ANEMIA

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ANEMIA

• Brian L Penza, D.O.
• Philadelphia College of Osteopathic Medicine

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General Characteristics

• Anemia defined as reduction in Hct (volume of
  RBCs) or Hb concentration
• Etiology either decreased RBC production or
  increased RBC destruction/loss
• When RBC concentration decreases, compensatory
  mechanisms maintain O2 delivery to tissues
• Increased cardiac output
• Increased oxygen extraction ratio
• Right shift of oxyhemoglobin curve (increased
  2,3-DPG)
• Expansion of plasma volume

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Blood Transfusion?

• Not recommended unless
• Hb lt 7 g/dL
• OR
• Patient requires increased O2 carrying capacity
• Pt. with CAD or other comorbid cardiopulmonary
  disease
• If anemia develops rapidly, more likely to be
  symptomaticno time for compensatory mechanisms
  to kick in
• Gradual onsetsymptoms minimal or absent

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Clinical Features

• NonspecificHA, fatigue, dizziness, poor
  concentration, tinnitus, vertigo, irritability,
  insomnia, diarrhea, nausea, abdominal discomfort,
  pica, wt loss, angular chelitis, atrophic
  glossitis
• Exercise dyspnea, reduced exercise tolerance,
  syncope
• Pallorseen best in conjunctiva (also skin,
  palms, nail beds)
• Hypotension, tachycardia, palpitations, systolic
  ejection murmur, wide PP, bounding pulses
• Signs of underlying causejaundice (hemolytic
  anemia), heme stool (GI bleed)
• Femalesincreased bleeding or amenorrhea
• Malesdecreased libido, impotence

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Historical Findings

• Family Historyhemophilia, G6PD deficiency,
  thalassemia
• MedsNSAIDS, ASA, steriods, antiretrovirals,
  anticonvulsants, chemotherapy
• Past illnessesGI diagnosis/surgery, recent
  trauma/surgery, thyroid disease
• Chronic illnessesex. Renal failure, HIV
• Alcoholismfolate, vit B12, iron deficiency
• Toxin exposurelead, benzene
• Diet

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Diagnosis Labs

• Hb and Hct
• Hb 3 Hct
• 1 unit PRBCs increases Hb by 1 point, Hct by 3
  points
• Reticulocyte index indicates whether effective
  erythropoiesis is occurring in bone marrow
• Reticulocyte index gt 2 ?excessive RBC
  destruction or loss
• Reticulocyte index lt 2 ?inadequate RBC
  production
• Blood smear and RBC indices (MCV, MCH etc.)

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Diagnosing the Cause of Anemia

• Reticulocyte index lt 2
• Microcytic? MCV lt 80
• Iron deficiency, chronic disease, thalassemias,
  sideroblastic anemias
• Macrocytic? MCV gt 100
• Nuclear defect, liver disease, stimulated
  erythropoiesis
• Normocytic?
• Aplastic anemia, bone marrow fibrosis, tumor,
  chronic disease, renal failure
• Reticulocyte index gt 2
• Suspect acute blood loss
• Suspect hemolysis

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Microcytic Anemias

• DIFFERENTIAL DX
• Iron Deficiency Anemia
• Thalassemias
• Sideroblastic Anemia
• Lead poisoning
• Anemia of chronic disease (usually normocytic)

MCV lt 80 Check also MCH, MCHC, RDW Next Lab
tests?Iron studies Serum Iron
TIBC/transferrin Serum Ferritin, sat
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Iron Deficiency Anemia

• Most common cause of anemia worldwide
• Causes chronic blood loss, dietary deficiency,
  increased requirements
• Clinical features pallor, fatigue, weakness,
  dyspnea on exertion, orthostatic lightheadedness,
  hypotension (if acute), tachycardia

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Iron Deficiency Anemia

• DiagnosisIron studies
• Decreased serum ferritinmost reliable test
  available
• Increased TIBC (total iron binding
  capacity)/transferrin
• Decreased serum iron
• Microcytic, hypochromic
• RBCs on blood smear
• RDW is usually abnormal
• Alsoguaiac stool test,
• bone marrow biopsy
• (rare)

