Normocytic anemia (increased hemolysis) Notes

NOTES NOTES NORMOCYTIC ANEMIA (INCREASED HEMOLYSIS) GENERALLY, WHAT IS IT? PATHOLOGY & CAUSES ▪ Inherited/acquired disorders resulting in premature destruction of normal red blood cells (RBCs) SIGNS & SYMPTOMS ▪ If hematopoietic compensation insufficient, anemic symptoms (e.g. pallor, fatigue, activity intolerance) ▪ Intravascular hemolysis → hemoglobinuria, iron deficiency ▪ Extravascular hemolysis → jaundice, splenomegaly, gallstone formation DIAGNOSIS LAB RESULTS ▪ Complete blood count (CBC) ▪ Peripheral blood smear analysis ▪ Measure plasma for hemolysis indicators ▫ Bilirubin, lactate dehydrogenase (LDH), haptoglobin ▪ Measure specific indicators of hemolysis in urine ▫ Hemoglobin, bilirubin, hemosiderin TREATMENT ▪ See individual disorders AUTOIMMUNE HEMOLYTIC ANEMIA (AHA) osms.it/autoimmune-hemolytic-anemia PATHOLOGY & CAUSES ▪ Anemia caused by immune destruction of red blood cells by autoantibodies against antigens on RBCs surface ▪ AKA AIHA TYPES Warm AIHA ▪ Most common ▪ “Warm” because optimum temperature for antibody to react with RBCs = normal body temperature (37°C/98.6°F) ▪ Predominant autoantibody: IgG (IgA and IgM may also be involved) ▪ Predominant RBC antigen: Rh ▪ Associated with immune deficiencies, malignancies, certain drugs ▪ Antibody fixes complement + binds to RBC membrane → antibody-coated RBCS destroyed in spleen ▫ Usual site of hemolysis: extravascular, by macrophages in spleen, liver OSMOSIS.ORG 425

Cold AIHA ▪ “Cold” because optimum temperature for antibody to react with RBCs = below normal body temperature (4°C/39.2°F) ▪ Predominant autoantibody: IgM ▪ Predominant RBC antigen: I, i, P ▪ Antibodies activate direct complement system attack ▪ Usual site of hemolysis: intravascular, complement-mediated ▪ Paroxysmal cold hemoglobinuria ▫ Most common in children ▫ Caused by Donath–Landsteiner antibody ▫ Associated with viral (e.g. measles, varicella) or bacterial (e.g. mycoplasma, H. influenza) infections ▪ Cold agglutinin syndrome ▫ Most common in adults > 70 years old ▫ Primarily biologically-female individuals ▫ Associated with lymphoproliferative disorders, autoimmune disorders, mycoplasma infections COMPLICATIONS ▪ Depend on type/degree of hemolysis ▪ Anemia, venous thromboembolism, cholelithiasis, renal insufficiency ▪ Older individuals: increased risk of cardiac complications SIGNS & SYMPTOMS ▪ Onset insidious/acute ▪ If hematopoietic compensation insufficient, anemic signs and symptoms (e.g. pallor, fatigue, activity intolerance) ▪ If severe anemia/underlying cardiac disease, a hyperdynamic state (e.g. bounding pulses, tachycardia, pulmonary congestion) ▪ Cold AIHA ▫ Hemoglobinuria after exposure to cold temperatures ▪ Paroxysmal cold hemoglobinuria ▫ Jaundice, hemoglobinuria, anemia after infection; pain in legs, back following exposure to cold ▪ Cold agglutinin syndrome ▫ Anemia, acrocyanosis, or Raynaud’s phenomenon DIAGNOSIS LAB RESULTS RISK FACTORS ▪ Exposure to cold ▪ Administration of offending drug ▪ Development of associated diagnosis ▫ Infection, malignancy, autoimmune disorder 426 OSMOSIS.ORG ▪ Evidence of hemolysis ▫ Increased lactate dehydrogenase (LDH) ▫ Increased indirect bilirubin ▫ Decreased haptoglobin ▪ Increased mean corpuscular volume (MCV) ▪ Low hemoglobin, hematocrit ▪ Reticulocytosis ▪ Direct antibody (DAT) ▫ Warm: positive for IgG/IgG + C3d ▫ Cold: positive for C3d ▪ Partial macrophage phagocytosis → spherocytosis

