Anemia PDF

Anemia 1. Introduction of Anemia What is anemia? A deficiency in the number of red blood cells or the oxygen-carrying hemoglobin characterizes anemia. Some symptoms related to anemia appear when the hemoglobin drops below 7.0 g/dL. What are the symptoms of anemia? 1- Fatigue. 2- Dizziness...

Anemia 1. Introduction of Anemia What is anemia? A deficiency in the number of red blood cells or the oxygen-carrying hemoglobin characterizes anemia. Some symptoms related to anemia appear when the hemoglobin drops below 7.0 g/dL. What are the symptoms of anemia? 1- Fatigue. 2- Dizziness and heart palpitations. 3- Headache and dyspnea. 4- reduced cognitive function. 5- lack of energy and weakness. What are the causes of anemia? According to the study of Hess et al (2023), there are three main causes of anemia: 1. Blood loss: Blood loss can lead to low iron levels, so the body draws water from tissues to help keep the blood vessels full. This additional water dilutes the blood, reducing the RBC count. 2. Decreased or impaired RBCs: Problems with bone marrow can also cause anemia. Aplastic anemia, for example, occurs when few or no stem cells are present in the marrow. 3. Destruction of RBCs: RBCs typically live 120 days. However, the body may destroy or remove them before they complete their natural life cycle in the bloodstream. Prevalence: The prevalence increases with age and is more common in women of reproductive age, pregnant women, and the elderly. The prevalence is more than 20% of individuals who are older than the age of 85. The incidence of anemia is 50%-60% in the nursing home population. In the elderly, approximately one-third of patients have a nutritional deficiency as the cause of anemia, such as iron, folate, and vitamin B12 deficiency. In another one-third of patients, there is evidence of renal failure or chronic inflammation (Turner et al., 2023). 1 2. Types of anemia 1- iron deficiency Anemia Iron deficiency anemia is the most common and treatable of all anemias, caused by a lack of sufficient iron in the body, leading to reduced production of hemoglobin. Hemoglobin is the protein in red blood cells that carries oxygen, so without enough iron, the body's tissues and organs receive less oxygen, resulting in fatigue, weakness, and Pica (craving non-food substances like dirt or ice). SYMPTOMS Iron deficiency can lead to symptoms both due to the lack of iron itself and due to the resultant anemia. Symptoms of anemia can include: - fatigue - tachycardia - lack of endurance - Pica - unusual cravings for eating ice or clay Biochemistry pathway 2 Figure 1. Biochemical Pathway for IDA Iron Deficiency Anemia (IDA) Pathway In the iron deficiency anemia (IDA) pathway, inadequate dietary iron intake or iron malabsorption (due to poor diet, gastrointestinal issues, or blood loss) results in insufficient iron availability. Iron absorption is still primarily attempted in the duodenum and jejunum, but reduced DMT1 activity or other factors (such as low hepcidin regulation) may limit the absorption of iron. Heme iron absorption may also be impaired, particularly in individuals with low iron stores, while non-heme iron absorption is especially affected. Despite the body’s attempt to regulate iron levels, hepcidin production decreases in response to low iron levels, allowing more iron to be absorbed from the gut and released into circulation. However, the overall iron stores are still insufficient to meet the body’s needs, and the amount of iron that can enter the bloodstream remains low. Iron binds to transferrin, but the amount of transferrin-bound iron is reduced due to the overall deficiency. In the bone marrow, transferrin still binds to transferrin receptor 1 (TfR1) on developing erythroblasts, but due to insufficient iron, the internalization of the transferrin-iron complex is limited. As a result, heme synthesis is impaired because there is not enough iron to form the heme molecule. The lack of heme results in reduced hemoglobin production. Consequently, the RBCs produced are microcytic (small) and hypochromic (pale) because there is not enough heme and hemoglobin for adequate oxygen transport. This leads to impaired erythropoiesis in the bone marrow, causing symptoms of anemia such as fatigue, weakness, pallor, and reduced oxygen delivery to tissues. The body attempts to compensate by increasing iron recycling from senescent RBCs through macrophages in the spleen and liver, but this mechanism is not enough to meet the iron demands for hemoglobin synthesis. As iron stores deplete, ferritin (the storage form of iron) becomes reduced, and low serum ferritin levels serve as a diagnostic marker of iron deficiency. To maintain iron balance, the body continues to increase iron absorption and recycling from old RBCs, while hepcidin levels decrease, allowing for more efficient iron absorption from dietary sources and stores, though the clinical symptoms of anemia still persist if the deficiency continues. 