Anaemia

ANAEMIA

Is present where there is a decrease in the number of circulating red cells, a decrease in the amount of haemoglobin in the blood or a haematocrit below the normal range.

DEFINITIONS IN HAEMATOLOGY Mean corpuscular volume (MCV)

Haematocrit Red cells count

N = 80 – 96 μ

Mean corpuscular = haemaglobin (MCH)

Haemaglobin x 10 Red cells count

N = 27 – 33 pg

Mean corpuscular = haemaglobin concentration (MHCH)

Haemaglobin x 10 Haematocrit

N = 32 – 35 g/dL

=

Clinical features Symptoms (all non - specific): – fatigue – headaches – faintness – breathlessness – angina of effort – intermitent claudication – palpitations

Signs: 2. Non / specific signs include: – pallor – tachycardia – a full pulse – systolic flow murmur – cardiac failure – ankle oedema – rarely papilloedema and retinal haemorrhage in an acute bleed 3. Specific signs: – koilonychia – spoon-shape nails seen in iron deficiency anaemia – jaundice – haemolytic anaemia – bone deformities – thalassemia major – leg ulcers – sickle cell disease

Classification: 2. Hypochromic microcytic with low mean corpuscular volume (MCV) 3. Normochromic normocytic with a normal MCV 4. Macrocytic with a high MCV

Special investigations: – bone marrow aspiration from the sternum or posterior illiac crest is performed to: – confirm a diagnostic made from peripheral blood count – determine the cellularity of the marrow – determine the type of erythropoiesis – determine the proportion of the various lines – see wether the marrow is unfiltrated – determine the size of the iron stores

MYCROCYTIC ANAEMIA – small cells (microcytes) – low MCV (< 80 μL) – ↓ iron content –ragged normoblasts

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Iron deficiency anaemia

– small cells (microcytes) – low MCV (< 80 μL) – normal iron content hyperplastic

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Thalassaemia Sideroblastic anaemia

1.IRON DEFICIENCY – the commonest cause of mycrocitic anaemia – the average daily diet contains 15 – 20 mg of iron, but only 10% is absorbed – absorption:  duodenum and jejunum  ferrous iron is absorbed better than ferric  gastric acidity helps to keep iron in the ferrous state and soluble in the upper gut

– transport in the blood:  transported in the plasma bound to transferin, beta globuline synthesized in the liver – iron stores – in the tissues as ferritin and haemosiderin (1000 – 1500 mg) – requirements:  each day 0.5 – 1 mg of iron are lost in the faeces, urine and sweat  menstruating women lose 0.7 mg iron / day of menstruation  pregnancy and groth ↑ iron demand

CAUSES OF IRON DEFICIENCY 2. Poor intake 3. Decreased absorption 4. Increased demands 5. Blood loss

The commonest cause of iron deficiency:  Blood lost from G.I. tract  Menstruation

Clinical features: – brittle nails – spoon – shaped nails (koilonychia) – atrophy of the papillae of the tongue – angular stomatitis – brittle hair – dysphagia and glossitis (plummer – Vinson or Paterson Brown Kelly syndrome) – parotid gland enlargement, splenomegaly and failure to grow

investigations: – the red cells are microcytic (MCV < 80 fL) and hypochromic (MCV < 27 pg) – poikilocytosis (variation in shape) and anisocytosis (variation in size) – target cells – hypersegmentation of polymorphs – serum iron falls – iron blinding capacity ↑ – bone marrow – erythroid hyperplasia with ragged normoblasts – ring sideroblast

other investigations: – the G.I. tract - endoscopy

Bone marrow in iron deficiency

1.sideroblastic anaemia

Classification: A. Congenital: – “X” linked disease – transmitted by females B. Acquired: – primary or idiopathic – secondary:  drugs  alcohol  lead  myeloproliferative disorders  leukaemias  secondary carcinoma  other systemic disorders (connective tissue disease)

1.thalassaemia Deficiency in the synthesis of the globin chains of haemoglobin in addition, the accumulation of abnormal chains within the red cell leads to its early destruction.

The severity of the thalassaemia will depend on the amount of the haemoglobin A2 and F present.

