes worsening vaso-occulsion
• This leads to pain and vaso-constriction
• The vaso-constriction can worsen the vaso-occlusion and cause tissue hypoxia
• The tissue hypoxia then worsens the sickling so the cycle increases

Question 20

Types of damage in sickle cell disease

Answer 20

• Ischaemia causing necrosis
• Release of neurotransmitters and other mediator molecules from nocioceptors
• Release of the red cells intracellular content into the blood stream: intravascular haemolysis
• This all leads to a chronic inflammatory response

Question 21

First aid of a sickle crisis

Answer 21

• Treat pain (opiates if necessary, and keep going until analgesia is achieved): go up the analgesic ladder quickly. PCA analgesia
• Hydrate (oral or IV if patient too sick to drink)
• Keep warm
• Treat infection: even minor
• Consider oxygen if hypoxia
• Consider transfusion (discuss with haematology)
• DVT prophylaxis
• Incentive spirometry to prevent progression to acute chest syndrome
• Do not transfuse in asymptomatic, uncomplicated anaemia
• Consider secondary effects eg chest crisis (sickling in the lungs causing hypoxia- has high mortality), priapism, stroke (involve a haematologist). Chest crisis and stroke can be reduced by red cell exchange transfusions.

Question 22

Management for sickle cell

Answer 22

• Monitor and treat for chronic complications; i.e. with penicillin prophylaxis and immunisation for hyposplenism
• Therapy to minimise crises: Hydroxycarbamide (works by increasing fetal Hb, ie a normal Hb), as different blood cell its unaffected by sickle mutation.
• Regular transfusions in some patients (less sickle cells in the blood).
• Consider bone marrow transplant- can cure but very risky
• Crizanlizumab: prevent red blood cells sticking to vessel walls
• Risks of transfusions is iron overload or antibody formation
• Pneumococcal vaccine every 5 years

Question 23

Acute sickle cell crisis 1

Answer 23

• Acute chest syndrome: A life-threatening complication, presents with fever, chest pain, cough, dyspnoea, and hypoxia. It may result from vaso-occlusion in pulmonary vasculature or infection leading to pneumonia.
• Splenic sequestration crisis: The rapid pooling of blood in the spleen leads to splenomegaly, hypovolemic shock, and potentially death if not promptly treated. More common in paediatric patients.

Question 24

Acute sickle cell crisis 2

Answer 24

• Aplastic crisis: Parvovirus B19 infection may precipitate transient red cell aplasia causing severe anaemia as it temporarily halts erythropoiesis.
• Haemolytic crisis: Accelerated destruction of both normal and sickled erythrocytes can lead to jaundice and worsening anaemia.
• Priapism: Obstruction of venous outflow from the corpora cavernosa by sickled cells may cause persistent penile erection accompanied by pain.

Question 25

Chronic complications of sickle cell disease 1

Answer 25

• Anaemia: Chronic haemolytic anaemia is a constant feature in sickle-cell patients
• Infections: Functional asplenia due to recurrent splenic infarctions increases susceptibility
• Leg ulcers: Chronic venous insufficiency resulting from vaso-occlusion can lead to non-healing leg ulcers
• Ocular complications: Retinal vessel occlusions may cause proliferative retinopathy, vitreous haemorrhage or retinal detachment leading to vision loss.

Question 26

Chronic complications of sickle cell disease 2

Answer 26

• Skeletal complications: Chronic bone infarcts can result in avascular necrosis of the femoral and humeral heads. Additionally, marrow hyperplasia may cause osteopenia and pathologic fractures.
• Renal complications: Repeated ischaemia can cause renal tubular dysfunction. This can manifest as nocturia, polyuria, proteinuria or even chronic kidney disease.
• Cardiopulmonary complications: Chronic anaemia can cause pulmonary hypertension and eventually right-sided heart failure (cor pulmonale).
• Neurological complications: ischemic or hemorrhagic strokes.
• Growth retardation and delayed puberty

Question 27

Definitive diagnosis for sickle cell disease

Answer 27

Haemoglobin electrophoresis

Question 28

Different types of sickle cell crisis

Answer 28

• Sickle cell crisis: an acute exacerbation caused by sickle cell disease
• Vaso-occlusive crisis: painful crisis due to sickle shaped RBC clogging capillaries causing distal ischaemia
• Acute chest syndrome
• Splenic sequestration crisis: red blood cells blocking blood flow through the spleen causing an acutely enlarged and painful spleen
• Aplastic crisis

Question 29

Red cell structure

Answer 29

• Haemoglobin- made of two alpha and two beta chains. Contains iron which bonds with oxygen
• Has anti-oxidants (to destroy free radicals) and proteins involved in glycolysis
• No nucleus
• Life span 3-4 months: broken down by Macrophages in the spleen or liver
• Membrane: strong and deformable to pass through capillaries

