Hematology chapter 11

• Anemia can result from affecting red blood cell production, increasing red blood cell destruction, or causing blood loss.
• Certain genetic conditions can predispose individuals to anemia.
• Chronic diseases, kidney disease, liver disease, and autoimmune disorders can disrupt red blood cell production or survival.
• Nutritional deficiencies, particularly iron, vitamin B12, and folate, are significant contributors to anemia.
• Bone marrow disorders directly impair the production of blood cells.

Genetic Disorders

• Thalassemia is an inherited blood disorder characterized by abnormal hemoglobin production.
• Genetic defects result in reduced or absent synthesis of globin chains composing hemoglobin molecules.
• The severity of thalassemia varies depending on the specific genetic mutation, ranging from mild anemia to severe, life-threatening conditions.
• Sickle cell anemia is a genetic disorder caused by a mutation in the gene that codes for hemoglobin, leading to the production of abnormal hemoglobin called hemoglobin S.
• Hemoglobin S causes red blood cells to become rigid and sickle-shaped, leading to chronic hemolytic anemia, vaso-occlusive crises, and organ damage.
• Hereditary spherocytosis is a genetic disorder affecting the red blood cell membrane, causing cells to become spherical and fragile, leading to hemolytic anemia.
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzyme deficiency that affects red blood cells, making them susceptible to oxidative damage and hemolysis.
• G6PD deficiency can cause acute hemolytic anemia in response to certain medications, infections, or foods.

Chronic Diseases

• Chronic kidney disease (CKD) often leads to anemia due to decreased production of erythropoietin, a hormone produced by the kidneys that stimulates red blood cell production in the bone marrow.
• Reduced erythropoietin levels in CKD result in decreased red blood cell production, leading to anemia of chronic kidney disease.
• Inflammatory conditions such as rheumatoid arthritis, lupus, and inflammatory bowel disease (IBD) can cause anemia of chronic inflammation (ACI).
• In ACI, chronic inflammation leads to the release of cytokines that interfere with iron metabolism, suppress erythropoietin production, and reduce the response of bone marrow to erythropoietin.
• Chronic liver disease, such as cirrhosis, can cause anemia through impaired production of clotting factors, increased risk of bleeding, and reduced production of proteins needed for red blood cell production.
• Liver disease can also lead to hypersplenism, where the spleen becomes enlarged and destroys blood cells, including red blood cells, contributing to anemia.
• Human immunodeficiency virus (HIV) infection can cause anemia through direct suppression of bone marrow function by the virus, opportunistic infections, and medication side effects.
• HIV-associated anemia can be multifactorial and may require a combination of treatments to manage.

Autoimmune Disorders

• Autoimmune hemolytic anemia (AIHA) is when the immune system mistakenly attacks and destroys red blood cells, leading to hemolytic anemia.
• AIHA can be caused by warm antibodies, which are active at body temperature, or cold agglutinins, which are active at lower temperatures.
• Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect various organs and systems, including the blood.
• In SLE, the immune system can produce antibodies that attack red blood cells, leading to autoimmune hemolytic anemia.
• Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects the joints but can also cause systemic complications, including anemia.
• Anemia in RA can be caused by chronic inflammation, iron deficiency, and medication side effects.

Nutritional Deficiencies

• Iron deficiency is one of the most common causes of anemia worldwide.
• Iron is an essential component of hemoglobin, and inadequate iron intake or absorption can lead to iron deficiency anemia, characterized by small, pale red blood cells (microcytic, hypochromic).
• Vitamin B12 deficiency can result in megaloblastic anemia, characterized by large, abnormal red blood cells (macrocytic).
• Vitamin B12 is necessary for DNA synthesis and red blood cell maturation; deficiency can occur due to inadequate intake, impaired absorption (e.g., pernicious anemia), or certain medical conditions.
• Folate deficiency, like vitamin B12 deficiency, can cause megaloblastic anemia.
• Folate is essential for DNA synthesis, and deficiency can occur due to inadequate intake, impaired absorption, or increased demand (e.g., pregnancy).
• Copper deficiency can lead to anemia, as copper is essential for iron metabolism and red blood cell production.
• Copper deficiency can occur due to malnutrition, malabsorption, or excessive zinc intake.
• Vitamin C deficiency can indirectly contribute to anemia by impairing iron absorption.
• Vitamin C enhances the absorption of non-heme iron from plant-based foods.

