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Hematology and Oncology Section 19 Section Editor: Sudhir Mehta Hematology and Oncology 226. Hemolytic Anemias: Diagnostic Approach 231. Immunotherapy in Clinical Practice Shubha Laxmi Margekar, Ashok Kumar, Purnima Margekar, Vineet Talwar, Amrith BP Venu Gopal Margekar 232. PNH—A Great Masquerader: When to Suspect? 227. Thalassemia in Adults—Management Issues Asish Rath, Jasmita Ramesh Aggarwal, Anupam Prakash 233. JAK2 Mutation—What Physicians Should Know? 228. Approach to Thrombocytopenia Tulika Seth Avinash Kumar Singh, Divya Krishna, Gautam Kumar Rakesh, Bhupendra Kumar 234. Approach to a Case of Polycythemia: More Blood May Be Bad…. 229. Management of CML in Resource-limited Settings Tuphan Kanti Dolai, Prakash Singh Shekhawat, Malini Garg Hemant Malhotra, Naveen Gupta, Ajay Yadav 230. Disability-free Hemophilia in India— Myth or Reality Sunita Aggarwal, Ranvijay Singh, Sandeep Garg MU-226 (Sec-19).indd 1445 29-01-2021 15:29:47 MU-226 (Sec-19).indd 1446 29-01-2021 15:29:47 CHAPTER Hemolytic Anemias: 226 Diagnostic Approach Shubha Laxmi Margekar, Ashok Kumar, Purnima Margekar, Venu Gopal Margekar Abstract Hemolytic anemias are an important type of anemia in which destruction of RBCs occurs. Manifestations occur in the form of development of anemia along with sign and symptoms of hemolysis. Usually the diagnosis is made by good clinical history relating the cause of anemia and evidence of hemolysis in laboratory evaluation. Therefore, a general approach for making etiological diagnosis of the hemolytic anemia is always needed for classification and management of anemia. In this chapter an effort has been made to provide a relevant approach for the evaluation of hemolytic anemia. Introduction Causes of anemia that can be treated (anemia due to nutritional deficiencies, gastrointestinal bleed, anemia Anemia is defined as decrease in hemoglobin (Hb) level, of renal origin, and hemolysis) should be looked for according to reference ranges specific for age, gender, and carefully, so that it is not missed. race. For men Hb <13 g/dL and for women Hb <12 g/dL is considered as anemia as per World Health Organization (WHO). Classification The mean life span of Red Blood Cells (RBCs) is 120 On the basis of etiology, hemolytic anemia can be days. Taking a good history followed by proper clinical classified as: examination along with laboratory investigations is still — Inherited or considered as the best approach for any case of anemia. — Acquired. In hemolytic anemias, there is premature destruction According to the site of hemolysis (Table 1), it is of RBC, that is, in less than 120 days (which defines the divided into: hemolytic disorder) which in turn to compensate, there — Intravascular, where RBCs destruction is in the is increase in the production capacity of RBCs by bone circulation or marrow. When the rate of destruction of red blood cell — Extravascular, where destruction occurs in the exceeds the capacity of producing more red cells by bone spleen or liver (within macrophages). marrow, the hemolytic disorder will manifest as hemolytic From the clinical perspective, hemolytic anemia can be anemias. — acute or Usually the diagnoses of hemolytic anemia are made — chronic. through the laboratory investigations but a clinical According to mechanism (location of the abnormality) history along with physical examination is also helpful for (Table 2), there may be providing useful information about presence of hemolysis — intrinsic (intracorpuscular) defect or and its probable etiology. — extrinsic (extracorpuscular) defects. MU-226 (Sec-19).indd 1447 29-01-2021 15:29:47 1448 SECTION 19 Hematology and Oncology TABLE 1 Classification according to site of hemolysis Intracorpuscular factors (Red cell abnormality) Extracorpuscular factors Hereditary Immune hemolytic anemias z Membrane defect (spherocytosis, elliptocytosis) z utoimmune hemolytic anemia z Metabolic defect (Glucose-6-Phosphate-Dehydrogenase (G6PD) — caused by warm-reactive antibodies deficiency, Pyruvate kinase (PK) deficiency) — caused by cold-reactive antibodies z Hemoglobinopathies (unstable hemoglobins, thalassemias, sickle z Transfusion of incompatible blood Nonimmune hemolytic cell anemia) anemias Acquired z Chemicals Membrane abnormality-paroxysmal nocturnal hemoglobinuria z Bacterial infections, parasitic infections (malaria), venons (PNH) z Hemolysis due to physical trauma — hemolytic-uremic syndrome (HUS) — thrombotic thrombocytopenic purpura (TTP) — prosthetic heart valve — Hypersplenism TABLE 2 Classification according to the location of the abnormality Intracorpuscular defects Extracorpuscular factors Hereditary z Hemoglobinopathies z Familial (atypical) hemolytic uremic Syndrome z Enzymopathies z Membrane-Cytoskeletal defects Acquired