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  • 1. ANEMIAS II: HEMOLYTIC ANEMIAS Clinical Medicine and Surgery I Pamela Jaffey MD
  • 2. OBJECTIVES
    • Identify general diagnostic findings of hemolytic anemia
    • Describe a classification system for hemolytic anemias:
      • Hereditary anemias ( defects within RBC )
      • Acquired anemias ( external causes )
    • Sickle Cell Anemia
      • identify clinical complications
      • identify diagnostic findings
      • describe treatment of sickle cell disease:
      • health care maintenance; painful crisis
  • 3. OBJECTIVES
    • Thalassemias
    • describe populations most affected
    • beta thalassemia major : describe complications; diagnostic findings
    • beta thalassemia minor ( trait ): describe clinical and diagnostic findings
    • define the 4 types of alpha thalassemia
    • Glucose-6-phosphate dehydrogenase
    • ( G6PD ) deficiency
    • identify populations affected with disease
    • identify causes of acute hemolytic crises
    • describe clinical presentation
  • 4. OBJECTIVES
    • Autoimmune hemolytic anemias
      • identify major causes of " warm" and "cold" autoimmune hemolytic anemias
      • describe how the following tests can help diagnose autoimmune hemolytic anemias : direct antiglobulin test ( direct Coomb’s test ) cold agglutinin titer
      • describe clinical presentation
      • describe emergency treatment for rapidly developing/ and or severe autoimmune hemolytic anemia
    • Identify hemolytic anemias occurring due to mechanical shearing of RBCs
  • 5. HEMOLYTIC ANEMIAS
    • Definition:
    • increased destruction of RBC outside the bone marrow resulting in shortened RBC lifespan; destruction may be within vessels ( intravascular ), within the spleen ( extravascular ), or both.
  • 6. HEMOLYTIC ANEMIAS
    • GENERAL DIAGNOSTIC FINDINGS
      • increased reticulocyte count
      • ( % reticulocytes /total RBC )
    • absolute reticulocyte count is more accurate: allows correction for anemia -decreased RBC count in denominator falsely increases reticulocyte count ( for reference )
    • absolute reticulocyte count = % reticulocytes x RBC/ u L
    • absolute reticulocyte count > 100,000/uL = hemolytic anemia
  • 7.  
  • 8. HEMOLYTIC ANEMIAS
    • GENERAL DIAGNOSTIC FINDINGS
      • B.increased serum unconjugated bilirubin (hyperbilirubinemia )
    • product of breakdown of hemoglobin released by lysed RBC
    • heme is enzymatically converted in macrophages to bilirubin , which is then transported in plasma by albumin
    • unconjugated bilirubin has not been metabolized ( conjugated to glucuronic acid ) in liver- to be discussed in liver function test lecture
  • 9.  
  • 10.  
  • 11. HEMOLYTIC ANEMIAS
    • GENERAL DIAGNOSTIC FINDINGS
      • decreased serum haptoglobin
    • serum haptoglobin binds free hemoglobin  complex is rapidly cleared  haptoglobin level decreases
  • 12. HEMOLYTIC ANEMIAS
    • GENERAL DIAGNOSTIC FINDINGS
      • increased lactate dehydrogenase: released upon lysis of RBC
      • ( is a cellular enzyme involved with anaerobic glucose metabolism which is contained in many cell types, and released upon cell necrosis )
      • both intravascular and extravascular hemolysis are associated with above findings- only intravascular hemolysis is associated with:
      • hemoglobinuria ( increased hemoglobin in urine )
      • hemoglobinemia ( increased free hemoglobin in blood )
  • 13. HEMOLYTIC ANEMIAS
    • CLASSIFICATION OF HEMOLYTIC ANEMIAS
      • DEFECTS WITHIN RBC ( hereditary )
        • synthesis of structurally abnormal hemoglobin e.g. SICKLE CELL ANEMIA
        • decreased synthesis of globin chains ( structurally normal ) e.g. THALASSEMIAS
        • enzyme abnormalities e.g. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
        • RBC membrane abnormalities ( for reference ) e.g. hereditary spherocytosis
  • 14. HEMOLYTIC ANEMIAS
    • CLASSIFICATION OF HEMOLYTIC ANEMIAS
      • EXTERNAL CAUSES OF HEMOLYTIC ANEMIAS (acquired)
        • Immune Mediated
          • autoimmune disease : e.g. systemic lupus erythematosus
          • infections ( e.g. Mycoplasma pneumoniae )
          • drugs
          • WBC malignancies ( e.g. chronic lymphocytic leukemia )
          • idiopathic ( cause unknown )
        • Mechanical trauma
          • disseminated intravascular coagulation
          • prosthetic heart valves
        • Parasitization of RBC e.g. Malaria
  • 15.  
