Red Blood Cell Disorders PDF

Red Blood Cell Disorders 55 ANEMIA I. BASIC PRINCIPLES A. Reduction in circulating red blood cell (RBC) mass B. Present...

Red Blood Cell Disorders 55 ANEMIA I. BASIC PRINCIPLES A. Reduction in circulating red blood cell (RBC) mass B. Presents with signs and symptoms of hypoxia 1. Weakness, fatigue, and dyspnea 2. Pale conjunctiva and skin 3. Headache and light headedness 4. Angina, especially with preexisting coronary artery disease C. Hemoglobin (Hb), hematocrit (Hct), and RBC count are used as surrogates for RBC mass, which is difficult to measure. 1. Anemia is defined as Hb < 13.5 g/dL in males and< 12.5 g/dL in females (normal Hb is 13.5-17.5 g/dL in males and 12.5-16.0 g/dL in females). D. Based on mean corpuscular volume (MCV), anemia can be classified as microcytic (MCV < 80 µm 3), normocytic (MCV = 80-100 µm3), or macrocytic (MCV > 100 µm3). MICROCYTIC ANEMIAS I. BASIC PRINCIPLES A. Anemia with MCV < 80 µm 3 B. Microcytic anemias are due to decreased production of hemoglobin. 1. RBC progenitor cells in the bone marrow are large and normally divide multiple times to produce smaller mature cells (MCV = 80-100 µm 3). 2. Microcytosis is due to an "extra" division which occurs to maintain hemoglobin concentration. C. Hemoglobin is made of heme and glob in; heme is composed of iron and protoporphyrin. A decrease in any of these components leads to microcytic anemia. D. Microcytic anemias include (1) iron deficiency anemia, (2) anemia of chronic disease, (3) sideroblastic anemia, and (4) thalassemia. II. IRON DEFICIENCY ANEMIA A. Due to decreased levels of iron 1. ↓i ron →↓heme →↓hemoglobin → microcytic anemia B. Most common type of anemia 1. Lack of iron is the most common nutritional deficiency in the world, affecting roughly 1/3 of world's population. C. Iron is consumed in heme (meat-derived) and non-heme (vegetable-derived) forms. 1. Absorption occurs in the duodenum. Enterocytes have heme and non-heme (DMT1) transporters; the heme form is more readily absorbed. 2. Enterocytes transport iron across the cell membrane into blood via ferroportin. 3. Transferrin transports iron in the blood and delivers it to liver and bone marrow macrophages for storage. 4. Stored intracellular iron is bound to ferritin, which prevents iron from forming free radicals via the Fenton reaction. pathoma.com pathoma.com 41 https://t.me/USMLEPathoma https://t.me/USMLEPathoma  42 FUNDAMENTALS OF PATHOLOGY D. Laboratory measurements of iron status 1. Serum iron-measure of iron in the blood 2. Total iron-binding capacity (TIBC) - measure of transferrin molecules in the blood 3. % saturation - percentage of transferrin molecules that are bound by iron (normal is 33%) 4. Serum ferritin - reflects iron stores in macrophages and the liver E. Iron deficiency is usually caused by dietary lack or blood loss. 1. Infants - breast-feeding (human milk is low in iron) 2. Children-poor diet 3. Adults (20-50 years) - peptic ulcer disease in males and menorrhagia or pregnancy in females 4. Elderly - colon polyps/carcinoma in the Western world; hookworm (Ancylostoma duodenale and Necator americanus) in the developing world 5. Other causes include malnutrition, malabsorption, and gastrectomy (acid aids iron absorption by maintaining the Fe 2+ state, which is more readily absorbed than Fe 3+). F. Stages of iron deficiency 1. Storage iron is depleted - ↓ferritin; ↑TIBC 2. Serum iron is depleted - ↓serum iron; ↓% saturation 3. Normocytic anemia - Bone marrow makes fewer, but normal-sized, RBCs. 4. Microcytic, hypochromic anemia - Bone marrow makes smaller and fewer RBCs. G. Clinical features of iron deficiency include anemia, koilonychia, and pica. H. Laboratory findings include 1. Microcytic, hypochromic RBCs with ↑red cell distribution width (RDW,Fig. 5.1) 2. ↓ferritin; ↑TIBC; ↓ serum iron; ↓% saturation 3. ↑Free erythrocyte protoporphyrin (FEP) I. Treatment involves supplemental iron (ferrous sulfate). J. Plummer-Vinson syndrome is iron deficiency anemia with esophageal web and atrophic glossitis; presents as anemia, dysphagia, and beefy-red tongue III. ANEMIA OF CHRONIC DISEASE A. Anemia associated with chronic inflammation (e.g., endocarditis or autoimmune conditions) or cancer; most common type of anemia in hospitalized patients B. Chronic disease results in production of acute phase reactants from the liver, including hepcidin. 