Haematology Session 3 Flashcards
What is sickle cell disease?
Abnormal globin chain (alpha/beta) variants that affect stability and function of Hb.
What are thalassaemias?
Reduced/absent expression of normal alpha or beta globin chains, that leads to a reduced level of haemoglobin. Cause an imbalance in the composition of a tetramer.
Do carriers of haemoglobinopathies show symptoms?
No - usually autosomal recessive.
What is the makeup of haemoglobin?*
- 2 alpha chains
- 2 beta chains
Each has an oxygen binding haem group
What are the 3 normal types of haemoglobin in the adult?
Hb A (2 alpha 2 beta) - 95% Hb A2 (2 alpha 2 delta) - 3% Hb F (2 alpha 2 gamma) - less than 1%
Why is different haemoglobin expressed during development?*
- Adaptive response to oxygen requirements
- Hb F before birth
- Hb A starts before birth and increases to be dominant after birth
What chromosome are the alpha globin genes encoded on?*
- Chromosome 16
- Each person has 2 copies on one chromosome
- So 4 in total - one maternal, one paternal
What chromosome are the other globin genes on?
- Chromosome 11
- Single beta gene
- So 2 copies in total, one maternal one paternal
What are thalassaemias?
Excess of chains of one certain type.
Alpha - alpha globin gene expression is affected
Beta - beta globin gene expression is affected
Where is thalassaemia most prevalent?
South Asian, mediterranean, Middle east and Far east.
What happens when one alpha globin gene is deleted?
- Asymptomatic
- Patient is a silent carrier
What happens when 2 alpha globin genes are deleted?
- Minimal/no anaemia
- Both genes on 1 or 2 genes on one chromosome can be deleted
- Microcytosis
- Hypochromia
What happens when 3 alpha globin genes are deleted?
- Hb H disease (moderately severe)
- Beta globin tetramers
- Microcytic, hypochromic cells
- Target cells and Heinz bodies present
- Haemolysis and splenomegaly
What happens when all 4 alpha globin genes are deleted?
- Hydrops fetalis
- Incompatible with life (intrauterine death)
- Unable to deliver oxygen to tissues
What is beta thalassaemia caused by?
Most often mutation rather than deletion
B0 = no globin chain, B+ = reduced production
What is beta-thalassaemia minor?
- Mild anaemia (microcytic, hypochromic)
- Asymptomatic
- Heterozygous, 1 normal and 1 abnormal gene
What is beta-thalassaemia intermedia?
- Severe anaemia
- Similar to Hb H disease
- Can be mild variant of homozygous/severe variant of heterozygous
- Genetically heterogeneous
What is beta-thalassaemia major?
- Severe
- Transfusion dependent
- 6-9 months after birth, switches from Hb F to Hb A
- Homozygous, Bo/Bo or B+/B+
What will a blood smear from a thalassaemic patient show?*
- Hypochromic and microcytic cells
- Anisopoikiloytosis (diff. sizes and shapes)
- Target cells, nucleated RBCs (escape bone marrow when it’s working hard) Heinz bodies
Why is the excess of unaffected globin chain a problem?
- Can form aggregates that get oxidised
- Premature death of precursors and therefore ineffective erythropoiesis
- Cells destroy spleen more - shorter RBC lifespan
What are the consequences of thalassaemia? ***!
- Reduced lifespan
- Iron overload from transfusions (not handled well) and from ineffective haematopoiesis
- Reduced O2 delivery = erythropoietin stimulation, makes more defective red cells
- Extramedullary haematopoiesis to compensate - splenomegaly, hepatomegaly (back to where it was as fetus)
- Can cause skeletal abnormalities (eg. bowing and swelling)
What are the treatments for thalassaemias?
- Red cell transfusion
- Iron chelation (binding iron to reduce binding to tissues and lower iron overload)
- Folic acid (erythropoiesis)
- Immunisation (hyposplenic)
- Holistic care to manage complications (eg. endocrinology, cardiac)
- Stem cell transplants to replace defective red cell production
- Pre conception counselling for couples at risk
What is sickle cell disease?*
- Mutation of B-globin gene
- Glutamic acid changed to valine at position 6
- Mutant Hb is Hb S
- Can be co-inherited with abnormal haemoglobin to cause disrorder
What are the symptoms of heterozygous carriers of sickle cell?
