ÐÏࡱá>þÿ z|þÿÿÿyÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿÿì¥Á5@ ð¿0?qbjbjÏ2Ï2 +r­X­X%Hÿÿÿÿÿÿˆ2222222FPPPP PlFMYò’P’P’P’P’P’P’P’PX’X’X’X’X’X’X$?ZR‘\R¶XQ2œQ’P’PœQœQ¶X22’P’PYˆTˆTˆTœQ(2’P2’PXˆTœQXˆTˆTžTÜTˆ22tX’P†P ?Ì.b¥ÁPÄQ:dXXY0MYlXã\þQtã\tXFF2222ã\2tX’P0ÂP"ˆTäPQœ’P’P’P¶X¶XFF„'Ê(D'rTFFÊ(ANAEMIAS Dr. Nusrum Iqbal Blood consists of: red cells white cells platelets plasma, in which the above elements are suspended Plasma is the liquid component of blood, which contains soluble fibrinogen. Serum is what remains after the formation of the fibrin clot The formation of blood cells (haemopoiesis) Blood islands are formed in the yolk sac in the third week of gestation Liver and spleen are the chief sites of haemopoiesis from 6 weeks to 7 months Bone marrow is the only source of blood cells during normal childhood and adult life Pathological processes interfering with normal haemopoiesis may result in resumption of haemopoietic activity in the liver and spleen, which is referred to as extramedullary haemopoiesis. All peripheral blood cells are derived from pluripotential stem cells by a number of differentiation steps Normal haemopoiesis is dependent on the presence of haemopoietic growth factors About 1—3% of bone marrow cells express the CD34 antigen, this population contains virtually all the myeloid and lymphoid precursor Haemopoietic Growth Factors Haemopoietic growth factors are glycoproteins which regulate the differentiation and proliferation of haemopoietic progenitor cells and the function of mature blood cells. Haemopoietic Growth Factors Pluripotent stem cells are under the influence of a number of haemopoietic growth factors including interleukin—3, IL 6, IL—l1, stem cell factor Colony stimulating factors as well as interleukins and erythropoietin regulate the lineage committed progenitor cells. Thrombopoietin along with IL-6 and IL-11 control platelet production Haemopoietic Growth Factors Factors inhibit the process include tumour necrosis factor (TNF) and transforming growth factor-² (TGF- ²). Many growth factors have been produced by recombinant DNA techniques are being used clinically Examples include G-CSF and erythropoietin Erythrocyte sedimentation rate (ESR) This is the rate of fall of red cells in a column of blood and is a measure of the acute phase response. A raised ESR reflects an increase in the plasma concentration of large proteins, such as fibrinogen and immunoglobulin C-reactive protein C-reactive protein is one of the proteins produced in the acute phase response. Rises within 6 hours of an acute event Erythropoiesis Nucleated red cells (normoblasts) are not normally present in peripheral blood but are present if there is extramedullary haemoposesis and in some marrow disorder Erythropoiesis is controlled by the hormone erythropoietin. Erythrnpoietin has a molecular weight of 30 400 and is produced in the peritubular cells in the kidneys (90%) and in the liver (10%) Production is increased if there is hypoxia from whatever cause – anaemia, cardiac pulmonary disease Requirements For Normal Erythropoiesis Iron for Hb synthesis Vitamin B12 and folate for normal DNA synthesis Other vitamins  B6 (pyridoxine), thiamin, riboflavin, and vitamins C and E Trace metals such as cobalt Hormones  androgens and thyroxine. Each normal adult Hb molecule (Hb A) has a molecule consists of two ± and two ² polypeptide chains (±2 ²2) Hb A comprises about 97% of the Hb in adults Hb A2 (±2 ´2) and HbF (±2 ³2) are found in adults in small amounts Haemoglobin synthesis occurs in the mitochondria of the developing red cell Function of Hemoglobin Hemoglobin becomes saturated with oxygen in the pulmonary capillaries where the partial pressure of oxygen is high and Hb has a high affinity for oxygen continued Haemoglobin is efficient for oxygen transport largely because the steepest part of the oxygen dissociation curve occurs at the partial pressure of oxygen which occur in the tissues The oxygen dissociation curve is influenced by 2, 3-DPG, the pH, the concentration of carbon diaoxide in the red cell, and the structure of Hb ANEMIA Anemia is present when there is a decrease in the level of hemoglobin in the blood below the reference level for the age and sex of the individual A reduction in the plasma volume will lead to a spuriously high Hb A raised plasma volume produces a spurious anemia, even when combined with a small increase in red cell volume as occurs in pregnancy There are three major types Hypochromic microcytic with a low MCV Normochromic normocytic with a normal MCV Macrocytic with a high MCV Clinical Features Patients with anemia may be asymptomatic Symptoms (all nonspecific) Fatigue Headaches