3 Diagnosis 1-Iron deficiency anemia: 1-Complete blood count (CBC): measures the amount of red blood cells, hemoglobin (the protein that carries oxygen in your red blood cells), white blood cells, and platelets. It can detect blood cancers, anemia, infections, and other conditions. 2-total iron-binding capacity (TIBC) test: measures your blood’s ability (capacity) to bind to iron and carry it throughout your body. a TIBC test shows the amount of transferrin in your blood. Transferrin is a protein your liver makes that regulates iron absorption into your blood. 3- serum ferritin test: A ferritin test measures the amount of ferritin in the blood. Ferritin is a blood protein that stores iron inside your cells. This test can be used to find out how much iron the body stores. If a ferritin test shows that the blood ferritin level is low, it means the body's iron stores are low. TREATMENT Iron supplements: also called iron pills or oral iron, help increase the iron in your body. This is the most common treatment for iron-deficiency anemia. It often takes three to six months to restore your iron levels. The long-established treatment of iron deficiency has been ferrous sulfate given 3 times a day. Also Eating a diet higher in bioavailable iron can help treat iron deficiency. The food richest in iron is meat. Intravenous or IV iron is sometimes used to put iron into your body through one of your veins. This helps increase iron levels in your blood. It often takes only one or a few sessions to restore your iron levels. People who have serious iron-deficiency anemia or who have long-term conditions are more likely to receive IV iron. Side effects include vomiting or headaches right after the treatment, but these usually go away within a day or two. 4 2- Haemolytic Anemia Introduction Hemolytic anemia occurs when red blood cells (RBCs) are destroyed faster than they can be produced (premature destruction of red blood cells). Hemolytic anemia can be inherited (sickle cell anemia, thalassemia, and enzyme deficiencies (e.g., G6PD deficiency, pyruvate kinase deficiency) or acquired (autoimmune disorders, infections, certain medications, or exposure to toxins). This destruction can be intrinsic, due to defects within the RBCs (like membrane abnormalities, hemoglobin disorders, or enzyme deficiencies), or extrinsic, due to external factors (like autoimmune reactions, infections, or mechanical damage). Symptoms can include: 1. Fatigue 2. Pallor (pale skin) 3. Jaundice (yellowing of the skin and eyes) 4. Shortness of breath 5 Biochemistry pathway Hemolytic Anemia Pathway: 1. Premature destruction of RBCs: Red blood cells (RBCs) are destroyed earlier than their typical lifespan (about 120 days). 2. Release of hemoglobin: The destruction of RBCs leads to the release of hemoglobin into the bloodstream. 3. Dissociation of hemoglobin: Hemoglobin is broken down into its components: heme and globin. 4. Degradation of heme: - Conversion to biliverdin: Heme is enzymatically degraded by heme oxygenase to form biliverdin. - Reduction to unconjugated bilirubin: Biliverdin is then reduced to unconjugated bilirubin. 5. Transport to the liver: Unconjugated bilirubin is transported to the liver. 6. Conjugation in the liver: In the liver, unconjugated bilirubin is conjugated by UDP- glucuronosyltransferase to form water-soluble conjugated bilirubin. 7. Excretion into bile: Conjugated bilirubin is excreted into bile and subsequently into the intestines. 8. Compensatory erythropoiesis: The increased destruction of RBCs triggers the bone marrow to enhance erythropoiesis, resulting in the release of more reticulocytes into the bloodstream. 6 Diagnosis 1- A peripheral blood smear (PBS) test is a technique used to examine your red and white blood cells and your platelets under a microscope and complete blood count (CBC). 2- A reticulocyte test: measures the number of reticulocytes, which are immature red blood cells, in the blood. It helps assess bone marrow function and red blood cell production. 3- Direct Coombs Test (Direct Antiglobulin Test): Detects antibodies attached to red blood cells, indicating immune-mediated hemolytic anemia. 4- Urinalysis: Checks for hemoglobinuria (hemoglobin in the urine) and hemosiderin, indicating red blood cell destruction. Treatment 1. Blood Transfusions Patients with beta-thalassemia major and severe forms of thalassemia intermedia, used Prevent complications like delayed growth, heart failure, and bone deformities by maintaining normal oxygen-carrying capacity. 2. Iron Chelation Therapy Regular transfusions cause iron overload that can damage the heart, liver, and endocrine organs, used Regular ferritin levels, MRI of the heart and liver to assess iron load. 3. Folic Acid Supplementation helps in the production of red blood cells and supports mild cases of thalassemia. 