ANAEMIA

1. ANAEMIA BY DR. C.C. OKANY

2. ANAEMIAS • Definition • Normal values Adult males 15.00 + 2gms/dl Adult females 13.5 + 1.5gms/dl Neonates 18.0 + 4gms/dl 1yr 12.6 + 1.5gms/dl 6-12yr 13.5 + 2gms/dl

3. CLASSIFICATION OF ANAEMIA 2 types Aetiological morphological

4. AETIOLOGICAL CLASSIFICATION • Blood loss • Impaired red cell production • Due to lack of nutrients essential for erythropoiesis Iron def. Vit B12 def Folate def Protein calorie malnutrition • Depression of erythropoietic activity Anaemia of chronic disorders e.g infections, connective tissue disorder, disseminated malignancies, anaemia of chronic renal failure, Aplastic anaemia, Anaemia due to replacement of normal marrow by leukaemia, lymphoma, myeloproliferative disease, myeloma, MDS

5. AETIOLOGICAL CLASSIFICATION (contd) • Excessive or premature destruction of RBCs • Due to intracorpuscular mechanism Congenital • Membrane defects • Hereditary spherocytosis “ Elliptocytosis • Haemoglobin defects • Haemoglobinopathies • Enzyme defects • Pyruvate kinase deficiency or other enzymes of the Embden Meyerhoff pathway • Due to 6GPD deficiency or other enzymes of the Pentose Phosphate shunt • Drug induced haemolytic anaemia and favism Acquired e.g. P.N.H

6. AETIOLOGICAL CLASSIFICATION (contd) b) Due to extra corpuscular mechanisms - Immune mechanism Haemolytic disease of the newborn Incompatible blood transfusion Drug induced haemolytic anaemia - Non-immune mechanism Cardiac haemolytic anaemia Microangiopathic haemolytic anaemia March haemoglobinuria

7. Morphological classification Normocytic • Assessment of size of red cell microcytic macrocytic • Assessment of central pallor normochromia hypochromia

8. EXAMINATION OF ANAEMIC PATIENT • Skin • Nails • Conjuctiva and sclera • Retina • Mouth (tongue) • Abdomen (splenomegaly, hepatomegaly abdominal masses) • Superficial lymphnodes • Bone tenderness • Rectal examination

9. Evidence of increased haemoglobin breakdown • Jaundice and hyperbilirubinaemia • Plasma haptoglobulin (2 glycoprotein, combines with Hb) • Plasma haemopexin  (-glycoprotein carries haem portion of Hb) • Plasma L.D.H  •  urinary urobilinogen •  fececal stercobilinogen • Haemoglobinaemia • Haemoglobinuria Evidence of intravascular • Haemosiderinuria haemolysis

10. Evidence of compensatory erythroid hyperplasa • Reticulocytosis & erythroblastaemia • Macrocytosis and polychromasia • Erythoid hyperplasia of bone marrow marrow space • X-ray shows changes in skull and tubular bone with thinning of cortex (congenital anaemia only).

11. Evidence of damage to the red cell • Spherocytosis and increased reduced fragility. • Fragmentation of red cells • Heinz bodies (aggregates of denatured globin)

12. Demonstration of shortened red cell life span • Cr51 labelling used for this.

13. Anaemia of systemic Disorders • These are anaemias that occur in association with a number of well defined systemic disorders. The peripheral blood in these anaemias characteristically shows normocytic and normochromic red cells, although occasionally, a macrocytic or even microcytic picture may be seen. Generally, these anaemias are moderate with PCV usually ranging from 30-40, the degree being related to the activity of the disease.