Mild asymptomatic anaemia
What are the symptoms of homozygous sickle cell anaemia?
Severe sickling syndrome
Why is the anaemia in sickle cell disease well tolerated, and why is there a problem?*
Hb S gives up oxygen more readily than Hb A, but cannot do so at low oxygen states (eg. cold, illness)
- Deoxygenated Hb S forms polymers which give sickle cells
- Sickle cells less deformable, cause occlusion of small vessels
Can sickled cells ‘bounce back’ to normal?*
Yes, however repeated sickling cycles will result in irreversibly sickled red blood cells.
What can occlusions in small blood vessels dues to sickle cell cause?
- Acute chest symdrome
- Stroke
- Kidney infarcts
- Splenic atrophy
- Avascular necrosis
What are the types of sickle cell crises?
- Vaso-occlusive: occlusion of capillaries - joint damage & pain (AVN) , stroke, acute chest syndrome
- Aplastic (bone marrow stops working)
- Haemolysis
End organ damage - thromboses, O2 deprivation
What are the consequences of sickle cell formation?
- Anaemia (haemolysis - shorter lifespan)
- Jaundice/gallstones (inc. bilirubin)
- Splenic atrophy (splenic infarction)
What infections does hyposplenia make you more susceptible to?
Encapsulated bacteria:
- Streptococcus pneumoniae
- Streptococcus meningitidis
What are treatments for sickle cell disease?
- Stem cell transplantation (rare to find match donors)
- Red cell exchange
- Vaccinations
- Folic acid
- Hydroxycarbamide to increase Hb F
What are inherited causes of haemolytic anaemias?*
- Pyruvate kinase deficiency
- G6PDH deficiency + oxidative damage
- Hereditary spherocytosis
- Haemoglobin defects
What are acquired causes of haemolytic anaemias?*
Mechanical, antibody, oxidant, heat and enzymatic damage.
Where can haemolysis occur?
- Intravascular
- Extravascular (spleen/RES)
When does anaemia develop?
When rate of haemolysis exceeds rate of cell production.
How much does the RBC lifespan result to in haemolysis?
20-30 days.
What are some consequences of haemolytic anaemias?
- Jaundice (high bilirubin)
- Splenomegaly (overwork)
Why can sudden haemolysis cause cardiac arrest?
- Reduced O2 delivery
- Potassium leaves cells leading to hyperkalaemia
What is hereditary spherocytosis?*
- Autosomal dominant
- Spherical shape
- Ankyrin, spectrin, protein 4.2 and band 3 defects
- Easily damaged, less flexible cells
- Disconnection of cytoskeleton
- Reduction in membrane surface area
What is a treatment of hereditary spherocytosis?
Splenectomy - improves anaemia as reduces removal
What is hereditary elliptocytosis?*
- Elliptical cells
- Spectrin defect most common
What is hereditary pyropoikilocytosis?*
- Spectrin defect
- Abnormal sensitivity to heat (similar to when burns damage)
What is microangiopathic haemolytic anaemia?*
- Acquired
- Damage by physical trauma
How do microangiopathic anaemias occur?
- Snagging on fibrin strands from clotting cascade (disseminated intravascular coagulation) - bleeding and clotting at same time
- Shear stress from passing through a narrow heart valve
What cell fragments are left behind and are an indication of microangiopathic haemolytic anaemia?*
Schistocytes
Why does G6PDH deficiency cause anaemia?
- Oxidative stress (NADPH depleted, no glutathione reformation)
- Damage
- Damaged cells removed by the spleen
- Protein damage (Heinz bodies)
- Should be screened for it before giving drugs causing haemolysis
Why can pyruvate kinase deficiency cause anaemia?
- RBCs have no mitochondria
- Inhibits ATP supply to them by inhibiting glycolysis
- Na/K ATPase activity halted
- Shrinking/haemolytic anaemia
- May need blood transfusion if severe
What are autoimmune haemolytic anaemias?
Caused by antibodies binding to red cell membranes.
What are the causes of autoimmune haemolytic anaemias?
- Infections
- Cancers of lymphoid system
- Drug reactions
What are those anaemias classified by and why?