Chapter 54 Normocytic Anemia (Increased Hemolysis) TREATMENT ▪ Cold AIHA: often no treatment required MEDICATIONS ▪ Corticosteroids ▪ Monoclonal antibody: rituximab ▪ Immunosuppressants SURGERY ▪ Splenectomy (reduces hemolysis) OTHER INTERVENTIONS Figure 54.1 A peripheral blood smear from an individual with warm autoimune hemolytic anemia. There are numerous spherocytes present due to degradation of the red cell membrane by macrophages. ▪ Eliminate triggers (e.g. cold, drugs) ▪ Correct anemia ▫ Folic acid supplements to support erythropoiesis ▫ Blood transfusion GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY osms.it/G6PD PATHOLOGY & CAUSES ▪ Hematological enzymopathy where deficient glucose-6-phosphate dehydrogenase (G6PD) causes premature hemolysis ▪ Inherited, X-linked mutation of G6PD gene ▪ Hemolysis can be acute/intermittent/chronic (rare) ▪ Inadequate G6PD, GSH → oxidative stress → build-up of free radicals, peroxides → precipitation of hemoglobin → disruption of cell membrane → increased cellular rigidity → extravascular hemolysis, accelerated removal of damaged RBCs by reticuloendothelial system in spleen; intravascular hemolysis may also occur ▪ Hemolysis precipitated by sources of oxidative damage that trigger hemolysis. ▫ RBCs with deficient G6PD have a decreased lifespan ▫ Certain drugs (sulfa drugs, antimalarials) and chemicals (e.g. henna compounds, aniline-based dyes, naphthalene) interact with hemoglobin + oxygen → hydrogen peroxide (H2O2), other oxidizing radicals within cell → hemoglobin precipitation ▪ Infections → possible generation of hydrogen peroxide by leukocytes/exposure to neutrophil produced oxidants → hemoglobin precipitation ▪ Ingestion of fava beans (favism) W.H.O. Classifications ▪ Based on degree of enzyme deficiency, resulting hemolysis ▪ Class I: G6PD < 10% of normal; chronic hemolytic anemia ▪ Class II: G6PD < 10% of normal; intermittent hemolysis when exposed to OSMOSIS.ORG 427

oxidative stress ▫ G6PD Mediterranean: majority of RBCs hemolyze in setting of oxidative stress; half-life of G6PD especially short (measured in hours) ▪ Class III: G6PD 10–60% of normal; intermittent hemolysis when exposed to trigger ▫ G6PD A- : only oldest RBCs hemolyze in setting of oxidative stress; G6PD halflife = 13 days (normal = 62 days) ▪ ▪ ▪ ▪ TYPES ▪ Acute hemolysis ▫ May be mild/severe (life-threatening) ▪ Kernicterus ▫ G6PD-related neonatal jaundice → kernicterus if not promptly treated ▪ Renal failure RISK FACTORS ▪ Most common in people of African, Asian, Mediterranean descent SIGNS & SYMPTOMS ▪ Generally asymptomatic until exposed to oxidative stress ▪ Acute hemolysis ▫ Pallor, jaundice, dark urine ▫ Abdominal/back pain due to increased splenic activity ▫ Renal insufficiency (severe hemolysis) ▪ Favism (potentially fatal acute hemolysis) DIAGNOSIS LAB RESULTS ▪ Decreased hemoglobin ▪ Heinz bodies ▫ Caused by precipitation of oxidized, denatured hemoglobin ▪ Bite cells ▫ Cells have bitten appearance where macrophages have removed bits of precipitated hemoglobin from RBC ▪ Blood chemistry demonstrates evidence of hemolysis 428 OSMOSIS.ORG ▪ ▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin Reticulocytosis Hemoglobinuria, hemosiderinuria G6PD assay ▫ Directly measures G6PD activity in RBCs; false-negative if testing done during/immediately after acute hemolytic episode Screening tests ▫ Fluorescent spot test: glucose6-phosphate + NADP added to hemolysate of individual’s RBCs → fluorescence of NADPH ▫ Methemoglobin reduction test: methylene blue measures transfer of hydrogen ions from NADPH to methemoglobin → indirectly estimates NADPH generation ▫ Newborn screening: blood analyzed for biochemical, genetic markers of G6PD, other inherited disorders Confirmatory test to assay NADPH formation performed after positive screening test/as initial test ▫ Spectrophotometric analysis of RBC hemolysate + glucose-6-phosphate + NADP measures NADPH generation rate TREATMENT MEDICATIONS ▪ Folic acid supplements (support erythropoiesis) OTHER INTERVENTIONS ▪ Eliminate triggers ▪ Manage acute hemolytic episodes ▫ Hydration ▫ Transfusions ▪ Phototherapy, exchange transfusion ▫ Neonatal jaundice