  • 16. HEREDITARY HEMOLYTIC ANEMIAS
    • SICKLE CELL ANEMIA
    • FORMS: ( autosomal recessive inheritance )
    • Homozygotes : sickle cell disease ( median life expectancy 5th decade- forties )
    • no normal, mature Hgb ( have Hgb S instead of normal Hgb A ): 1/400 African American births ( also seen in other groups; e.g. Caucasians )
    • Heterozygotes : sickle cell trait – in 8-10% African Americans ( normal lifespan )
    • 60% Hgb is normal ( Hgb A) and mature; 40% of Hgb is Hgb S
    • There is enough normal Hgb to prevent most complications which develop in homozygotes; complications which develop among heterozygotes will be discussed for reference
  • 17.  
  • 18. HEREDITARY HEMOLYTIC ANEMIAS
    • SICKLE CELL ANEMIA
    • PATHOGENESIS ( for reference only )
    • 1. mutation at position 6 in beta globin chain of hemoglobin:
    • glutamic acid is replaced by valine on outer surface
    • 2. physiochemical properties of Hgb are altered:
    • Hgb aggregates upon deoxygenation 
    • RBC become sickled with rigid, abnormal membranes which are abnormally adhesive to endothelial cells
    • 3. chronic hemolysis occurs in spleen and blood vessels
    • 4. repeated painful crises ( vasoocclusive episodes ) occur due to occlusion of microvasculature in various tissues by abnormal sickle cells, because they stick to endothelial cells
    • 5. heterozygotes mainly spared of problems because normal and abnormal hemoglobins don’t aggegate well together
  • 19.  
  • 20. HEREDITARY HEMOLYTIC ANEMIAS
    • COMPLICATIONS OF SICKLE CELL DISEASE
    • Chronic Hemolytic Anemia
    • Mean RBC lifespan = 17 days ( normally 120 days )
    • Hgb = 6-10 gm/dL; Reticulolyte count = 3- 15%
    • AGE AT PRESENTATION:
      • may present in infancy
      • 61% by 2 years
      • 96% by 8 years
    • Most Common Presenting Symptoms:
      • dactylitis ( acute pain in hands and/or feet )
      • acute painful crisis ( to be discussed )
      • splenic sequestration ( to be discussed )
  • 21.  
  • 22. SICKLE CELL DISEASE
    • PAINFUL CRISIS ( most frequent reason why homozygotes seek medical attn )
    • A. Precipitating events :
    • deoxygenation; infection ( and fever ); dehydration ; stress; menses; cold; alcohol consumption; often no identifyable cause  widespread occlusion in microvasculature
    • B. Clinical presentation
    • often severe pain anywhere but most typically: back, chest, extremities abdomen
    • other symptoms: fever, swelling, tenderness, increased respiratory rate, nausea and vomiting (may last a few hours – 2 weeks )
  • 23. SICKLE CELL DISEASE
    • PAINFUL CRISIS ( most frequent reason why homozygotes seek medical attn )
    • C. Incidence of hospitalizations for pain per year : ( disease severity variable in different patients )
    • 1/3rd patients none ; 1/3rd: 2-6x;
    • 1/3rd: > 6 x
    • D. Consequences necrosis in various tissues ( spleen; bones; lungs; kidneys; brain; skin etc.)
  • 24. SICKLE CELL DISEASE:COMPLICATIONS
    • INFECTION
    • A. results from lack of protection from bacterial infection normally provided by spleen ( splenic macrophages engulf and clear bacteria ; spleen is important in activation of alternative complement pathway )
      • in early childhood, spleen is enlarged and congested with abnormal RBC
      • infarction of spleen occurs by adolesence or early adulthood ( from vasoocclusion by abnormal RBC: “autosplenectomy” )
  • 25.  
  • 26. SICKLE CELL DISEASE: COMPLICATIONS
    • INFECTION
    • NOTE: splenic infarction can develop at high altitude in patients with sickle cell trait ; occurs more commonly in Caucasians rather than patients of African ancestry ( for reference )
  • 27. SICKLE CELL DISEASE: COMPLICATIONS
    • INFECTION CONTINUED:
    • B. infection is important cause of death in children: (young children are treated prophylactically with penicillin )
    • C. patients have increased episodes of pneumonia, sepsis, meningitis ( infection of brain coverings ), osteomyelitis ( bone infection ) important organisms: patients especially vulnerable for infections by encapsulated bacteria :
    • Streptococcus pneumoniae; Hemophilus influenzae type b
    • Other important bacteria causing infection:
    • Salmonella and Staphylococcus aureus (osteomyelitis )
  • 28. SICKLE CELL DISEASE: COMPLICATIONS
    • PULMONARY COMPLICATIONS
    • both acute and chronic problems occur : a leading cause of death
    • ACUTE CHEST SYNDROME : 30% patients
    • Symptoms: shortness of breath, chest pain, fever, increased respiratory rate, leukocytosis, infiltrate on chest x-ray
    • Consequences : life-threatening
    • extreme deoxygenation in blood ( hypoxemia) can result in widespread vaso-occlusion and failure of multiple organs  ”crash”
    • can be associated with infection due to Streptococcus pneumoniae, Hemophilus influenzae type b, Mycoplasma pneumoniae, and Chlamydia pneumoniae
  • 29. SICKLE CELL DISEASE: COMPLICATIONS
    • Neurologic : ( 30% patients )
    • seizures; transient ischemic attack
    • ( 11% ); cerebral infarction ( 54%- peaks in young children and adults > 29yrs; ); cerebral hemorrhage ( 34%- peaks in adults in twenties )
  • 30. SICKLE CELL DISEASE: COMPLICATIONS
    • Renal: abnormal function of renal tubules ( concentrating ability etc. )
    • infarction of renal papilla results in hematuria (blood in urine )
    • homozygotes may also have glomerular disease
    • AND may develop chronic renal failure
    • NOTE: heterozytotes may also have : ( for reference )
    • episodes of hematuria; impaired concentrating ability of renal tubules (less severe and presents later than in homozygotes); may have increased # of urinary tract infections
  • 31.  