14. Anaemia of systemic Disorders (contd) The main disorders normally associated with these anaemias are: • Infection • Renal failure • Malignant disease • Liver disease • Endocrine disease • Connective tissue disorders • Protein malnutrition • Vitamin deficiencies

15. ANAEMIA OF INFECTION A mild to moderate anaemia usually occurs in most chronic infections and in some acute infections. The most common infections causing anaemias include the following: • Pelvic inflammatory disease • Puerperal infection • Urinary tract infection • Lung abscesses, empyema, bronchiectasis • Pneumonias • Tuberculosis • Bacterial endocarditis • Chronic osteomyelitis • Typhoid

16. ANAEMIA OF INFECTION (Contd) Except in septicaemias very severe anaemia is rare in these conditions. The degree of anaemia is usually directly proportional to the degree of infection

17. PATHOGENESIS OF ANAEMIA DUE TO INFECTIONS • There is a mild haemolytic element with shortened red cell life span, especially when the bone marrow is unable to increase its production to compensate for this. This impaired marrow response is due to impaired erythropoietin production or utilisation.

18. PATHOGENESIS OF ANAEMIA DUE TO INFECTIONS (Contd) b) There is disturbance of iron metabolism with impairment of iron flow from the reticulo-endothelial cells to the erythroblasts. This gives rise to the paradoxical picture of increased stainable iron in the marrow when there is hypochromia – the so called “Starvation in the midst of plenty”. Serum ferritin level is typically raised in chronic infection.

19. PATHOGENESIS OF ANAEMIA DUE TO INFECTIONS (Contd) c) Blood loss and acute haemolysis occasionally contribute to anaemia of patients with infection. Acute severe anaemia may follow septicaemia or virulent acute infections. This may be due to toxic depression of erythropoiesis or due to haemolysis. For example, Clostridium Welchii septicaemia can cause severe haemolysis.

20. PATHOGENESIS OF ANAEMIA DUE TO INFECTIONS (Contd) Occasionally,viral infections like Cytomegalovirus, HIV, and infectious mononucleosis can cause autoimmune haemolytic anaemia. In patients with G6PD deficiency who have acute infections, a haemolytic anaemia can be triggered off by the infection per se or by the drugs used for treating the infection. Apart from causing anaemias by some of the mechanisms listed above, tuberculosis can also cause anaemia by causing: • Secondary myelofibrosis leading to a leuco-erythroblastic anaemia • A splenomegaly which can lead to hypersplenism and anaemia.

21. Anaemia of chronic renal failure Anaemia is such a common feature of chronic renal failure that renal function tests should be part of the routine investigation of any patient, especially on adult presenting with an uneasily explained anaemia. It is not uncommon for patient with chronic renal failure to present for the first time with symptoms of anaemia. The degree of anaemia doe not depend on the type of disease causing the renal failure but seems proportional to the level of blood urea.

22. Anaemia of chronic renal failure (Contd) The anaemia is characteristically of the normochronic and normocytic type although occasionally slight microcytosis, hypochromia or rarely macrocytosis may occur. Neutrophil hypersegmentation can occur. The anaemia of renal failure is attributable to several mechanisms: • Depression of erythropoiesis either due to retained metabolic products or depressed plasma erythropoietin. • Decreased red cell survival mainly due to extracorpuscular mechanisms. • Infection, like in acute pyelonephritis when the marrow will also be depressed. • Blood loss from haematuria, bleeding tendency in uraemia and epistaxis. • Anorexia – leading to folate deficiency • Chronic dialysis

23. Anaemia of chronic renal failure (Contd) Micro-angiopathic haemolytic anaemia is the haematological picture seen in some forms of progressive renal failure especially when the causative disorder is associated with intravascular thrombosis or deposition of fibrin clot. The peripheral blood film classically shows fragemented red cells, microspherocytes and Burr cells. Micro-angiopathic haemolytic anaemia is usually seen in conditions associated with disseminated intravascular coagulation which will include the following. • Haemolytic uraemic syndrome • Disseminated carcinoma • Malignant hypertension • Eclampsia

24. Anaemia in Malignant disorders Anaemia is a common accompaniment of malignant disorders. A number of factors usually contribute to this anaemia and include the following: • Blood loss • Infection • Bone marrow metastasis • Disturbance of nutrition (anorexia or malabsorption) • Impairment of renal function • Haemolytic anaemia (usually auto-immune as in lymphoma) • Bone marrow depression from treatment.