4-sickle cell anemia Definition of SCA: Sickle cell anemia is a genetic disorder caused by a mutation in the (HBB) hemoglobin beta gene, which leads to the production of abnormal hemoglobin called hemoglobin Sickle (HbS). This causes red blood cells to become rigid, sticky, and crescent or "sickle" shaped. These misshaped cells can block blood flow, leading to pain and tissue damage, and have a shorter lifespan than normal red blood cells, leading to anemia 7 Causes: Sickle cell disease (SCD) is caused by a genetic mutation affecting hemoglobin, specifically a point mutation in the HBB gene on chromosome 11, resulting in the production of abnormal hemoglobin called HbS This mutation involves the substitution of adenine with thymine, which alters the sixth position of the beta-globin chain, replacing glutamic acid with valine. The presence of HbS leads to polymerization under low oxygen conditions or dehydration, causing red blood cells to become sickle-shaped, rigid, and prone to hemolysis. These deformed cells obstruct blood flow, resulting in vaso-occlusion, tissue ischemia, and organ damage Symptoms: Pain Crises (Vaso-occlusive crises): Sudden episodes of severe pain due to blocked blood flow, typically in the chest, joints, and bones Swelling: Particularly in the hands and feet (dactylitis) in children Frequent Infections: Due to spleen damage, making the body more vulnerable to infections Delayed Growth: In children and adolescents due to chronic anemia Vision Problems: Damage to blood vessels in the eyes can lead to vision issues Organ Damage: Long-term complications can include damage to the liver, kidneys, lungs, and heart Acute chest syndrome: A serious condition with chest pain, fever, cough, and difficulty breathing, often caused by infections or blockages in the lungs Stroke: Higher risk of stroke, especially in children, caused by blood vessel blockages in the brain 8 Biochemistry Pathway Biochemical Events: 1. Genetic mutation in the β-globin gene leads to the production of hemoglobin S (HbS). 2. HbS polymerizes under low oxygen conditions, causing red blood cells to take on a sickle shape. 3. Sickled cells have a shortened lifespan and break down quickly, causing chronic hemolytic anemia. 4. Sickle-shaped cells can block blood vessels, leading to vaso-occlusion and ischemia. 5. Oxidative stress, inflammation, and nitric oxide depletion worsen the clinical picture, leading to complications like pain crises, organ damage, and chronic disease progression. 9  Molecular pathophysiology of sickle cell disease. (a) A single-nucleotide polymorphism in the β-globin gene leads to substitution of valine for glutamic acid at the sixth position in the β-globin chain. Following deoxygenation, the mutated hemoglobin (HbS) molecules polymerize to form bundles. The polymer bundles result in erythrocyte sickling (clockwise), which in turn results in (b) impaired rheology of the blood and aggregation of sickle erythrocytes with neutrophils, platelets, and endothelial cells to promote stasis of blood flow, referred to as vaso-occlusion. Vaso-occlusion promotes ischemia-reperfusion (I-R) injury (clockwise). (a) Hemoglobin (Hb) polymer bundles also promote hemolysis or lysis of erythrocytes (counterclockwise), which (c) releases cell-free Hb into the blood circulation. Oxygenated Hb (Fe2+) promotes endothelial dysfunction by depleting endothelial nitric oxide (NO) reserves to form nitrate (NO3−) and methemoglobin (Fe3+). Alternatively, Hb can also react with H2O2 through the Fenton reaction to form hydroxyl free radical (OH ) and methemoglobin (Fe3+). Also, NADPH oxidase, xanthine oxidase (XO), and uncoupled endothelial NO synthase (eNOS) generate oxygen free radicals to promote endothelial dysfunction. Methemoglobin (Fe3+) degrades to release cell-free heme (counterclockwise), which is a major erythrocyte damage-associated molecular pattern (DAMP). (d) Reactive oxygen species (ROS) generation, Toll-like receptor 4 (TLR4) activation, neutrophil extracellular trap (NET) generation, release of tissue or cell-derived DAMPs, DNA, and other unknown factors (?) triggered by cell-free heme or I-R injury can contribute to sterile inflammation by activating the inflammasome pathway in vascular and inflammatory cells to release IL-1β. Finally, sterile inflammation further promotes vaso-occlusion through a feedback loop by promoting the adhesiveness of neutrophils, platelets, and endothelial cells. Diagnosis 1- Hemoglobin Electrophoresis: separates different types of hemoglobin and can identify the presence of hemoglobin S (HbS), which is responsible for sickle cell disease. A hemolysate prepared from the blood is subjected to an electric field in both an alkaline and an acidic medium. The separation of the hemoglobin depends on the 10  charge that the globin protein carries. The charge carried by the globin protein is determined by the polypeptide chains that constitute the make-up of the protein. Hemoglobin A (HbA): Normal adult hemoglobin Hemoglobin S (HbS): Abnormal hemoglobin present in sickle cell disease. 