PBL Topic 2 Case 7 Flashcards
Explain how haemoglobin is involved in the return of CO2 to the lungs
- Contains carbonic anhydrase
- Allows CO2 to react with H2O
- To form bicarbonate ions
What does mean corpuscular volume measure?
- Size of red blood cells
What is the normal range of the mean corpuscular volume?
- 80 - 99 femtolitres (fL)
What is the mean diameter, thickness and volume of red blood cells?
- Diameter: 7.8 uM
- Thickness: 2.5 uM
- Volume: 90-95 cubic uM
How does the average number of red blood cells differ in males and females?
- Males: 5,200,000
- Females: 4,700,000
What is meant by the term hematocrit?
- Percentage of blood composed of red blood cells
What is the normal value of hematocrit?
- 45 per cent
Where are red blood cells produced in early embryonic life?
- Yolk sac
Where are red blood cells produced during the second trimester?
- Liver
- Spleen
- Lymph Nodes
Where are red blood cells produced during the final month of gestation and after birth?
- Bone marrow
In which types of bones does the marrow typically produce red blood cells after birth?
- Membraneous bones
- Including sternum, ribs and vertebrae
What is a pluripotential haematopoietic stem cell?
- Type of cell from which all cells of the circulating blood are derived
What is a committed stem cell?
- Type of cell that differentiates to form other types of cell
What is a CFU-E?
- Colony-Forming-Unit Erythrocyte
- A committed stem cell that produces erythrocytes
What is a CFU-GM?
- Colony-Forming-Unit Granulocyte and Monocyte
- A committed stem cell that produces granulocytes and monocytes
Identify factors that affect the formation of growth and differentiation inducers in erythrocytes
- Exposure to low oxygen in the blood
Identify factors that affect the formation of growth and differentiation inducers in lymphocytes
- Exposure to a pathogen in the blood
What is CFU-M?
- Colony-Forming-Unit Megakaryocyte
- A committed stem cell that produces platelets
What is the role of erythropoietin?
- Stimulates proliferation of erythrocyte progenitor cells
- Stimulates their differentiation in mature erythrocytes
What is the role of thrombopoeitin?
- Stimulating of megakaryocyte production
- Via its c-mpl receptor
Identify the roles of 3 different colony stimulating factors
- GM-CSF: Increases stem cell commitment to granulocyte and monocyte production
- G-CSF: Increases stem cell commitment to granulocyte production
- M-CSF: Increases stem cell commitment to monocyte production
Identify the roles of IL-3, IL-5 and IL-11
- IL-3: Growth and reproduction of all types of stem cells
- IL-5: Growth and differentiation of eosinophils
- IL-11: Promotes megakaryocyte production
Identify the role of Stem Cell Factor
- Synergises with IL-3 and GM-CSF
- To increase proliferation of many types of stem cells
Identify the six generations of erythrocytes
- Proerythroblast
- Basophil Erythroblast
- Polychromatophil Erythroblast
- Orthochromatic Erythroblast
- Reticulocyte
- Erythrocyte
What occurs during the successive stages of red cell differentiation?
- Accumulation of haemoglobin (B)
- Nucleus is absorbed (B)
- Endoplasmic reticulum is absorbed (B)
- Passage from the bone into the capillaries by diapedesis (R)
Where is erythropoietin produced?
- Kidneys
Explain how erythropoietin stimulates erythropoietic activity?
- Under hypoxic conditions
- Binds to Hypoxia Inducible Factor
- Which binds to Hypoxia Response Element
- Activates gene transcription
- Via the combined effects of nuclear factor and co-activator p300
- Increased proportion of committed cells to erythropoiesis
- Stimulation and differentiation of CFU-E
Explain how under normal conditions HIF is controlled
- The HIF-alpha subunit is hydroxylated
- Which promotes interaction with von Hippel-Lindau E3 ubiquitin ligase
- Resulting in degradation of HIF
What is the lifespan of an erythrocyte?
- 120 days
Identify five roles of the cytoplasmic enzymes contained within erythrocytes
- Glucose metabolism
- Maintain pliability
- Membrane transport
- Maintain ferrous iron
- Prevents oxidation of proteins
What is the role of Kupffer cells?