25. Anaemia in Malignant disorders (Contd) The type of anaemia depends on the dominant underlying mechanism causing the anaemia. Most of the time the anaemia is normochromic and normocytic. Occasionally, a leuco-erythroblastic blood picture, in which nucleated red cells and granulocyte precursors are prominent, is seen when there is marrow metastasis. Other haematological changes often seen occasionally in malignant disorders include leucocytosis, thrombocytosis and eosinophilia.

26. Anaemia in Liver Disease Anaemia is a frequent manifestation of liver disease and occurs in about two-thirds of patients with liver cirrhosis. It is usually moderate but occasionally severe. Many aetiologic factors have been implicated in the anaemia associated with liver disease. These include: • Liver disease itself. The pathogenesis is not clear but is somehow related to the impaired liver function. The degree of the anaemia does not correlate with the severity of the liver damage as estimated by the liver function test, neither does it correlate with the duration of liver disease. There is usually both depression of erythropoiesis and accelerated red cell destruction. In chronic alcoholic cirrhosis, alcohol exerts a toxic effect on the bone marrow.

27. Anaemia in Liver Disease (Contd) • Blood loss from oesophageal varices, peptic ulcers and haemorrhoids can also worsen the anaemia in chronic liver disease patients. • Nutritional folate deficiency, especially in chronic alcoholics is also a contributing factor • Hypersplenism in patients with portal hypertension and splenomegaly. • Frank haemolytic anaemia can rarely occur, either as part of Zieve’s syndrome (acute haemolysis, alcoholic fatty liver and extreme hyperlipidaemia) or auto-immune haemolytic anaemia secondary to chronic active hepatitis

28. Anaemia in Liver Disease (Contd) • Acute viral hepatitis especially one due to hepatitis A, can on very rare occasions be complicated by an irreversible aplastic anaemia. Blood picture: The anaemia of liver disease is usually normochromic and normocytic although a macrocytic picture is also often seen.

29. Anaemia is Endocrine Diseases: Many hormones (in addition to erythropoietin) participate in the regulation of erythropoiesis, and patients lacking such hormones often develop hypoplastic anaemia. The hormones most often involved in development of hypoplastic anaemia are those of thyroid, pituitary, adrenal cortex and gonads. Hypothyroidism: A mild to moderate anaemia occurs is about one third of patients with myxoedema. The anaemia is often normochromic normocytic but may be microcytic – hypochromic due to iron deficiency resulting from menorrhagia (a frequent complication), achlorhydria and intestinal malabsorption of iron.

30. Anaemia is Endocrine Diseases:(Contd) Occasionally hypothyroidism coexists with true pernicious anaemia. The anaemia of hypothyroidism normally responds well to thyroxin therapy. Hyperthyroidism: Although the thyroid hormone has a haemopoietic effect, on rare occasions patients with hyperthyrodism may also have an associated pernicious anaemia. Hypopituitarism: Mild to moderate anaemia is usually seen is most patients with hypopituitarism. This anaemia is usually refractory to haematinics until the hypopituitarism is adequately treated. Addison’s Disease: The anaemia in patients with Addison’s disease is often masked by the reduction in plasma volume. The treatment is that of the primary condition.

31. Anaemia in Connective tissue diseases Rheumatoid arthritis: Mild to moderate anaemia frequently accompanies rheumatoid arthritis with haemoglobin ranging from 9 to 11gms/dl. Two forms of anaemia are usually recognised: • A normochromic – normocytic anaemia due to rheumatoid arthritis per se, with the severity varying with the activity of the disease. This is due to poor iron entry into the erythrocytes. • A hypochromic – microcytic anaemia usually secondary to the gastric erosion and blood loss complicating the medication with salicylates and other NSAID.