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Iron Deficiency Anemia

• TREATMENT
• Oral iron replacement (ferrous sulfate)
• Side effects constipation, nausea, dyspepsia
• IV or IM iron dextran
• If pt cannot tolerate PO, poor PO absorption, or
  greater requirements than PO can provide
• Blood transfusionNOT recommended unless anemia
  is severe or pt has cardiopulmonary disease

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Thalassemia

• Inherited disorders
• Classified according to deficient chain, severity
  varies based on mutations
• a-thalassemia
• ß-thalassemia
• Inadequate production of either the alpha- or
  beta-globin chain of Hb
• Microcytic, hypochromic
• RDW usually normal
• High RBC count
• Can see tear drop cells, target cells
• Normal or increased iron
• Dx by Hb electrophoresis

Thalassa means sea in Greek
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Sideroblastic Anemia

• Caused by abnormality in RBC iron metabolism
• Hereditary or acquired
• Acquired causes include drugs, lead exposure,
  collagen vascular disease, neoplastic disease
• Lab findings
• normal or increased serum iron and ferritin
• normal TIBC
• ringed sideroblasts in bone marrow
• normal RDW
• Treatment remove offending agents, consider
  pyridoxine (Vit.B6)

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Lead Poisoning

• One cause of sideroblastic
• anemia
• Common in children
• May cause microcytosis if lead
• level in blood gt100µg/dL
• (could also be normocytic)
• Can see basophilic stippling
• If lead levels 45-69µg/dL
• Find and remove lead source
• Administer EDTA 5.0mg/kg in two divided doses,
  slow IV infusion for 5 days, ample fluids
• AlternativeDMSAorally acting chelating agent,
  for use in children
• Use both agents if level gt69µg/dL

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Macrocytic Anemias

• DIFFERENTIAL DX
• Vitamin B12 Deficiency (MCVgt115)
• Folate Deficiency (MCVgt115)
• Liver disease (MCV up to 115)
• Stimulated erythropoiesis (MCV up to 110)

MCV gt 100 Next labs to check serum vit B12
serum folate serum homocysteine serum
methylmalonic acid Intrinsic factor Ab
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Vitamin B12

• Involved in 2 important reactions
• As a cofactor in homocysteine ? methionine
• As a cofactor in methylmalonyl CoA ? succinyl CoA
• Stores are plentiful in liver, can sustain
  individual 3 years or more
• Main sourcesmeat, fish
• Bound to intrinsic factor, absorbed in terminal
  ileum

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Vitamin B12 Deficiency

• Causesmost due to poor absorption
• Pernicious anemia (lack of intrinsic factor)
• Gastrectomy
• Poor diet
• Alcoholism
• Crohns disease, ileal resection
• Organisms competing for Vit B12
• If untreated can lead to demyelination in
  posterior columns, lateral corticospinal tracts,
  spinocerebellar tracts

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Vitamin B12 Deficiency

• Diagnosis
• Peripheral blood smearmacrocytic RBCs,
  hypersegmented neutrophils
• Low serum vitamin B12 (lt100pg/mL)
• Methylmalonic acid, homocysteine levels are
  elevated
• Shilling test
• Treatment
• Cyanocobalamin (vit B12) IM once per month

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Folate Deficiency

• Stores are limited, can become depleted over 3
  month period
• Main sourcegreen vegetables
• Causestea and toast diet, alcoholism, long
  term oral antibiotic use, increased demand,
  pregnancy, hemolysis, methotrexate use,
  anticonvulsants (phenytoin), hemodialysis
• Clinicalsimilar to Vit B12 deficiency, without
  the neurologic symptoms
• Treatdaily oral folic acid replacement

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Normocytic Anemias

• DIFFERENTIAL DX
• Anemia of chronic disease
• Aplastic Anemia
• Renal, liver, or endocrine disease

MCV 80 100 Next Labs Iron
studies Platelets, WBC counts LFTs TSH etc
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Anemia of Chronic Disease

• Chronic infection, inflammation or malignancy
• TB, lung abscess, HIV
• RA, SLE, or other autoimmune dz
• Malignancy
• Release of inflammatory cytokines suppresses
  erythropoiesis
• Hallmarkslow serum iron, low TIBC/transferrin,
  normal/increased ferritin
• Treat underlying process. Do not give iron.
  Anemia is usually mild.