  • 32. SICKLE CELL DISEASE:COMPLICATIONS
    • Priapism:
    • prolonged, painful erection (may last long enough to require medical intervention)
    • Incidence: 6 –42% males; peak ages: 5-13yrs and 21-29 yrs (may occur in pre-adolescent males)
    • Bone:
    • significantly increased production of RBC in bone marrow expands it and results in “ bossing of forehead”
    • infarction of bone secondary to vaso-occlusion  e.g. aseptic necrosis of femoral head ; extreme pain may be associated with infarction
    • osteomyelitis ( infection of bone)
  • 33.  
  • 34. SICKLE CELL DISEASE: COMPLICATIONS
    • Leg Ulcers: ( also called “ stasis ulcers” )
    • major cause of disability- frequent, chronic, resistant to treatment
    • increased incidence in teenagers; at medial or lateral malleolus
    • caused by tissue necrosis associated with occlusion and stasis in skin microvasculature ; may be associated with infection
  • 35.  
  • 36. SICKLE CELL DISEASE: COMPLICATIONS
    • Cardiac Complications:
    • chronic anemia compensated by high cardiac output resulting in enlargement of heart ( cardiomegaly ) and decreased cardiac reserve
    • heart at increased risk of going into failure with transfusions and fluid overload
    • myocardial infarction may occur
    • “ Cor pulmonale” ( right sided heart failure ) secondary to lung disease ( necrosis of lung tissue; pulmonary hypertension caused by chronic hypoxia )
  • 37. SICKLE CELL DISEASE: COMPLICATIONS
    • Hepatobiliary System
    • bilirubin gallstones ( term for gallstones = cholelithiasis )
  • 38.  
  • 39. SICKLE CELL DISEASE: COMPLICATIONS
    • Splenic sequestration
    • occurs in young children; spleen is significantly enlarged and congested with red blood cells; shock can occur due to significantly decreased blood volume ( hypovolemia )
  • 40. CASE
    • Splenomegaly secondary to acute sequestration crisis in a 20-month-old female with sickle cell disease:
    • An enlarged spleen was palpated on physical examination .
  • 41. X-RAY SHOWING NORMAL SIZED SPLEEN IN AN ADULT
    • 1. note the spleen outlined by the adjacent bowel
    • 2. note how the spleen is on the left and does not cross the midline
  • 42.  
  • 43. SPLEEN IN YOUNG CHILD WITH SPLENIC SEQUESTRATION CRISIS
    • 1. note the enormous spleen which crosses the midline extending into the right side of the patient
    • 2. the spleen is enlarged due to extreme sequestration of abnormal sickled red blood cells within it
  • 44.  
  • 45. SICKLE CELL DISEASE:COMPLICATIONS
    • Retinopathy ( due to occlusion of retinal vessels: hemorrhage and eventual detachments ); visual loss can occur
    • Aplastic crisis:
    • temporary; caused by Parvovirus B19 ( this virus causes aplastic crisis in patients with hereditary hemolytic anemias in general )
  • 46. SICKLE CELL DISEASE: COMPLICATIONS
    • note: patients with sickle cell trait at higher risk of rhabdomyolysis ( muscle necrosis which may result in renal failure and death ) during:
    • prolonged physical conditions ( e.g. a military recruit undergoing a long march )
    • during exercise at high altitude
    • ( for reference )
  • 47.  
  • 48. DIAGNOSIS OF SICKLE CELL ANEMIA
    • Note: only homozygotes have abnormal CBC and sickle cells on peripheral blood smear
    • sickle cells seen on peripheral blood smear
    • Hgb = 6-10gm/dL; reticulocyte count = 3- 15%
    • MCV = normocytic ( 80-100fL ); may be macrocytic due to reticulocytes
    • hemoglobin electrophoresis : abnormal band seen ( called Hgb S ): both homozygotes and heterozygotes
    • solubility test ( homozygotes and heterozygotes )
    • prenatal diagnosis : DNA analysis of fetal cells ( e.g. chorionic villus sampling )
    • testing of all neonates occurs in most states in the US currently
  • 49.  
  • 50.  