1. Hepcidin sequesters iron in storage sites by (1) limiting iron transfer from macrophages to erythroid precursors and (2) suppressing erythropoietin (EPO) Fig. 5.1 Microcytic, hypochromic RBCs of iron Fig. 5.2 Ringed sideroblasts (Prussian blue stain). deficiency anemia. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Red Blood Cell Disorders 43 production; aim is to prevent bacteria from accessing iron, which is necessary for their survival. 2. ↓available iron→↓heme →↓hemoglobin→microcytic anemia C. Laboratory findings include 1. ↑ ferritin,↓ TIBC,↓ serum iron, and↓ % saturation 2. ↑ Free erythrocyte protoporphyrin (FEP) D. Treatment involves addressing the underlying cause. IV. SIDEROBLASTIC ANEMIA A. Anemia due to defective protoporphyrin synthesis 1. ↓protoporphyrin → ↓ heme →↓ hemoglobin →microcytic anemia B. Protoporphyrin is synthesized via a series of reactions. 1. Aminolevulinic acid synthetase (ALAS) converts succinyl CoA to aminolevulinic acid (ALA) using vitamin B6 as a cofactor (rate-limiting step). 2. Aminolevulinic acid dehydratase (ALAD) converts ALA to porphobilinogen. 3. Additional reactions convert porphobilinogen to protoporphyrin. 4. Ferrochelatase attaches protoporphyrin to iron to make heme (final reaction; occurs in the mitochondria). C. Iron is transferred to erythroid precursors and enters the mitochondria to form heme. If protoporphyrin is deficient, iron remains trapped in mitochondria. 1. Iron-laden mitochondria form a ring around the nucleus of erythroid precursors; these cells are called ringed sideroblasts (hence, the term sideroblastic anemia, Fig. 5.2). D. Sideroblastic anemia can be congenital or acquired. 1. Congenital defect most commonly involves ALAS (rate-limiting enzyme). 2. Acquired causes include i. Alcoholism - mitochondrial poison ii. Lead poisoning - inhibits ALAD and ferrochelatase iii. Vitamin B6 deficiency - required cofactor for ALAS; most commonly seen as a side effect of isoniazid treatment for tuberculosis E. Laboratory findings include ↑ferritin, ↓ TIBC, ↑serum iron, and ↑ % saturation (iron-overloaded state). V. THALASSEMIA A. Anemia due to decreased synthesis of the globin chains of hemoglobin 1.↓globin →↓hemoglobin → microcytic anemia B. Inherited mutation; carriers are protected against Plasmodium falciparum malaria. C. Divided into a - and b -thalassemia based on decreased production of alpha or beta globin chains. 1. Normal types of hemoglobin are HbF (a 2g 2) , HbA (a 2b 2) , and HbA 2 (a 2d 2). Table 5.1: Laboratory Findings in Microcytic Anemia STATE FERRITIN TIBC SERUM IRON % SATURATION Normal 300 µg/dL 100 µg/dL 33% Iron Deficiency Anemia Low High Low Low Anemia of Chronic Disease High Low Low Low Sideroblastic Anemia High Low High High Pregnancy and oral contraceptives High Low https://t.me/USMLEPathoma https://t.me/USMLEPathoma  44 FUNDAMENTALS OF PATHOLOGY D. α-Thalassemia is usually due to gene deletion; normally, 4 alpha genes are present on chromosome 16 1. One gene deleted - asymptomatic 2. Two genes deleted - mild anemia with ↑ RBC count; cis deletion is associated with an increased risk of severe thalassemia in offspring. i. Cis deletion is when both deletions occur on the same chromosome; seen in Asians ii. Trans deletion is when one deletion occurs on each chromosome; seen in Africans, including African Americans 3. Three genes deleted-severe anemia; b chains form tetramers (HbH) that damage RBCs; HbH is seen on electrophoresis. 