Anemia - Systemic Pathology PDF

ANEMIA Systemic Pathology Dr. Warda Musah 2/3/2024 1  Anemia A reduction of the total circulating red cell mass below normal limits. – Anemia reduces the oxygen –carrying capacity of the blood causing...

ANEMIA Systemic Pathology Dr. Warda Musah 2/3/2024 1  Anemia A reduction of the total circulating red cell mass below normal limits. – Anemia reduces the oxygen –carrying capacity of the blood causing tissue ischemia. Normal RBC range – Men 4.7-6.1 million/ul – Women 4.2-5.4 million /ul 2/3/2024 2  Classification of Anemia I. Etiologic Classification 1. Blood loss 2. Excessive destruction 3. Impaired RBC production II. Morphologic Classification 1. Anisocytosis: variation in Red cell size (macrocytic, normocytic, microcytic). 2. Variation in color: Degree of hemoglonization / color of the cells (normochromic, hypochromic). 3. Poikilocytosis: variation in Shape of the red cells: spherocytes, sickle cells. 2/3/2024 3 2/3/2024 4 Mean cell volume (MCV): Normocytic- MCV= 80-99 femtoliter. Microcytic- MCV< 80 femtoliter. Macrocytic- MCV > 100 fl. Mean cell hemoglobin ( MCH): Normochromic- MCHC= 27-30 picogram/cell. Hypochromic- MCHC < 26 pg/cell. 2/4/2024 5 2/3/2024 6  Anemia of Blood Loss: Hemorrhage 1. Acute blood loss : trauma Anemia : normocytic normochromic Rise in the erythropoietin level. Reticulocytosis. 2. Chronic blood loss: gynocologicl disturbance(menorrhagia GIT Lesions. Iron stores are gradually depleted. Iron is essential for hemoglobin synthesis and effective erythropoiesis. Anemia: Microcytic hypochromic 2/3/2024 7  Excessive Destruction of RBC: Hemolytic anemia  Animas that are associated with accelerated destruction of red cells are termed hemolytic anemia.  Intra corpuscular (INTRINSIC)red cell defect:  Usually inherited.  Extra corpuscular (EXTRINSIC) factors  Usually acquired. 2/3/2024 8 2/3/2024 9  General features of hemolytic anemias 1. Increased rate of red cells destruction. 1. erythroid hyperplasia within the marrow. – Expansion of the marrow leads to bone resorption and secondary new bone formation, resulting in prominent cheekbones and changes in the skull that resemble a “crew cut” on x-ray studies. 2/3/2024 10 2/3/2024 11 3. Reiculocytosis 4. Hemoglobinemia and hemoglobinurea. Jaundice due to unconjugated hyperbilirubinemia 5. Decrease in haptoglobin. – Free hemoglobin will bind haptoglobin causes a decline in haptoglobin level. 6. Cholelethiasis. (pigment stone) 2/3/2024 12 7. Extramedullary hematopoiesis: spleen, liver and lymph node. Moderate splenomegaly is characteristic of Hereditary Spherocytosis (500-1000 gm). B- thalasemia, it weigh as much as (1500 gm). 8. The retention by the body of the products of red cell destruction (including iron) – Hemosidersis and hemochromatosis. – The deposited iron often damages organs, most notably the heart, liver, and pancreas. 2/3/2024 13 extravascular (EV) hemolysis, splenomegaly results if the EV hemolysis occurs in the spleen and hepatomegaly results if the EV hemolysis occurs in the liver. EV hemolyis shows increased bilirubin and decreased haptoglobin, but not to the degree with intravascular hemolysis. In EV hemolysis, there is an absence of hemoglobinemia, hemoglobinuria, and methemoglobin formation 2/3/2024 14 2/4/2024 15 2/3/2024 16  Hereditary spherocytosis (HS)  (HS) is an autosomal dominant disorder(75% of cases) that is due to a defect involving ankyrin and spectrin (most commonly affecting the ankyrin molecule) in the erythrocyte membrane; this causes a decrease in the erythrocyte surface membrane (spherocytosis).  less deformable, and vulnerable to splenic sequestration and destruction.  25% of patients has a more severe AR form of the disease. 2/3/2024 17  Role of the red cell membrane skeleton in hereditary spherocytosis. 