Snapshot A 4-year-old African American boy presents to the emergency room for sudden onset severe abdominal pain. He has a history of sickle cell anemia. On physical exam, he is pale, and he has a left upper quadrant palpable mass. Complete blood count is significant for hemoglobin of 7.3 g/dL. Serum unconjugated bilirubin and reticulocyte count are elevated. (Acute splenic sequestration) Introduction Overview sickle cell anemia is an autosomal recessive disease that results in abnormal hemoglobin characterized by hemoglobin S (HbS), resulting in hemolytic anemia and vaso-occlusion sickle cell disease is an overarching term including sickle cell anemia, as well as patients with a sickle mutation (HbS) and a different mutation in the ß-globin gene (e.g., ß-thalassemia or hemoglobin C disease) homozygosity (HbSS) sickle cell anemia heterozygotes (HbSA) sickle cell trait, usually asymptomatic and may confer some resistance to malaria may have painless hematuria as a result of renal papillary necrosis hemoglobin SC disease (HbSC) HbS and HbC hemoglobin C disease (HbC) point mutation in ß-globin gene where glutamic acid is replaced with lysine Epidemiology demographics blacks are most commonly affected risk factors family history Pathogenesis pathophysiology recall that hemoglobin (Hb) is a soluble tetramer composed of 2 α-globins and 2 ß-globins HbS results from point mutation of ß-globin gene that substitutes valine for glutamic acid due to hydrophobic interactions from valine, hemoglobin can polymerize in red blood cells this makes the hemoglobin tetramer poorly soluble and results in distortion of red blood cells (RBCs) into a sickle shape this form causes vaso-occlusion clinical severity is determined by presence of other Hb mutations elevated 2,3-diphosphoglycerate sickled RBCs undergoes hemolysis every 17 days (1/7th that of normal RBC lifespan) hemolysis generates reactive oxygen species Genetics inheritance pattern autosomal recessive mutations chromosome 11 ß-globin gene Prognosis overall survival is reduced prognosis is better with comprehensive care and clinical monitoring Presentation Clinical presentation acute events anemia vaso-occlusive events acute painful episodes previously called “sickle cell crises” may occur on top of chronic pain triggers include cold temperature, stress, alcohol, and menses dactylitis acute pain in hands and feet particularly common in children acute chest syndrome cerebrovascular accidents myocardial infarction priapism renal infarction splenic infarction by 2-4 years of age, patients have functional asplenia venous thromboembolism chronic events pain hemolytic anemia contributing factors include low erythropoietin concentration (can be due to renal disease) and folate deficiency neurologic deficits stunted growth and development renal disease painless hematuria due to papillary infarcts medication toxicities urinary concentrating defect Physical exam splenomegaly jaundice pallor bone/joint tenderness Imaging Radiographs indications acute chest syndrome findings new pulmonary infiltrate of one or more lung segments Studies Prenatal testing currently not routinely used Newborn screening methodology varies by state but can be detected via high performance liquid chromatography (preferred), tandem mass spectrometry, DNA testing, or isoelectric focusing (gel electrophoresis) Serum labs decreased hemoglobin and hematocrit increased reticulocyte count mildly elevated fetal hemoglobin (HbF) normocytic anemia Peripheral blood smear Howell-Jolly bodies nuclear remnants of RBCs that have not been phagocytosed due to functional asplenia sickled cells Differential ß-thalassemia key distinguishing factors microcytic