  • 51. TREATMENT OF SICKLE CELL DISEASE
    • HEALTH CARE MAINTENANCE
    • immunization of children against Streptococcus pneumoniae ;
    • Hemophilus influenzae type B ; hepatitis B virus , and influenza virus
    • ( immunization important for patients with splenectomy in general )
    • prophylactic penicillin for children 5yrs years and less
    • for reference: 125 mg penicillin V orally 2X/day until 2-3 years, then 250 mg penicillin V orally 2X/day through 5 years
  • 52. TREATMENT OF SICKLE CELL DISEASE
    • HEALTH CARE MAINTENANCE
    • hydroxyurea : ( increases production of fetal Hgb ) decreases painful crises and acute chest syndrome; may help prevent strokes ; decreases mortality due to sickle cell disease ( note: newer findings indicate that drug has another helpful effect in addition to stimulating production of fetal Hgb )
    • if hydroxyurea alone does not give good treatment response, add erythropoietin
    • assess and treat a febrile child immediately : physical exam; CBC ( look for “ left shift” ); urine culture; chest x-ray- hospitalization, blood culture and lumbar puncture ( to assess for meningitis ) may be needed
  • 53. TREATMENT OF SICKLE CELL DISEASE
    • HEALTH CARE MAINTENANCE
    • education :
    • e.g. parents instructed how to detect early signs of infection and enlarging spleens in young children; genetic counseling
    • folate supplements : rapid turnover of RBC increases demand for folate
    • dose: 1mg oral folate/day
  • 54. TREATMENT OF SICKLE CELL DISEASE
    • HEALTH CARE MAINTENANCE
    • transcranial doppler ( TCD ) to assess blood flow velocity in large intracranial vessels; can predict patients at risk for stroke
    • patients with increased risk are given chronic exchange transfusions of packed red blood cells; is protective against stroke
    • for reference: serial testing is needed, because normal flow velocity on a single test does not “assure continued low risk status”
    • retinal evaluation begun at school age ( due to ocular complications: e.g. early, proliferative sickle retinopathy)
  • 55. TREATMENT OF SICKLE CELL DISEASE
    • CURATIVE THERAPY
    • a successful bone marrow
    • ( or hematopoietic stem cell) transplant from a HLA-matched sibling; cord blood stem cells from a sibling are also used for transplantation
  • 56. TREATMENT OF COMPLICATIONS
    • PAINFUL CRISIS:
    • “ MOHA”: M orphine; O xygen; H ydration; A ntibiotics
    • relieve severe pain rapidly and safely ( narcotics typically needed; avoid respiratory depression )
    • IV MORPHINE often given first
    • can be given as patient controlled analgesia delivered via a pump:
    • basal continuous rate of morphine with a bolus that can be delivered to the patient if the patient needs it, at a specified dose and interval )- for reference
    • note: morphine can also be given orally or as rectal suppository
    • Other narcotic drugs:
      • hydromorphone hydrochloride ( Dilaudid ): can be given orally, by injection, or as a suppository
      • fentanyl citrate (Sublimaze): can be given as IV infusion or worn as a patch
  • 57. TREATMENT OF COMPLICATIONS
    • Drugs with low risk for respiratory depression:
    • a. ketorolac ( Toradol ) ( a potent non-steroidal anti-inflammatory drug ) is especially good for bone pain
    • note: is given by injection or orally over 5 days with H2 blocker because of severe GI side effects )
    • b. tramodol hydrochloride( Ultram) : may be used for outpatient management of painful crisis: given orally; low risk for abuse or addiction
    • 2. give OXYGEN
    • HYDRATION with oral or IV fluid
    • evaluate for infection and give ANTIBIOTIC if present
  • 58. TREATMENT OF COMPLICATIONS OF SICKLE CELL DISEASE
    • Priapism: ( painful, prolonged erection: may persist for very long time )
    • IV hydration and pain medication: if persists 12 hrs 
    • partial exchange transfusion ( to decrease abnormal Hgb) : if persists 
    • further medical intervention: if persists  surgery ( urologist )
    • ( treatment of priapism is for reference )
  • 59. TREATMENT OF COMPLICATIONS OF SICKLE CELL DISEASE
    • Indications for Transfusion: ( for reference )
    • Aplastic crisis: to increase oxygen carrying capacity of blood
    • Splenic sequestration and hypovolemia : to expand blood volume
    • Before surgery ( to decrease perioperative complications )
    • Acute chest syndrome : to protect from widespread deoxygenation and vaso-occlusion resulting in multi-organ failure ( partial exchange transfusion is needed emergently- remove some of patient's blood and replace it with donor blood )
    • Stroke prevention in high risk patients ( chronic exchange transfusions given )
    • Avoid transfusing to Hgb much above 10gm/dL to avoid hyperviscosity and occlusive complications
  • 60.  
  • 61. THALASSEMIAS
    • PATIENTS AFFECTED
    • Mediterranean ( Greece; Italy ), Southeast Asian , Asian Indian , African extraction
    • PATHOGENESIS OF THALASSEMIAS ( for reference only )
    • decreased synthesis of alpha or beta globin chains of hemoglobin
    • severity depends on extent of decreased chain production
    • beta thalassemias : decreased production of beta chains
    • alpha thalassemias : decreased production of alpha chains
  • 62.  
