Anaemia

ANAEMIA

Submitted By • Dr. NAVDEEP GILL B.D.S

INTRODUCTION • It is defined as a Hb. Concentration in blood below the lower limit of the normal range for the age & sex of the individual • Normal count:• In adults:For males-13.0 g/dl For females-11.5 g/dl In infants:15 mg/dl(lower limit)

CLASSIFICATION • Pathophysiologic • Morphologic

Pathophysiologic Classification 1.Anaemia due to increased blood loss a)Acute post-haemorrhagic Anaemia b)Chronic blood loss 2.Anaemia due to impaired red cell production a)Cytoplasmic maturation defects Deficient haem synthesis:Iron deficiency anaemia

Pathophysiologic Classification • Deficient globin synthesis:Thalassaemia b)Nuclear maturation defectsVit. B12 &/or folic acid deficiency:Megaloblastic anaemia c)Defect in stem cell proliferation & differentiation- Aplastic anaemia Pure red cell aplasia

Pathophysiologic Classification d) Anaemia of chronic disorders e) Congenital anaemia 3. Anaemia due to increased red cell destruction (haemolytic anaemia) d) Extrinsic(extracorpuscular) red cell abnormalities e) Intrinsic(intracorpuscular) red cell abnormalities

Morphologic Classification A) Microcytic, Hypochromic B) Normocytic, Normochromic C) Macrocytic, Macrochromic

Sideroblastic Anaemia •

Comprise a group of disorders of diverse etiology in the bone marrow, show characterstic“ring sideroblasts”. • Classification: 1. Hereditary (Congenital) sideroblastic anaemia 2. Acquired sideroblastic anaemia E. Primary acquired sideroblastic anaemia F. Secondary acquired sideroblastic anaemia

B. Secondary acquired sideroblastic anaemia ii) Drugs and chemicals and toxins e.g. isoniazide, cycloserine, chloramphenicol, alcohol & lead. iv) Haematological disorders e.g. Myelofibrosis, polycythaemia vera, acute leukaemia, myeloma & lymphoma. vi) Misc. e.g. Carcinoma, myxoedema & SLE.

Lab Investigation - Moderate to severe degree of anaemia - Blood picture shows Hypochromic anaemia which may be microcytic or there may be some nomocytic RBCs. - Absolute values: (MCV, MCH, MCHC) are reduced in hereditary type but MCV is often raised in acquired type

Lab Investigation - Bone marrow examination shows erythroid hyperplasia usually macro-normoblastic erythropoiesis. Marrow iron stores areraised and ringed sideroblasts are raised. - Serum ferritin levels raised. - Increased iron deposition in the tissue.

Megaloblastic Anaemia • Are disorders caused by impaired DNA synthesis & are characterized by a distinctive abnormality in the haematopoietic precursors in the bone marrow in which the maturation of the nucleus is delayed relative to that of the cytoplasm.

Classification 1. Vitamin B12 deficiency A) Inadequate dietary intake e.g. Breast fed infants C) Malabsorption iv) Gastric causes:- pernicious anaemia, gastrectomy, congenital lack of intrinsic fectors. v) Intestinal causes:- Tropical sprue, coeliac disease, fish tapeworm infestation

Classification 2. Folate deficiency A) Inadequate dietary intake e.g. in alcoholics, infants, old age, poverty etc. B) Malabsorption:e.g.:-Tropical sprue, coliac disease, partial gastrectomy, crohn’s disease. C)Exess demand i)Physiological: Pregnancy, lactation, infancy

Classification ii)Pathological: Malignancy, tuberculosis, rheumatoid arthritis etc. D)Excess urainary folate loss e.g. in active liver disease, CHF. 3. Other causes A) Impaired metabolism e.g. inhibitors of DHF reductase such as methotrexate & pyrimethamine ,alcohol etc.

Classification • Unknown etiology :e.g.-In De Guglielmo’s syndrome, congenital dyserythropoietic anaemia, refractory megaloblastic anaemia.