Chapter 54 Normocytic Anemia (Increased Hemolysis) HEMOLYTIC DISEASE OF THE NEWBORN osms.it/hemolytic-disease-of-the-newborn PATHOLOGY & CAUSES ▪ Anemia caused by hemolytic destruction of fetal/neonatal erythrocytes by maternal antibodies ▪ AKA alloimmune HDFN/erythroblastosis fetalis CAUSES ▪ Fetomaternal hemorrhage exposes maternal circulation to antigens present on fetal RBCs → maternal sensitization → formation of maternal IgG antibodies against fetal RBCs → IgG antibodies small enough to cross placenta → antibody attachment to fetal cells → agglutination (clumping) → microcirculatory impairment → hemolysis, destruction of RBCs by macrophages in reticuloendothelial system ▫ Involves Rhesus (Rh) blood group/A, B, AB, O blood groups ▪ Causes of maternal sensitization include normal delivery, spontaneous/induced abortion, chorionic villus sampling, amniocentesis, antenatal hemorrhage, maternal trauma, idiopathic ▫ Small amount (0.1mL) of fetal blood needed to induce maternal immune response ▪ Rh incompatibility ▫ Rh negative mother exposed to Rh positive fetal RBCs → maternal anti-D antibodies formed ▫ Usually will not affect first pregnancy when initial exposure occurs; adversely affects subsequent pregnancies ▫ Decreasing occurrence due to availability of Rh(D) immune globulin prophylaxis ▪ ABO incompatibility ▫ More common, less severe morbidity, mortality than with Rh incompatibility ▫ Occurs in type O mother with naturallyoccurring Anti-A and Anti-B antibodies + Type A/Type B fetus ▫ Can occur in first and all subsequent pregnancies RISK FACTORS ▪ Blood group incompatibility, fetomaternal hemorrhage COMPLICATIONS ▪ Anemia, hyperbilirubinemia, kernicterus ▪ Growth restriction, hydrops fetalis, erythroblastosis fetalis ▫ Increased immature RBCs in fetal circulation SIGNS & SYMPTOMS ▪ Hemolytic disease caused by ABO incompatibility ▫ Mild to moderate hyperbilirubinemia within first 24h of life ▫ Mild to moderate anemia ▪ Hemolytic disease caused by Rh incompatibility (more severe) ▫ Hyperbilirubinemia, kernicterus: possible ▫ Symptomatic anemia: pallor, lethargy, tachycardia, tachypnea ▫ Hydrops fetalis: related to severe anemia-induced hypoxia; subcutaneous edema, pleural/pericardial effusion, ascites, signs and symptoms of shock ▪ Antenatal presentation ▫ Intrauterine growth restriction signals problems with ongoing hemolysis, hypoxia OSMOSIS.ORG 429