  • 63. PATHOGENESIS OF THALASSEMIA MAJOR
    • there is severe deficiency of globin chain production:
    • a. globin chain produced is in excess and can’t find complementary chain  precipitates; is toxic to RBC; causes RBC membrane defect and impairs DNA synthesis  abnormal RBCs made in bone marrow
    • b. vast majority of RBCs produced in bone marrow are “rejects”, and are destroyed in bone marrow  only few RBC released into circulation  many RBC released are hemolyzed in spleen
    • c. profound anemia results; spleen enlarges ( (splenomegaly)
  • 64. PATHOGENESIS OF THALASSEMIA MAJOR
    • beta thalassemias more severe than alpha thalassemias:
    • excess of alpha globin chains made with beta thalassemias is more toxic to the RBC than the excess of beta globin chains made with alpha thalassemias
  • 65. BETA THALASSEMIAS
    • BETA THALASSEMIA MAJOR ( homozygotes )
    • Presentation:
    • 1. 4-12 months (after fetal hemoglobin disappears)
    • 2. pallor; irritability; growth retardation; jaundice and scleral icterus due to hyperbilirubinemia ; abdominal swelling due to hepatosplenomegaly ( hepatosplenomegaly due to RBC destruction and attempts at production of RBCs in these organs )
  • 66. BETA THALASSEMIA MAJOR
    • Complications:
    • bony abnormalities ( initially of skull and face )
    • significant expansion of bone marrow occurs due to extreme attempts to produce RBC  cortex thinned  new bone formed on external aspect of skull
      • “ crew haircut” or “hair on end” appearance of skull on x-ray due to perpendicular radiations of new bone formation on the outer table
      • large maxilla with malocclusion : " chipmunk facies"
      • thinning of cortex of other bones predisposes to fractures
  • 67.  
  • 68.  
  • 69. BETA THALASSEMIA MAJOR
    • Complications:
    • bilirubin gallstones ( due to hyperbilirubinemia : increased serum unconjugated bilirubin: 2-4mg/dL )
    • profound anemia  heart failure; death in early childhood if untreated  treated by regular blood transfusions
    • IRON OVERLOAD – secondary hemochromatosis
      • causes : regular transfusions with packed red blood cells ( big source of iron ) and increased absorption of iron from GI tract
      • consequences : iron accumulates in various organs and is toxic
        • chronic liver failure with fibrosis ( cirrhosis )
        • endocrine organ involvement  results in hormonal insufficiency
        • cardiac disease ( cardiomyopathy ) 
    • results in heart failure; arrhythmias
  • 70. BETA THALASSEMIA MAJOR
    • Diagnostic Findings:
    • CBC: Hgb 3-4gm/dL ; severe hypochromia ( decreased MCH) and severe microcytosis (decreased MCV)
    • peripheral blood smear : target cells (RBCs have a “bull’s eye” appearance )
    • prenatal diagnosis: DNA study of fetal cells
  • 71.  
  • 72. BETA THALASSEMIA MAJOR
    • Treatment: ( for reference )
    • regular packed RBC transfusions to maintain Hgb level at 9-10gm/dL
    • iron chelation therapy with deferoxamine (iron binding agent which rids body of iron)- to prevent iron overload
    • splenectomy when transfusion requirements very excessive
    • ( so RBC no longer destroyed in spleen)
    • immunizations and prophylactic penicillin needed as with sickle cell disease
  • 73. BETA THALASSEMIA MAJOR
    • Treatment: ( for reference )
    • frequent monitoring of cardiac function
    • folic acid supplementation because of increased RBC production in bone marrow
    • treat endocrine deficiencies resulting from iron overload
    • good screening; genetic counseling; prenatal diagnosis
    • bone marrow or stem cell transplantation donated by HLA-matched relative: only chance for cure ( 90% cure when performed on younger child with minimal liver pathology and receiving adequate iron chelation therapy with deferoxamine )
    • stem cell transplantation: harvesting progenitor blood cells in peripheral blood
  • 74. BETA THALASSEMIA MAJOR
    • Prognosis:
    • survival significantly shortened, but at least into 3rd decade if transfusion therapy performed with iron chelation
    • bone marrow or stem cell transplant only chance for cure ( see above )
  • 75.  