Clinically β-thalassaemia can be divided into: –thalassaemia mayor, with severe anaemia –intermedia, transfusion

with

moderate

anaemia

rarely

–minor, the symptomless heterozygous carrier state

requiring

symptoms: – failure

to thrive

– intermittent infection – severe anaemia – extramedullary haemopoiesis → hepatosplenomegaly and bone expansion thalassaemic facies

investigation: – blood count:  moderate to severe anaemia (↓MCV, MCH↓)  reticulocyte ↑  white cells and platelets = N – blood film:  hypochromic and microcytic picture  Howell – Jolly bodies – high ferritin levels – haemoglobin electrophoresis (HbF ↑; HbA absent)

β-Thalassaemia trait (minor) – asymptomatic – no anaemia, red cells hypochromic and microcytic

α-Thalassaemia – two main form:  deletion of only alpha chain gene deletion of both alpha chain genes → no alpha chains are produced

Thalassemia major

Thalassemia minor

Macrocytic anaemia The presence in the bone marrow of erytroblasts with delayed nuclear maturation because of defective DNA synthesis (megaloblasts). Occurs in: –vitamin B12 deficiency –folic acid deficiency –diseritropoetic anaemia Haematological values: –anaemia –MCV > 96 fL –blood film (peripheral): macrocytes and hypersegmented polymorphs –neutropenia –thrombocytopenia

vitamin b12 (Addison – Biermer anaemia) – average

daily diet 5 – 30 μg B12

–average adult stores 1000 μg – liver –absorption and transport: gut → binder complex (R binder + B12) → intrinsec factor (glycoprotein from the gastric juice) Transcobalamin Ileum → → → → → → → → → → Marrow

Pernicious anaemia (Addison – Biermer) affect: – particularly nordic people: fair – haired; blue – eyed. –association with other autoimmune diseases: thyroid disease, Addison’s disease, vitiligo – higher incidence of gastric carcinoma

Causes of vitamin b12 deficiency:

– low dietary intake (vegans) – impaired absorption: A. stomach (gastrectomy) B. small bowel: – coeliac disease – tropical sprue – bacterial overgrowth – ileal disease or resection C. pancreas: – chronic pancreatic disease – Zollinger – Ellison syndrome D. miscellaneous and rare: – fish tape worm (diphyllobothrium latum) – congenital deficiency: – intrinsec factor – transcobalamin III – nitrous oxide (inactivates B12)

Clinical features: 2. Anaemic syndrome 3. Neurological syndromes:  Peripheral neuropathy progressively involving posterior and lateral columns of the spinal cord: – symmetrical paraesthesia in the fingers and toes – loss of vibration sense and proprioception – progressive weakness and ataxia – paraplegia  Mental changes: – somnolence – irritability – psychosis – dementia

the

1. Digestive syndrome: – glossitis (red sore tongue) – angular stomatitis – hepatosplenomegaly – gastric atrophy and achlorhydria 2. Others: – skin – lemon-yellow tint due to hyperbilirubinaemia – heart – failure – fever

Investigations: –peripheral blood film shows features of megaloblastic anaemia: ↓ reticulocytes –the serum bilirubin ↑ –bone marrow → megaloblastic erythropoiesis –the Schilling test (a radioactive dose of B12 is given orally and the total body activity is measured) –G.I. investigations → endoscopy

Bone marrow pernicious anaemia

Folic acid Daily requirement 100 μg Causes of folate deficiency: – poor intake: – old age – poor social conditions – starvation – alcohol excess – poor intake due to anorexia: – G.I. disease (partial gastrectomy, coeliac disease, Crohn’s disease, cancer) – excess utilization

clinical features: B. Physiological:  pregnancy  lactation  prematurity C. Pathological:  haemolysis  malignant disease  inflammatory disease  metabolic disease  haemolysis – malabsorption – antifolate drugs

Normocytic anaemia 1. Acute blood loss 2. Aplastic anaemia 3. Anaemia of chronic disease 4. Haemolytic anaemia

1.Acute blood loss Stage I: – Hb, Ht, Rc, N or ↑ – white cells ↑ – platelets ↑ Stage II (2 – 4 days): – Hb, Ht, Rc ↓ – reticulocytosis – ↓ white cells – ↓ platelets

