Disorders of red blood cells - anaemia Flashcards
a) define anaemia
b) overview of haematopoiesis
a) a reduction in the total circulating red cell mass, with reduced oxygen carrying capacity of the blood. Usually measured as a reduction in haemoglobin concentration of the blood. Anaemia arises because of an imbalance between the rate of production of red blood cells (RBC) and the rate of loss or destruction
b) see image
a) names of erythroid progenitors
b) normal RBC count in males and females
c) normal haemoglobin concentration in males and females
d) normal RBC size
e) normal RBC lifespan
f) types of haemoglobin, name abbreviation and what chains are present
a) eryrthrobloasts (normoblasts) and reticulocytes
b) male: 6.5 x 10¹². female: 5.8 x 10¹²
c) male: 16.5 g/dl. female: 15 g/dl
d) between 6.0 - 9.5 µm
e) around 120 days, then they are destroyed in the spleen
f) see image
Clinical consequences of anaemia
Signs and symptoms are common to all forms of anaemia, but vary according to the severity of the disease
Skin and nails thin, mucous membranes pale
Hypoxic damage in viscera (myocardium, kidney, liver, brain) - weaknes, malaise, easy fatigability, angina pectoris, headache, dimness of vision, faintness
Compensatory changes - raised cardiac rate and output, increased breathing rate (often breathlessness on mild exertion), hyperplasia of haematopoietic tissue in bone marrow
Majot causes of anaemia
Blood loss (haemorrhage)
Impaired generation of RBC or their constituents (dyserythtopoiesis) - i) abnormalities of stem cells (aplastic anaemias) ii) abnormalities of erythroblasts and red cell production: defective DNA sythesis (megaloblastic anaemia), defective haemoglobin synthesis (defective haem synthesis, iron deficiency, / defective globin synthesis, thalassaemias)
Increased destruction of red cells (haemolytic anaemias) - i) intrinsic abnormalities of erythrocyte (usually hereditary) ii) extrinsic abnormalities (usually acuqired)
Dyserythropoiesis - Impaired DNA synthesis (megaloblastic anaemias)
a) overview of these types of anaemia
b) changes in megaloblastic anaemias (7)
a) due to a deficiency of vitamin B12 or folic acid, co-enzymes in synthesis of thymidine (a nucleoside required in DNA). Cells show impaired DNA synthesis. Nuclear maturation is defective and cell doesn’t divide. The cell continues to make RNA and protein, therefore enlarges
b) i) Ineffective haemopoiesis (RBC, granulocytes and platelets reduced in number - pancytopenia) ii) expansion of haemopoietic tissue iii) RBC precursors enlarged (megaloblasts) and may appear in the blood iv) RBC enlarged (macrocytosis) and oval shaped) v) RBC different sizes (anisocytosis) and shapes (poikilocytosis) vi) Iron cannot be utilised normally and is depositied in various organs vii) Effects in other cells and tissues (eg neutrophils and megakaryocytes large with hypersegmented nuclei, enlarged nuclei in gut epithelial cells)
Dyserythropoiesis - Impaired DNA synthesis (megaloblastic anaemias): vitamin B12 deficiency
a) overview of function of vitamin B12
b) normal vitamin B12 utilisation
c) causes of B12 deficiency
a) (cobalamin) is required for the conversion of the transport form of folic acid, methyl tetrahydrofolate (me-FH4), to tetrahydrofolate (FH4). FH4 enables transfer of one-carbon units and is required for thymidine synthesis
b) humans are entirely dependent on dietary B12, all from animal sources. Minimal daily requirement is 1µg, the average diet has hundreds of µg. Absorbed in the terminal ileum - requires intrinsic factor from gastric mucosa. Storage in liver (normally provides for 5 years)
c) Deficiency slow to develop because of liver stores. Caused by: i) inadequate intake (vegans) ii) increased requirements (pregnancy, anaemia, malignancy) iii) malabsorption due to gastric causes (pernicious anaemia is intrinsic factor deficiency due to autoimmune destruction of gastric mucosa) iv) malabsorption due to pancreatic deficiency v) malabsorption due to ileal disease
Folate deficiency
a) normal folate utilisation
b) causes of folate deficiency
a) Humans are entirely dependent on dietary folate (vegetables, fruit). Minimun daily requirement is 50 µg. Average western diet contains 650 µg, but 90% lost by cooking. Absorption in jejunum. Storage provides 100 days reserve.
b) Caused by i) inadequate intake (elderly, chronic alcoholics) ii) increased requirements (pregnancym anaemia, malignancy) iii) inadequate absorption in small bowel disease (coeliac) iv) impaired utilisation (folic acid antagonist mexthotrexate)
Dyserythropoiesis - iron deficiency anaemia
a) overview
b) normal iron utilisation
c) causes of iron deficiency
a) Iron deficiency anaemia is the commonest anaemia in the UK and the commonest nutritional disease in the world. RBC (and precursors) are microcytic and hypochromic, may also be poikilocytosis
b) daily requirement - 7mg for male, 15mg for female. Average daily dietary intake 15-20mg. Major source is organic (haem) iron in animal produce (~25% absorbed). Also inorganic (non-haem) iron from vegetable produce. Iron storage pool is bound in ferritin, which is converted to haemosiderin if there is iron overload. Iron balance is maintained through regulation of iron absorption in the duodenum. There is negative feedback via hepcidin, which is released by the liver if hepatic iron levels rise and prevents iron absorption. Instead, iron is converted to ferritin in mucosal cells, which are shed.
c) i) impaired absorption (eg small bowel disease) ii) increased demand (pregnancy, childhood) iii) chronic blood loss to exterior (gastro-intestinal due to peptic ulcer or malignancy, gastro-urinal due to malignancy) iv) low dietary intake (poverty, old age).