Question 30

Red cell disorder inheritance and progression

Answer 30

Many red cell disorders are protective against malaria for carriers of x-linked or recessive

In red cell conditions the damaged red cells will be removed earlier, increased red cell destruction leads to jaundice and tendency to form gallstones. If bone marrow cant compensate will cause anaemia

Question 31

Pyruvate kinase deficiency

Answer 31

• Affects the Glycolysis pathway. Enzyme involved in the last part of the pathway. Deficiency causes lack of energy for active processes in the cell. Inability to maintain red cell membrane in ideal confirmation
• Autosomal recessive- very rare
• Marked red cell changes on blood film, haemolysis and anaemia
• Decreases active processed leading to cellular dehydration and lysis

Question 32

Glucose 6 phosphate dehydrogenase deficiency

Answer 32

• Affects antioxidant properties of RBC
• X-linked
• Causes inability to scavenge for free free radicals leading to premature lysis or catastrophic lysis in presence of oxidants
• If mild may be asymptomatic

Question 33

Hereditary spherocytosis and Hereditary elliptocytosis

Answer 33

• Affects the RBC cell membrane
• Autosomal dominant inheritance
• Causes inability to maintain RBC shape leading to premature lysis

Question 34

Thalassaemia

Answer 34

• Occurs when globin chains are not produced properly. Imbalance in alpha to be beta chains. Disorders of haemoglobin production. Causes anaemia and microcytosis
• Alpha thalassaemia: not enough alpha chains. Effects foetuses, new-borns, children and adults
• Beta thalassaemia: not enough beta chains. Affects children (from around 6 months) and adults. Mutation to HBB gene on chromosome 11, autosomal recessive inheritance

Question 35

Beta thalassaemia genetics

Answer 35

• 2 abnormal genes = beta thalassaemia (major) wont produce any beta thalassaemia. Requires lifelong regular blood transfusion
• 1 abnormal gene = beta thal carrier, beta thalassaemia trait. Causes mild anaemia and microcytosis. Few if any symptoms
• BUT… some genes are more abnormal than others. Some people have beta genes which work just not well, will make some beta chains just not enough
• Thalassaemia intermedia (with perhaps 2 slightly abnormal genes or one very abnormal one). Are at increased risks of anaemic complications in high physiological stress like pregnancy
• Dominant negative beta thalassaemia: only one abnormal gene but the protein product inhibits the function of the normal protein

Question 36

Features of thalassaemia major

Answer 36

• Frontal bossing(prominent forehead)
• Enlarged maxilla(prominent cheekbones)
• Depressed nasal bridge(flat nose)
• Protruding upper teeth
• Normally presents with severe anaemia and failure to thrive in childhood
• Management; regular transfusions, iron chelation and splenectomy. Bone marrow transplant can be curative

Question 37

Alpha thalassaemia genetics

Answer 37

• The alpha globin protein is encoded by 2 near identical genes both on chromosome 16
• “Normal” people have 4 alpha globin genes. Though overall same amounts of alpha and beta globin chains are produced
• Severity of alpha thalassaemia depends on how many genes you have lost:
• 0 working genes = incompatible with life unless intrauterine transfusion and post-natal bone marrow transplant. Hydrops fatalis
• 1 working gene: HbH. Marked anaemia and microcytosis but normally fairly well
• 3 working genes = asymptomatic, often not anaemia, only clue is slightly small RBC. Alpha thalaessaemia trait

Question 38

Globin chains

Answer 38

• balanced production of globin chains is more important then amount of Hb.
• Unbalanced Hb is unstable and toxic meaning there is ineffective erythropoiesis. This stimulates the body to make more Hb.
• In severe cases (like beta thalassaemia major) the bone marrow runs out of space for RBC production, patients develop expanded bones with facial and other bony deformity, risk fractures.
• Will also produce RBC in liver and spleen forming masses of haematopoietic tissue which can invade like tumours, causing spinal cord compression.

Question 39

Alpha thalassaemia presentation

Answer 39

• Reduced effective haematopoiesis
• Increased erythropoietic drive
• Increased iron absoprtion: can cause iron overload even without transfusion. Can cause cardiac arrhythmias and hepatocellular carcinomas, diabetes, eye issues, arthritis
• Increased extramedullary haematopoiesis
• Bone deformity (’hair on end’ skull radiograph, thalassaemic facies)

Question 40

Beta thalassaemia presentation

Answer 40

• Reduced effective haematopoiesis
• Increased erythropoietic drive
• Increased iron absorption
• Increased extramedullary haematopoiesis
• Beta thalassaemia is life threatening if untreated
• Results in anaemia (due to a greater rate of haemolysis), slower rate of erythropoiesis, and less haemoglobin made.