Lab investigation of megaloblastic anaemia A. General lab findings :2. Blood – iii) Red cell morphology: - macrocytic red cell v) Absolute values : - MCV-elevated - MCH-elevated - MCHC-normal or less iii) Leucocytes : WBCs count may reduced

Lab investigation of megaloblastic anaemia iv) Platelets- Moderately reduced in severly anaemic patients. Bizzarre form of platelets seen. 2. Bone marrow findings:v) Marrow erythropoiesis- Megaloblastic vi) Bone marrow stores- Increased vii) Erythropoiesis : Megaloblasts- Abnormal, large, nucleated d erythroid precursors, having nuclear cytoplasmic asynchrony (i.e. nuclei is less mature than development of cytoplasm)

Lab investigation of megaloblastic anaemia iv) Marrow iron : Increase in number & size of iron granules in erythroid precursors. Iron in reticulum cells increased.

Lab investigation of megaloblastic anaemia 3. Biochemical findings : ii) Rise in serum unconjugated bilirubin & LDH as a result of Ineffective erythropoiesis causing marrow cell breakdown. iii) Serum iron & ferritin raised or normal.

Lab investigation of megaloblastic anaemia 4) Special Test :ii) Serum Vitamin B12 assay iii) SCHILLING TEST iv) Serum enzyme level – Test performed in 3 stages a. Without IF b. With IF c. Test for malabsorption

Haemolytic Anaemia • Are defined as anaemias resulting from an increases in the rate of red cell destruction

Classification 1. Acquired (Extacorpuscular) A) Antibody : Immunohaemolytic Anaemias i) Autoimmune haemolytic anaemia(AIHA) a. Warm antibody AIHA b. Cold antibody AIHA ii) Drug induced Immunohaemolytic Anaemia iii) Isoimmune haemolytic anaemia

Classification B) Mechanical Trauma: Microangiopathic haemolytic anaemia C) Direct toxic effects: Malaria, bacterial infection & other agents. D) Acquired red cell membrane abnormalities: paroxysmal nocturnal haemoglobinuria (PNH) E) Splenomegaly

Classification 2. Hereditary (Intracorpuscular) B) Abnormalities of red cell membrane iii. Hereditary spherocytosis iv. Hereditary ovalocytosis v. Hereditary stomatocytosis B) Disorders of red cell interior vii. Red cell enzyme defects a) Defects in the HMP-shunt:G6PD Deficiency

Classification b) Defects in the glycolytic pathway : Pyruvate kinase ii) Disorders of haemoglobin: c) Structurally abnormal Hbs(haemoglobinopathies) , sickle syndromes , other haemoglobinopathies d) Reduced globin chain synthesis : Thalassaemias

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Lab Findings Of AIHA • -

Warm antibody AIHA Mild to moderate chronic anaemia Reticulocytosis Prominent spherocytosis in the PBF Positive direct Coombs’ (antiglobulin) test for presence of warm antibodies on the red cell, best detected at 37 C.

Lab Findings Of AIHA • Cold antibody AIHA - Chronic anaemia - Low reticulocyte count since young red cells are affected more. - Spherocytosis is less marked - Positive direct Coombs’ test - Donath-Landsteiner test : Cold Ab. Titre is very high at 4 C & very low at 37 C.

Lab Findings Of Hereditary Haemolytic Anaemia A) -

Hereditary abnormalities of red cell membrane – Anaemia : mild to moderate degree Reticulocytosis : usually 5-20 % Blood film : abnormality of RBCs in the form of microspherocytes MCV : normal or decreased MCHC : increased Osmotic fragility test : in testing the spheroidal nature of RBCs ( lysing more readily in sol. of low salt conc. ) i.e. osmotic fragility decreased. Autohaemolyses test negative Direct COOMB’s test negative

Lab Findings Of Hereditary Haemolytic Anaemia B) Hereditary disorders of red cell interior – 2. During period of acute haemolysis : - Rapid fall in haematocrit by 25-30 %. - Features of intravascular haemolysis : rise in plasma Hb. haemglobinuria rise in unconjugated bilirubin fall in plasma haptoglobin

Lab Findings Of Hereditary Haemolytic Anaemia - Formation of Heinz bodies called Heinz body haemolytic anaemia .They aren’t seen for first 2 days as they are removed by spleen leading to formation of BITE CELLS . 2. Between the crises – - Affected patient has no anaemia - Red cell survival shortened

Thalassaemia • Thalassaemias are a group of hereditary disorders in which there is reduced rate of synthesis of one or more of the globin polypeptide chains .