4. Four genes deleted-lethal in utero (hydrops fetalis); g chains form tetramers (Hb Barts) that damage RBCs; Hb Barts is seen on electrophoresis. E. b -Thalassemia is usually due to gene mutations (point mutations in promoter or splicing sites); seen in individuals of African and Mediterranean descent 1. Two β genes are present on chromosome 11; mutations result in absent (β0) or diminished (β+) production of the β-globin chain. 2. β-Thalassemia minor (β/β+) is the mildest form of disease and is usually asymptomatic with an increased RBC count. i. Microcytic, hypochromic RBCs and target cells are seen on blood smear (Fig. 5.3). ii. Hemoglobin electrophoresis shows slightly decreased HbA with increased HbA 2 (5%, normal 25%). and HbF (2%, normal 1%). 3. β-Thalassemia major (β0/β0) is the most severe form of disease and presents with severe anemia a few months after birth; high HbF (α2γ 2) at birth is temporarily protective. i. Unpaired α chains precipitate and damage RBC membrane, resulting in ineffective erythropoiesis and extravascular hemolysis (removal of circulating RBCs by the spleen). ii. Massive erythroid hyperplasia ensues resulting in (1) expansion of hematopoiesis into the skull (reactive bone formation leads to 'crewcut' appearance on x-ray, Fig. 5.4) and facial bones ('chipmunk fades'), (2) extramedullary hematopoiesis with hepatosplenomegaly, and (3) risk of aplastic crisis with parvovirus B19 infection of erythroid precursors. iii. Chronic transfusions are often necessary; leads to risk for secondary hemochromatosis iv. Smear shows microcytic, hypochromic RBCs with target cells and nucleated red blood cells. v. Electrophoresis shows HbA2 and HbF with little or no HbA. Fig. 5.3 Target cells. Fig. 5.4 'Crewcut' appearance. (Reproduced with Fig. 5.5 Hypersegmented neutrophil in permission, www.orthopaedia.com/x/xgGvAQ) macrocytic anemia. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Red Blood Cell Disorders 45 MACROCYTIC ANEMIA I. BASIC PRINCIPLES A. Anemia with MCV > 100 µm 3; most commonly due to folate or vitamin B12 deficiency (megaloblastic anemia) B. Folate and vitamin B12 are necessary for synthesis of DNA precursors. 1. Folate circulates in the serum as methyltetrahydrofolate (methyl THF); removal of the methyl group allows for participation in the synthesis of DNA precursors. 2. Methyl group is transferred to vitamin B12 (cobalamin). 3. Vitamin B12 then transfers it to homocysteine, producing methionine. C. Lack of folate or vitamin B12 impairs synthesis of DNA precursors. 1. Impaired division and enlargement of RBC precursors leads to megaloblastic anemia. 2. Impaired division of granulocytic precursors leads to hypersegmented neutrophils. 3. Megaloblastic change is also seen in rapidly-dividing (e.g., intestinal) epithelial cells. D. Other causes of macrocytic anemia (without megaloblastic change) include alcoholism, liver disease, and drugs (e.g., 5-FU). II. FOLATE DEFICIENCY A. Dietary folate is obtained from green vegetables and some fruits. 1. Absorbed in the jejunum B. Folate deficiency develops within months, as body stores are minimal. C. Causes include poor diet (e.g., alcoholics and elderly), increased demand (e.g., pregnancy, cancer, and hemolytic anemia), and folate antagonists (e.g., methotrexate, which inhibits dihydrofolate reductase). D. Clinical and laboratory findings include 1. Macrocytic RBCs and hypersegmented neutrophils (> 5 lobes, Fig. 5.5) 2. Glossitis 3. ↓serum folate 4. ↑ serum homocysteine (increases risk for thrombosis) 5. Normal methylmalonic acid III. VITAMIN B12 DEFICIENCY A. Dietary vitamin B12 is complexed to animal-derived proteins. 1. Salivary gland enzymes (e.g., amylase) liberate vitamin B12, which is then bound by R-binder (also from the salivary gland) and carried through the stomach. 2. Pancreatic proteases in the duodenum detach vitamin Bl2 from R-binder. 3. Vitamin Bl2 binds intrinsic factor (made by gastric parietal cells) in the small bowel; the intrinsic factor-vitamin B12 complex is absorbed in the ileum. B. Vitamin B12 deficiency is less common than folate deficiency and takes years to develop due to large hepatic stores of vitamin B12. C. Pernicious anemia is the most common cause of vitamin B12 deficiency. 