- Types of macrophages produce by the liver
- Phagocytosis of haemoglobin from worn out red blood cells
What is the role of Transferrin?
- Transport of iron from the haemoglobin from worn out red blood cells to the bone marrow
- For either production of new red blood cells or storage as ferritin
What happens to the porphyrin portion of the haemoglobin of worn out red blood cells?
- Converted into bilirubin my macrophages
- Removed from the body by secretion through the liver into the bile
Explain how red blood cells may self-destruct in the spleen
- Squeeze through red pulp into the trabeculae
Explain how a molecule of pyrrole is produced in the formation of Haemoglobin
- Succinyl coenzyme A is formed in the Krebs cycle
- It binds with glycine to form Pyrrole
Explain how protoporphyrin IX is produced in the formation of Haemoglobin
- Four molecules of pyrrole combine
Explain how haem is formed formed protoporphyrin IX
- Protoporphyrin IX reacts with ferrous iron (Fe2+)
Explain how a haemoglobin chain is produced from haem
- Haem combines with globulin
Which chains make up Haemoglobin A?
- 2 x Alpha Chain
- 2 x Beta Chain
How many molecules of oxygen can be transported by a molecule of haemoglobin? Why is this the case?
- Four
- There are four haem group
- Which contain a single iron atom
- That can form a loose bond with oxygen
How does the T conformation of haemoglobin differ to the R conformation?
- T: Globin chains are held tight together
- R: Oxygen binding sites are more exposed
- Therefore R conformation has a higher affinity for oxygen
Why is haemoglobin considered an allosteric protein
- Binding of one oxygen molecule increases oxygen affinity of the remaining binding sites
- This explains the sigmoid shape of the oxygen dissociation curve
What is the effect of binding of hydrogen ions and carbon dioxide to haemoglobin?
- Reduced affinity for oxygen
- Bohr Effect
- Oxygen dissociation curve shifts right and downwards
What is the effect of oxygenation on haemoglobin?
- Reduced affinity for Carbon Dioxide
- Haldane Effect
What is the effect of 2,3-BPG on haemoglobin?
- Stabilises T-conformation
- Reduced affinity for oxygen
- Oxygen dissociation curve shifts right and downwards
Explain the role of ferrireductase
- Conversion of ferric iron (Fe3+) to ferrous iron (Fe2+)
Explain the role of DMT1 (Divalent Metal Transporter)
- Divalent Metal Transporter
- Transports iron across the luminal surface of the mucosal cells in the small intestine
Explain the role of HCP1
- Haem Carrier Protein 1
- Transports haem across the luminal surface of the mucosal cells in the small intestine
Explain the role of FPN-1
- Ferroportin 1
- Transports iron out of mucosal cell
- Requires hephaestin
Explain the role of Hepcidin
- Regulation of iron absorption
- By binding to iron-exporting protein Ferroportin 1
- Causing its degradation
- Decreasing iron efflux
What is the role of apotransferrin
- Combines with iron to form transferrin
- Which is transported in the plasma
Identify two locations where iron is deposited
- Liver
- Bone Marrow
Explain how haemoglobin is produced from circulating iron
- Transferrin attaches to surface receptor on erythrocyte
- Iron is released and transported to mitochondria
- Iron combines with protoporphyrin to form haem
Explain how iron is stored from circulating iron
- Transferrin attaches to surface receptor on erythrocyte
- Iron combine with apoferritin to form ferritin
How does ferritin differ from hemosiderin
- Ferritin is soluble
- Hemosiderin is insoluble
Identify three causes of iron deficiency
- Blood loss, typically from GI tract
- Demands of growth and pregnancy
- Decreased absorption
- Poor intake
Identify the four generations of granulocytes
- Myeloblast
- Promyelocyte
- Myelocyte
- Metamyelocyte
What are band forms?
- Immediate precursor of mature granulocytes
- With irregular horseshoe shaped nucleus
What is the difference between left and right shift?