2- Genetic Testing: DNA analysis can confirm the presence of mutations in the HBB gene and help identify carriers of the sickle cell trait. 3- Newborn Screening: newborns are screened for sickle cell using blood tests from the baby’s heel shortly after birth. Treatment: Pain Management: Primarily managed with opioids and other painkillers. Blood Transfusions: Used to treat severe anemia or complications like stroke, but this increased the risk of iron overload. Hydroxyurea: Introduced in the 1990s, it was the first drug to reduce the frequency of pain crises by increasing fetal hemoglobin (HbF) levels. Bone Marrow Transplants: Offered as a potential cure, but only feasible for a small number of patients with matching donors. 5- Thalassemia Definition: Thalassemia is a genetic blood disorder characterized by the reduced production of hemoglobin, the protein in red blood cells that carries oxygen. The disorder is caused by mutations in the genes responsible for hemoglobin production, leading to an imbalance in the globin chains that make up hemoglobin. Symptoms 1. Anemia: Fatigue, weakness, and pallor due to low hemoglobin levels. 2. Splenomegaly: Enlargement of the spleen, which may cause discomfort or fullness in the abdomen. 3. Jaundice: Yellowing of the skin and eyes due to increased bilirubin from hemolysis. 4. Delayed Growth: Children may experience delayed growth and development. 11 5. Bone Deformities: Changes in bone structure, particularly in the face and skull, due to increased marrow expansion. Pathway of beta-thalassemia Hemoglobin is a tetramer of two alpha globin chains combined with two non-alpha globin chains. Fetal hemoglobin (HbF) is the primary hemoglobin until six months of age and consists of two alpha chains and two gamma chains. Adult hemoglobin is primarily hemoglobin A (HbA), consisting of two alpha chains and two beta chains. A smaller component of adult hemoglobin is hemoglobin A2 (HbA2), consisting of two alpha chains and two delta chains. The pathogenesis of beta-thalassemia is two-fold. First, there is decreased hemoglobin synthesis causing anemia and an increase in HbF and HbA2 as there are decreased beta chains for HbA formation. Second, and of most pathologic significance in beta-thalassemia major and intermedia, the relative excess alpha chains form insoluble alpha chain inclusions that cause marked intramedullary hemolysis. This ineffective erythropoiesis leads to severe anemia and erythroid hyperplasia with bone marrow expansion and extramedullary hematopoiesis. The bone marrow expansion leads to bony deformities, characteristically of the facial bones which cause frontal bossing and maxillary protrusion. Biochemical signaling from marrow expansion involving the bone morphogenetic protein (BMP) pathway inhibits hepcidin production causing iron hyperabsorption. Inadequately treated patients and transfusion-dependent patients are at risk for end-organ damaging iron overload. Hepatosplenomegaly from extramedullary hematopoiesis and ongoing hemolysis also causes thrombocytopenia and hepatic dysfunction. 12 Diagnosis 1- Complete Blood Count (CBC) 2- Hemoglobin Electrophoresis 3- Genetic Testing 4- Iron Studies * Iron studies are crucial in differentiating thalassemia from other types of anemia, such as iron deficiency anemia. The key components measured in iron studies include: 1. Serum Iron: Measures the amount of circulating iron in the blood. 2. Ferritin: Reflects the stored iron in the body. 3. Total Iron Binding Capacity (TIBC): Measures the blood's capacity to bind iron with transferrin. - Abnormal in thalassemia: Often reduced or normal, contrasting with iron deficiency anemia, where TIBC is usually elevated. 4. Transferrin Saturation: Calculated using serum iron and TIBC; it indicates how much iron is bound to transferrin. - Abnormal in thalassemia: Typically normal or low. 5- Bone Marrow Aspiration Bone marrow aspiration can be a valuable diagnostic tool in assessing thalassemia, especially when the diagnosis is uncertain. procedure involves extracting a small sample of bone marrow, usually from the hip bone, for examination. Treatment 1. Blood transfusions: Blood transfusions are the main way to treat moderate or severe thalassemia. This treatment gives you red blood cells with healthy hemoglobin. 