1. Autoimmune destruction of parietal cells (body of stomach) leads to intrinsic factor deficiency D. Other causes of vitamin B12 deficiency include pancreatic insufficiency and damage to the terminal ileum (e.g., Crohn disease or Diphyllobothrium latum [fish tapeworm]); dietary deficiency is rare, except in vegans. E. Clinical and laboratory findings include 1. Macrocytic RBCs with hypersegmented neutrophils 2. Glossitis 3. Subacute combined degeneration of the spinal cord https://t.me/USMLEPathoma https://t.me/USMLEPathoma  46 FUNDAMENTALS OF PATHOLOGY i. Vitamin B12 is a cofactor for the conversion of methylmalonic acid to succinyl CoA (important in fatty acid metabolism). ii. Vitamin B12 deficiency results in increased levels of methylmalonic acid, which impairs spinal cord myelinization. iii. Damage results in poor proprioception and vibratory sensation (posterior column) and spastic paresis (lateral corticospinal tract). 4. ↓serum vitamin B12 5. ↑ serum homocysteine (similar to folate deficiency), which increases risk for thrombosis 6. ↑ methylmalonic acid (unlike folate deficiency) NORMOCYTIC ANEMIA I. BASIC PRINCIPLES A. Anemia with normal-sized RBCs (MCV = 80-100 µm 3) B. Due to increased peripheral destruction or underproduction 1. Reticulocyte count helps to distinguish between these two etiologies. II. RETICULOCYTES A. Young RBCs released from the bone marrow 1. Identified on blood smear as larger cells with bluish cytoplasm (due to residual RNA, Fig. 5.6) B. Normal reticulocyte count (RC) is 1-2%. 1. RBC lifespan is 120 days; each day roughly 1-2% of RBCs are removed from circulation and replaced by reticulocytes. C. A properly functioning marrow responds to anemia by increasing the RC to > 3%. D. RC, however, is falsely elevated in anemia. 1. RC is measured as percentage of total RBCs; decrease in total RBCs falsely elevates percentage of reticulocytes. E. RC is corrected by multiplying reticulocyte count by Hct/45. 1. Corrected count > 3% indicates good marrow response and suggests peripheral destruction. 2. Corrected count < 3% indicates poor marrow response and suggests underproduction. III. PERIPHERAL RBC DESTRUCTION (HEMOLYSIS) A. Divided into extravascular and intravascular hemolysis; both result in anemia with a good marrow response. B. Extravascular hemolysis involves RBC destruction by the reticuloendothelial system (macrophages of the spleen, liver, and lymph nodes). Fig. 5.6 Reticulocyte. Fig. 5.7 Spherocytes. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Red Blood Cell Disorders 47 1. Macrophages consume RBCs and break down hemoglobin. i. Globin is broken down into amino acids. ii. Heme is broken down into iron and protoporphyrin; iron is recycled. iii. Protoporphyrin is broken down into unconjugated bilirubin, which is bound to serum albumin and delivered to the liver for conjugation and excretion into bile. 2. Clinical and laboratory findings include i. Anemia with splenomegaly, jaundice due to unconjugated bilirubin, and increased risk for bilirubin gallstones ii. Marrow hyperplasia with corrected reticulocyte count > 3% C. Intravascular hemolysis involves destruction of RBCs within vessels. 1. Clinical and laboratory findings include i. Hemoglobinemia ii. Hemoglobinuria iii. Hemosiderinuria - Renal tubular cells pick up some of the hemoglobin that is filtered into the urine and break it down into iron, which accumulates as hemosiderin; tubular cells are eventually shed resulting in hemosiderinuria. iv. Decreased serum haptoglobin NORMOCYTIC ANEMIAS WITH PREDOMINANT EXTRAVASCULAR HEMOLYSIS I. HEREDITARY SPHEROCYTOSIS A. Inherited defect of RBC cytoskeleton-membrane tethering proteins 1. Most commonly involves ankyrin, spectrin, or band 3 B. Membrane blebs are formed and lost over time. 1. Loss of membrane renders cells round (spherocytes) instead of disc-shaped. 