2/3/2024 18  As a result of these alterations, – the life span of the affected red cells is decreased on average to 10 to 20 days from the normal 120 days. – splenomegaly with a mild to moderate hemolytic anemia, – increased bilirubin and an increased risk for jaundice and pigment gallstones secondary to chronic hemolysis, – and increased risk for acute red-cell aplasia due to parvovirus B l 9 infection. –. 2/3/2024 19 – Laboratory testing shows increased osmotic fragility (Pink test) and normal MCH with increased MCHC. it is only condition where mchc is increased. – Treatment is with splenectomy – The vaccination against encapsulated organisms like pneumococccus and H. influenza is also must. 2/4/2024 20 2/4/2024 21  Morphology  The most specific morphologic finding is spherocytosis. – is distinctive but not pathognomonic.(seen in other disorders associated with membrane loss, such as in autoimmune hemolytic anemia). 2/3/2024 22  Glucose-6-Phosphate Dehydrogenase Deficiency Abnormalities in the hexose monophosphate shunt or glutathione metabolism resulting from deficient or impaired enzyme function reduce the ability of red cells to protect themselves against oxidative injuries and lead to hemolysis. G6PD deficiency is a recessive X-linked trait, 2/3/2024 23 1. RBCs are normally exposed to oxidative stress, in particular H20 2 2. Glutathione (an antioxidant) neutralizes H,Q,, but becomes oxidized in the process. 3. NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione. 4. ↓G6PD → ↓NADPH→ ↓reduced glutathion →oxidative injury by H20 2→ intravascular hemolysis 2/4/2024 24 Conditions increasing oxidative stress: Food (fava beans) Infectionsviral hepatitis, pneumonia, and typhoid fever (WBC induced free radicals) Drugs (antimalarials, sulphonamide) 2/4/2024 25  Morphology Exposure of G6PDdeficient red cells to high levels of oxidants causes the cross-linking of reactive sulfhydryl groups on globin chains, which become denatured and form membrane bound precipitates known as Heinz bodies. Heinz bodies can damage the membrane sufficiently to cause intravascular hemolysis. As inclusion-bearing red cells pass through the splenic cords, macrophages pluck out the Heinz bodies. As a result of membrane damage, partially devoured cells retain an abnormal shape, appearing to have a bite taken out of them. Bite cells ,extravascular hemolysis 2/3/2024 26 The morphology bite cells Heinz bodies (denatured globin) These are seen as dark inclusions within red cells stained with crystal violet Note: Oxidants cause both intravascular and extravascular hemolysis in G6PD-deficient individuals. 2/3/2024 27  Clinical features: 2-3 days following exposure of G6PD-deficient individuals to oxidants: Acute intravascular hemolysis, marked by – anemia, – Hemoglobinemia – hemoglobinuria. The recovery phase is indicated by reticulocytosis. Splenomegaly and cholelithiasis ( features of chronic hemolysis) are absent. – Because hemolytic episodes related to G6PD deficiency occur intermittently. 2/3/2024 28  Haemoglobin abnormalities (haemoglobinopathies) Haemoglobinopathies are caused by either: decreased a- or b-globin synthesis—the a- and b thalassaemias Or synthesis of abnormal haemoglobin—e.g. sickle-cell disease, unstable haemoglobins. Anaemias are usually a combined result of both dyshaemopoiesis and haemolysis. 2/3/2024 29  Sickle cell disease. Is a common hereditary hemoglobinopathy. This is characterized by the presence of an abnormal type of hemoglobin called HbS. It results from a point mutation that causes the glutamic acid to be replaced by valine at the b6 position of the globin chain. If the individual is homozygous, it is represented as HbSS (1 gene each from both the parents) whereas the heterozygous is HbAS (1 gene from one parent is for HbS and the other gene is for HbA). Heterozygotes 2/4/2024 are protected against falciparum malaria.30  Sickle cell trait: – About 8% to 10% of African Americans. – heterozygous for HbAS. – a largely asymptomatic condition. – The offspring of two heterozygotes has a 1 in 4 chance of being homozygous for the sickle