  • 76. BETA THALASSEMIAS
    • BETA THALASSEMIA MINOR ( TRAIT ): heterozygotes
    • asymptomatic or symptoms of mild anemia : may be discovered on routine exam in older children or adults
    • during pregnancy, anemia often more severe and transfusions may be necessary
    • important to distinguish from iron deficiency anemia : iron can worsen anemia
    • HOWEVER : if a patient with thalassemia minor develops iron deficiency anemia, “ they should not be denied iron ”: www.uptodate.com - Treatment of beta thalassemia retrieved on 10/13/09
  • 77. BETA THALASSEMIAS
    • BETA THALASSEMIA MINOR ( TRAIT ): heterozygotes
    • diagnostic findings
      • mild anemia ( Hgb rarely < 10gm/dL)
      • striking microcytosis ( MCV < 75fL: as low as 55fL ) and hypochromia ( decreased MCH )
      • abnormal pattern on hemoglobin electrophoresis ( increased Hgb A2 ; is not always present )
      • iron studies : total iron binding capacity normal iron and ferritin normal or may be increased ( due to mild iron absorption from GI tract )
      • peripheral blood smear: target cells
      • normal or increased RDW; normal reticulocyte count
    • iron therapy won't help ( may worsen anemia )
  • 78.  
  • 79. BETA THALASSEMIAS
    • BETA THALASSEMIA INTERMEDIA ( for reference )
    • Some clinical manifestations of thalassemia major presenting later in life due to chronic hypoxia and iron overload ( heart failure, pulmonary hypertension ); patients are less transfusion dependent
    • Note: hydroxyurea, which is used in the treatment of sickle cell disease to stimulate fetal Hgb synthesis is helpful in some patients with beta thalassemia intermedia
  • 80. THALASSEMIAS
    • ALPHA THALASSEMIAS
    • alpha thalassemia minima: MCV may be slightly low; patients asymptomatic; Hgb electrophoresis normal; important for genetic counseling
    • alpha thalassemia minor : (similar to, but may be milder than beta thalassemia trait: MCV 60 – 75fL ) MCV often low; hypochromia ; target cells ; normal Hgb electrophoresis ( no increase in Hgb A2 )
    • Hbg H disease : chronic hemolytic anemia presenting at birth;
    • neonatal jaundice ( severity like beta thalassemia intermedia )
    • Hgb Barts : usually death in utero or at birth
  • 81. HEMOGLOBINOPATHIES
    • NOTE: patients can have a combination of sickle cell anemia and thalassemia (beta or alpha):
    • e.g. sickle cell trait/ beta thalassemia minor
    • Other anemias with hemoglobin mutations and abnormal structure exist: e.g. Hgb C; Hgb SC; Hgb D; Hgb G
    • In general:
    • hemoglobinopathies are hemolytic anemias in which the Hgb is abnormal in structure or amount
  • 82.  
  • 83. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Pathogenesis:
    • deficiency of the G6PD enzyme increases susceptibility of RBC to oxidative damage by certain agents such as antimalarial drugs (e.g. Primaquine); sulfonamides; nitrofurantoin; fava beans; infections ( ex. viral hepatitis; pneumonia; Salmonella; Ecoli; beta-hemolytic Streptococci; Rickettsia ); diabetic ketoacidosis
  • 84. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Incidence: x-linked recessive inheritance
    • typically affects males; female carriers are rarely affected
    • different disease variants; most common variants of disease:
    • G6PD A- : 10-11% African Americans; moderate enzyme deficiency
    • G6PD Mediterranean: Middle East; more severe enzyme deficiency
  • 85. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Clinical Presentation: patient has intermittent acute hemolytic episodes and is healthy with normal CBC in between episodes
    • self-limited acute hemolytic crisis occuring within hours – a few days of exposure to oxidant stressor ; is self- limited because only old RBC are lysed: when only “younger RBC” remain, episode is over
    • symptoms: sudden onset of jaundice, pallor and dark urine (due to hemoglobinuria) with or without abdominal and back pain
  • 86. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Clinical Presentation: patient has intermittent acute hemolytic episodes
    • 3. abrupt fall in Hgb by 3- 4gm/dL ; increased unconjugated bilirubin reticulocytosis is present upon recovery (within 5 days after onset )
    • 4. Favism:
    • occurs in young children in Italy or Greece ( with more severe form of G6PD deficiency ); presentation hours after consumption of fava beans results in a fatal anemia if children are not transfused )
  • 87. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Diagnosis:
    • Assay can assess enzyme function
    • Peripheral blood smear during hemolytic crisis : “bite cells”- oxidized denatured Hgb “puddles” to 1 side of the RBC, leaving a clear zone adjacent to the RBC membrane on the opposite side which looks like a “bite” in an “oreo cookie”
  • 88.  
  • 89. GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY (G6PD deficiency)
    • Treatment: ( for reference )
    • avoidance of drugs precipitating hemolytic crises
    • during hemolytic crisis :
      • transfuse if anemia is sufficiently severe
      • withdraw precipitating agent
  • 90.  
  • 91. HEREDITARY SPHEROCYTOSIS
    • Pathophysiology:
    • structural defect in RBC membrane results in spheroidal shape and lack of deformability of RBC
    • hemolysis in spleen results from lack of deformability ( RBC cannot get back into sinuses and general circulation, so are phagocytosed by macrophages in the spleen)
  • 92.  
  • 93.  