32. Anaemia in Connective tissue diseases (Contd) Aplastic anaemic is a rare complication of a drug like phenylbutazone which is often used to treat rheumatoid arthritis. Auto immune haemolytic anaemia is also a rare complication. Secondary amyloidosis can also contribute to the anaemia, especially when it leads to chronic renal failure. Felty’s syndrome (Splenomegaly, neutropenia in a patient with rhematoid arthritis) is often associated with significant anaemia.

33. Anaemia in Connective tissue diseases (Contd) Systemic Lupus Erythematosis: Anaemia is present in up to 75% of these patients and is mostly of the normochromic – normocytic type, although in 5% of these patients a Coomb’s Test positive autoimmune haemolytic anaemia is present. Other haematological features of these patients include leucopenia, immune thrombocytopenia and very high ESR. Mild anaemia is also occasionally seen in other connective tissue diseases like dermatomyositis and scleroderma

34. Anaemia of Protein malnutrition The human body has such a high priority for the available protein for haemoglobin synthesis that protein deficiency alone does not often act as a limiting factor in haemoglobin synthesis and cause anaemia. Very considerable depletion of body protein must occur before interference in haemoglobin synthesis occur. In the situations where protein malnutrition exists, there are often deficiencies of other nutrients, such as folic acid, vitamin B12, riboflavin vitamin A and vitamin D.

35. Anaemia of Protein malnutrition (Contd) Anaemia due to protein deficiency frequently occurs in the tropics, particularly in pregnant women, and in children with Kwashiorkor. The anaemia is usually mild to moderate in degree and often responds to high protein diet.

36. Anaemia of Scurvy Scurvy is a deficiency of the C vitamin and usually causes anaemia which in adults is normocytic or slightly macrocytic. In children a hypochromic – microcytic picture might be due to associated iron deficiency caused by inadequate iron intake and blood loss. Like folic acid, ascorbic acid is heat labile, so that the two deficiencies often coexist in infantile anaemias and in elderly people who live in institutions. The anaemia is proportional to the severity of the scurvy. Ascorbic acid tablets or fruits like oranges which are rich in ascorbic acid promptly correct the anaemia in these patients.

37. Treatment of anaemia of systemic disorders The mainstay of management of the anaemia secondary to these systemic disorders is the correction of the primary disorders. In cases, however, when the associated anaemias are severe and the primary disorders are chronic and irreversible, then blood transfusion often becomes the only way to correct the anaemia. Blood transfusion should be given only if the anaemia is very severe and life threatening. In recent times, however perenteral administration of recombinant human erythropoietin is revoluntionising the management of anaemia of patients with chronic renal failure and malignant disease.

38. Anaemia of Bone marrow Failure Causes of impaired marrow erythropoietic activity: Quantitative Haemopoietic cell defect • Aplastic anaemia • Erythropoietic factor • Renal insufficiency • Endocrine hypofunction (thyroid, pituitary) • Marrow replacement • Myelofibrosis • Osteomyelosclerosis • Malignant lymphomas & leukeamia • Qualitative • Dyserythropoiesis

39. Leuco-erythroblastic (myelophthistic) Anaemia This term used to describe a form of anaemia in which nucleated RBCs and granulocyte precursors appear in the peripheral blood. Red cells show anisocytosis and poikilocytosis Nucleated RBCs often present in large numbers. WBC is normal or mildly  with many immature granulocytes. Platelet counts normal or reduced.

