Anemia Management in Adults and Children

Anemia Management

1. Haematology Anaemia Dr. Kofi .B. Mensah (Pharmacy Practice)

2. Learning objectives Understand the basic definition of anaemia including reference range, global prevalence, etc. Understand the pathophysiology underlining anaemia. Understand classification of anaemia. Understand signs and symptoms. Understand laboratory findings. Understand the different types of anaemia.

3. Introduction Anaemia is defined as a reduction in the concentration of circulating haemoglobin or oxygen-carrying capacity of blood below the level that is expected for healthy persons or ref. range of same age and sex in the same environment . It is one of the most common clinical and laboratory manifestations of disease, and always requires further investigation. It is not a diagnosis in itself, but rather an objective sign of a disease or a finding that can point to primary bone marrow disease, dietary inadequacies or a wide variety of systemic diseases. Structure of haemoglobin Iron (Fe 2+ ) containing pigment called Haem attached with protein – Globin . Haem is Iron –porphyrin complex called IRON PROTOPORPHYRIN IX . Globin – Protein.

4. Sex Haemoglobin (g/dl) PCV (%) Sex/Age Adult males Haemoglobin (g/dl) 13–17 PCV (%) 40–50 Adult females (nonpregnant) 12–15 38–45 Adult females (pregnant) 11–14 36–42 Children, 6–12 years 11.5–15.5 37–46 Children, 6 months–6 years 11–14 36–42 Infants, 2–6 months 9.5–14 32–42 Newborns 13.6–19.6 44–60 Normal levels of haemoglobin and packed cell volume

5. Pathophysiology In healthy adults, there is a steady-state equilibrium between the rate of release of new red cells from the bone marrow into the circulation and the removal of senescent red cells from the circulation. Erythropoietin ( epo ) is the main agent responsible for translating tissue hypoxia into increased red cell production to maintain this balance. For anaemia to arise : inadequate production of red cells (e.g. insufficient erythroid tissue in the marrow or poor quality erythroid maturation). increased rate of red cell loss (e.g. blood loss or haemolysis ).

6. NB: The reticulocyte count is a useful marker to differentiate anaemia caused by failure of production from that caused by accelerated red cell destruction. Although the reticulocyte count is an important part of the assessment of any patient with anaemia, it may not be straightforward to interpret. Read further. Other mechanisms leading to anaemia Blood loss Decreased red cell lifespan ( haemolytic anaemia) mineral deficiency (iron, zinc, selenium) Congenital defect (e.g. sickle cell disease) infection (hookworm, schistosomiasis, malaria) Acquired defect (e.g. Thalassaemia) Impairment of red cell formation: Insufficient erythropoiesis Ineffective erythropoiesis Pooling and destruction of red cells in an enlarged spleen Increased plasma volume (pregnancy)

7. Morphological classification of anaemia In terms of red cell size: characteristic changes in the size of red cells (mean cell volume, MCV). red blood cell distribution width(RDW):an index of RBC size variation Degree of haemoglobinization : mean cell haemoglobin (MCH): the amount of hemoglobin in a single red blood cell. MCH = (hemoglobin / RBC) x 10 mean cell hemoglobin concentration (MCHC): the average hemoglobin concentration of packed red cells expressed as a percentage. MCHC = (hemoglobin / hematocrit) x 100 Different aetiologies : Microcytic-hypochromic (low MCV and low MCH). Macrocytic-normochromic (high MCV). Normocytic -normochromic (normal MCV)

8. Microcytic-hypochromic Normocytic- normochromic Macrocytic MCV <80fL MCV 80–95fL MCV >95fL MCH <27pg MCH ≥27pg Megaloblastic: vitamin B12 or folate deficiency Non‐megaloblastic: alcohol, liver disease, etc. Iron deficiency Haemolytic anaemia Marked reticulocytosis . Thalassaemia Anaemia of chronic disease Myelodysplastic syndromes Anaemia of chronic disease Haemorrhagic anaemia (After acute blood loss) Acquired sideroblastic anaemia Sideroblastic anaemia Bone marrow failure (e.g. post‐ chemotherapy, infiltration by carcinoma, etc.) Myxoedema. Aplastic anaemia

9. Detection (signs and symptoms) Decreased oxygen-carrying capacity of the reduced red cell mass resulting in decrease perfusion to non-vital tissues (e.g., skin, mucous membranes, extremities) and vital organs (e.g., brain, heart, kidneys). Slowly developing anemias can be asymptomatic initially or include symptoms such as slight exertional dyspnea, increased angina, fatigue or malaise, palpitation, headaches, dizziness or lightheadedness, cold hands and feet, pallor of mucous membranes or nail beds. In severe anaemia, symptoms include; systolic murmurs, angina pectoris, high output congestive heart failure, pulmonary congestion, ascites, and edema.