  • 94. HEREDITARY SPHEROCYTOSIS
    • NOTE ON ADDITIONAL SIGNIFICANCE OF SPHEROIDAL SHAPE OF RBCs:
    • spheroidal shape is associated with a increased concentration of Hgb per RBC area, therefore, the mean cell hemoglobin concentration (MCHC) is increased
  • 95. HEREDITARY SPHEROCYTOSIS
    • Incidence: highest in people of Northern European extraction : 1/5000
    • Clinical Presentation and Course:
    • major clinical features: anemia, splenomegaly, and jaundice
    • variation in severity: from asymptomatic to presentation at birth
    • Treatment:
    • Splenectomy
  • 96.  
  • 97. ACQUIRED HEMOLYTIC ANEMIAS
    • AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Pathogenesis:
    • Autoantibodies directed against RBCs are bound to RBCs and increase clearance of RBCs in spleen by macrophages:
    • antibody binds to receptors on splenic macrophages and causes macrophages to phagocytize the RBCs
    • activation of complement by autoantibody may also occur
  • 98. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Classification:
    • “ Warm” Autoimmune Hemolytic Anemia autoantibodies preferentially reacting at body temperature
      • primary ( no known cause )- many cases have no known cause
  • 99. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Classification:
    • “ Warm” Autoimmune Hemolytic Anemia
    • B. Secondary (known causes)
        • malignancies of white blood cells ( e.g. chronic lymphocytic leukemia )
        • autoimmune disease ( e.g. SLE)
        • drugs: many
          • penicillin; cephalosporins ( antibiotics ) especially after very large intravenous dose; sulfonamides
          • alpha-methyl dopa ( anti-hypertensive drug used in pregnancy ) 1% patients on alpha methyl dopa have clinically significant disease
          • various other drugs : e.g. NSAIDs; quinine/quinidine
        • viral infections ( usually in children )
  • 100. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Classification:
    • “ Cold” Autoimmune Hemolytic Anemia autoantibodies preferentially react at cold temperatures (4-18 o C)
      • chronic : typically cause is unknown ; WBC malignancies ( e.g. lymphoma ) may be a known cause ) acrocyanosis: dark, purple-grey discoloration of fingertips, toes, nose, and ears due to RBC agglutination at cold temperature
  • 101.  
  • 102. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Classification:
    • “ Cold” Autoimmune Hemolytic Anemia autoantibodies preferentially react at cold temperatures (4-18 o C)
      • acute: post-infectious
        • Mycoplasma pneumoniae ( primary atypical pneumonia ); Epstein Barr Virus
        • abrupt onset occurring during recovery; self limited; typically clinical findings of cold autoimmune hemolytic anemia not present
  • 103. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Diagnostic Findings:
    • POSITIVE DIRECT ANTIGLOBULIN TEST
    • ( direct Coomb’s test ): detection of autoantibodies on patient’s RBC
    • CBC:
      • mild –severe decrease in Hgb
      • increased reticulocyte count
    • cold agglutinin titer increased in cold autoimmune hemolytic anemia: e.g. acute, post-infectious autoimmune hemolytic anemias ( with Mycoplasma pneumonia )
  • 104. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Presentation of Autoimmune Hemolytic Anemias:
    • slight jaundice and scleral icterus; pallor
    • may have shortness of breath or dyspnea on exertion
    • splenomegaly ( enlarged spleen ) in many patients ( secondary to increased hemolysis in spleen ): occurs especially after several months of anemia
    • presentation can vary in mode of onset and severity :
      • gradual ; patients relatively asymptomatic
      • rapid development with severe anemia and severe symptoms e.g. high-output heart failure
  • 105. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Treatment: (of symptomatic, unstable disease )
    • Immunosuppressive therapy
    • a. corticosteroids (prednisone): first line therapy
    • b. cytotoxic drug therapy: cyclophosphamide: azathioprine
    • (if dependence on high dose of prednisone or bad side effects from steroid)
    • splenectomy: removes primary site of RBC destruction
    • If a drug is causing hemolysis, terminate drug
  • 106. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Treatment: (of symptomatic, unstable disease )
    • for rapidly developing and/or severe anemia:
    • 4. transfusion with packed RBC is needed
    • Hgb <7gm/dL (or higher in patient with preexisting cardiac disease):
    • Patient can develop high output cardiac failure and pulmonary edema, MI, and/or cardiac arrythymias due to severe hypoxemia
    • patient may also need oxygen therapy
  • 107. AUTOIMMUNE HEMOLYTIC ANEMIAS
    • Treatment:
    • 5. cold agglutinin disease: prevention - patients should avoid cold and dress warmly even in summer
  • 108.  
  • 109. PARASITIZATION OF RBC
    • malarial parasites: Plasmodium falciparum , vivax , malariae, or ovale
    • pathogenesis : cycles ( for reference only )
    • parasite is engulfed by RBC after binding RBC receptor  takes over RBC metabolic machinery  ingests Hgb  bursts out of RBC  cycle repeats again
  • 110.  
  • 111.  