anemia no sickle cells on peripheral blood smear Treatment Lifestyle prophylactic treatments modalities daily folic acid penicillin until 5 years of age pneumococcal vaccine prevents pneumococcal sepsis Medical supportive care indications acute attacks modalities hydration oxygen analgesia exchange transfusion indications acute vaso-occlusive events hydroxyurea indications decreases frequency and severity of attacks increases production of fetal hemoglobin, which has a higher affinity for oxygen may consider addition of Gardos channel blocking agent prevents RBC dehydration by inhibiting K+ efflux Surgical hematopoietic cell transplantation indications the only curative treatment Complications Functional asplenia by an early age at increased risk for encapsulated bacterial infection (e.g., Streptococcus and Salmonella) may result in splenic sequestration of RBCs and extravascular hemolysis Aplastic crisis associated with parvovirus B19 infection or splenic sequestration crisis low reticulocyte count supplement with daily folic acid Chronic lung disease and pulmonary hypertention secondary to acute chest syndrome Renal disease can present as inability to concentrate urine, resulting in frequent urination Retinopathy secondary to retinal artery occlusion Cardiomyopathy left-sided diastolic dysfunction with or without pulmonary hypertension due to pulmonary hypertension, chronic anemia and hypoxemia with increased cardiac output, transfusion overload, and hypertension Cholelithiasis secondary to chronic hemolysis
QUESTIONS 1 of 11 1 2 3 4 5 6 7 8 9 10 11 Previous Next Lab Values Blood Hematologic Cerebrospinal Sweat, Urine, and BMI Blood, Plasma, Serum Reference Range ALT 8-20 U/L Amylase, serum 25-125 U/L AST 8-20 U/L Bilirubin, serum (adult) Total // Direct 0.1-1.0 mg/dL // 0.0-0.3 mg/dL Calcium, serum (Ca2+) 8.4-10.2 mg/dL Cholesterol, serum Rec: < 200 mg/dL Cortisol, serum 0800 h: 5-23 μg/dL //1600 h: 3-15 μg/dL 2000 h: ≤ 50% of 0800 h Creatine kinase, serum Male: 25-90 U/LFemale: 10-70 U/L Creatinine, serum 0.6-1.2 mg/dL Electrolytes, serum Sodium (Na+) 136-145 mEq/L Chloride (Cl-) 95-105 mEq/L Potassium (K+) 3.5-5.0 mEq/L Bicarbonate (HCO3-) 22-28 mEq/L Magnesium (Mg2+) 1.5-2.0 mEq/L Estriol, total, serum (in pregnancy) 24-28 wks // 32-36 wks 30-170 ng/mL // 60-280 ng/mL 28-32 wk // 36-40 wks 40-220 ng/mL // 80-350 ng/mL Ferritin, serum Male: 15-200 ng/mLFemale: 12-150 ng/mL Follicle-stimulating hormone, serum/plasma Male: 4-25 mIU/mL Female: premenopause: 4-30 mIU/mL midcycle peak: 10-90 mIU/mL postmenopause: 40-250 pH 7.35-7.45 PCO2 33-45 mmHg PO2 75-105 mmHg Glucose, serum Fasting: 70-110 mg/dL2-h postprandial:<120 mg/dL Growth hormone - arginine stimulation Fasting: <5 ng/mLProvocative stimuli: > 7ng/mL Immunoglobulins, serum IgA 76-390 mg/dL IgE 0-380 IU/mL IgG 650-1500 mg/dL IgM 40-345 mg/dL Iron 50-170 μg/dL Lactate dehydrogenase, serum 45-90 U/L Luteinizing hormone, serum/plasma Male: 6-23 mIU/mL Female: follicular phase: 5-30 mIU/mL midcycle: 75-150 mIU/mL postmenopause 30-200 mIU/mL Osmolality, serum 275-295 mOsmol/kd H2O Parathyroid hormone, serume, N-terminal 230-630 pg/mL Phosphatase (alkaline), serum (p-NPP at 30° C) 20-70 U/L Phosphorus (inorganic), serum 3.0-4.5 mg/dL Prolactin, serum (hPRL) < 20 ng/mL Proteins, serum Total (recumbent) 6.0-7.8 g/dL Albumin 3.5-5.5 g/dL Globulin 2.3-3.5 g/dL Thyroid-stimulating hormone, serum or plasma .5-5.0 μU/mL Thyroidal iodine (123I) uptake 8%-30% of administered dose/24h Thyroxine (T4), serum 5-12 μg/dL Triglycerides, serum 35-160 mg/dL Triiodothyronine (T3), serum (RIA) 115-190 ng/dL Triiodothyronine (T3) resin uptake 25%-35% Urea nitrogen, serum 7-18 mg/dL Uric acid, serum 3.0-8.2 