2. Spherocytes are less able to maneuver through splenic sinusoids and are consumed by splenic macrophages, resulting in anemia. C. Clinical and laboratory findings include 1. Spherocytes with loss of central pallor (Fig. 5.7) 2. ↑ RDW and ↑ mean corpuscular hemoglobin concentration (MCHC) 3. Splenomegaly, jaundice with unconjugated bilirubin, and increased risk for bilirubin gallstones (extravascular hemolysis) 4. Increased risk for aplastic crisis with parvovirus B19 infection of erythroid precursors D. Diagnosed by osmotic fragility test, which reveals increased spherocyte fragility in hypotonic solution E. Treatment is splenectomy; anemia resolves, but spherocytes persist and Howell-Jolly bodies (fragments of nuclear material in RBCs) emerge on blood smear (Fig. 5.8). II. SICKLE CELL ANEMIA A. Autosomal recessive mutation in β chain of hemoglobin; a single amino acid change replaces normal glutamic acid (hydrophilic) with valine (hydrophobic). B. Gene is carried by 10% of individuals of African descent, likely due to protective role against falciparum malaria. C. Sickle cell disease arises when two abnormal β genes are present; results in >90% HbS in RBCs D. HbS polymerizes when deoxygenated; polymers aggregate into needle-like structures, resulting in sickle cells (Fig. 5.9). l. Increased risk of sickling occurs with hypoxemia, dehydration, and acidosis. 2. HbF protects against sickling; high HbF at birth is protective for the first few months of life. Treatment with hydroxyurea increases levels of HbF. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  48 FUNDAMENTALS OF PATHOLOGY E. Cells continuously sickle and de-sickle while passing through the microcirculation, resulting in complications related to RBC membrane damage. 1. Extravascular hemolysis - Reticuloendothelial system removes RBCs with damaged membranes, leading to anemia, jaundice with unconjugated hyperbilirubinemia, and increased risk for bilirubin gallstones. 2. Intravascular hemolysis - RBCs with damaged membranes dehydrate, leading to hemolysis with decreased haptoglobin and target cells on blood smear. 3. Massive erythroid hyperplasia ensues resulting in i. Expansion of hematopoiesis into the skull ('crewcut' appearance on x-ray) and facial bones ('chipmunk fades') ii. Extramedullary hematopoiesis with hepatomegaly iii. Risk of aplastic crisis with parvovirus B19 infection of erythroid precursors F. Extensive sickling leads to complications of vaso-occlusion. 1. Dactylitis - swollen hands and feet due to vaso-occlusive infarcts in bones; common presenting sign in infants 2. Autosplenectomy - shrunken, fibrotic spleen. Consequences include i. Increased risk of infection with encapsulated organisms such as Streptococcus pneumoniae and Haemophilus influenzae (most common cause of death in children); affected children should be vaccinated by 5 years of age. ii. Increased risk of Salmonella paratyphi osteomyelitis iii. Howell-Jolly bodies on blood smear 3. Acute chest syndrome - vaso-occlusion in pulmonary microcirculation 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 4. Pain crisis 5. Renal papillary necrosis - results in gross hematuria and proteinuria G. Sickle cell trait is the presence of one mutated and one normal chain; results in< 50% HbS in RBCs (HbA is slightly more efficiently produced than HbS) 1. Generally asymptomatic with no anemia; RBCs with < 50% HbS do not sickle in vivo except in the renal medulla. i. Extreme hypoxia and hypertonicity of the medulla cause sickling, which results in microinfarctions leading to microscopic hematuria and, eventually, decreased ability to concentrate urine. H. Laboratory findings 1. Sickle cells and target cells are seen on blood smear in sickle cell disease, but not in sickle cell trait. r7\.Pjr "5 H! 2. Metabisulfite screen causes cells with any amount of HbS to sickle; positive in both disease and trait 3. Hb electrophoresis confirms the presence and amount of HbS. “ & 0 * *,, *O L © Fig. 5.8 Fragment of nuclear remnant (Howell-Jolly body) within RBC. m.