Stage III (2 – 3 weeks): –Hb, Ht, Rc –Wc –Platelets

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N

1.Aplastic anaemia Aplasia of the bone marrow with peripheral blood pancytopenia. Causes: – congenital: Fanconi’s anaemia – acquired: – chemicals, drugs, insecticides – ionizing radiation – infections: viral hepatitis measles – miscellaneous infection: tuberculosis – tyhmona – pregnancy – unknown

clinical features: – anaemia – bleeding (ecchymoses, bleeding gums and epistaxis) – infection (fungal infections)

investigations: – elevated serum iron – low haemoglobin – white cell – count 500 / mmc – platelet 20,000 / mmc – reticulocytes virtual absent – hypocellular or aplastic bone marrow

1.Haemolytic anaemia The red cells normally survives about 120 days, but in haemolysis the cell survival times are considerably shortened. Causes of haemolytic anaemia: D. Inherited: 1. red cell membrane defect: – hereditary spherocytosis – hereditary eliptocytosis 2. haemoglobin abnormalities: – thalassaemia – sickle cell disease 3. metabolic defects: – glucose 6 phosphate dehydrogenize deficiency – pyruvate kinase deficiency

(Causes of haemolytic anaemia) B. Acquired: 1. immune: – autoimmune – isoimmune (Rh or ABO incompatibility) 2. non-immune: – membrane defects: paroxysmal nocturnal haemoglobinuria, liver disease, renal disease – mechanical: damaged vessels, valve prosthesis, march haemoglobinuria 3. miscellaneous: – infections – drugs and chemicals – hypersplenism

site of haemolysis: 3. Intravascular – red cells are rapidly destroyed within the circulation, haemoglobin is liberated; 4. Extravascular – red cells are removed from the circulation by macrophages in the reticuloendothelial system (liver and spleen)

evidence for haemolysis: Increased red cell breakdown leads to: – iron ↑ – stercobilinogen ↑ – elevated serum bilirubin (unconjugated) – excess urinary urobilinogen – reduced plasma haptoglobin – abnormal red cell fragments in peripheral blood

Increased red cell production leads to: – reticulocytosis – erythroid hyperplasia of the bone marrow

clinical findings: – skin – jaundice – splenomegaly – abdominal pain (infarction or acute sequestration as in sickle syndromes) – gall stones – growth impaired (e.g. spherocytosis) – ulcers on the leg – dark urine (in haemolytic crises) – black in pmn – septic necrosis of the bone (sickle sdr.) – papillary necrosis affecting the kidney → haematuria (S.S.) – painful priaprism – cerebral damage

Peripherical blood in hemolytic anaemia

Polycythaemia Is defined as a haemoglobin level greater than 18 g/dL, a red cell count above 6x1012/L. The red cell volume is greater than 36 mL/kg in males and 32 mL/kg in females.

Causes of polycythaemia Primary: – Polycythaemia vera

Secondary: A. due to an appropriate increase in erythropoetin: – high altitude – lung disease – cardiovascular disease (right left shunt) – heavy smoking B. due to an inappropriate increase in erithropoetin: – renal disease, carcinoma, Wilms tumor – hepatocellular carcinoma – adrenal tumors – cerebellar haemangioblastoma – massive uterine fibroma Relative: – stress or spurious polycythaemia – dehydration – burns

Policitemia vera Caused by chronic sustained proliferation of the erithroid population of the bone marrow. ↑ red cell volume ↑ blood viscosity

compensated by an increase plasma volume and cardiac output

Ht ↑ ↑ ↑  myocardial infarction stroke

clinical findings:  tiredness  depression  vertigo  tinitus and visual disturbance  hypertension  angina  intermitent claudication  tendency to bleed  itching after bath  peptic ulcerations

investigations:  ↑ Hb, ↑ Ht, ↑WBC, ↑platelets  erythroid hyperplasia and abnormal megakaryocytes in bone marrow  red cell volume ↑  serum uric acid levels ↑  leucocyte alkaline phosphatase (LAP) ↑  vitamin B12 binding protein is ↑

The white cell The five types of leucocytes found in peripheral blood are: • polymorphonuclear leucocytes (neutrophil leucocytes) • eosinophil leucocytes • basophil granulocytes • lymphocytes • monocytes