- Warm (IgG): react best at body temperature, recognise epitopes on red cell membrane
- Cold (IgM): react best at colder temperatures, complement also fixed
Why can IgM anaemia cause ischaemic conditions?
- Create large agglutinates which block small capillaries
- Fall off at warmer temperatures
Why does splenomegaly occur in autoimmune anaemias?
Spleen is working hard to replenish cells and there’s a high cell turnover
What is the direct Coombe test?
Used to detect which antibody is bound to surfact
- Mixed with anti-human globulin antibody
- Will attach to any antibodies and cells will clump together
What are myoproliferative neoplasms?
- Diseases of the bone marrow in which excess cells are produced
- Genetic mutations in precursors of myeloid lineage
What are the 4 main types of myoproliferative neoplasms?
- Polycythaemia vera (+ RBC)
- Essential thrombocythaemia (+ Megakaryocytes)
- Primary myelofibrosis (replacement by fibrous tissue + therefore pancytopenia)
- Chronic myeloid leukaemia (+ Granulocytes)
What are the diagnostic criteria for polycythaemia vera?*
- Haematocrit above 52% (men) or 48% (women)
- Can be caused by an increase in erythrocytes (absolute polycythaemia)
- Decrease in plasma volume
What is polycythaemia vera?
- Arises from a myoproliferative neoplasm in BM
- Overproduction of erythrocytes (sometimes WBC and platelet too)
What gene mutates to cause 95% of polycythaemia vera?
- JAK2 (Janus kinase 2), a tyrosine kinase
- Normal function is stimulate signalling pathways leading to increased erythropoiesis to respond to EPO
- Continuous proliferation and survival with mutation
What clinical features are associated with PV?
- Venous and arterial thrombosis
- Haemorrhage
- Headache
- Burning pain in hands/feet, erythromelagia
- Arthritis
- Gout
TRANSFORMATION TO MYELOFIBROSIS/ACUTE LEUKAEMIA
What is the treatment for polycythaemia vera?
- Phlebotomy (haematocrit below 45%)
- Aspirin 75mg (anti-platelet, reduces risk of thrombosis)
- Cytoreduction by hydroxycarbamide if patient has poor toleration of venesection or shows progression evidence
What are secondary causes of polycythaemia?
Increased stimulation by EPO, caused by:
- Living at high altitude (physiologically appropriate)
- Chronic hypoxia (eg. COPD), pathological
- Renal disease
- Tumours secreting EPO
What is relative polycythaemia?*
Decrease in plasma volume.
What is absolute polycythaemia and what are its causes?
Increased number of erythrocytes.
Primary: polycythaemia vera
Secondary: responses & abnormal production of EPO
What is essential thrombocythaemia?
Chronic blood cancer characterised by overproduction of platelets by large and excess megakaryocytes in bone marrow.
What is thrombocythaemiea caused by?
Around 50% caused by JAK2 mutation or mutations in thrombopoietin receptor.
What are the most common symptoms of thrombocythaemia?
- Extremity numbness
- Thrombosis (stroke, gangrene)
- Hearing and vision disturbances
- Headaches
- Erythromelagia
When is thrombocythaemia normal?
- Response to infection
- Response to inflammation
- Hospitalised patients
What are the reasons for thrombocytosis?
- Primary: essential thrombocythaemia
- Secondary: response to normal stimulus
- Redistributional: platelets from splenic pool to bloodstream
What is the management for patients with essential thrombocythaemia?
- High risk of clotting: hydroxycarbamide to reduce platelet count
- Low risk of clotting: aspirin
- Managing any cardiovascular risk factors
What are the other causes of a high platelet count?
- Infection and inflammation
- Tissue injury
- Cancer
- Haemorrhage
- Redistribution post-splenectomy
What is thrombocytopenia?*
Abnormally low platelet count.
What are inherited reasons for thrombocytopenia?
Rare inherited syndromes, eg. Fanconi anaemia
What are acquired causes for thrombocytopenia?
- Decrease in platelet production (B12/folate, sepsis, leukaemia)
- Increased consumption of platelets (DIC, haemorrhage)
- Increased destruction of platelets (autoimmune thrombocytopenic purpura, splenic pooling)
- NSAID/aspirin use
- Myeloproliferative disorders
What are the symptoms of a low platelet count?