2. Bone marrow transplant: A bone marrow transplant, also called a hematopoietic stem cells transplant, replaces blood-forming stem cells that aren’t working properly with healthy donor cells. A stem cell transplant is the only treatment that can cure thalassemia. However, only a small number of people who have severe thalassemia are able to find a good donor match and are a good fit for the procedure 13 6- G6PD Deficiency Anemia: Definition: G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency anemia is a genetic disorder characterized by a deficiency of the G6PD enzyme, which is essential for the proper functioning of red blood cells. Symptoms Fatigue and Weakness: Due to reduced red blood cell count. Jaundice: Yellowing of the skin and eyes. Dark Urine: A sign of hemolysis (breakdown of red blood cells). Shortness of Breath: Especially during physical activity. Increased Risk of Infections: Due to compromised red blood cell function. Biochemistry Pathway Pathophysiology of hemolytic anemia caused by G6PD Deficiency The G6PD enzyme is part of the pentose monophosphate shunt (is also called the oxidative pentose pathway and the hexose monophosphate shunt because it involves some reactions of the glycolytic pathway) G6PD is the catalyst in the first step of the pentose phosphate pathway, which uses glucose- 6-phosphate to convert nicotinamide adenine dinucleotide phosphate (NADP) into its reduced form nicotinamide adenine dinucleotide phosphate (NADPH). 14 In red blood cells, NADPH is critical in preventing damage to cellular structures caused by oxygen-free radicles. It does this by serving as a substrate for the enzyme glutathione reductase. Reduced glutathione can be used to convert hydrogen peroxide to water and prevent damage to cellular structures, particularly the cell wall of red blood cells (RBCs), since they have limited capacity for repair once they mature. When the red cell is challenged by an oxidant stress, for example fava beans, infections, or certain medications, the red cell membrane become oxidized as there is not enough reduced glutathione produced to convert the increased level of oxidants (hydrogen peroxide) to water. Hemoglobin denatures and precipitates intracellular to become Heinz bodies. The presence of Heinz bodies causes the red cell to be trapped in the spleen and sometimes splenic macrophages surgically excise the portion of the red cell that contains a Heinz body. In these circumstances, the red cell may escape with a gap, appearing as bite cells. These rigid and fragmented cells may also lead to intravascular hemolysis The pentose phosphate pathway is the only source for NADPH in red blood cells. Therefore, red blood cells depend on G6PD activity to generate NADPH for protection. Thus, red blood cells are more susceptible to oxidative stresses than other cells. Diagnosis The diagnostic tests for G6PD anemia: 1- Complete blood count (CBC) 2- Peripheral blood smear: A blood smear may show red blood cells with bite cells (cells that appear as if a "bite" has been taken out) and Heinz bodies (denatured hemoglobin) inside red blood cells. These are characteristic findings in G6PD deficiency, indicating oxidative damage. 3- G6PD Enzyme Activity Test: The definitive diagnosis is made through a G6PD enzyme assay. This test measures the activity of the G6PD enzyme in red blood cells. In G6PD deficiency, enzyme activity will be significantly reduced. G6PD is crucial in the pentose phosphate pathway, which helps protect red blood cells from oxidative damage. How the Test is Performed: A blood sample is collected from a vein. The test is typically performed using spectrophotometric or fluorometric methods to quantify the G6PD enzyme’s ability to produce NADPH (nicotinamide adenine dinucleotide phosphate), which is a marker of the enzyme’s activity. The activity is measured by determining the rate of NADPH formation as G6PD catalyzes the conversion of glucose-6-phosphate into 6-phosphogluconate. If enzyme activity is reduced, the rate of NADPH formation will be lower. 15  Timing of the Test: Timing is crucial for accurate results. It is recommended to conduct the test when the patient is not undergoing an acute hemolytic episode. 4- Bilirubin and Lactate Dehydrogenase (LDH) Levels: The red blood cells are destroyed faster than they can be replaced, leading to an increase in unconjugated bilirubin and LDH levels, and a decrease in haptoglobin. However elevated LDH is a non-specific marker because it can rise in a variety of conditions involving tissue damage, but in combination with other signs (like low haptoglobin and elevated bilirubin), it is strongly suggestive of hemolysis. Treatment Avoidance: The primary treatment is to avoid triggers (certain foods, medications, and infections). Supportive Care: o Hydration and rest during a hemolytic crisis. o Blood transfusions may be necessary in severe cases of anemia. Monitoring: Regular check-ups to manage symptoms and prevent complications 6. Risk Factors associated with anemia Anemia is defined as a hemoglobin level