Faintness Breathlessness Angina of effort Intermittent claudication palpitations Signs Pallor Tachycardia Systolic flow murmur Cardiac failure Papilledema retinal hemorrhages after an acute bleed (can be accompanied by blindness) Specific Signs Koilonychia – spoon-shaped nails seen in iron deficiency anemia Jaundice – found in hemolytic anemia Bone deformities – found in thalassemia major Leg ulcers – occur in association with sickle cell disease It must be emphasized that anemia is not a diagnosis, and a cause must be found Investigations Peripheral Blood A low haemoglobin should always be considered in relation to: The white blood cell (WBC) count The platelet count The reticulocyte count (as this indicates marrow activity) The blood film, as abnormal red cell morphology may indicate the diagnosis Investigations Where two populations of red cells are seen, the blood film is said to be dimorphic For example Combined iron and folate deficiency in celiac disease or following treatment of anemic patients with the appropriate hematinic Bone Marrow The following are assessed: Cellularity of the marrow Types of erythropoiesis (e.g. normoblastic or megaloblastic) Cellularity of the various cell lines Infiltration of the marrow Iron stores MICROCYTIC ANEMIAS Iron deficiency is the most common cause of anaemia in the world Anemia of chronic disease, sideroblastic anemia thalassemia IRON Haem iron forms the main part of dietary iron and is derived from haemoglobin myoglobin in red or organ meats Haem iron is better absorbed than non-haem iron Absorption Takes place in the duodenum and jejunum Absorption is favored by factors such as the acidity of the stomach keeping the iron soluble and in the ferrous rather than the ferrric form Transport in the Blood The normal serum iron level is about 11-30 umol L-1; there is a diurnal rhythm with higher levels in the morning. Iron is transported in the plasma bound to transferrin In an average adult male, 20 mg of iron, chiefly obtained from red cell breakdown in the macrophages of the reticuloendothelial system, is incorporated into Hb every day About two-thirds of the total body iron is in the circulation as haemoglobin (2.5-3 g stored in reticuloendothelial cells, hepatocytes and skeletal muscle cells Ferritin is a water-soluble complex of iron and protein. It is more easily mobilized than hemosiderin for Hb formation Hemosiderin is in insoluble iron-protein complex found in macrophages in the bone marrow, liver and spleen Each day 0.5-1.0 mg of iron is lost in the faeces, urine and sweat. Menstruating women lose 40 mL of blood per month average of about 0.7 mg of iron per day Demand for iron also increases during growth and pregnancy (1-2 mg per day) Iron Deficiency Anemia Iron deficiency anemia develops when there is inadequate iron for hemoglobin synthesis Causes Blood loss increased demands such as growth and pregnancy decreased absorption (e.g. postgastrectomy) poor intake The most common cause of iron deficiency worldwide is blood loss from the gastrointestinal tract resulting from hookworm infestation Clinical Features Symptoms of Anemia Brittle nails Spoon-shaped nails (koilonychia) atrophy of the papillae of the tongue angular stomatitis brittle hair a syndrome of dysphagia and glossitis (Plummer-Vinson or Paterson-Brown-Kelly) Diagnosis Clinical History questions about dietary intake, regular self-medication non-steroidal anti-inflammatory drugs presence of blood in the feces a sign of hemorrhoids carcinoma of the lower bowel careful innquiry about the duration of periods, number of sanitary towels or tampons (normal 3-5/day) used should be made Investigations Blood count and film Red cells are microcytic (MCV < 80 ft) hepochromic cells are microcytic (MCH < 27 pg) poikilocytosis (variation in shape) anisocytosis (variation in size) Target cells are seen Serum Ferritin Level of serum ferritin reflects the amount of stored iron Investigations Serum iron and iron-binding capacity serum iron falls and the total iron-binding capacity (TIBC) rises compared with nroaml iron deficiency is regularly present when the transferrin saturation (I.e. serum iron divided by TIBC) falls below 19% Serum soluble transferrin receptor Investigations Bone Marrow Erythroid hyperplasia with ragged normoblasts are seen in the marrow in iron deficiency staining using Perls’ reaction (acid ferrocyanide) does not show the characteristic Prusian-blue granules of stainable iron in the bone marrow fragments or in the erythroblasts Other Investigations Investigations of the gastrointestinal tract are often required Differential Diagnosis Thalassaemia, sideroblastic anaemia anaemia of chronic diseases Treatment