- Left shift involves mobilisation of metamyelocytes
- Right shift involves further maturation
Identify five locations in which lymphocytes and plasma cells are produced
- Bone marrow
- Spleen
- Thymus
- Lymph Glands
- Peyer’s Patches underneath epithelium in gut wall
What is anaemia?
- Reduction in haemoglobin
- Below the reference level for the age and gender of the individual
Identify three types of anaemia, how are they classified?
- Microcytic Anaemia
- Normocytic Anaemia
- Macrocytic Anaemia
- Classified based on MCV
Identify two mechanisms that occur, resulting in an asymptomatic patient of anaemia
- Enhancement of oxygen carrying capacity of blood
- Rise in 2,3-BPG allowing for oxygen dissociation at the tissues
Identify 7 general symptoms of anaemia
- Fatigue
- Headache
- Faintness
- Breathlessness
- Angina
- Claudication
- Palpitations
What is claudication?
- Pain in limb
- That occurs on exercise
- Due to obstruction of an artery
Identify 7 signs of anaemia
- Pallor
- Tachycardia
- Systolic Flow Murmur
- Koilonychia (spoon shaped nails)
- Jaundice
- Bone deformities
- Leg ulcers
How can exercise be used to assess the effects of anaemia?
- Exercise causes angina and intermittent claudication
Identify five evaluation tools when a patient presents with a low haemoglobin count
- Red blood cell indices
- White blood cell count
- Platelet count
- Reticulocyte count (as this indicates marrow activity)
- Blood film
What is meant by the term dimorphic and when may this be seen on a blood film?
- Two populations of red cells are seen
- In patients with double deficiencies
- For example iron and folate deficiency in coeliac disease
What is meant by the term poikilocytosis?
- Variation in cell shape
- As demonstrated in microcytic anaemia
What is mean by the term anisocytosis?
- Variation in cell size
- As demonstrated in microcytic anaemia
Identify two methods of obtaining and examining bone marrow
- Aspiration provides a film which can be examined by microscopy
- Trephine provides a core of bone which is processed on a histological specimen
Identify five components that are assessed when examining bone marrow
- Cellularity
- Type of erythropoiesis
- Cellularity
- Infiltration of marrow e.g. by cancer cells
- Iron stores
What is the most common cause of microcytic anaemia?
- Iron deficiency
- Chronic disease (Crohn’s)
- Sideroblastic Anaemia
- Thalassaemia
Identify seven clinical features of microcytic anaemia
- Brittle nails
- Koilonychia (spoon-shaped nails)
- Brittle hair
- Atrophy of the papillae of the tongue
- Angular stomatitis
- Dysphagia
- Glossitis
What would a blood count and film show in iron-deficiency anaemia?
- MCV < 80 fL
- Poikilocytosis and Anisocytosis
How are serum iron, ferritin, transferrin receptors and iron-binding capacity affected in iron-deficiency anaemia?
- Serum iron is reduced
- Serum ferritin is reduced
- Transferrin receptors is increased
- Total iron-binding capacity is increased
How are serum iron, ferritin, transferrin receptors and iron-binding capacity affected in anaemia of chronic disease?
- Serum iron is reduced
- Serum ferritin is reduced
- Transferrin receptors are normal
- Total iron-binding capacity is is reduced
Identify two causes of sideroblastic anaemia?
- Inherited as an X-linked disease
- Acquired through myelodysplasia, myeloproliferative disorders or myeloid leukaemia
How can Perl’s reaction be used to demonstrate sideroblastic anaemia?
- Accumulation of iron in mitochondria
- Due to disordered haem synthesis
What is the treatment for iron-deficiency anaemia?
- Fasted ferrous sulphate
What is the treatment of sideroblastic anaemia?
- Withdrawal of alcohol and drugs
- Pyridoxine
How are serum iron, ferritin, transferrin receptors and iron-binding capacity affected in sideroblastic anaemia?
- Serum iron is raised
- Serum ferritin is raised
- Transferrin receptors are raised
- Total iron-binding capacity is normal
Identify two causes of normocytic anaemia
- Endocrine disorders e.g. hypopituitarism, hypothyroidism
- Haematological disorders e.g. aplastic anaemia, haemolytic anaemia
What is a megaloblast?
