Anemia

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Anemia

• Blood Loss
• Acute
• Chronic
• IN-creased destruction (HEMOLYTIC)
• DE-creased production

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Hypoproliferative
Marrow damage gt Infiltration fibrosis gt
Aplasia gt Myelodysplasia gt Drug or radiation
injury Iron deficiency B12 deficiency Folate
deficiency Stimulus gt Inflammation gt
Endocrine defect gt Renal disease Hypersplenism
Clues from morphology
microcytic, normocytic, or macrocytic poikilocyto
sis anisocytosis nucleated red cells target
cells Howell-Jolly bodies hypersegmented polys
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Retics normal or increased
Hemorrhage and Hemolysis
Clues from morphology
Blood loss Hemolysis gt Antibody-mediated gt
Membrane defect gt Metabolic defect gt Red cell
fragmentation Hemoglobinopathy
microcytic, normocytic, or macrocytic red cell
fragmentation red cell clumping nucleated red
cells target cells
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Features of All Anemias

• Pallor, where?
• Tiredness
• Weakness
• Dyspnea, why?
• Palpitations
• Heart Failure (high output), why?

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Blood Loss

• Acute
• Trauma
• Chronic
• Lesions of gastrointestinal tract, gynecologic
  disturbances. The features of chronic blood loss
  anemia are the same as iron deficiency anemia,
  and is defined as a situation in which the
  production cannot keep up with the loss.

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Hemolytic

• Hereditary
• MEMBRANE disorders e.g., spherocytosis
• ENZYME disorders e.g., G6PD deficciency
• HGB disorders (hemoglobinopathies)
• Acquired
• MEMBRANE disorders (PNH)
• ANTIBODY MEDIATED, transfusion or autoantibodies
• MECHANICAL TRAUMA
• INFECTIONS
• DRUGS, TOXINS
• HYPERSPLENISM

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Impaired Production

• Disturbance of proliferation and differentiation
  of stem cells aplastic anemias, pure RBC
  aplasia, renal failure
• Disturbance of proliferation and maturation of
  erythroblasts
• Defective DNA synthesis (Megaloblastic)
• Defective heme synthesis (Fe)
• Deficient globin synthesis (Thalassemias)

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Modifiers

• MCV, microcytosis, macrocytosis
• MCHC, hypochromic
• RDW, anisocytosis

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Hemolytic Anemias

• Life span LESS than 120 days
• Marrow hyperplasia (ME), EPO
• Increased catabolic products, e.g., bilirubin,
  serum HGB, hemosiderin

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Hemolysis

• INTRA-vascular (vessels)
• EXTRA-vascular (spleen)

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ME Ratio normally 31
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HEREDITARY SPHEROCYTOSIS
Genetic defects affecting ankyrin, spectrin,
usually autosomal dominant Children,
adults Anemia, hemolysis, jaundice,
splenomegaly, gallstones
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Glucose-6-Phosphate Dehydrogenase (G6PD)
Deficiency
A- and Mediterranean are most significant types
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Features of G6PD Defic

• Genetic Recessive, X-linked
• Can be triggered by foods (fava beans), oxidant
  substances drugs (primaquine, chloroquine), or
  infections
• HGB can precipitate as HEINZ bodies
• Acute intravascular hemolysis can occur
• Hemoglobinuria
• Hemoglobinemia
• Anemia

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Sickle Cell Disease

• Classic hemoglobinopathy
• Normal HGB is a2 ß2 ß-chain defects
  (Val-gtGlu)
• Reduced hemoglobin sickles in homozygous
• 8 of American blacks are heterozygous

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Clinical features of HGB-S disease

• Severe anemia
• Jaundice
• PAIN (pain CRISIS)
• Vaso-occlusive disease EVEREWHERE, but
  clinically significant bone, spleen
  (autosplenectomy)
• Infections Pneumococcus, Hem. Influ., Salmonella
  osteomyelitis