DIAGNOSIS DIAGNOSTIC IMAGING Doppler ultrasound ▪ Antenatal (maternal testing) ▪ Notes growth restriction/presence of hydrops LAB RESULTS ▪ Antenatal (maternal testing) ▫ Positive indirect antiglobulin test: IAT, indirect Coombs test; demonstrates IgG antibodies in maternal serum ▫ Kleihauer–Betke test: positive if fetomaternal hemorrhage has occurred ▫ Percutaneous umbilical blood sampling (PUBS): measures hemoglobin, hematocrit, identifies fetal blood type ▫ Spectrophotometric amniotic fluid analysis: increased bilirubin if significant hemolysis has occurred ▪ Postnatal (neonatal testing) ▫ Blood typing: confirm incompatibility of maternal, neonatal blood types ▫ Positive direct antiglobulin test: DAT, direct Coombs test; evidence of maternal antibodies on RBC surface ▫ Positive indirect antiglobulin test: IAT, indirect Coombs test; evidence of maternal antibodies in serum ▫ Transcutaneous bilirubin (TcB), serum bilirubin: increased ▫ CBC: decreased RBCs, reticulocytosis, decreased hemoglobin and hematocrit ▫ Peripheral blood smear analysis: evidence of hemolysis; polychromasia, microspherocytosis (seen in ABO incompatibility) 430 OSMOSIS.ORG TREATMENT MEDICATIONS ▪ Hematopoietic agents (epoetin alfa/ darbepoetin), iron supplements ▫ Anemia OTHER INTERVENTIONS ▪ RBC transfusion ▫ Anemia, hydrops fetalis ▪ Exchange transfusion ▫ Hyperbilirubinemia, hydrops fetalis ▪ Phototherapy ▫ Hyperbilirubinemia ▪ Intravenous immunoglobulin (IVIG) ▫ Hyperbilirubinemia ▫ Reduces hemolysis, bilirubin production ▪ Pericardiocentesis, paracentesis, thoracentesis ▫ Hydrops fetalis; as indicated for pericardial effusion, pleural effusion, ascites ▪ Intrauterine RBCl transfusion ▫ Hydrops fetalis if diagnosed antenatally

Chapter 54 Normocytic Anemia (Increased Hemolysis) HEREDITARY SPHEROCYTOSIS osms.it/hereditary-spherocytosis PATHOLOGY & CAUSES ▪ Inherited RBC membrane defect causing destabilization of cellular membrane, resulting in chronic, premature extravascular hemolysis ▪ Autosomal dominant (75%) or autosomal recessive (25%) ▪ Mutations of genes encoding for proteins that secure RBC membrane skeleton to plasma membrane → membrane destabilization → rigidity, resistance to deformability → hemolysis TYPES Mild (20–30%) ▪ Mild anemia, splenomegaly, jaundice; modest reticulocytosis; normal hemoglobin ▪ Adolescents/adults most commonly diagnosed Moderate (60–70%) ▪ Moderate anemia, reticulocytosis, hyperbilirubinemia ▪ Require occasional transfusions ▪ Infants/children most commonly diagnosed Severe (5%) ▪ Marked anemia, hyperbilirubinemia, splenomegaly ▪ Regular transfusions needed RISK FACTORS ▪ Most common in people of Northern European descent COMPLICATIONS ▪ Transient aplastic crisis caused by infections (e.g. parvovirus B19) ▪ Megaloblastic anemia related to folate deficiency ▪ Neonatal icterus; non-immune hydrops fetalis with fetal death if disease = severe SIGNS & SYMPTOMS ▪ Jaundice ▪ Anemic signs and symptoms (e.g. pallor, fatigue, activity intolerance) ▪ Splenomegaly DIAGNOSIS LAB RESULTS ▪ Decreased hemoglobin ▪ Reticulocytosis ▪ Spherocytosis ▫ Morphology = sphere-shaped (normal = biconcave) ▪ Presence of schistocytes (RBC fragments) ▪ Slightly decreased to normal MCV ▫ Spherocytes: decreased MCV ▫ Reticulocytes: increased MCV ▪ Elevated mean cell hemoglobin concentration (MCHC) ▫ Secondary to dehydration, loss of cellular membrane ▪ Elevated red cell distribution width (RDW) ▪ Evidence of hemolysis ▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin ▪ Osmotic fragility test, acidified glycerol lysis test (AGLT) ▫ Identifies spherocytes which lyse in hypotonic solutions at higher rate than normal RBCs ▪ Cryohemolysis test ▫ Uses hypertonic solution, temperature manipulation to identify spherocytes which lyse at higher rate than normal RBCs ▪ Eosin-5-maleimide (EMA) binding test ▫ Flow cytometric test to observe cell membrane protein interaction with eosin-5-maleimide dye OSMOSIS.ORG 431