mg/dL Hematologic Reference Range Bleeding time 2-7 minutes Erythrocyte count Male: 4.3-5.9 million/mm3Female: 3.5-5.5 million mm3 Erythrocyte sedimentation rate (Westergren) Male: 0-15 mm/hFemale: 0-20 mm/h Hematocrit Male: 41%-53%Female: 36%-46% Hemoglobin A1c ≤ 6 % Hemoglobin, blood Male: 13.5-17.5 g/dLFemale: 12.0-16.0 g/dL Hemoglobin, plasma 1-4 mg/dL Leukocyte count and differential Leukocyte count 4,500-11,000/mm3 Segmented neutrophils 54%-62% Bands 3%-5% Eosinophils 1%-3% Basophils 0%-0.75% Lymphocytes 25%-33% Monocytes 3%-7% Mean corpuscular hemoglobin 25.4-34.6 pg/cell Mean corpuscular hemoglobin concentration 31%-36% Hb/cell Mean corpuscular volume 80-100 μm3 Partial thromboplastin time (activated) 25-40 seconds Platelet count 150,000-400,000/mm3 Prothrombin time 11-15 seconds Reticulocyte count 0.5%-1.5% of red cells Thrombin time < 2 seconds deviation from control Volume Plasma Male: 25-43 mL/kgFemale: 28-45 mL/kg Red cell Male: 20-36 mL/kgFemale: 19-31 mL/kg Cerebrospinal Fluid Reference Range Cell count 0-5/mm3 Chloride 118-132 mEq/L Gamma globulin 3%-12% total proteins Glucose 40-70 mg/dL Pressure 70-180 mm H2O Proteins, total < 40 mg/dL Sweat Reference Range Chloride 0-35 mmol/L Urine Calcium 100-300 mg/24 h Chloride Varies with intake Creatinine clearance Male: 97-137 mL/minFemale: 88-128 mL/min Estriol, total (in pregnancy) 30 wks 6-18 mg/24 h 35 wks 9-28 mg/24 h 40 wks 13-42 mg/24 h 17-Hydroxycorticosteroids Male: 3.0-10.0 mg/24 hFemale: 2.0-8.0 mg/24 h 17-Ketosteroids, total Male: 8-20 mg/24 hFemale: 6-15 mg/24 h Osmolality 50-1400 mOsmol/kg H2O Oxalate 8-40 μg/mL Potassium Varies with diet Proteins, total < 150 mg/24 h Sodium Varies with diet Uric acid Varies with diet Body Mass Index (BMI) Adult: 19-25 kg/m2 Calculator ( ) xy AC 7 8 9 ÷ 4 5 6 × 1 2 3 - 0 . = + Sorry, this question is for PEAK Premium Subscribers only Upgrade to PEAK Sorry, this question is for PEAK Premium Subscribers only Upgrade to PEAK Sorry, this question is for PEAK Premium Subscribers only Upgrade to PEAK (M1.HE.15.4666) A 24-year-old African American male with sickle cell disease has been followed by a hematologist since infancy. Two years ago, he was started on hydroxyurea for frequent pain crises but has not achieved good control. The addition of a Gardos channel blocking agent is being considered. What is the mechanism of action of this class of medications? Review Topic | Tested Concept QID: 107109 Type & Select Correct Answer 1 Prevents RBC dehydration by inhibiting K+ efflux 39% (15/38) 2 Increases production of hemoglobin F 16% (6/38) 3 Prevents dehydration of RBCs by inhibiting Ca2+ efflux 16% (6/38) 4 Encourages alkalinization of the blood by facilitating H+/K+ antiporter activity 18% (7/38) 5 Increases water diffusion by increasing activity of aquaporin-1 receptors 0% (0/38) L 3 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 1 Review tested concept Sorry, this question is for PEAK Premium Subscribers only Upgrade to PEAK (M1.HE.15.74) A 5-year-old African American boy presents with extreme abdominal pain. He has a history of several such episodes, as well as acute episodes of extreme bone pain. He has previously presented with the findings illustrated in Figure A. A peripheral blood smear is obtained, and is shown in Figure B. What is the most likely mechanism responsible for this patient's disorder? Review Topic | Tested Concept QID: 106635 FIGURES: A B Type & Select Correct Answer 1 Tri-nucleotide repeat amplification 2% (4/170) 2 Mutation in the gene coding for hemoglobin-alpha 5% (9/170) 3 Point mutation at the 6th position of the ß-hemoglobin chain 86% (146/170) 4 Increased levels of hemoglobin-F 2% (3/170) 5 Reduced