The correct management of iron deficiency is to find and treat the underlying cause, and to give iron to correct the anaemia replace iron stores expected rise in haemoglobin of 1 g per week oral iron is all that is required in most cases ferrous sulphate (600 mg daily, 120 mg ferrous iron) ferrous glucomate (600 mg daily, only 70 mg ferrous iron) Oral iron should be given for long enough to correct the Hb level and replenish the iron stores six months Failure of Response to oral iron may be due to: Lack of compliance continuing hemorrhage severe malabsorption another cause for the anemia Parentral iron is required by occasional patients intolerance of oral preparations with severe malabsorption chronic gastrointestinal diseases such as the ulcerative colitis or Crohn’s disease Parenteral iron can be given as repeated deep intramuscular injections of iron-sorbitol Anemia of Chronic Disease One of the most common types of anaemia in hospital patients occuring in patients with chronic infections such as infective endocarditis tuberculosis osteomyelitis rheumatoid arthritis, systemic lupus erythematosus (SLE) polymyalgia rheumatica there is decreased release of iron from the bone marrow to developing erythroblasts inadequate erythropoietin response to the anaemia decreased red cell survival Mediated by the inflammatory cytokines such as IL-1, tumour necrosis factor and interferons serum iron is low TIBC is also low serum Feritin is normal or raised stainable iron present in the bone marrow therefore, patients do not respond to iron therapy Iron is not seen in the developing erythroblasts treatment is in general that of the underlying disorder Sideroblastic Anaemia Sideroblastic anaemias are inherited or acquired disorders characterized by a refractory anaemia, hypochromic cells in the peripheral blood excess iron and ring sideroblasts in the bone marrow presence of ring siderobasts is the diagnostic feature of sideroblastic anaemia accumulation of iron in the mitochondria of erythroblasts owing to disordered haem synthesis ring of iron granules is formed around the nucleus that can be seen with Perls’ reaction Treatment Drugs or alcohol are withdrawn if these are the causative agents response to pyridoxine folic acid may be required to treat accompanying folate deficiency Treatment Sideroblastic anaemia, due to inhbition by lead of several enzymes involved in haem synthesis, including ALA synthetase haemolysis, which is usually mild, resulting from change to the red cell membrane punctate basophilia (basophilic stiplling: the blood film shows red cells with small, round, blue particles) aggregates of RNA in red cells owing to inhibition by lead of pyrimidine-5-nucleotidase Normocytic Anaemia Normocytic, normochromic anaemia is seen in anaemia of chronic disease endocrine disorders (hypopituitarism, hypothyroidisim and hypoadrenalism) some haematological disorders (e.g. aplastic anaemia and some haemolytic anaemias acutely following blood loss Macrocytic Anaemias Divided into megaloblastic and non-megaloblastic types Megaloblastic Anaemia Megaloblastic anaemia is characterized by the presence in the bone marrow of erythroblasts with delayed nuclear nacturation because of defective DNA synthesis (megaloblasts) megaloblasts are large and have large immature nuclei a characteristic abnormality of white cells, giant metamyelocytes, is frequently seen in megaloblastic anaemia Megaloblastic changes occur in Vitamin B12 deficiency or abnormal vitamin B12 metabolism Folic acid deficiency or abnormal folate metablosim other defects of DNA synthesis therapy with drugs interfering with DNA synthesis (e.g. hydroxyurea, azathioprine, azidothymidien-AZT) myelodysplasia due to dyserythropoiesis Haematological values Anaemia may be present the MCV is characteristically > 9 fl unless there is a coexisting cause of microcytosis peripheral blood film shows macrocytes with hypersegmented polymorphs with six or more lobes in the nucleus (leucopenia thrombocytopenia) The most common cause of vitamin B12 deficiency in adults is penicious anaemia pernicious anaemia (PA) is condition in which there is atrophy of the gastric mucosa with consequent failure of intrinisic factor production and vitamin B12 malabsorption It can be seen in all races, but is particularly common in fair-haired and blue-eyed people. It is more common in females than males association with othe autoimmune diseases, particularly thyroid disease addison’s disease and vitiligo one half of all patients with PA have thyroid antibodies higher incidence of gastric carcinoma in males with PA than in the general poplulation Parietal cell antibodies are present in the serum in 