mutation, a state that produces symptomatic sickle cell disease. Sickle cell disease: Almost all the hemoglobin in the red cell is HbS (α2βS2). – about 70,000 individuals with sickle cell disease in the 2/3/2024 31  Pathogenesis When deoxygenated, HbS molecules becomes insoluble, undergoes aggregation and polymerization producing a sickle cell or holly leaf shape of the RBCs. Initially, this process is reversible (on getting oxygenated, the cells attain there normal shape) but repeated attacks of aggregation can cause irreversible sickling of the RBCs which also causes oxidative damage to the red cells. Reversible sickled cells exhibit increased adhesiveness within the microcirculation of organs with sluggish blood flow thereby causing episodes of hypoxia and infarction called as vasoocclusive crisis or pain crisis. Hemoglobin released from the lysed red cells causes inactivation of NO thereby increasing the severity of ischemia. Irreversible sickled cells get sequestrated in the spleen thereby contributing 2/3/2024 to extravascular hemolysis. 32 Sickle Cell Anemia Clinical features.  Increased erythrocyte destruction causes a severe hemolytic anemia, which is accompanied by erythroid hyperplasia in the bone marrow and increased bilirubin leading to jaundice and gallstone (pigment) formation.  Capillary thrombi result from sickle cells blocking small vessels and may cause vaso-occlusive (painful) crisis; hand- foot syndrome (swelling) in children; and autosplenectomy, which is seen in older children and adults.  Howell-Jolly bodies will appear in peripheral blood after autosplenectomy, and the lack of a functional spleen predisposes for increased incidence of infections (encapsulated organisms), 2/3/2024 34  Increased incidence of Salmonella osteomyelitis (leg pain), leg ulcers, and risk of a plastic crisis (especially with parvovirus Bl9 infection). avascular necrosis of femoral head Emergencies that may occur include priapism(stagnation in corpora cavernosa) and acute chest syndrome. i. Presents with chest pain, shortness of breath, and lung infiltrates ii. Often precipitated by pneumonia iii. Most common cause of death in adult patients 2/3/2024 35  Howell–Jolly bodies Howell-Jolly bodies (small nuclear remnants) are also present in some red cells due to the asplenia basophilic nuclear remnants (clusters of DNA)in circulating erythrocytes 2/3/2024 36  Laboratory findings: Peripheral smear : , presence of sickle cells Howell Jolly bodies (composed of chromatin aggregates in red cells) are seen particularly after autosplenectomy. ESR is low because roleaux formation is not seen with sickle cells. Hb electrophoresis confirms the presence and amount of HbS. 2/3/2024 37 2/3/2024 38  Thalassemia syndromes It is a group of autosomal recessive inherited disorders characterized by decreased synthesis of either α or β globin chain of HbA. It is the most common type of hemoglobinopathy in the world. β and α thalassemia is caused by deficient synthesis of β and α chains respectively. α-thalassaemia—mainly caused by deletion (rather than mutation) of parts of the α-globin genes 2/3/2024 39  β-thalassemia Caused by mutations that diminish the synthesis of β-globin chains. Molecular pathogenesis.. These are of two types: 1. β0 thalassemia – Characterized by total absence of β chains in the homozygous state. 2. β+ thalassemia – Characterized by reduced synthesis of β chains in the homozygous state. 2/3/2024 40  α-thalassemias are caused by inherited deletions that result in reduced or absent synthesis of α-globin chains. Note: Normally, there are four α-globin genes, and the severity of α-thalassemia depends on how many α- globin genes are affected. 