▪ Osmotic gradient ektacytometry ▫ Measures surface area to volume, cell hydration, membrane deformability TREATMENT SURGERY ▪ Splenectomy OTHER INTERVENTIONS ▪ Blood transfusions ▪ Phototherapy, exchange transfusions ▫ Neonatal hyperbilirubinemia ▪ Folic acid supplements ▫ Support hematopoiesis Figure 54.2 A peripheral blood smear demonstrating sphere shaped erythrocytes in an individual with hereditary spherocytosis. The erythrocytes have lost their biconcave shape. PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH) osms.it/paroxysmal-nocturnal-hemoglobinuria PATHOLOGY & CAUSES ▪ Inherited, X-linked hematologic stem cell disorder resulting in nocturnal hemolysis, hemolytic anemia, bone marrow failure, thrombosis CAUSES ▪ Mutation of PIGA gene in hematopoietic stem cells ▫ PIGA required for synthesis of glycosylphosphatidylinositol (GPI) protein on cell surface ▫ GPI anchors glycoproteins on erythrocyte surface, protecting cell from lysis by attenuating activity of complement ▪ GPI protein absence or deficiency → ↑ 432 OSMOSIS.ORG susceptibility to complement activity → complement-mediated intravascular hemolysis ▪ Three phenotypes of RBCs categorized according to amount of GPI-anchored proteins on cell surface ▫ Type I: normal ▫ Type II: decreased ▫ Type III: absent RISK FACTORS ▪ Hemolysis in PNH cases increases in setting of increased complement activation ▫ Infections ▫ Surgery ▫ Blood transfusions ▫ Strenuous exercise ▫ Excessive alcohol use

Chapter 54 Normocytic Anemia (Increased Hemolysis) COMPLICATIONS ▪ Intravascular, extravascular hemolysis → anemia ▪ Consequences of hemoglobin-mediated nitric oxide scavenging ▫ Intravascular hemolysis → free hemoglobin → ↑ consumption of nitric oxide → smooth muscle dystonia, vasospasm (abdominal pain, esophageal spasm, erectile dysfunction) ▪ Venous, arterial thrombosis ▫ Multifactorial etiology related to proinflammatory complement activity, decreased availability of nitric oxide with resulting vasoconstriction, endothelial cell activation, associated platelet aggregation/clot formation ▫ Hepatic vein thrombosis (Budd–Chiari syndrome) → hepatomegaly, jaundice, ascites, gastric and/or esophageal varices ▫ Intestinal vein thrombosis → ischemic colitis ▫ Cerebral vein thrombosis → headache, neurologic effects ▪ Microvascular hemolysis + iron deposits in renal tubules → chronic kidney disease ▪ Bone-marrow failure, aplastic anemia related to hematopoietic stem cell injury ▪ Eculizumab treatments associated with Increased risk of life-threatening neisserial infections SIGNS & SYMPTOMS ▪ Variable according to degree of GPIanchored protein loss → hemolysis ▪ Intermittent episodes (paroxysms) of hemoglobinuria ▫ Dark urine ▫ Hemolysis during night ▪ Clinical manifestations of anemia; e.g. pallor, fatigue, exertional dyspnea DIAGNOSIS LAB RESULTS ▪ Range from normal to abnormal according to degree of GPI-anchored protein loss, resulting hemolysis ▪ RBCs normal morphologically (pancytopenia may be evident in setting of bone marrow failure) ▪ Occasional poikilocytosis, anisocytosis ▪ Normochromic ▪ Normal to extremely decreased serum hemoglobin ▪ Reticulocyte count ranges from normal to decreased ▪ Evidence of hemolysis ▫ Elevated bilirubin ▫ Decreased haptoglobin ▫ Elevated LDH ▪ Direct antiglobulin (DAT/Coombs) positive ▪ Hemoglobinuria, hemosiderinuria OTHER INTERVENTIONS ▪ Bone marrow examination may indicate hypocellularity ▪ Flow cytometry TREATMENT MEDICATIONS ▪ Eculizumab ▫ Monoclonal antibody, reduces complement-mediated hemolysis ▫ Vaccinate against Neisseria meningitidis ▪ Iron, folic acid supplements support erythropoiesis ▪ Therapeutic anticoagulation and/or thrombolysis, as indicated for thrombosis ▪ Immunosuppressive therapy if aplastic anemia present SURGERY ▪ Allogeneic hematopoietic stem cell transplant OTHER INTERVENTIONS ▪ Red blood cell transfusions as needed OSMOSIS.ORG 433