- Erythroblast with delayed nuclear division
- Due to defective DNA synthesis
- Large immature nuclei
Identify two causes of megaloblastic macrocytic anaemia
- Vitamin B12 deficiency or abnormal B12 metabolism
- Folic acid deficiency or abnormal folate metabolism
What would a blood count and film show in megaloblastic macrocytic anaemia
- MCV > 96 fL
- Megaloblasts with large immature nuclei
- Macrocytes with six or seven lobes in the nucleus
Outline the pathophysiology of pernicious anaemia
- Replacement of chief cells by mucin-secreting cells
- Atrophic gastritis
- Reduced HCl secretion (achlorhydria)
- Absence of intrinsic factor production
- Resulting in B12 malabsorption
Identify three autoimmune diseases that are associated with Pernicious anaemia
- Thyroid Disease
- Addison’s Disease
- Vitiligo
Identify the clinical features of pernicious anaemia
- Jaundice and pallor caused be breakdown of haemoglobin
- Glossitis and angular stomatitis
- Neurological changes, including polyneuropathy caused by low levels of B12
Why is serum bilirubin reduced in pernicious anaemia?
- Ineffective erythropoiesis
Identify the treatment for pernicious anaemia
- Intramuscular hydroxocobalamin
OR
- Oral B12
Identify three unwanted effects of intramuscular hydroxocobalamin
- Iron deficiency
- Hypokalaemia
- Hyperuricaemia
Identify 8 causes of non-megaloblastic macrocytic anaemia
- Pregnancy
- Alcohol excess
- Liver disease
- Reticulocytosis
- Hypothyroidism
- Aplastic Anaemia
- Sideroblastic Anaemia
- Hydroxycarbamide
- Azathioprine
- Cold agglutinins
What is aplastic anaemia?
- Pancytopenia with hypocellularity of the bone marrow
What is meant by pancytopenia?
- Deficiency of all three cellular components of the blood
- Erythrocytes, leukocytes and platelets
What is meant by hypocellularity?
- Reduced number of cells in the bone marrow
Outline the pathophysiology of aplastic anaemia
- Reduced number of pluripotential stem cells
- Due to immune mechanisms
- Such as activated cytotoxic T cells
Identify a genetic cause of aplastic anaemia
- Fanconi’s anaemia
- Due to mutations of BRCA2
Outline four drugs that may cause aplastic anaemia
- Cytotoxic: Busulifan, Doxorubicin (Chemotherapy)
- Non-Cytotoxic: Chloramphenicol, Gold and Carbimazole
Outline three clinical features of aplastic anaemia
- Bleeding (blood blisters in mouth)
- Infection
- Anaemia
Why are broad-spectrum antibiotics given in aplastic anaemia?
- To prevent infection
Why are transfusions given in aplastic anaemia?
- Pancytopenia
When are antithymocyte globulin and cyclosporin prescribed?
- Patients with severe disease over 40
- Younger patients with severe disease with an HLA-identical sibling donor
- Patients who do not have severe disease but who are transfusion dependent
What is the main cause of haemolytic anaemia?
- Increased destruction of red blood cells
What is compensated haemolytic disease?
- Increased red blood cell output from bone marrow
- By increasing number of cells committed to erythropoiesis
- Compensates destruction of red blood cells
Where does most of the destruction of red blood cels take place?
- Extravascular destrcution
Outline the pathophysiology of haemolytic anaemia
- Haemoglobin is oxidised to methaemoglobin
- Which dissociates into ferrihaem and globulin
- Ferrihaem binds to haemopexin, or
- Ferrihaem binds to albumin to form methaemalbumin (seen on Schumm’s test)
Outline the pathogenesis of hereditary spherocytosis
- Autosomal dominant condition
- Affecting roughly 1 in 5000
Outline the pathophysiology of hereditary spherocytosis
- Defect in erythrocyte structural protein spectrin
- Increased permeability to sodium
- Increased active transport of sodium, out of cell
- Reduced surface-to-volume ratio
- Cell become spherical
How do spherocytes differ to erythrocytes?