2/3/2024 41  Clinical and Genetic Classification of Thalassemias Clinical syndromes Genetics Clinical features Molecular genetics α-Thalassemias Silent carrier −/α α/α Asymptomatic; no red cell Mainly gene abnormality deletions α-Thalassemia trait −/− α/α (Asian) Asymptomatic, like β- thalassemia minor −/α −/α (black African, Asian) HbH disease −/− −/α Severe; resembles β- thalassemia intermedia Hydrops fetalis −/− −/− Lethal in utero without transfusions 2/3/2024 42 2/3/2024 43  Megaloblastic Anemias The chief feature in this anemia is impaired DNA synthesis resulting in delayed mitosis while RNA and protein synthesis is not impaired. This leads to nuclear/cytoplasmic asynchrony. Causes : – Vitamin B 12 deficiency. – Folic acid deficiency. 2/3/2024 44  Certain peripheral blood findings are shared by all megaloblastic anemias. The marrow is usually markedly hypercellular as a result of increased hematopoietic precursors, which often completely replace the fatty marrow. The presence of red cells that are macrocytic and oval (macro- ovalocytes) is highly characteristic. There is marked variation in the size (anisocytosis) and shape (poikilocytosis) of red cells. The reticulocyte count is low. Nucleated red cell progenitors occasionally appear in the circulating blood when anemia is severe. 2/3/2024 45  The MCHC is not elevated.* The earliest manifestation of megaloblastic anemia is presence of hypersegmented neutrophils. Diagnosis is made if even a single neutrophil with ≥ 6 lobes is seen or > 5% neutrophils with 5 lobes are seen. A peripheral blood smear shows a hypersegmented neutrophil. 2/3/2024 46  The presence of ineffective erythropoiesis can result in pancytopenia associated with features of hemolytic anemia including jaundice and increased levels of serum bilirubin and LDH enzyme. 2/3/2024 47  Anemia of Vitamin B 12 deficiency: pernicious anemia Pernicious anemia is a specific form of megaloblastic anemia caused by an autoimmune gastritis that impairs the production of intrinsic factor, which is required for vitamin B12 uptake from the gut. 2/3/2024 48  Normal Vitamin B12 Metabolism. 2/3/2024 49 2/3/2024 50 Note: Vitamin B-12 deficiency Achlohydria Loss of pepsin is associated with disorders secretion other than pernicious anemia. Gastrectomy Loss of exocrine pancreatic function Ileal resection or 2/3/2024 ileal disease 51  Note : The diagnosis is confirmed by an outpouring of reticulocytes and a rise in hematocrit levels beginning about 5 days after parenteral administration of vitamin B12. Persons with atrophy and metaplasia of the gastric mucosa associated with pernicious anemia have an increased risk of gastric carcinoma. Elevated homocysteine levels are a risk factor for atherosclerosis 2/3/2024 52  Anemia of Folate Deficiency Megaloblastic anemia caused due to folic acid deficiency is clinically indistinguishable from vitamin B12 deficiency anemia. However, folic acid deficiency is NOT associated with neurological abnormalities. 2/3/2024 53  Etiology The three major causes of folic acid deficiency are: decreased intake. increased requirements. impaired utilization. 2/3/2024 54 2/3/2024 55  Iron Deficiency Anemia Deficiency of iron is the most common nutritional disorder in the world and results in a clinical signs and symptoms that are mostly related to inadequate hemoglobin synthesis. 2/3/2024 56  Iron metabolism. Iron absorbed from the gut is bound to plasma transferrin and transported to the marrow, where it is delivered to developing red cells and incorporated into hemoglobin. Mature red cells are released into the circulation and, after 120 days, are ingested by macrophages, primarily in the spleen, liver, and bone marrow. Here iron is extracted from hemoglobin and recycled to plasma transferrin. At equilibrium, iron absorbed from the gut is balanced by losses in shed keratinocytes, enterocytes, and (in women) endometrium. 2/3/2024 57  Etiology Iron deficiency can result from dietary lack. impaired absorption. increased requirement. chronic blood loss. 2/3/2024 58  Dietary lack. – To maintain a normal iron balance, about 1 mg of iron must be absorbed from the diet every day.