Bone Marrow Disorders

• Aplastic anemia is a rare and life-threatening condition in which the bone marrow fails to produce enough blood cells, including red blood cells, white blood cells, and platelets.
• Aplastic anemia can be caused by autoimmune disorders, viral infections, exposure to toxins, or certain medications.
• Myelodysplastic syndromes (MDS) are disorders where the bone marrow produces abnormal blood cells, leading to cytopenias, including anemia.
• MDS can progress to acute myeloid leukemia (AML) in some cases.
• Leukemia is a cancer of the blood and bone marrow characterized by the overproduction of abnormal white blood cells, which can crowd out normal blood cells, leading to anemia, thrombocytopenia, and increased risk of infection.
• Myelofibrosis is a chronic bone marrow disorder characterized by the replacement of normal bone marrow tissue with fibrous tissue, leading to anemia, splenomegaly, and other complications.

Other Disorders

• Chronic blood loss, such as from heavy menstrual bleeding, gastrointestinal bleeding, or frequent blood donations, can lead to iron deficiency anemia.
• Hypothyroidism, or underactive thyroid, can cause anemia by reducing erythropoietin production and slowing down metabolism.
• Lead poisoning can interfere with hemoglobin synthesis and cause hemolytic anemia.
• Alcohol abuse can lead to anemia through direct toxicity to bone marrow, nutritional deficiencies, and increased risk of bleeding.
• Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired genetic disorder characterized by complement-mediated hemolysis, leading to chronic hemolytic anemia, thrombosis, and bone marrow failure.

Anemia and Erythrocyte Kinetics

• Normal erythrocyte kinetics involve a balance between red blood cell production (erythropoiesis), red blood cell lifespan, and red blood cell destruction (hemolysis).
• Anemia arises when this balance is disrupted, leading to a decrease in the number of circulating red blood cells or a reduction in their hemoglobin content.
• Anemia can be caused by decreased erythropoiesis, where the bone marrow fails to produce enough red blood cells to replace those lost or destroyed.
• Increased red blood cell destruction (hemolysis) can also lead to anemia, as the rate of destruction exceeds the rate of production.
• Blood loss, whether acute or chronic, can result in anemia if the rate of loss exceeds the body's ability to replace red blood cells.
• Understanding the specific disruption in erythrocyte kinetics – whether it's impaired production, increased destruction, or blood loss – is crucial for diagnosing and treating different types of anemia.

Clinical Signs and Symptoms of Anemia

• Anemia symptoms arise primarily from reduced oxygen delivery to tissues due to the decreased number of red blood cells or reduced hemoglobin.
• Common complaints include fatigue, weakness, and general lack of energy due to insufficient oxygen reaching muscles and organs.
• Dyspnea (shortness of breath), especially during exertion, occurs because the body tries to compensate for reduced oxygen-carrying capacity.
• Palpitations and tachycardia (rapid heart rate) develop as the heart works harder to circulate the available oxygen.
• Dizziness or lightheadedness can occur due to reduced oxygen supply to the brain.
• Headaches are another common symptom resulting from cerebral hypoxia.
• Pale skin, conjunctiva, and nail beds (pallor) are visual signs of reduced hemoglobin concentration.
• Angina (chest pain), can be exacerbated or develop in individuals with pre-existing heart disease due to increased myocardial oxygen demand.
• Cognitive difficulties such as impaired concentration and memory problems may manifest due to chronic oxygen deprivation of brain tissue.
• In severe cases, symptoms can progress to heart failure due to the heart's inability to maintain adequate circulation.
• Specific types of anemia may present with unique symptoms such as pica (unusual cravings for non-food items like ice or dirt) in iron deficiency anemia.
• Jaundice (yellowing of the skin and eyes) may occur in hemolytic anemias due to increased bilirubin production from red blood cell breakdown.