z Paroxysmal nocturnal hemoglobinuria (PNH) z Mechanical destruction (microangiopathic) z Infectious z Autoimmune z Toxic agents z Drugs Mechanisms involved in anemia include: Hemoglobin disorders: Abnormal hemoglobin is because Inadequate production: Stem cell damage or defective of inherited gene in some people. Abnormal hemoglobin red cell maturation. can lead to easy destruction of red blood cells. Disorder Excessive destruction (hemolysis): Intrinsic defect in red includes sickle cell anemia and the thalassemias. cell leading to shortened lifespan or external factors in Physical damage to RBCs: blood or blood vessels destroy red cells. — During heart-lung surgery Blood loss (bleeding) — In patients with artificial heart valves (as blood flows near devices) Causes of hemolytic anemia include: — In a patients with severe burn (exposure to extreme Inherited red blood cell membrane abnormalities: heat) There is change in the shape of cell due to membrane Physical damage to RBCs: defects and this change in shape is identified as — During heart-lung surgery abnormal by spleen and destroyed it. — In patients of artificial heart valves Inherited enzyme deficiencies in red blood cells: — In patients with severe burn due to exposure to Abnormalities in enzyme levels makes the red blood extreme heat cell fragile, which makes red blood cell prone to get — Autoimmune hemolytic anemia: It can occur in destroyed easily. autoimmune conditions like lupus, certain types MU-226 (Sec-19).indd 1448 29-01-2021 15:29:48 Hemolytic Anemias: Diagnostic Approach CHAPTER 226 1449 of infections, and use of some drugs. This happens Features of Hemolysis when the red blood cells of the body gets destroyed Hemoglobin—Normal to severely reduced by immune mechanism of its own body. MCV, MCH—Usually increased — Hypersplenism: The spleen is enlarged and Bilirubin is raised (mostly unconjugated) becomes overactive. It traps the circulating red LDH is raised (up to 10 times of normal with intra- blood cells and destroys it. vascular hemolysis Reticulocytes, n-RBC—Raised General Features of Hemolytic Disorders Haptoglobins are reduced to absent Hemolytic anemias can be differentiated from other Urinary hemosiderin, Urobilinogen are +ve anemias by presence of signs and symptoms arising ↓ because of hemolysis. Blood Smear ↓ General examination: Jaundice, Pallor, Bossing of Skull Spherocytes— — DCT +ve (Autoimmune hemolysis) Physical findings: — DCT –ve (H. Sherocytosis, malaria, clostridium) Enlarged spleen (as a preferential site of hemolysis) No spherocytes—Hereditery enzymopathies leading to neutropenia and/or thrombocytopenia Fragmentation—Microangiopathic, Traumatic Enlarged liver (in some cases) Skeletal changes, because of bone marrow over activity (seen in severe congenital forms) Laboratory Evaluation of Hemolysis Hemoglobin—From normal to severely reduced See Table 3. MCV—Usually increased Reticulocytes—Increased (sign of the erythropoietic Metabolic Manifestations of Increased response by the bone marrow) Red Cell Turnover Bilirubin—Increased (mostly unconjugated) There is significant iron loss (requiring treatment), LDH—Increased due to persistent hemoglobinuria because of chronic Haptogloin—Reduced to absent intravascular hemolysis. If frequent blood transfusions are needed or if erythropoiesis is massively increased Two main principles for diagnosis: then iron overload is very common. This iron overload First is to confirm the diagnosis of hemolysis leads to hemochromatosis affecting liver and heart Second is to determine its etiology muscles eventually leading to cirrhosis and heart failure The etiology of hemolytic anemia can be determined respectively. by: A good clinical history Morphological Abnormalities of RBCs in The peripheral blood film Hemoltyic Anemias Schistocytes—thrombotic microangiopathies or Clinical Presentation cardiac prosthetic valves New onset pallor or anemia Spherocytes—hereditary spherocytosis, immune hem. Hemolytic faces—Chipmunk facies anemia, burns, chemical injury to RBC Jaundice Sickled cells—sickle cell disease Splenomegaly, bossing of skull (in severe congenital Elliptocytes—hereditary elliptocytosis cases) Echinocytes—pyruvate kinase deficiency Gall stones Heinz bodies—G6PD deficiency Dark colored urine Basophilic stipplings—thalassemia, Wilson’s disease, Leg ulcers and lead poisoning MU-226 (Sec-19).indd 1449 29-01-2021 15:29:48 1450 SECTION 19 Hematology and Oncology TABLE 3 Laboratory evaluation of hemolysis Extravascular Intravascular Hematologic z Peripheral blood film z Polychromatophilia z Polychromatophilia z Reticulocyte count z Raised z Raised z Bone marrow examination z Erythroid hyperplasia z Erythroid hyperplasia Plasma or serum z Bilirubin z Unconjugated decreased z Unconjugated
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