Classification • 2. 3. 4. • 1. 7. 8.

α-Thalassaemias :Hydrops foetalis Hb-H disease α-Thalassaemia trait β-Thalassaemia :β-Thalassaemia major β-Thalassaemia intermedia β-Thalassaemia minor

Lab Investigations • α-Thalassaemias :- Moderate anaemia ( Hb = 8-9 g/dl ) - Blood film : Severe microcytosis Hypochromia Basophillic stippling Target cells Normoblasts

Lab Investigation • β-Thalassaemia :- Anaemia severe - Blood Film: -

Severe Microcytic hypochromic RBCs morphology Marked an isopoikilocytosis Basophilic stippling Presence of many target cells Tear drop cells

- Serum bilirubin (Unconjugated) raised

Lab Investigations -

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Mild reticulocytosis HbH inclusions as Heinz bodies Hb electrophoresis – 2-4 % HbH Remainder : HbA , HbA2 & HbF α-Thalassaemia trait :Hb normal or reduced Blood film : hypochromic red cell morphology No evidence of haemolysis or anaemia MCV, MCH & MCHC INCREASED Hb ELECTROPHORESIS: Small amount of Hb-Bart’s in neonatal period.

Lab Investigations -

Reticulocytosis present MCV, MCH & MCHC reduced WBC count raised Platelet Count normal or reduced in patients with spleenomegaly - Osmotic fragility decreased - Hb electrophoresis: HbA2 increased , HbA absent.

Lab Investigations - Bone marrow examination : Normoblastic erythroid hyperplasia with predominance of intermediate & late normoblasts • β-Thalassaemia minor :- Mild anaemia - Blood film shows anisopoikilocytosis , microcytes & hypochromia,basophilic stippling with occasional target cells. - Serum bilirubin normal or raised

Lab Investigations -

Mild reticulocytosis present MCV,MCH,MCHC reduced Osmotic fragility decreased Hb electrophoresis shows about two fold increase in HbA2 & slight elevation in HbF

The Thalassaemias • Management – Regular transfusion – Iron chelation – Splenectomy – Immunisation – Bone marrow transplantation – Reduced life expectancy

Aplastic Anaemia • It is defined as pancytopenia ( i.e. simultaneous presence of anaemia , leucopenia & thrombocytopenia )resulting from aplasia of the bone-marrow

Lab Investigations 1.

Anaemia : Hb level moderately reduced Blood picture shows normocytic normochromic anaemia Reticulocyte count is reduced or 0. 2. Leucopenia : Granulocyte count is low with lymphocytosis 3. Thrombocytopenia : Reduced 4. Bone marrow aspiration : Reveals patchy areas in a hypocellular or aplastic marrow due to replacement by fat. severe depression of myeloid cells , megakaryocytes or erythroid cells. Marrowchiefly composed of lymphocytes & plasma cells.

Lab Investigations • A sample of bone marrow in a patient with Aplastic Anaemia

Case history (1) • 45yr old female • 3 month history of fatigue and shortness of breath on exertion • O/E pallor ++ • FBC – Hb 6.2g/dl

Case history (1) • What further results are important in the full blood count? • What further details are important in the clinical history and examination? • What further investigations should be carried out? • How should the patient be managed?

Full Blood Count • What further results are important in the full blood count? • • • • •

Hb 6.2 g/dl (12-16) WCC 7.0 x 109/l (4-11) Platelets 300 x 109/l (140-440) MCV 60fl (76-96) MCH 24 pg (27-32)

• WCC differential –N • Blood Film

Some causes of microcytic anaemia….. • Acquired – Iron deficiency – Anaemia of chronic disease – Myelodysplastic syndromes – Lead poisoning

More causes of microcytic anaemia….. • Inherited – Beta Thalassaemia trait – Beta Thalassaemia major – Alpha Thalassaemia trait – Sickle cell trait – Congenital sideroblastic anaemia

Hypochromic Anaemia Ferritin

Reduced Iron deficiency Anaemia of Chronic disorders

Normal

Haemoglobinopathy

Increased Sideroblastic Anaemia Other causes of high ferritin

What further details are important in the clinical history? • • • • • • •

Dietary intake of iron Symptoms of malabsorption / weight loss Overt GI blood loss Menorrhagia Pregnancy Oral iron therapy Bleeding history/ family history of bleeding disorder

Iron Requirements • • • •

Males 0.5-1mg per day Menstruating females 1-2mg per day Pregnant females 1.5-2.5mg per day Children 1mg per day

• An adequate diet contains 15mg of iron, 10% of which is absorbed.