levels of folic acid 2% (4/170) L 1 Question Complexity B Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 Review tested concept (M1.HE.15.74) A 4-year-old African American boy presents with extreme abdominal pain. He has had similar episodes in the past. A peripheral smear is obtained, and shows the findings illustrated in Figure A. Which of the following is a mechanism which can precipitate this condition? Review Topic | Tested Concept QID: 106614 FIGURES: A Type & Select Correct Answer 1 Elevated cellular pH 16% (14/89) 2 Elevated 2,3-diphosphoglycerate 62% (55/89) 3 Elevated arterial oxygen concentration 4% (4/89) 4 Elevated hemoglobin F levels 7% (6/89) 5 Travel from high to low elevation geographical area 10% (9/89) L 1 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 2 Review tested concept (M1.HE.14.52) A 17-year-old African-American male presents to his family physician after noticing red-tinged urine the week before, when he was suffering from a cold. The patient states that he had experienced that before. His father is with him and says that this happens to him on occasion as well. What is the most likely diagnosis for this patient? Review Topic | Tested Concept QID: 104499 Type & Select Correct Answer 1 Acute cystitis 0% (0/40) 2 Acute interstitial nephritis 2% (1/40) 3 Sickle cell trait 68% (27/40) 4 Acute glomerulonephritis 12% (5/40) 5 Hemophilia 15% (6/40) L 2 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 Review tested concept (M1.HE.14.11) Patients with the diagnosis of sickle cell anemia make a specific type of hemoglobin known as HgbS. This mutation results in the sickling of their red blood cells when exposed to inciting factors such as hypoxic conditions. Patients are often treated with hydroxyurea, which has which of the following direct effects on their hemoglobin physiology? Review Topic | Tested Concept QID: 104651 Type & Select Correct Answer 1 Increases oxygen carrying capacity of hemoglobin 9% (11/120) 2 Decreases oxygen carrying capacity of hemoglobin 3% (4/120) 3 Increases levels of fetal hemoglobin (HgbF) 82% (99/120) 4 Decreases levels of HgbS 2% (3/120) 5 Decreases levels of fetal hemoglobin (HgbF) 2% (2/120) L 1 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 Review tested concept (M1.HE.13.33) A 7-year-old girl with a history of painful crises and impaired growth presents for evaluation of sickle cell disease. You perform hemoglobin gel electrophoresis, and diagnose her with homozygous sickle cell disease. Which of the gel electrophoresis lanes in Figure A is hers (Lanes 1 and 5 contain the reference marker samples including Hemoglobin variants A, F, S, C)? Review Topic | Tested Concept QID: 100098 FIGURES: A Type & Select Correct Answer 1 Lane 2 3% (6/174) 2 Lane 3 3% (5/174) 3 Lane 4 82% (142/174) 4 Lane 6 5% (9/174) 5 Lane 7 5% (9/174) L 2 Question Complexity E Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 Review tested concept (M1.HE.13.86) An 8-year-old boy complains of extremity pain and difficulty "catching his breath" while running on the playground. His mother also reports that he complains of intermittent abdominal pain. Physical examination reveals splenomegaly. The patient's blood smear is shown in Figure A. What is the most likely mutation present? Review Topic | Tested Concept QID: 100151 FIGURES: A Type & Select Correct Answer 1 Deleted tryptophan 2% (3/191) 2 Deleted glycine 2% (3/191) 3 Glutamic acid to valine 69% (131/191) 4 Glutamine to valine 21% (41/191) 5 Inserted lysine 1% (2/191) L 2 Question Complexity D Question Importance Select Answer to see Preferred Response SUBMIT RESPONSE 3 Review tested concept
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