Polymorphonuclear leucocytes originate in the bone marrow and are carried to tissues via the blood, where they are involved in immune defense and may continue to circulate between the lymphatic tissue and blood stream.

neutrophilis The neutrophil granulocyte originates in the bone marrow as myeloblast → promyelocyte → myelocyte (stored up to 10 days) Function – ingest and kill bacteria – accumulation of degenerate neutrophils gives rise to pus Neutrophil luecocytosis  rise in the number of neutrophils to > 10x105/l in bacterial infection or tissue damage  exercise  corticosteroid administration

Neutrophil leucocytosis  leukaemia  myeloproliferative disease  leukaemoid reaction  leucoerytroblastic anaemia  the leucocytosis may be accompanied by a pyrexia due to the production of a leucocyte pyrogen  a leukaemoid reaction (the overproduction of white cells, many of them primitive) may occur in - severe infections - tuberculosis -malignant infiltration

neutrophilis Neutropenia and agranulocytosis  defined as a circulatory neutrophil count below 1,5x109/l  the absence of heutrophilis is called agranulocytosis

causes of neutropenia  rasial (neutropenia is common in black rases)  viral infection  severe bacterial infection (typhoid)  Felty’s syndrome  megaloblastic anaemia  drugs  pancytopenia from any cause

Clinical features:  infections  glazed mucositis occurs in the mouth and ulceeration is common  septicaemia

investigation  blood film shows neutropenia  bone marrow – absence of cells from the neutrophil granulocyte series

eosinophils – Occur when the number of eosinophils is > 1x109/l

causes of eosinophils

 Parasitic infestation – ascaris – strongyloides

 Allergic disorders – hayfever (allergic rhinitis) – other hypersensitivity reactions, including drug reactions  Skin disorders – urticaria – eczema – pemphigus

 Pulmonary disorders – bronchial asthma – tropical pulmonary eosinophilia – allergic bronchopulmonary aspergillosis – polyarteritis nodosa (Churg – Strauss syndrome)  Malignant disorders – lymphoma – carcinoma – melanoma – eosinophilic leukemia  Miscellaneous – sarcoidosis – hypoadrenalism – eosinophilic gastroenteritis – hypereosinophilic syndrome

lymphocytes • Form nearly the circulating white cells • Originate in the lymph glands, spleen, Peyer’s patches, bone marrow, thymus 2 types:  thymus dependent or T lymphocytes concerned with cellular immunity  “bursa – dependent” or B lymphocytes concerned with humoral immunity Lymphocytosis occurs in: • viral infections: Epstein – Barr, cytomegalvirus • chronic infections: syphilis, tuberculosis • acute viral infections: pertussis, brucellosis

The leukaemias Characterized by the proliferation of a single malignantly transformed progenitor cell in the haemopoietic system.

clasification There are TWO MAJOR of acute leukemia: F. Acute lymphoblastic leukaemia G. Acute non-lymphocytic leukaemia (called also acute myelogenous leukaemia) The CHRONIC FORMS of these conditions are: Chronic granulocytic leukaemia Chronic lymphatic leukaemia

incidence – the commonest childhood leukaemia is acute lymphoblastic in type (80%) – adults B and in elderly – chronic forms

aetiology – remains unknown Genetic factors: – are important: low frequency of all in black children – a high incidence of leukaemia in the identical twin – ↑ risk of developing acute leukaemia in children with Down’s syndrome (who have chromosomal abnormalities)

Enviromental factors:  radiation (in survivors of the atomic bomb of Hiroshima)  chemicals  drugs and chemotherapeutic agents  viruses (human leukaemia virus type I) which was first discovered in Japanese with T cell leukaemia and hypercalcaemia