Anemia Classification by Erythrocyte Size

• Anemias are often classified based on the mean corpuscular volume (MCV), which indicates the average size of red blood cells.
• This classification results in three main categories: microcytic, normocytic, and macrocytic anemias.
• Microcytic anemias are characterized by small red blood cells (MCV below normal range).
• Normocytic anemias involve red blood cells of normal size (MCV within the normal range).
• Macrocytic anemias are defined by large red blood cells (MCV above normal range).
• Examples of macrocytic anemias include vitamin B12 deficiency and folate deficiency.
• Pathological megaloblastic anemias include pernicious anemia, a condition characterized by impaired vitamin B12 absorption due to a lack of intrinsic factor.

Limitations of Using Erythrocyte SIze for Anemia Classification

• Relying solely on erythrocyte size can oversimplify the underlying causes of anemia.
• Some anemias can present with mixed populations of red blood cells, leading to a normal MCV (normocytic anemia) despite the presence of distinct subpopulations of microcytes and macrocytes.
• The MCV is an average value and may not reflect the true heterogeneity of red blood cell sizes in certain conditions.
• Certain conditions can cause changes in MCV that do not accurately reflect the primary pathology.
• For example, reticulocytosis (increased production of young red blood cells) can increase the MCV, potentially masking an underlying microcytic process.
• A more comprehensive approach to anemia diagnosis involves evaluating other red blood cell indices, peripheral blood smear morphology, reticulocyte count, and biochemical markers.

Pathophysiological Basis of Anemia Categories

• Anemias can be classified based upon underlying pathophysiology.
• Impaired red blood cell production results in insufficient quantities of erythrocytes.
• Increased red blood cell destruction (hemolysis) leads to a shortened red cell lifespan, which results in anemia.
• Blood loss, which may be acute or chronic, causes a reduction in red blood cell mass and subsequent anemia.
• Impaired production can arise from deficiencies in essential nutrients like iron, B12, or folate, each critical to erythropoiesis.
• Bone marrow disorders such as aplastic anemia or myelodysplastic syndrome disrupt the production of all blood cells.
• Hemolytic anemias can be intrinsic, where defects within the red cells themselves (e.g., sickle cell anemia, G6PD deficiency) cause premature destruction.
• Hemolytic anemias can be extrinsic, where external factors (e.g., autoimmune antibodies, mechanical trauma, infections) provoke red cell lysis.
• Blood loss can be due to acute hemorrhage from trauma or surgery, or chronic loss from gastrointestinal lesions or heavy menstruation.

Supplementary Assays for Anemia Diagnosis

• Iron studies, including serum iron, ferritin, transferrin, and total iron-binding capacity (TIBC), are vital in diagnosing iron-related anemias.
• Vitamin B12 and folate levels help identify deficiencies causing megaloblastic anemia.
• A peripheral blood smear allows morphological examination of red blood cells, identifying abnormalities like spherocytes, sickle cells, or fragmented cells (schistocytes).
• A reticulocyte count assesses the bone marrow's response to anemia, helping differentiate between production defects and hemolytic processes.
• Direct antiglobulin test (DAT), or Coombs test, detects antibodies or complement proteins on the surface of red blood cells in autoimmune hemolytic anemia.
• Hemoglobin electrophoresis identifies abnormal hemoglobin variants, such as in sickle cell anemia or thalassemia.
• Bone marrow aspiration and biopsy evaluate the cellularity and morphology of bone marrow cells, useful in diagnosing aplastic anemia, myelodysplastic syndromes, and leukemia.
• Erythropoietin levels can help differentiate between anemia due to decreased production (low erythropoietin) and anemia due to peripheral destruction or blood loss (high erythropoietin).
• Liver and kidney function tests can identify underlying organ dysfunction contributing to anemia of chronic disease.
• Genetic testing can confirm inherited anemias like thalassemia, sickle cell anemia, or G6PD deficiency.
• Osmotic fragility test assesses the red blood cell's resistance to lysis in hypotonic solutions, useful in diagnosing hereditary spherocytosis.
• Lactate dehydrogenase (LDH) and bilirubin levels can indicate hemolysis, as they are released when red blood cells are destroyed.