® / Fig. 5.9 Sickle cell disease. f,I %_ 8~ * Fig. 5.10 Hemoglobin C crystal. I https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Red Blood Cell Disorders 49 i. Disease - 90% HbS, 8% HbF, 2% HbA2 (no HbA) ii. Trait - 55% HbA, 43% HbS, 2% HbA2 III. HEMOGLOBIN C A. Autosomal recessive mutation in β chain of hemoglobin 1. Normal glutamic acid is replaced by lysine. 2. Less common than sickle cell disease B. Presents with mild anemia due to extravascular hemolysis C. Characteristic HbC crystals are seen in RBCs on blood smear (Fig. 5.10). NORMOCYTIC ANEMIAS WITH PREDOMINANT INTRAVASCULAR HEMOLYSIS I. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) A. Acquired defect in myeloid stem cells resulting in absent glycosylphosphatidylinositol (GPI); renders cells susceptible to destruction by complement 1. Blood cells coexist with complement. 2. Decay accelerating factor (DAF) on the surface of blood cells protects against complement-mediated damage by inhibiting C3 convertase. 3. DAF is secured to the cell membrane by GPI (an anchoring glycolipid). 4. Absence of GPI leads to absence of DAF, rendering cells susceptible to complement-mediated damage. B. Intravascular hemolysis occurs episodically, often at night during sleep. 1. Mild respiratory acidosis develops with shallow breathing during sleep and activates complement. 2. RBCs, WBCs, and platelets are lysed. 3. Intravascular hemolysis leads to hemoglobinemia and hemoglobinuria (especially in the morning); hemosiderinuria is seen days after hemolysis. C. Sucrose test is used to screen for disease; confirmatory test is the acidified serum test or flow cytometry to detect lack of CD55 (DAF) on blood cells. D. Main cause of death is thrombosis of the hepatic, portal, or cerebral veins. 1. Destroyed platelets release cytoplasmic contents into circulation, inducing thrombosis. E. Complications include iron deficiency anemia (due to chronic loss of hemoglobin in the urine) and acute myeloid leukemia (AML), which develops in 10% of patients. II. GLUCOSE-6-PHOSPHATE DEHYDROGENASE (G6PD) DEFICIENCY A. X-linked recessive disorder resulting in reduced half-life of G6PD; renders cells susceptible to oxidative stress 1. RBCs are normally exposed to oxidative stress, in particular H2O2 2. Glutathione (an antioxidant) neutralizes H2O2, but becomes oxidized in the process. 3. NADPH, a by-product of G6PD, is needed to regenerate reduced glutathione. 4. ↓G6PD ↓→ NADPH ↓→ reduced glutathione → oxidative injury by H2O2 → intravascular hemolysis B. G6PD deficiency has two major variants. 1. African variant - mildly reduced half-life of G6PD leading to mild intravascular hemolysis with oxidative stress 2. Mediterranean variant - markedly reduced half-life of G6PD leading to marked intravascular hemolysis with oxidative stress 3. High carrier frequency in both populations is likely due to protective role against falciparum malaria. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  50 FUNDAMENTALS OF PATHOLOGY C. Oxidative stress precipitates Hb as Heinz bodies. 1. Causes of oxidative stress include infections, drugs (e.g., primaquine, sulfa drugs, and dapsone), and fava beans. 2. Heinz bodies are removed from RBCs by splenic macrophages, resulting in bite cells (Fig. 5.11). 3. Leads to predominantly intravascular hemolysis D. Presents with hemoglobinuria and back pain hours after exposure to oxidative stress E. Heinz preparation is used to screen for disease (precipitated hemoglobin can only be seen with a special Heinz stain, Fig. 5.12); enzyme studies confirm deficiency (performed weeks after hemolytic episode resolves). III. IMMUNE HEMOLYTIC ANEMIA (IHA) A. Antibody-mediated (IgG or IgM) destruction of RBCs B. IgG-mediated disease usually involves extravascular hemolysis. 1. IgG binds RBCs in the relatively warm temperature of the central body (warm agglutinin); membrane of antibody-coated RBC is consumed by splenic macrophages, resulting in spherocytes. 