PIRUVATE KINASE DEFICIENCY osms.it/piruvate-kinase-deficiency PATHOLOGY & CAUSES ▪ Hematological enzymopathy caused by deficient pyruvate kinase, resulting in chronic, premature hemolysis of RBCs, hyperactive erythropoiesis ▪ Inherited, autosomal recessive mutation of (PK-LR) pyruvate kinase-LR (liver-red cell) gene ▫ Homozygous for single PK-LR mutation/ heterozygous for two mutations ▪ Hemolysis primarily extravascular (within spleen); intravascular hemolysis variable ▪ Pyruvate kinase ▫ Tetramer enzyme, catalyzes transphosphorylation of phosphoenolpyruvate into pyruvate, ATP during glycolysis ▫ Pyruvate kinase deficiency-related block in glycolysis → accumulation of 2,3-bisphosphoglycerate (2,3-BPG) → shifts oxyhemoglobin dissociation curve to right → improved oxygen delivery to tissues → better tolerance of hemolytic anemia CAUSES ▪ Hemolytic mechanism is unclear; possibly ▫ ATP deficiency ▫ Apoptosis of erythroid progenitors in spleen (ineffective erythropoiesis) RISK FACTORS ▪ Most common in white people of Northern European descent, Asian people of Chinese descent, genetically-isolated communities of Swiss/German descent COMPLICATIONS ▪ Pigmented gallstone formation ▪ Iron overload-associated organ damage ▪ Megaloblastic anemia related to folate deficiency 434 OSMOSIS.ORG ▪ Accelerated hemolysis during pregnancy/ with oral contraceptive use ▪ Neonatal icterus/non-immune hydrops fetalis ▪ Transient aplastic crisis induced by infections (e.g. parvovirus B19) SIGNS & SYMPTOMS ▪ Variable presentation ranging from compensated disease to transfusiondependent anemia ▪ Anemic signs and symptoms ▫ Pallor, shortness of breath, activity intolerance ▪ Jaundice, splenomegaly DIAGNOSIS LAB RESULTS Decreased RBC count, reticulocytosis Increased serum glycolytic 2,3-BPG Hemoglobinuria, hemosiderinuria Evidence of hemolytic anemia with one or both of ▫ Low levels of erythrocytic PK enzymatic activity ▫ PK-LR gene mutation ▪ Evidence of hemolysis ▫ Elevated indirect bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Decreased haptoglobin ▪ ▪ ▪ ▪ OTHER DIAGNOSTICS ▪ Clinical evidence of hemolysis ▫ Jaundice, pigmented (bilirubin) gallstones

Chapter 54 Normocytic Anemia (Increased Hemolysis) TREATMENT SURGERY ▪ Splenectomy ▫ Reduces hemolysis ▪ Allogeneic hematopoietic cell transplantation ▫ May be curative OTHER INTERVENTIONS ▪ RBC transfusions ▫ Often chronic ▪ Chelation therapy ▫ Reduces iron-related organ damage ▪ Folic acid supplementation ▫ Supports erythropoiesis ▪ Phototherapy, exchange transfusion ▫ Treats neonatal jaundice SICKLE-CELL ANEMIA osms.it/sickle-cell-anemia PATHOLOGY & CAUSES ▪ Hemolytic anemia caused by sickle-cell disease (SCD) ▪ A group of inherited hemoglobinopathies caused by point mutation of beta globin gene → produces hemoglobin S (HbS) ▪ RBCs containing HbS tend to polymerize, deform into sickle/crescent-shaped forms when deoxygenated ▫ Triggers for deoxygenation: cold, dehydration, insomnia, alcohol consumption, stressful situations, overexertion, hormonal changes ▫ Deoxygenation may be idiopathic ▪ Sickled cells less deformable than normal RBCs ▫ Decreased lifespan due to hemolysis TYPES HbSS ▪ Sickle-cell disease ▫ Homozygous for HbS ▫ Chronic hemolytic anemia HbSC ▪ Milder form of sickle-cell disease ▫ Heterozygous for HbS + abnormal hemoglobin C HbSA ▪ Sickle-cell trait/benign carrier state ▫ Heterozygous for HbS + hemoglobin A (normal hemoglobin) HbS beta thalassemia ▪ Heterozygous for HbS + one beta thalassemia gene HbSD, HbSE, HbSO ▪ Rare ▪ Heterozygous for HbS + one other abnormal hemoglobin (D, E, or O) COMPLICATIONS ▪ Affect all body systems ▪ Hematologic ▫ Anemia related to aplastic crisis involving temporary arrest of erythropoiesis ▪ Pain ▫ Vaso-occlusion, tissue ischemia, infarction; dactylitis (acute pain in small bones of hands/feet especially in children) ▪ Increased risk of infection ▫ Related to hyposplenism/asplenism, decreased tissue perfusion ▪ Central nervous system ▫ Ischemic/hemorrhagic stroke; transient ischemic attack, seizures OSMOSIS.ORG 435