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Aplastic Anemia

• Rare
• Low reticulocyte accompanied by pancytopenia
• Causes
• Idiopathic (majority)
• CongenitalFanconi anemia
• Radiation exposure
• Medschloramphenicol, sulfonamides, gold,
  carbamazepine
• Viral infectionhuman parvovirus, HepB, HepC,
  EBV, CMV, HZV, HIV
• Chemicalsbenzene, insecticides

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Aplastic Anemia

• Clinical
• Fatigue, dyspnea, petechiae, easy bruising,
  frequent infections
• Can transform into acute leukemia
• Diagnosis
• Bone marrow biopsydefinitivehypocellular
  marrow, absence of progenitors
• Treatment
• Bone marrow transplant, transfuse with PRBCs and
  platelets if necessary, immunosuppression

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Hemolytic Anemias

• Reticulocyte index gt 2
• From excessive RBC destruction or loss
• If erythropoiesis cannot keep up with
  destruction, anemia results
• Acute or chronic
• Abnormally shaped RBCs in peripheryspherocytes
  or fragmented RBCs (schistocytes and helmet
  cells)
• Increased LDH, elevated indirect bilirubin,
  decreased serum haptoglobin
• Sudden onset anemia, jaundice, splenomegaly
• Classified based on mechanism OR based on site of
  hemolysis

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Hemolytic Anemias

• Classified based on mechanism
• Due to factors external to RBC defects (most are
  acquired)
• Immune hemolysis
• Mechanical hemolysisprosthetic heart valves,
  microangiopathic hemolytic anemia
• Medications, burns, toxins, infection
• Due to intrinsic RBC defects (most are inherited)
• Hemoglobin abnormalitysickle cell, hemoglobin C
  disease, thalassemias
• Membrane defectsspherocytosis, paroxysmal
  nocturnal hemoglobinuria
• Enzyme defectsG6PD deficiency, pyruvate kinase
  deficiency
• Classified based on site of hemolysis
• Intravascularwithin circulation
• Extravascularprimarily in the spleen

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Hemolytic Anemias

• Sickle Cell Anemia
• Hereditary Spherocytosis
• Glucose-6-Phosphate Dehydrogenase Deficiency
• Autoimmune Hemolytic Anemia (AIHA)
• Paroxysmal Nocturnal Hemoglobinuria (PNH)

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Sickle Cell Anemia

• Autosomal recessiveHbA replaced by mutant HbS
• Under reduced O2 conditions, Hb molecules
  polymerize and RBCs sicklecauses vaso-occlusive
  crises in microcirculation
• Acidosis, hypoxia, temp changes, dehydration,
  infection
• Sickle trait
• Heterozygous
• 1 in 12 people of African descentalso in
  Italians, Greeks, Saudi Arabians
• Not anemic, live normal life
• Sickle cell disease
• Homozygous
• Survival correlates with frequency of
  vaso-occlusive crises
• gt3 crises/yearmedian age of death is 35
• Fewer crises a yearmay live into their 50s
• In general, reduces life expectancy by 25-30 years

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Sickle Cell Anemia

• Clinical features
• Severe, lifelong hemolytic anemiajaundice,
  pallor, gallstone disease, high-output heart
  failure, aplastic crises (provoked by parvovirus
  B19 infection)
• Painful bone crisesmost common
  manifestationmultiple sites
• Hand-foot syndrome (dactylitis)vascular necrosis
  of metacarpals/tarsals
• Acute chest syndromepulmonary infarcts
• Repeated splenic infarctions ? autosplenectomy
• Avascular necrosis of jointsmost common is hip
• Priaprism
• CVAs--children
• Ophthalmologic complications
• Renal papillary necrosis with hematuriacommon
  complication
• Chronic leg ulcerstypically over lateral
  malleoli
• Abdominal crisismimics acute abdomen
• Infectionsencapsulated bacteria H. influenzae,
  S. pneumoniae
• Osteomyelitis Salmonella
• Delayed growth and maturation