- Nosebleeds
- Bleeding gums
- Heavier periods
- Spontaneous bleeding/petechiae
What is immune thrombocytopenic purpura?
- Autoimmune disease characterised by thrombocytopenia
- Presents either due to symptoms or accidentally on a blood count
- Mucosal bleeding, severe bleeding after trauma, easy bruising
What are the causes of immune thrombocytopenic purpura?
- Autoantibodies against platelets (Glycoprotein IIb/IIIa)
- T cell activity against platelets and megakaryocytes
- Secondary to autoimmune disorders, eg. rheumatoid arthritis or systemic lupus erythrematosus, leukaemia, HIV)
What are the treatments for immune thrombocytopenic purpura?
- Immunosuppression
- Corticosteroids
- Immunoglobulin
- Splenectomy
- Platelet transfusions don’t work as would also get destroyed
What is a quantitative platelet disorder?
Low platelet count
What is a qualitative platelet disorder?
Normal count but defective platelet function
What is the key role of platelets?
- Adhesion to damaged endothelial wall
- Activation to change shape and release granules
- Aggregation: clumping of more platelets to form plug
What is primary myelofibrosis?*
Proliferation of mutated haematopoietic stem cells results in reactive bone marrow fibrosis, eventually leading to collagen deposition and therefore replacement with scar tissue.
(JAK2 association)
Why do cells in a primary myelofibrosis blood film look like teardrops?
They got deformed trying to squeeze through the bone marrow.
Why do patients with primary myelofibrosis present with hepatomegaly and massive splenomegaly?
Mutated progenitor cells colonise the liver and spleen, leading to extramedullary haematopoiesis.
What is secondary myelofibrosis?
When the disease develops from polycythaemia vera or essential thrombocythaemia.
What are clinical features of myelofibrosis?
- Progressive pancytopenia due to fibrosis and hypersplenism
- Fatigue, sweats when advanced
- Pain, early satiety and splenic infarction due to splenomegaly
- Progressive marrow failure
- TRANSFORMATION TO LEUKAEMIA
- Early death
What are some treatments for myelofibrosis?
- Hydroxycarbamide
- Folic Acid
- Blood transfusions
- Splenectomy
- JAK2 inhibitors
- Poor prognosis
What is the difference between chronic and acute leukaemias?
- Acute leukaemias cause bone marrow failure due to many immature blast cells
- Chronic leukaemias slower to cause symptoms, picked up by chance
What is chronic myeloid leukaemia?
Unregulated growth of myeloid cells in bone marrow which leads to accumulation of mature granulocytes (neutrophils) in blood.
What is associated with chronic myeloid leukaemia?**
- Chromosomal translocation = PHILADELPHIA CHROMOSOME
- Reciprocal translocation between chromosomes 9 and 22
- Causes oncogenic gene fusion (BCR-ABL) with tyrosine kinase activity
What does increased tyrosine kinase activity result in?*
- Proliferation
- Diferentiation
- Inhibition of apoptosis
What are tyrosine kinase inhibitors?*
- Drugs that drastically improved survival rates in CML
- IMATINIB binds to site and inhibits substrate binding
- Cancer cell can’t proliferate
What is pancytopenia?
Reduction in white cells, red cells and platelets
How can pancytopenia be caused by increased removal of cells?
- Splenic pooling (massive splenomegaly)
- Haemophagocytosis (WBCs phagocytosing other blood components)
- Immune destruction
What can cause reduced red cell production?*
- B12/folate deficiency
- Bone marrow infiltration by cancer/fibrosis
- Idiopathic aplastic anaemia
- Radiation
- Drugs
- Viruses (eg. EBV, HIV)
- Congenital bone marrow failure (eg. Fanconi’s anaemia)
What is aplastic anaemia?
A rare disease resulting in damage to the bone marrow and haematopoietic stem cells, leading to pancytopenia.
Inability of the stem cells to generate mature blood cells.
What are the features of aplastic anaemia?
- Proneness to bleeding
- No fibrosis
- Fat deposits in marrow
- Neutropenic infection (high mortality)
What are the causes of aplastic anaemia?
- Genetic
- Autoimmunity
- Chemical/drugs/radiation exposure