- Rigid and less deformable
- Unable to pass through splenic microcirculation
- Shorter lifespan
Identify five clinical features of spherocytosis
- Jaundice
- Anaemia
- Splenomegaly
- Leg Ulcers
Identify the main course of action with spherocytosis and its associated therapies
- Splenectomy
- Appropriate immunisation and lifelong penicillin prophylaxis
Briefly describe foetal haemoglobin
- HbF-aa/YY
- 2 x Alpha Chain
- 2 x Beta Chain
What is BCL IIA and what is its role?
- Zinc finger protein
- Suppresses the Y gene expression of HbF
What is Haemoglobin A?
- A2B2
- Comprises 97% of adult Hb
What is Haemoglobin A2?
- A2D2
- Comprises 2% of adult Hb
What is Haemoglobin F?
- A2Y2
- HB of foetus
- Increased in B-thalassaemia
What is Haemoglobin H?
- B4
- Found in a-thalassaemia
- Biologically useless
What is Haemoglobin Barts?
- Y4
- Comprises 100% of Hb in homozygous a-thalassaemia
- Biologically useless
What is Haemoglobin S?
- a2B2s
- Substitution of valine for glutamine in position 5 of B chain
What is Haemoglobin C?
- a2B2c
- Substitution of lysine for glutamic acid in position 6 of B chain
What is meant by B0 and B+ and what is their cause?
- In homozygous B-thalassaemia
- B0 = No B-chain produced
- B+ = Reduced B-chain produced
- Caused by point mutations
Identify three types of Hb that are present in B-thalassaemia
- HbA2
- HbF
- Small amounts of HbA
Outline the clinical features of Thalassaemia Minor?
- Carrier state
- Asymptomatic
Outline the clinical features of Thalassaemia Intermedia?
- Splenomegaly
- Leg ulcers
- Gallstones
Outline the clinical features of Thalassaemia Major (Cooley’s Anaemia)
- Bacterial infections
- Severe anaemia
- Hepatosplenomegaly, giving rise to thalassaemic facies
- ‘Hair on end’ appearance of bony trabeculation
What is the main cause of a-Thalassaemia
- Gene deletions
- Duplications
What is the four gene deletion?
- Hb Barts (Y4)
- Hydrops fetalis
What is the three gene deletion?
- HbH (B4)
- Moderate anaemia and splenomegaly
What is the two gene deletion?
- HbA (a2B2)
- Microcytosis with mild anaemia
What is the one gene mutation?
- HbA (a2B2)
- Very mild anaemia or no anaemia
Outline how the pathogenesis of Sickle Syndromes
- Single base mutation of adenine to thymine
- Substitution of valine for glutamic acid
In which country is the sickle gene most common?
- Africa
Outline the pathophysiology of sickle cell anaemia
- HbS molecules are rigid and take up sickle appearance
- Lose membrane flexibility due to dehydration
- Caused by potassium leaving through Gados Channel
- Resulting in shortened cell survival
- And impaired passage through the microcirculation
Identify five factors that precipitate cell sickling
- Infection
- Dehydration
- Cold
- Acidosis
- Hypoxia
Outline the three clinical syndromes that can occur in Sickle Syndromes
- Homozygous HbSS (most severe)
- Combined heterozygosity HbSC (intermediate)
- Heterozygous HbAS (least severe)
Explain why dactylitis occurs in sickle cell anaemia
- Pain in hands and feet
- Due to vaso-occlusion
- Adhesion proteins such as VCAM-1
- Trapping of rigid sickle cells
Explain why pulmonary hypertension occurs in sickle cell anaemia
- Haemolysis leads to increased cell-free plasma Hb
- Which consumes NO
- A vasodilator substance
Explain why Acute Chest Syndrome occurs in sickle cell anaemia
- Infections
- Fat embolism from necrotic bone marrow
- Pulmonary infarction due to sequestration of sickle cells
What does a blood count show in sickle cell anaemia?
- Hb range of 60-80 g/L
What does a blood film show in sickle cell anaemia?
- Hyposplenism
- Sickling
What does a Sickle Cell Solubility Test show in Sickle Cell anaemia?