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Sickle Cell Anemia

• Diagnosis
• Peripheral smear, hemoglobin electrophoresis,
  newborn screening tests
• Treatment
• Avoid high altitudes, stay hydrated, treat
  infections promptly
• Early vaccinations
• Prophylactic penicillin
• Folic acid supplements (due to hemolysis)
• Manage painfluids, morphine, keep warm,
  supplemental O2
• Hydroxyureainterferes with sickling process
• Blood transfusionnot used unless necessary
  (acute chest syndrome, stroke, priaprism that
  doesnt respond, cardiac decompensation)
• Bone marrow transplantnot routinely performed,
  but may be more cost-effective in long run
• Gene therapy

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Hereditary Spherocytosis

• Autosomal dominant, defect in gene coding for
  spectrin and other RBC proteins
• RBCs are spherical, become trapped and destroyed
  in spleen
• Clinicalhemolytic anemia, jaundice,
  splenomegaly, gallstones, occasional hemolytic
  crises
• DiagnosisRBC osmotic fragility to hypotonic
  saline, elevated retic count, elevated MCHC,
  spherocytes on smear, direct Coombs negative
• Treatmentsplenectomy

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G6PD Deficiency

• X-linked recessive (affects men)
• Deficiency of G6PD results in accumulation of
  unneutralized H2O2, which denatures Hb,
  precipitating Heinz body formation within RBCs
• Heinz bodies attach to RBCs, making them more
  susceptible to sequestration by spleen
• Clinicaldrug-induced hemolytic anemia, dark
  urine, jaundice
• Sulfonamides, nitrofurantoin, primaquine,
  dimercaprol, fava beans, infection
• Diagnosisbite cells, Heinz bodies, deficient
  NADPH, G6PD normal or reduced
• Treatmentavoid drugs that precipitate hemolysis,
  maintain hydration, PRBC transfusion when
  necessary

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G6PD Deficiency
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Autoimmune Hemolytic Anemia

• Autoantibodies toward RBC membrane antigens
• Type of antibody (IgG or IgM) determines
  prognosis and treatment
• Warm AIHAIgG
• Binds optimally to RBC at warm temps37C
• Results in extravascular hemolysis?sequestration
  in spleen
• Causes idiopathic, 2 to lymphomas, leukemias,
  SLE, methydopa
• Cold AIHAIgM
• Binds optimally to RBC at cold temps0 to 5C
• Produces complement activation, intravascular
  hemolysis?sequestration in liver
• Causes idiopathic (elderly), infection (M.
  pneumoniae or infectious mononucleosis)

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AIHA

• Clinicalanemia, jaundice, hemolysis, underlying
  disease
• DiagnosisDirect Coombs test
• Positive test ? Warm AIHA
• Spherocytes may be present
• Treatmentoften no treatment necessary for
  either, hemolysis is mild
• Warm AIHAglucocorticoids, splenectomy,
  immunosuppression, RBC transfusions, folic acid
  supplements
• Cold AIHAavoid exposure to cold, RBC
  transfusions if necessary, chemotherapeutic
  agents, steroids NOT beneficial

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Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Acquired disorderaffects hematopoietic stem
  cells, and cells of all blood lineages
• Caused by deficiency of complement-inactivating
  anchor proteinsresults in complement-mediated
  lysis of RBCs, WBCs, platelets
• Clinicalchronic intravascular hemolysis,
  hemoglobinuria, elevated LDH, pancytopenia,
  thrombosis of venous systems (Budd-Chiari
  syndrome), abdom/back/musculoskel pain
• Diagnosis
• Hams test
• Sugar water test
• Flow cytometry of anchored cell surface proteins
  (CD55, CD59)more sensitive/specific for PNH
• TreatmentGlucocorticoids (prednisone), bone
  marrow transplant

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Systemic Disorder

• Anemia can be the first manifestation of a
  systemic disorder
• Look for other nonspecific complaintsfever,
  weight loss, anorexia, malaise
• Additional testsU/A, CXR, serum creatinine,
  LFTs, ESR