90% of patients with PA, intrinsic factor antibodies, although found in only 50% of patients with PA, are specific two types, blocking antibody, pericipitating antibody Atrophic gastritis is present with plasma cell and lymphoid inflitration achlorydria and absent secretion of intrinsic factor O Onset of PA is insidious lemon-yellow colour owing to a combination of pallor and mild jaundice caused by excess breakdown of haemoglobin due to ineffective erythropoiesis in the bone marrow red sore tongue (glositis) angular stonatits neurological changes if left untreated they can be irreversible Polyneuropathy progressively involving the peripheral nerves and the posterior eventually the lateral columns of the spinal cord (subacute combined deeneration) symmetrical paraesthesia proprioception progressive weakness ataxia paraplegia dementia optic atrophy Investigations Haematological findings: shows the features of a megaloblastic anaemia bone marrow: shows the typical features of megaloblastic erythropoeisis serum billirubin: may be raised as a result of ineffectie erythropoiesis Serum vitamin B12: is usually well below the normal level of 160 ng L-1 serum folate level: is normal or high the red dell folate is normal or reduced owing to inhibition of normal folate synthesis Absorption tests The absorption of B12 can be measured using the schilling test A normal result is retention of 50% of more of the 1 ug dose of radioactive B12 Gastrointstinal Investigations Intubation studies can be performed to confirm this Endoscopy or barrium neal examination of the stomach is performed only if gastric symptoms are present The main cause is poor intake which may occur alone or in combination with excessive utilization or malabsorption body’s reserves of folate are low may be asymptomatic but may present with symptoms of anemia or glossits neuropathy does not occur Investigations The haematological findings are those of a megaloblastic anaemia Blood Measurements Serum and red cell folate are assayed by radioisotope dillution levels of serum folate are 4-18 ug L-1 The amount of folate in the red cells is a better measure of tissue folate normal range is 160-640 ug mL-1 Further Investigations In many cases of folate deficiency the cause is not obvious from the clinical picture occult gastrointestinal disease should then be suspected and appropriate investigations, such as jejunal biopsy, should be performed Treatment demands on the type of deficiency blood transfusion is not indicated in chronic anaemia folic acid may produce a haematological response in vitamin B12 deficiency but may aggravate the neuropathy Hydroxocoblamin 1000 ug can be given intramuscularly to a total of 5-6 mg over the course of three weeks; 1000 ug is then necessary every three months for the rest of the patient’s life clinical improvement may occur within 48 hours reticulocytosis can be seen some 2-3 days after starting therapy improvement of polyneuropathy may occur over 6-12 months Hypokalaemia occur and, if severe, supplements should be given iron deficiency often develops in the first few weeks of therapy hyperuricaemia occurs in patients who have had a total gastrectomy an ileal resection, vitamin B12 should be monitored; prphylactic vitamin B12 injections should be given Folate deficiency can be corrected by giving 5 mg of folic acid daily prophylactic folic acid (400 ug daily) is recommended for all women planning a pregnancy many authorities also recommend prophylactic administration of folate throughout pregnancy Women who have had a child with a neural tube defect should have 5 mg folic acid before and during a subsequent pregnancy Prophylactic folic acid is also given in chronic haematological disorders where ther is rapid cell sufficient A raised MCV with macrocytosis on the peripheral blood film can occur with a normoblastic rather than a megaloblastic bone marrow common cause of macrocytosis pregnancy newborn Common Pathological causes Alcohol excess liver disease reticulocytosis hypothyroidism haematological disorders (e.g. aplastic anaemia, sideroblastic anaemia, pure red cell aplasia) Common Pathological causes Drug (e.g. cytotoxics - azathioprine) spurious (agglutinated red cells measured on red cell counters) cold agglutinins due to  0 9 $ @ í pƒû ×þZváóš /?_nw†e q Á!Å!d"o"$#;#æQp>q?qöïèöïöïöïöïöïöïöïöïöïöïöïöïöïöïöïöïöïæïâh÷ŒU h÷Œ5\ h÷Œh÷Œh÷Œh÷Œ5\( 0:FP‚ƒ 9 Ï $ % á M N Ÿ $ @ í úúúúúòòòòúúúêêêúââúêêúÚú & Fgd÷Œ & Fgd÷Œ & Fgd÷Œ & Fgd÷Œgd÷Œ?qþ › &°èÀ@jøpƒû ®ëq×þ(ˆ X ÷÷÷òêêêòââòÚòÒÒÒÒòÊÊÊÊÊ & Fgd÷Œ & Fgd÷Œ & Fgd÷Œ & Fgd÷Œ & Fgd÷Œgd÷Œ & Fgd÷Œ ¢zÔZò©³h÷þ‘ÔZvœÆáó7?ISúòòòòúêúòòúâââúÚÚÚúÒúêêê & Fgd÷Œ & 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