- Turbid (cloudy) appearance
- Due to precipitation of HbS
Outline the management of Sickle Cell anaemia
- Prophylactic penicillin and vaccination
- Blood transfusions
- Inhaled nitric oxide
- Stem cell transplantation
Identify three causes of acquired haemolytic anaemias
- Autoantibodies
- Drug-induced antibodies
- Alloantibodies
What are warm agglutinins?
- Autoantibodies that react with red blood cells at 37 degrees
- Typically IgG
What are cold agglutinins?
- Autoantibodies that react with red blood cells at less than 37 degrees
- Typically IgM
What are agglutinogens?
- Antigens on the surface of red blood cells
- Either type A or type B
What is type O?
- When neither A or B agglutinogens are present
What is type A?
- When only type A agglutinogens are present
What is type B?
- When only type B agglutinogens are present
What is type AB?
- When both type A and B agglutinogens are present
What blood type is a person who has the genotype OO?
- Type O
What blood type is a person who has the genotype OA or AA?
- Type A
What blood type is a person who has the genotype OB or BB?
- Type B
What blood type is a person who has the genotype AB?
- Type AB
List the genes in order of frequency from most frequent
- O
- A
- B
- AB
When do anti-A agglutinins develop?
- When type A agglutinogen is not present
When do anti-B agglutinins develop?
- When type B agglutinogens is not present
What are agglutinins?
- Gamma globulins produced in the bone marrow and lymph glands
- That produce IgM or IgG antibodies
Identify two occasions in which agglutinins develop
- Food
- Bacteria
What occurs when blood is mismatched?
- Agglutinins bind to agglutinin
- 2 with IgG, 10 with IgM
- Cells clump together
- Phagocytosis results in haemolysis
What is the difference between the O-A-B system and the Rh system?
- In the Rh system, spontaneous agglutinins almost never occur
- Person must first be exposed to an Rh antigen before agglutinins cause a significant transfusion reaction
Identify the six types of Rh factors
- C
- D
- E
- c
- d
- e
What is the relationship between CDE and cde
- A person has either a CDE or a cde
Which Rh antigen is most prevalent?
- D
What is meant by the term Rh positive?
- A person possessing the D antigen
How does the percentage of Rh positive individuals differ in white and black populations?
- 85% of white people are Rh positive
- 95-100% of black people are Rh positive
What is meant by alloimmunisation?
- Immune response
- Against foreign RBC antigens
Outline the pathophysiology of of an immediate haemolytic transfusion reaction
- Complement activation by the antigen-antibody reaction
- Caused by IgM antibodies
- Leads to rigors, lumbar pain, hypotension and renal failure
Outline the pathophysiology of of a delayed haemolytic transfusion reaction
- Secondary immune response
- Caused by IgG antibodies
- Anaemia and jaundice
- Blood film shows spherocytosis and reticulocytosis
Identify three documentation errors that may occur prior to a blood transfusion
- Failure to check identify of donor when taking the sample
- Mislabelling blood sample with wrong name
- Failure to perform patient identify check before blood is transfused
Why may urticarial reactions occur during a blood transfusion?
- Plasma protein incompatibility
What is the treatment for a urticarial reaction during a blood transfusion?
- Administration of chlorphenamine
- Slowing or stopping treatment
Why may anaphylactic reactions occur during a blood transfusion?
- Anti-IgA in a patient lacking IgA
- Is mixed with transfused blood containing IgA
-
What is the treatment for an anaphylactic reaction during a blood transfusion?
- Adrenaline
- Or chlorphenamine
Which viruses are screened and tested for prior to blood transfusion?
- HBV
- HCV
- HIV-1
- HTLV-1
Why are patients asked about recent travel prior to giving blood?
- Exclude risk of West Nile Virus
- Which is the causal agent of meningoencephalitis
Identify a microorganism that can proliferate in red cell and platelet concentrates
- Yersinia enterocolitica
Identify three measures to avoid bacterial contaminates when taking blood
- Donor arm cleaning
- Diversion of initial collection of samples for testing
- Bacterial detection system for platelet concentrates
Why is each donation test using the TPHA?
- Treponema Palladium Haemagglutination Assay
- Test for syphilis