Dietary iron • Red meat , liver • Absorbed in the duodenum and jejunum • Absorption enhanced by ascorbic acid, citrus fruits • Absorption reduced by phytates, alkalis, tea, tetracyclines

Causes of iron deficiency anaemia • Inadequate intake

• Dietary iron • Iron supplements

• Failure of absorption

• Gastrointestinal symptoms • Hx of Coeliac disease

• Increased blood loss

• Increased

• Overt blood loss from bowel or change of bowel habit • Menorrhagia

Common causes of gastrointestinal bleeding • Oesophagus • Stomach

• Small bowel

• • • • • • • •

Hiatus hernia Varices Gastritis Ulcer Carcinoma Ulcer Meckels diverticulum Carcinoma

Common causes of gastrointestinal bleeding • Colon

• Ulcerative colitis • Carcinoma • Diverticulitis

• Rectum

• Haemorrhoids • Ulceration • Carcinoma

Iron loss in pregnancy • Obligatory iron loss 150-200 mg • Fetal iron 200-370 mg • Iron in placenta and cord 30-170 mg • Iron in blood lost at delivery 90-310 mg • Total iron loss 1050mg

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What further investigations should be carried out? • • • • • • •

Serum ferritin +/- serum iron B12 / folate FOBs Bioprofile +/- Coeliac screen +/- Gastroscopy and/or colonoscopy +/- Gynaecology referral

What further investigations should be carried out? If indicated: • Coagulation screen • VWD screen • Haemoglobin electrophoresis

Causes of raised ferritin levels • • • • •

Acute inflammation Acute liver disease Lymphomas Solid tumours Haemochromatosis

How should the patient be managed? • Treat the underlying cause • Oral iron supplements – correct anaemia – replenish iron stores

• IV iron – malabsorption – intolerance

• Is there a role for blood transfusion?

Failure to respond to oral iron • • • •

Is the diagnosis correct? Is the patient taking the iron? Is there evidence of malabsorption? Is there evidence of persistent blood loss?

Anaemia of chronic disease • Causes – Chronic infection eg abscess, TB – Rheumatoid arthritis – Ulcerative colitis – Malignancy

Anaemia of chronic disease • Mechanisms – Shortened red cell survival – Impaired marrow response to anaemia – Impaired erythropoietin production – Defective iron transport

Anaemia of chronic disease • Laboratory findings – Hypochromic or normochromic cells – Reduced serum iron – Increased iron stores in RE system – Low or high ferritin

Case History (2) • History : This 13 month old cat presented with pale mucous membranes, an increased heart rate and general malaise. Flea infestation was apparent

Lab abnormalities included • PBF :-

Lab abnormalities included • Reduced PCV of 22, lowered haemoglobin of 6.1, reduced red cell count, redcued MCV and abnormal blood film morphology as above

Diagnosis: Iron Deficiency Anaemia •

In iron deficiency, red cells do not develop the normal complement of iron–containing haemoglobin and the cells that form in the bone marrow are small (microcytic, low MCV) and hypochromic (low MCH and MCHC). The process of red cell maturation becomes prolonged so young red cells no longer contain large amounts of RNA and therefore do not appear polychromatic. As a result the anaemia is non- regenerative, with inappropropriately low reticulocyte counts. There is often a marked increase in variation in red cell shape (poikilocytosis) and red cell fragments (schistocytes) are often seen, as above. In cats, the red cells are often so small that platelets appear larger than red cells and this overlap in sizing can contribute to apparently very high platelet counts as some automated counters include some small red cells in the platelet count. Iron deficiency anaemia reflects chronic external blood loss, either through the gut associated with bleeding tumours or ulcers or occasionally with severe flea burdens and parasitic blood loss.