  • 112. MECHANICAL CAUSES: SHEARING STRESS ON RBC
    • Macrovascular: prosthetic heart valves ( 10% artificial aortic prostheses ) turbulent blood flow through narrow openings occurs, causing RBC shearing (e.g. seen with paravalvular leaks)
    • anemia can be severe: 5-7gm/dL ; diagnostic findings of intravascular hemolysis are present ( increased reticulocyte count; decreased haptoglobin ; hemoglobinemia, and hemoglobinuria ); schistocytes ( fragmented RBCs ) are present
  • 113. MECHANICAL CAUSES: SHEARING STRESS ON RBC
    • Microvascular : “microangiopathic hemolytic anemia”
    • diseases with widespread formation of thrombi ( clots ) in microcirculation ; red blood cells are torn as they pass through clots 
    • fragments = schistocytes
    • 1. disseminated intravascular coagulation (DIC )
    • 2. thrombotic thrombocytopenic purpura – hemolytic uremic syndrome ( TTP – HUS )
  • 114.  
  • 115. CONCLUSION
    • DIC and TTP-HUS to be discussed in lecture on thrombotic complications
    • SUMMARY: CLASSIFICATION OF ANEMIAS BY MCV : pages 18-20
    • TABLE 1: USE OF IRON STUDIES TO DIFFERENTIATE BETWEEN:
    • Iron Deficiency Anemia; Anemia of Chronic Disease; Thalassemia Minor Page18
  • 116.  
  • 117. MCV<80 fL Iron Deficiency Chronic Disease Thalassemias Sideroblastic Anemias Lead intoxication MCV 80–100 fL  Reticulocyte >100 k/  L  Reticulocyte <100 k/  L Megaloblastic Hereditary Vit B 12 deficiency Folate deficiency Non-megaloblastic Schistocytes Autoimmune hemolytic anemia Malaria DIC TTP-HUS Prosthetic heart valves Acquired WBC PLT Normal Acute blood loss Early iron defic Chronic Dz Chronic renal failure Sickle cell anemia G6PD defic spherocytosis WBC &/or PLT Low Infection Medications Aplastic anemia Leukemia Hypersplenism Hypothyroidism Liver Dz Alcoholism Aplastic anemia Classification of Anemias by MCV MCV >100 fL No Yes
  • 118. IRON STUDIES nml or  serum iron & ferritin Normal TIBC
    • serum iron & ferritin
    •  TIBC
    find source of bleeding
    • serum iron
    • nml or  ferritin,  TIBC
    thalassemia minor  HgbA2 on electrophoresis Molecular studies beta thalassemia alpha thalassemia striking  MCV, mild  Hgb iron deficiency +  RDW chronic disease MCV 70 – 80fL bone marrow Bx ringed sideroblasts sideroblastic anemia  serum lead level lead intoxication basophilic stippling peripheral blood smear Work-up of Microcytic Anemias
  • 119. Work-up of Normocytic Anemias Absolute Retic Count < 100,000/  L IRON STUDIES SERUM FERRITIN  1 st then  Serum iron,  TIBC BONE MARROW BIOPSY RENAL FUNCTION TESTS normal or  ferritin  TIBC Find bleeding source early iron deficiency chronic disease HYPOCELLULAR VERY FATTY HYPERCELLULAR REPLACEMENT APLASTIC ANEMIA LEUKEMIA UA CHRONIC RENAL FAILURE ACUTE BLOOD LOSS
  • 120. SERUM HAPTOGLOBIN  25 mg/dL  serum LDH,  total bilirubin, indirect bilirubin HEMOLYTIC ANEMIAS Hemoglobin electrophoresis Direct antiglobulin (Coomb’s) test HbS other hemoglobinopathies HbC, HbSC, HbD etc. sickle cell anemia NEG POS Peripheral blood smear autoimmune hemolytic anemia POS NEG platelets  nml G-6-P-D deficiency spherocytosis heterozygotes homozygotes Nml CBC NEG POS Sickle RBC PT, PTT, D-dimers  nml Prosthetic heart valve DIC TTP - HUS schistocytes Work-up of Normocytic Anemias Absolute Retic Count > 100,000/  L
  • 121. MCV 80-100 fL megaloblastic + microcytic early megaloblastic Bone marrow Biopsy aplastic anemia >110 – 115 fL megaloblastic anemia Serum vitamin B 12 level Serum folate level < 200 pg/mL < 2 ng/mL Vitamin B 12 deficiency anti-intrinsic Factor Ab parietal cell Ab pernicious anemia Schilling test Folate deficiency alcohol abuse 100 – 110 fL  LFT TFT Liver disease hypothyroidism
    • retic count
    hemolytic anemias NEG POS Work-up of Macrocytic Anemias
  • 122. TABLE 2: USE OF IRON STUDIES TO DIFFERENTIATE BETWEEN: Iron Deficiency Anemia - Anemia of Chronic Disease - Thalassemia Minor NL NL or  NL or  Thalassemia Minor  NL or   Anemia of Chronic Dz    Iron Deficiency Anemia TIBC FERRITIN SERUM IRON
  • 123.