▪ Cardiovascular ▫ Myocardial infarction, dysrhythmias, cardiomyopathy, heart failure, venous thromboembolism, leg ulcers, sudden death ▪ Respiratory ▫ Acute chest syndrome (fever, chest pain, hypoxemia, wheezing, cough, respiratory distress), pulmonary hypertension, disordered breathing during sleep with nocturnal hypoxemia ▪ Genitourinary, reproductive ▫ Priapism, erectile dysfunction; pregnancy complications, fetal/neonatal or maternal (e.g. intrauterine growth restriction, fetal death, low birthweight; preeclampsia, thromboembolic events) ▪ Endocrine ▫ Delayed growth, development ▪ Skeletal ▫ Osteoporosis, bone infarction ▪ Sensory ▫ Proliferative retinopathy, retinal detachment ▪ Systemic ▫ Multiorgan failure related to ischemia and/or infarction SIGNS & SYMPTOMS ▪ Mild to moderate anemia (e.g. fatigue, activity intolerance, extertional dyspnea) ▪ Hypersplenism ▪ Pain from acute vaso-occlusive crisis DIAGNOSIS ▪ Findings variable depending on inheritance pattern, degree of hemolysis ▪ Pain indicates cell sickling, vaso-occlusion LAB RESULTS ▪ Vaso-occlusion, hemolysis, splenic sequestration → decreased hemoglobin, hematocrit, RBC count ▪ Reticulocytosis ▪ Increased white blood cell (WBC) count ▪ Peripheral blood smear analysis 436 OSMOSIS.ORG ▪ Mostly normochromic, normocytic cells; polychromasia may be present secondary to reticulocytosis ▪ Sickled cells present in SCD but not sicklecell trait ▪ Canoe-shaped (partially sickled) RBCs ▪ Howell Jolly bodies ▫ Related to hyposplenia ▪ Normal-to-increased mean corpuscular volume (MCV) ▪ Target cells ▪ Diagnostic tests to determine organ damage (e.g. urinalysis → hematuria, albuminuria from renal papillary damage) ▪ Evidence of hemolysis ▫ Elevated unconjugated bilirubin ▫ Elevated lactate dehydrogenase (LDH) ▫ Low haptoglobin ▪ Positive solubility test (Sickledex) ▪ Hemoglobin electrophoresis provides definitive diagnosis (90–95% HbS) TREATMENT ▪ Prevent/reduce occurrence of crises (e.g. immunizations to prevent infection, manage stress, prevent deoxygenation) MEDICATIONS ▪ Hydroxyurea ▫ Increases cell deformability, decreases RBC endothelial adhesion, increases hemoglobin F levels; reduces sickling ▪ L-glutamine ▫ Reduces sickling ▪ Pain management ▫ Analgesics, adjunctive, nonpharmacological therapies SURGERY ▪ Hematopoietic cell transplantation OTHER INTERVENTIONS ▪ Blood transfusions ▪ Folic acid supplements ▪ Manage iron deficiency

Chapter 54 Normocytic Anemia (Increased Hemolysis) Figure 54.3 A recoloured scanning electron micrograph demonstrating a sickled erythrocyte. Figure 54.4 An abdominal CT scan in the axial plane demonstrating autosplenectomy in an individual with sickle cell disease. The splenic remnant is densely calcified. Figure 54.5 A peripheral blood smear containing sickled erythrocytes in an individual with sickle cell disease. OSMOSIS.ORG 437