Question 41

Thalassaemia treatment

Answer 41

• Blood transfusion (all b thalassaemia major): to keep haemoglobin >95 at all times to supress ineffective erythropoiesis, preventing bony deformity
• Hydroxycarbamide may help some with beta chain abnormalities, increases fetal haemoglobin
• New agents eg luspatercept: decreases transfusion burden, enhanced erythroid maturation
• Consider bone marrow transplant
• Gene therapy
• Genetic counselling: for reproductive choices including pre-implantation genetic diagnosis
• Iron supplementation if deficiency

Question 42

Presenting features of thalassaemia

Answer 42

• Microcytic anaemia(lowmean corpuscular volume)
• Fatigue
• Pallor
• Jaundice
• Gallstones
• Splenomegaly
• Poor growth and development

Question 43

Issues with iron overload

Answer 43

• Due to regular blood transfusions, iron accumulates in tissues. Causes:
• Diabetes
• Growth
• Cardiac dysfunction: death from arrhythmia
• Hepatic toxicity: cirrhosis or hepatocellular carcinoma
• Stunted growth
• Monitor for toxic effects

Question 44

Rare inherited anaemias i.e. Hereditary spherocytosis

Answer 44

• Often completely asymptomatic till illness increases oxygen requirements
• Chronic anaemia
• Treatment generally supportive
• Increased haemolysis leads to increased red cell production (would expect increased reticulocyte count)
• Enlarged spleens due to RBC breakdown: benefit from splenectomy
• May need folate replacement
• Increased thrombotic risk
• Increased risk of pulmonary hypertension

Question 45

Inherited anaemias complications

Answer 45

• Specific risk from parvovirus B19 infection (slapped cheek syndrome): Causes temporary halt in production of RBCs. Can lead to profound anaemia in patients with high red cell turnover (ie anyone with a red cell disorder). Treatment is transfusion and supportive
• G6PD deficiency: causes acute haemolysis when exposed to oxidants i.e. broad beans or drugs. Profound haemolysis can be fatal. X-linked. Risky drugs: Antimalarials, some antibiotics, some chemotherapy

Question 46

Investigations for beta thalassaemia

Answer 46

• Screening for beta thalassaemia major and minor is routinely offered to pregnant women (antenatal screening) and expectant fathers if the mother has the beta-thalassemia trait
• In high risk trusts, all women who have accepted screening are tested for haemoglobin variants and thalassemia.
• In low risk trusts, screening for thalassemia is based on the FBC. A Family Origin Questionnaire (FOQ) is also used to determine the need for partner testing.
• Can self refer
• FBC shows microcytic anaemia with normal to moderately low Hb, low MCH, low MCV
• Haemoglobin electrophoresis with hemoglobin F and A2 quantitation

Question 47

Disseminated intravascular coagulopathy (DIC)

Answer 47

The widespread activation of intravascular coagulation in small and medium sized vessels that is not localised to a specific site or injury. Occurs spontaneously with an inhibition of fibrinolysis and a depletion of physiological anticoagulants.

Question 48

DIC steps

Answer 48

• Something triggers the formation of blood clots in small blood vessel (if lots can lead to further organ damage with ischaemia)
• There is a depletion of clotting factors and platelets- increased bleeding risk
• The breakdown of blood clots is inhibited
• DIC leads to both clotting and bleeding
• Shearing of red blood cells over intravascular fibrin strands leads to microangiopathic haemolytic anaemia (MAHA)
• Associated with higher mortality and morbidity than the underlying condition
• High DIC scores associated with worse outcomes

Question 49

Normal clotting procress

Answer 49

• Tissue factor is expressed on damaged endothelium
• Sets of clotting cascade get thrombin
• Thrombin breaks down Fibrinogen forming a clot
• Fibrin then surrounds RBC forming a clot
• You then have fibrinolysis where tissue plasminogen activator is released from the endothelium to break down the fibrin clots
• Fibrin breaks down into fibrin degradation products i.e. D-dimer

Question 50

Conditions that cause DIC

Answer 50

• All create or release pro-thrombotic factors into the blood
• Sepsis (e.g. lipopolysaccharide on the surface of gram negative bacteria is very thrombogenic)
• Cancer (e.g. tissue factor expression on tumour cells is very pro-thrombotic)
• Obstetric causes (e.g. placental disruption means that placental tissue that expresses tissue factor enters the maternal circulation or retained foetal products)
• Shock (causing ischaemic tissue injury leads to expression of tissue factor intravascularly- causing widespread activation of clotting)