Acute leukaemia Cellular types 3. Acute lymphoblastic leukaemia – blast cells involved may vary – histologically: L1, L2 and L3 types – the phenotypic markers have proved to be of considerable importance assessing the likelihood importance of response and the long-term outlook 4. Acute non-lymphocytic leukaemia

classification

M1

M2 M3 M4 M5 M5 A M6

• predominant myeloblasts, distinct nucleoli • few granules Auer rods – rare • myeloblasts and promyelocytes predominant • further maturation abnormal • auer rods – many • promyelocytes predominate Acute promyelocytic hipergranular • auer rods – rare leukaemia • myelocytic and monocytic maturation Acute myelomonocytic evident may be peripheral leukaemia • auer rods – rare Acute monocytic • promonocytes predominant with differentiation leukaemia Acute monoblastic • completely with differentiation leukaemia • undifferentiated blast cells • bizzare, multinucleated megaloblasted Erytroleukaemia erythroblasts predominate • myeloblasts also present

Acute myelocytic leukaemia without differentiation Acute myelocytic Leukaemia with Differentiation

Acute leukaemia clinical features Hystory short  symptoms of anaemia and maladive  acute infections such as mouth ulceration, sore throat, pneumonia, perianal and skin infections  painful and enlarging lymphadenopathy  bruising and bleeding  bone pain (particularly common in children with all)  symptoms due to infiltration of tissues with leukaemic blast cells, marked gum hypertrophy  headache, nausea, vomiting and blurred vision (raised intracranial pressure)

Signs These may be relatively few, but commonly they are:  pallor  bruising, petechial haemorrages, bleeding gums and gum hypertrophy  lymphadenopathy  splenomegaly and hepatomegaly  haemorrhages in the optic fundi with characteristic central white deposit in the middle of the fundal haemorrhage → leukaemic retinopathy  meningeal leukaemia  boys – hard enlarged testicles (infiltrated with leukaemic tissue)

investigation 2. Peripheral blood film and bone marrow – normochromic and normocytic anaemia – the white cell count may be normal or raised; rarely a few blast cells may be seen in the peripheral blood, or none at all – the platelet count is usually reduced – hypercellular bone marrow with characteristic blasts in the trail of the fragments on the microscope slide 3. The CSF should be examined – will contain blasts cells if meningeal leukaemia is present 4. Test of renal function 5. Serum uric acid 6. Serum calcium 7. Serum electrolytes (potassium) 8. Blood cultures 9. Chest X ray (to determine the presence of a mediastinal mass)

Gum-hypertrophy ALL

Blasts-and-Auer-body

ALL

ALL Blast

ALL-L1-Marrow

Chronic granulocytic leukaemia – occurs in middle-aged and elderly people – it occurs in the myeloproliferative syndromes, which include: polycythaemia vera, myelofibrosis, essential trombocytosis – it is characterised by the presence of chromosome

Philadelphia

Clinical features  often of insidious onset (may only be discovered on a routine blood count)  anaemia  bruising and bleeding manifestations  pain or discomfort due to a very large spleen → gastrointestinal disturbance  sweating, fever and loss of weight as the result of a high metabolic rate

Phisical signs  anaemia  lymphadenopathy (uncommon)  a large spleen (common)  haemorrhage and thrombosis; bruising, bleeding, priapism may occur  gout

Investigations  normal Hb (initially), than a normocytic, normochromic anaemia  white cell count is greater than 100 000 /mmc (100 000 – 500 000 /mmc)  blood film: abundance of neutrophils, mielocytes and even a few blast cell are present  platelets count: N or ↑  bone marrow: hypercellular marrow with the granulocyte precursors markedly increased  a chromosome preparation shows the Philadelphia chromosome  the leucyte alkaline phosphatase (lap) is very low  levels of serum vit. B12 and B12 binding proteins are elevated

Chronic lymphatic leukaemia  disease of late middle-aged and elderly people  disorder of B cells, with accumulation of mature lymphocytes in the tissues and peripheral blood  few cases the lymphocytes are T cells and skin involvement can occur (mycosis fungoides, the Sézary syndrome, peripheral T cell lymphoma)

clinical features • the onset is insidous • lethargy • fever and sweating • loss of weight

signs  moderate enlargement of lymph nodes in the neck, axilla and groin  splenic and hepatic enlargement, but not usually massive

investigations  mild anaemia, normochromic, normocytic  white cell count > 15x109 &l, which more than 40% lymphocytes  platelet count is usually normal as the disease progresses, anaemia may become severe due to Coombs positive haemolysis and the number of lymphocytes ↑