In severe iron deficiency there is loss of function of iron-containing enzymes (cytochromes, catalase), leading to malabsorption and changes in nails, hair, tongue etc
Haemolytic anaemias
a) overview
b) causes (2)
a) anaemias due to red cell destruction (extravascular - removal by macrophages, largely in spleen which enlarges. intravascular - lysis within the circulation). Response includes increased erythropoiesis, with expansion of red marrow and extra-medullary haematopoiesis. Blood contains increased numbers of reticulocytes and may contain erythroblasts
b) Abnormalities intrinsic to red cell: defects usually hereditary. Erythrocytes are deformed and cannot travel through sinusoids in the spleen. Once trapped they are phagocytosed by macrophages. Structural defects - eg hereditary spherocytosis (defects in red cell skeleton produces deformed spheroidal cells). Enzyme defects - eg pyruvate kinase deficiency (reduced ATP from glycolysis). Abnormalities of haemoglobin - haemoglobinopathies
Abnormalities extrinsic to red cell: defects usually acquired. Immune - eg haemolytic disease of the newborn. Physical - eg valve replacements. Chemical - eg lead poisoning. Infection - eg malaria
Haemoglobinopathies - production of structurally abnormal globin chains
a) what is the most common
b) what is seen in homozygotes with the disease
c) consequences
d) what is seen in heterozygotes with the disease
a) Many structural variants of haemoglobin and described, which occur due to mutation or delection. Clinically significant variants affect the globin chain. Most common is sickle cell disease. Caused by a point mutation that changes a polar amino acid on the external surface of the β globin protein. HbS (α2β2 6 glu →val)
b) in homozygotes, dehydration, infection ↓pO2, ↓pH cause HbS to aggregate and polymerise. this causes distortion of red cells (eg sickle or holly leaf shapes), which is initially reversible, but becomes irreversible
c) May occur acutely in a sickle cell crisis. i) Haemolysis, mostly seen in spleen ii) occlusion of small blood vessels with reduced O₂ delivery to organs, and more sickling (the microvascular beds most likely to be occluded are those where flow is slow, eg spleen, bone marrow, sites of inflammation) iii) tissue hypoxia/infarction can cause pain (eg bones, lungs, brain) iv) may also be chronic tissue hypoxia (affecting growth, kidneys, heart, lungs etc)
d) in heterozygotes (sickle cell trait), only 40% of Hb is HbS - sickling only occurs if severe ↓pO2, ↓pH. Prevalence of heterozygosity is up to 30% in some African populations. A/S children are less likely to die of malaria and have reduced parasite density, compared with A/A children. The protection is probably due to increased clearance of parasatised red cells following sickling
Haemoglobinopathies - diminished production of globin chains: Thalassaemias
Overview and consequences
Absent or reduced syntheiss of globin chains of HbA (α2β2). endemic in many parts of the world. Heterozygotes are protected against malaria. Wide variations in genotype and phenotype
Consequences - i) Reduced production of RBCs (low globin levels, red cells hypochromic, microcytic, may be anisocytosis ii) Relative excess of other chain (α4, β4) which precipitate as inclusions (cause damage to cell membrane and impaired DNA synthesis. There is destruction of erythroblasts ,ineffective haemopoiesis, and RBCs, haemolysis in spleen
Haemoglobinopathies - diminished production of globin chains: Thalassaemias
a) β thalassaemias
b) α thalassaemias
a) β chains are coded by a single gene on each chromosome 11. Mutations cause either a loss of β chains (β0) or inadequate synthesis (β+). Mutations may affect gene transcription (promoter mutations), RNA splicing (splice sites destroyed or new ones created), translation (nonsense or frameshift mutations). Compensatory increase in HbF and sometimes HbA2. (see image for details of genotype and features). Ineffective erythropoiesis leads to bone marrow expansion with erosion of cortical bone (eg skull), also extra-medullary haemopoiesis (eg liver and spleen), and excessive absorption of dietary iron, producing iron overload (eg heart)
b) α chains encoded by two duplicated genes on each chromosome 16. Each gene contributes 25% of the α globin protein. α thalassaemia is usually caused by deletion of these genes. The level of α chain synthesis are dependent on the number of deleted genes. Free β and γ chains are more soluble than free α chains. Ineffective haemopoiesis and haemolysis in α thalassaemia are therefore less severe than in β thalassaemia. (see image for details of genotype and features)