10. Physical signs Common signs: Pallor of the conjunctiva, lips, skin and mucous membranes. Colour of the skin is unreliable because of skin pigmentation and the amount of fluid in the subcutaneous tissues. Most reliable are the palm of the hand, conjunctiva, and nail bed.

11. Detection (laboratory findings) A full laboratory evaluation is necessary to confirm the diagnosis, establish its severity, and determine its cause. The laboratory investigation is called full/complete blood count (FBC/CBC). Microscopic evaluation of the peripheral blood smear can detect the presence of macrocytic (large) RBC, which usually are present when anaemia results from a vitamin B12 or folic acid deficiency. Microcytic (small) RBC usually are associated with iron deficiency anemia. Acute blood loss generally is associated with normocytic cells. When uncertainty exists or an abnormal peripheral blood smear is noted, a bone marrow aspiration with biopsy is indicated.

12. Laboratory evaluation for anaemia Workup Full blood count (FBC): Hgb, Hct , RBC count, red cell indices (MCV, MCH, MCHC), WBC count (and differential) Platelet count Total iron binding capacity (TIBC) Red cell morphology Reticulocyte count Bilirubin and LDH Serum iron, serum ferritin, transferrin saturation Peripheral blood smear examination (blood film) Stool examination for occult blood Bone marrow aspiration and biopsy

13. Routine lab. Investigation- FBC/CBC Normal ranges may vary among age groups, institutions, and geographic locations.

14. Type of anaemia Iron deficiency anemia Iron deficiency is a state of negative iron balance in which the daily iron intake and stores are unable to meet the RBC and other body tissue needs. The body contains approximately 3.5g of iron, of which 2.5 g are found in Hgb. A significant amount of iron is stored as ferritin or aggregated ferritin (hemosiderin) in the reticuloendothelial cells of the liver, spleen, and bone marrow and by hepatocytes. Only a small fraction of iron is found in plasma (100 to 150 mcg/dL), and most is bound to transferrin, the transport protein. About 0.5 to 1 mg/day of iron is lost from urine, sweat, and the sloughing of intestinal mucosal cells. (men and in non-menstruating women). Menstruating women lose abt. 0.6% to 2.5% iron per day whiles Pregnancy and lactation are other sources of iron loss. Individuals with normal iron stores absorb roughly 10% of ingested dietary iron.

15. Cont. Iron is absorbed from the duodenum and upper jejunum by an active transport mechanism in an acidic gastric environment. Dietary iron is primarily in the ferric state, converted to the more readily absorbed ferrous form in the acid environment and binds to transferrin for its journey to the bone marrow, where it is incorporated into the Hgb of mature erythrocytes. Animal sources of iron, heme iron, are better absorbed than plant sources, non-heme iron. Iron deficiency anaemia is the most common nutritional deficiency worldwide. Although it has many causes, blood loss is considered one of the major causes.

16. Causes Blood Loss (Menstruation, gastrointestinal (e.g., peptic ulcer), trauma). Decreased Absorption (Medications, gastrectomy). Increased Requirement (Infancy, pregnant/lactating women). Impaired Utilization (Hereditary, Iron use). Treatment Fe2+ is usually absorbed from the gut, hence satisfactory response is achieved in most patients when iron salts are given orally. Ferrous sulphate should be used unless gastrointestinal adverse effects are severe. The duration of treatment, and its success, depends on the underlying cause of the anaemia. Haemoglobin should rise by approximately 1 g/dL/week. Dose : Ferrous sulphate is given at a dose of 200 mg t.i.d until anaemia is corrected and iron stores are replenished. Read on oral Fe2+ and Parenteral iron. 4

17. Macrocytic anaemia Macrocytic anaemia can be divided into those showing megaloblastic erythropoiesis and those with normoblastic erythropoiesis. Megaloblastic erythropoiesis describes abnormal red cell development characterized by a lack of synchrony between the maturation of the red cell nucleus (large immature nucleus) and its cytoplasm. It arises as a consequence of disordered DNA synthesis but RNA and protein synthesis remain unaffected, and the cytoplasm matures normally. Normoblastic erythropoiesis describes the normal appearance of red cell maturation, but may still be associated with a macrocytosis in the peripheral blood.