40. Leuco-erythroblastic (myelophthisia) Anaemia (Contd) Causes • Metastatic Ca • Myelosclerosis • Myelofibrosis • Refractory anaemia • Haemolytic disease of newborn • Hodgkins disease • Myeloma • Primary lipid storage disease • Gaucher’s disease • Niemann Pick disease • Hands Schuller – Christian disease • Occasional causes • After severe haemorrhage • Some severe sepsis • After irradiation

41. PANCYTOPENIA This is the simultaneous presence of anaemia, leucopenia and thrombocytopenia. Patients with pancytopenia usually present with symptoms attributable to anaemia, thrombocytopenia and leucopenia. Causes • Aplastic anaemia • Subleukaemic leukaemia • Administration of cytotoxic agents • Radiotherapy • Myelodysplastic disorders

42. Causes Contd • Marrow infiltration or replacement • Hodgkins Disease • Multiple myeloma • Metastatic Ca in the marrow • Myelopfibrosis • Hypersplenism • Megaloblastic anaemia (especially severe ones) • S.L.E • Paroxysmal Nocturnal Haemoglobinuria (PNH) • Overwhelming infection

43. APLASTIC ANAEMIA Defn: This is a disorder characterised by pancytopenia, reduction in the no. of redcells, neutrophils, and platelets in the peripheral blood, a marked decrease in the amount of haemopoietic tissue in the bone marrow and absence of evidence of involvement of the marrow by diseases such as leukaemia, myeloma or carcinoma.

44. CLASSIFICATION OF APLASTIC ANAEMIA Acquired of Causes • Inevitable (if dose is sufficient) • Ionising radiation • Cytotoxic drugs • Idiosyncratic • Idiopathic • Drug induced • Viral (hepatitis, EB, vira, HIV dengue) • Industrial • Benzene (usually dose dependent, proliferative disorders more common) • Immune • Drug Induced • Viruses (e.g. EB virus) • SLE

45. CLASSIFICATION OF APLASTIC ANAEMIA (CONTD) • Miscellaneous causes • Diffuse eosinophilic fascitis • Pregnancy • Simmond’s Disease • Sclerosis of the thyroid Familial Causes • Fanconi’s Anaemia • Dyskeratosis congenita • Schwachman – Diamond syndrome (Pancreatic insufficiency and pancytopenia)

46. Drug associated with idiosyncratic Aplastic anaemia Antibiotics - Chloramphenicol* - Sulphonamides - Cotrimoxazole - Nitrofuradantoin Anti-malarials - Quinacrine* - Chloroquin Anti-inflammatories - Phenylbutazone* - Indomethacine - Sulindac - Diclofenac - Ibuprofen - Piroxicam

47. Drug associated with idiosyncratic Aplastic anaemia (Contd) Anti-thyroids - Potassium perchlorate - Carbimazole - Methimazole - Methylthiouracil Psychotropic/ - Phenothiazines Antidepressants - Dothiapine Anti-convulsants - Carbamazepine - Phenytoin - Mesatoin* - Ethusuximide Anti-diabetics - Tolubutamide - Chlorpropamide Miscellaneous - Gold salt* - Penicillamine - Allopurinol

48. Haematological findings in Aplastic anaemias • Normochromic, normocytic anaemia • Low absolute reticulocyte count • Neutropenia • Thrombocytopenia •  serum and urinary erythropoietin level • Markedly hypocellular marrow (majority of cells seen are plasma cells, lymphocytes and macrophages.

49. Pathogenesis of aplastic anaemia There is evidence to suggest that aplastic anaemia may be heterogenous in its pathogenesis. • May develop as a result of a stem cell defect Evidence – Bone marrow culture experiments confirms deficiency, - Success of marrow transplantations in some identical twins - Chromosomal abnormalities found in those with Fanconi’s anaemia - Defects found in all the cell lines in PNH • Defect in marrow environment • Evidence from animal studies involving irradiation

50. Pathogenesis of aplastic anaemia (Contd) • Impaired production or effectiveness of haemopoietic growth factors Cytokines with inhibitory activity on haemopoiesis are usually increased in aplastic anaemia. -interferon, interleukin-2, and -tumor necrosis factor are all known to be increased. • Immunologically mediated damage. Alteration in cytokines as above may be taken as evidence for an immune basis for aplastic anaemia. In vitro culture of cells from patients could be enhanced by T-cell depletion and depressed by T-cell restitution.