2. Associated with SLE (most common cause), CLL, and certain drugs (classically, penicillin and cephalosporins) i. Drug may attach to RBC membrane (e.g., penicillin) with subsequent binding of antibody to drug-membrane complex ii. Drug may induce production of autoantibodies (e.g., α-methyldopa) that bind self antigens on RBCs 3. Treatment involves cessation of the offending drug, steroids, IVIG, and, if necessary, splenectomy. C. IgM-mediated disease can lead to intravascular hemolysis. 1. IgM binds RBCs and fixes complement in the relatively cold temperature of the extremities (cold agglutinin). 2. RBCs inactivate complement, but residual C3b serves as an opsonin for splenic macrophages resulting in spherocytes; extreme activation of complement can lead to intravascular hemolysis. 3. Associated with Mycoplasma pneumoniae and infectious mononucleosis. D. Coombs test is used to diagnose IHA; testing can be direct or indirect. 1. Direct Coombs test confirms the presence of antibody- or complement-coated RBCs. When anti-IgG/complement is added to patient RBCs, agglutination occurs if RBCs are already coated with IgG or complement. This is the most important test for IHA. 2. Indirect Coombs test confirms the presence of antibodies in patient serum. Anti- IgG and test RBCs are mixed with the patient serum; agglutination occurs if serum antibodies are present. w f Fig. 5.11 Bite cell. Fig. 5.12 Heinz bodies (Heinz preparation). Fig. 5.13 Schistocyte. https://t.me/USMLEPathoma https://t.me/USMLEPathoma  Red Blood Cell Disorders 51 IV. MICROANGIOPATHIC HEMOLYTIC ANEMIA A. Intravascular hemolysis that results from vascular pathology; RBCs are destroyed as they pass through the circulation. 1. Iron deficiency anemia occurs with chronic hemolysis. B. Occurs with microthrombi (TTP-HUS, DIC, HELLP), prosthetic heart valves, and aortic stenosis; when present, microthrombi produce schistocytes on blood smear (Fig. 5.13). V. MALARIA A. Infection of RBCs and liver with Plasmodium (Fig. 5.14); transmitted by the female Anopheles mosquito B. RBCs rupture as a part of the Plasmodium life cycle, resulting in intravascular hemolysis and cyclical fever. 1. P falciparum - daily fever 2. P vivax and P ovale - fever every other day C. Spleen also consumes some infected RBCs; results in mild extravascular hemolysis with splenomegaly ANEMIA DUE TO UNDERPRODUCTION I. BASIC PRINCIPLES A. Decreased production of RB Cs by bone marrow; characterized by low corrected reticulocyte count B. Etiologies include 1. Causes of microcytic and macrocytic anemia 2. Renal failure - decreased production of EPO by peritubular interstitial cells 3. Damage to bone marrow precursor cells (may result in anemia or pancytopenia) II. PARVOVIRUS B19 A. Infects progenitor red cells and temporarily halts erythropoiesis; leads to significant anemia in the setting of preexisting marrow stress (e.g., sickle cell anemia). B. Treatment is supportive (infection is self-limited). III. APLASTIC ANEMIA A. Damage to hematopoietic stem cells, resulting in pancytopenia (anemia, thrombocytopenia, and leukopenia) with low reticulocyte count B. Etiologies include drugs or chemicals, viral infections, and autoimmune damage. C. Biopsy reveals an empty, fatty marrow (Fig. 5.15). Fig. 5.14 Erythrocytes infected with Pfalciparum. Fig. 5.15 Aplastic anemia. (Courtesy of Paulo Mourao, MD) https://t.me/USMLEPathoma https://t.me/USMLEPathoma  52 FUNDAMENTALS OF PATHOLOGY D. Treatment includes cessation of any causative drugs and supportive care with transfusions and marrow-stimulating factors (e.g., erythropoietin, GM-CSF, and G-CSF). 1. Immunosuppression may be helpful as some idiopathic cases are due to abnormal T-cell activation with release of cytokines. 2. May require bone marrow transplantation as a last resort IV. MYELOPHTHISIC PROCESS A. Pathologic process (e.g., metastatic cancer) that replaces bone marrow; hematopoiesis is impaired, resulting in pancytopenia. https://t.me/USMLEPathoma https://t.me/USMLEPathoma