18. Folic acid is required for DNA synthesis. Vitamin B12 (cobalamin ) is needed for regeneration of tetrahydrofolate – the form of folate that is critical for the pyrimidine synthesis. Causes folic acid deficiency vit.B12 deficiency inherited defects associated with decreased ability to utilize vitamin B12 or folic acid. The main clinical features in more severe cases are those of anaemia. Anorexia is usually marked and there may be weight loss, diarrhoea or constipation. Other particular features include glossitis, angular cheilitis, a mild fever in the more severely anaemic patients, Loss of position sense in 2nd toe,etc.

19. Treatment The underlying cause must be treated where possible. Folic acid supplementation orally is generally sufficient to treat folic acid deficiency. 5mg a day for about 4–6 months replenishes depleted stores. B12 supplementation orally is appropriate and also improve neurological signs. Hydroxycobalamin is retained in the body for longer than cyanocobalamin and treatment can be given every 3 months. Given by intramuscular injection, initial dose: 1 mg every 2–3 days for five times. Maintenance dose: given every 3 months.

20. Pernicious anemia Pernicious anemia can result in vitamin B12 deficiency. It can be caused by reduced intrinsic factor and hydrochloric acid secretion or acquired as a result of gastrectomy, pancreatic disease, or malnutrition. It occurs commonly in patients with thyrotoxicosis, Hashimoto’s thyroiditis, vitiligo, rheumatoid arthritis, or gastric cancer. The onset of the pernicious anemia is insidious. Patients generally do not feel well for 6 to 12 months and often complain of at least two of the following of symptoms: weakness, sore tongue, and symmetric numbness or tingling in the extremities. The cause of vitamin B12 deficiency may be determined by the use of antibody testing (anti-parietal cells and anti-intrinsic factor antibodies).

21. Laboratory Evaluation A Full blood cell count ( FBC). Examination of a blood smear (peripheral smear) under a microscope, often performed in association with a FBC. Blood vitamin B-12 level measurements. Tests for the presence of antibodies to intrinsic factor or stomach lining cells. Blood levels of iron and iron-binding capacity. Serum folate levels (which are often reduced when vitamin B-12 levels are low). Blood levels of homocysteine, which may be sensitive indicators of vitamin B-12 deficiency. Finally, bone marrow aspiration or bone marrow biopsy may be recommended in some cases if bone marrow disorders are suspected

22. Treatment Vitamin B-12 is typically given as an intramuscular injection. 1000 micrograms (1 mg) of vitamin B-12 is generally given every day for one week, followed by 1 mg every week for four weeks and then 1 mg every month thereafter. Alternatively high-dose oral vitamin B-12, since a lower-efficiency absorption system for vitamin B-12 exists in the intestine that does not require the presence of IF. The oral dose required for this type of therapy (1 to 2 milligrams/day) is more than 200 times higher than the minimum daily vitamin B-12 requirement for adults.

23. Aplastic anaemia This occurs when cellular activity in the bone marrow is suppressed and is usually associated with the suppression of white cell and platelet formation. There are two different types: Acquired aplastic anemia Inherited aplastic anemia Inherited aplastic anemia is caused by gene defects, and is most common in children and young adults. Acquired aplastic anemia is more common in adults. Researchers believe something triggers problems in the immune system. The possibilities include: Viruses like HIV or Epstein-Barr Certain medications e.g. Find out Toxic chemicals Radiation

24. common symptoms for each: Low red blood cell count: Tiredness, shortness of breath, dizziness, pale skin, headaches, chest pain, irregular heartbeat. Low white blood cell count: Infections, fever Low platelet count: easy bruising and bleeding, nosebleeds. Treatment bone marrow or stem cell transplant Autoimmune medications to stop the attack of the immune syst. On the bone marrow.