* – Heme iron is much more absorbable than inorganic iron, the absorption of which is influenced by other dietary contents.** enhanced by ascorbic acid, citric acid, amino acids, and sugars in the diet, and inhibited by tannates (found in tea), carbonates, oxalates, and phosphates. 2/3/2024 59  impaired absorption. Impaired absorption is found in fat malabsorption (steatorrhea), and chronic diarrhea. Gastrectomy impairs iron absorption by decreasing the acidity of the proximal duodenum (which enhances uptake), and also by increasing the speed with which gut contents pass through the duodenum. Specific items in the diet can also affect absorption. 2/3/2024 60  increased requirement. Increased requirement is an important cause of iron deficiency in : – growing infants, children, and adolescents, as premenopausal women, particularly during pregnancy. – Economically deprived women having multiple, closely spaced pregnancies are at exceptionally high risk. 2/3/2024 61  chronic blood loss. Is the most common cause of iron deficiency in the Western world. External hemorrhage or bleeding into the gastrointestinal, urinary, or genital tracts depletes iron reserves. Iron deficiency in adult men and postmenopausal women in the Western world must be attributed to gastrointestinal blood loss until proven otherwise. 2/3/2024 62  Pathogenesis. Whatever its basis, iron deficiency produces a hypochromic microcytic anemia. At the outset of negative iron balance,  reserves in the form of ferritin and hemosiderin may be adequate to maintain normal hemoglobin and hematocrit levels as well as normal serum iron and transferrin saturation. 2/3/2024 63  Progressive depletion of these reserves first lowers serum iron and transferrin saturation levels without producing anemia. In this early stage there is increased erythroid activity in the bone marrow. Anemia appears only when iron stores are completely depleted and is accompanied by lower than normal serum iron, ferritin, and transferrin saturation levels. 2/3/2024 64  MORPHOLOGY The bone marrow reveals: – a mild to moderate increase in erythroid progenitors. – A diagnostically significant finding is the disappearance of stainable iron from macrophages in the bone marrow, which is best assessed by performing Prussian blue stains on smears of aspirated marrow. 2/3/2024 65  MORPHOLOGY In peripheral blood smears: the red cells are small (microcytic) and pale (hypochromic). In established iron deficiency the zone of pallor is enlarged; hemoglobin may be seen only in a narrow peripheral Rim. Poikilocytosis in the form of small, elongated red cells (pencil cells) is also characteristically seen. 2/3/2024 66 Normal red cells with sufficient hemoglobin have a zone of central pallor measuring about one third of the cell diameter. 2/3/2024 67  Clinical features The clinical manifestations of the anemia are nonspecific. * In severe and long-standing iron deficiency, depletion of iron-containing enzymes in cells throughout the body also causes other changes, including koilonychia, alopecia, atrophic changes in the tongue and gastric mucosa, and intestinal malabsorption. Depletion of iron from the central nervous system may lead to the appearance of pica.** Esophageal webs together with microcytic hypochromic anemia and atrophic glossitis to complete the triad of major findings in the rare Plummer-Vinson syndrome. 2/3/2024 68 2/3/2024 69  Diagnostic criteria Hemoglobin and hematocrit are depressed, usually to a moderate degree. Hypochromia, microcytosis, and modest poikilocytosis. The serum iron and ferritin are low, The total plasma iron-binding capacity (reflecting elevated transferrin levels) is high. Reduced iron stores inhibit hepcidin synthesis, and its serum levels fall. 2/3/2024 70 2/3/2024 71  In uncomplicated iron deficiency, oral iron supplementation produces an increase in reticulocytes in about 5 to 7 days that is followed by a steady increase in blood counts and the normalization of red cell indices. 2/3/2024 72