25. Haemolytic Anemia This is defined as anaemia that result from an increase in the rate of red cell destruction. Because of erythropoietic hyperplasia and anatomical extension of bone marrow, red cell destruction may be increased several‐fold before the patient becomes anaemic – compensated haemolytic disease. Haemolytic anaemia may not be seen until the red cell lifespan is less than 30 days. In the majority of haemolytic anaemias, the macrophages in the spleen, liver and bone marrow remove red cells from the circulation by phagocytosis. This is termed extravascular haemolysis . In intravascular haemolysis , the red cells are caused to rupture and release their haemoglobin (Hb ) directly into the circulation

26. Classification (1) Hereditary haemolytic anaemias: the result of ‘ intrinsic ’ red cell defects. Such as, Haemoglobin (Genetic abnormalities (Hb S, Hb C). Metabolism (G6PD deficiency). Membrane (Immune Hereditary spherocytosis). (2) Acquired haemolytic anaemias: the result of an extracorpuscular ’ or environmental change. Such as, Infections (Malaria, clostridia) Chemical and physical agents (drugs, industrial/domestic substances) Secondary (Liver and renal disease) Autoimmune(Warm antibody type, Cold antibody type)

27. Laboratory evidence Many tests are used to diagnose hemolytic anemia. These tests can help confirm a diagnosis, look for a cause, and find out how severe the condition is. Test FBC-the first test used to diagnose anemia. Reticulocyte count (the number of young red blood cells in the blood)- indicative of whether the bone marrow is making red blood cells at the correct rate. Peripheral smear (microscopic examination)- Some types of hemolytic anemia change the normal shape of red blood cells. Coombs' test: To check whether the body is making antibodies to destroy red blood cells. Haptoglobin, bilirubin, and liver function tests- low level of haptoglobin in the bloodstream is a sign of hemolytic anemia. High levels of bilirubin in the bloodstream may be a sign of hemolytic anemia (rule out liver disease).

28. Cont. Hemoglobin electrophoresis- This test looks at the different types of hemoglobin in your blood. It can help diagnose the type of anemia you have. Paroxysmal nocturnal hemoglobinuria- A rare acquired, life-threatening disease characterized by destruction of red blood cells. Osmotic fragility test- This test looks for red blood cells that are more fragile than normal. These cells may be a sign of hereditary spherocytosis (an inherited type of hemolytic anemia). Testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency. Urine Test- Presence of free hemoglobin. Bone marrow tests- Aspiration and biopsy.

29. Mandatory test Newborn Testing for Sickle Cell Anemia and G6PD Deficiency- It is a requirement to screen for sickle cell anemia as part of newborn screening programs. Some hospital/health facilities also mandate screening for G6PD deficiency. Diagnosing these conditions as early as possible is important so that children can get proper treatment.

30. Anemia of chronic disease (ACD) ACD refers to a mild to moderate anemia associated with a number of disorders (e.g., rheumatoid arthritis, chronic infections, chronic renal failure, acquired immunodeficiency syndrome [AIDS], neoplastic disease). Most often, ACD is a normochromic-normocytic anemia, although red cells may be hypochromic and microcytic in some patients. Serum iron and total iron-binding capacity are most often decreased, whereas iron stores (serum ferritin) are usually normal or increased. Signs and symptoms : Same as iron deficiency anaemia. Feeling tired or weak. Having pale skin. Having shortness of breath. Sweating. Being dizzy or feeling faint. Rapid heartbeat. Having headaches.

31. Pathogenesis Pathogenesis is not well understood, inflammatory cytokines (Interferon-α(IFN-α), -β (IFN-β), -γ (IFN-γ), tumor necrosis factor-α) are thought to play a major role through multiple mechanisms. Competition for EPO receptors by cytokines may possibly lead to EPO resistance. Inhibition of hepatic and renal expression of EPO messenger RNA (mRNA), further contributing to the development of ACD. Interleukin-6 (IL-6) promotes expression of hepcidin, which alters iron hemostasis by decreasing duodenal iron absorption and inhibiting the release from iron stores. This affect bone morrow erythrocyte production.

32. Treatment Management of mild to moderate ACD usually focuses on the underlying disease process. Patients may require blood transfusions for symptomatic anemia. Unless a concurrent deficiency of vitamin B12, folate, or iron exists, administration of vitamin supplements is not of value. Recombinant human EPO ( rhEPO ) has been used successfully to treat ACD in patients with RA, AIDS, some neoplastic diseases, and chronic kidney disease. Patients are less likely to respond to rhEPO if baseline serum EPO and inflammatory cytokine levels are elevated. Although serum iron often is decreased, reticuloendothelial iron stores are usually adequate, and treatment with iron is not warranted.