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THALASSEMIAS

• A WIDE VARIETY of diseases involving GLOBIN
  synthesis, COMPLEX genetics
• Alpha or beta chains deficient synthesis involved
• Often termed MAJOR or MINOR, depending on
  severity, silent carriers and traits are seen
• HEMOLYSIS is uniformly a feature, a microcytic
  anemia
• A crew cut skull x-ray appearance may be seen

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Hemoglobin H Disease

• Deletion of THREE alpha chain genes
• HGB-H is primarilly Asian
• HGB-H has a HIGH affinity for oxygen
• HGB-H is unstable and therefore has classical
  hemolytic behavior

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Hydrops Fetalis

• FOUR alpha chain genes are deleted, so this is
  the MOST SEVERE form of thalassemia
• Many/most never make it to term
• Children born will have a SEVERE hemolytic anemia
  as in the erythroblastosis fetalis of Rh disease
• Pallor (as in all anemias)
• Edema (hence the name hydrops)
• Massive hepatosplenomegaly (hemolysis)

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Paroxysmal Nocturnal Hemoglobinuria (PNH)
GlycosylphosPhatidylInositol

• ACQUIRED, NOT INHERITED like all the previous
  hemolytic anemias were
• ACQUIRED mutations in phosphatidylinositol glycan
  A (PIGA)
• It is P and N only 25 of the time

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Immunohemolytic Anemia

• All of these have the presence of antibodies
  and/or compliment present on RBC surfaces
• NOT all are AUTOimmune, some are caused by drugs

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IMMUNOHEMOLYTIC ANEMIAS

• WARM (IgG), will NOT hemolyze at room temp
• Primary Idiopathic (most common)
• Secondary (Tumors, especially leuk/lymph, drugs)
• COLD AGGLUTININS (IgM), WILL hemolyze at room
  temp
• Mycoplasma pneumoniae, HIV, mononucleosis
• COLD HEMOLYSINS (IgG) Cold Paroxysmal
  Hemoglobinuria, hemo-LYSIS in body, ALSO often
  follows mycoplasma pneumoniae

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Coombs Test

• DIRECT Patients CELLS are tested for surface
  Abs
• INDIRECT Patients SERUM is tested for Abs.

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Direct anti-globulin test
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HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA

• Mechanical heart valves breaking RBCs
• MICROANGIOPATHIES
• TTP
• Hemolytic Uremic Syndrome

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NON-Hemolytic Anemiasi.e., DE-creased Production

• Megaloblastic Anemias
• B12 Deficiency (Pernicious Anemia)
• Folate Deficiency
• Iron Deficiency
• Anemia of Chronic Disease
• Aplastic Anemia
• Pure Red Cell Aplasia
• OTHER forms of Marrow Failure

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MEGALOBLASTIC ANEMIAS

• Differentiating megaloblasts (marrow) from
  macrocytes (peripheral smear, MCVgt94)
• Impaired DNA synthesis
• For all practical purposes, also called the
  anemias of B12 and FOLATE deficiency
• Often VERY hyperplastic/hypercellular marrow

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• Decreased intake
• Inadequate diet, vegetarianism
• Impaired absorption
• Intrinsic factor deficiency
• Pernicious anemia
• Gastrectomy
• Malabsorption states
• Diffuse intestinal disease, e.g., lymphoma,
  systemic sclerosis

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• Ileal resection, ileitis
• Competitive parasitic uptake
• Fish tapeworm in
• Fish tapeworm infestation
• Bacterial overgrowth in blind loops and
  diverticula of bowel
• Increased requirement
• Pregnancy, hyperthyroidism, disseminated cancer

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Vit-B12 Physiology

• Oral ingestion
• Combines with INTRINSIC FACTOR in the gastric
  mucosa
• Absorbed in the terminal ileum
• DEFECTS at ANY of these sites can produce a
  MEGALOBLASTIC anemia

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Please remember that ALL megaloblastic anemias
are also MACROCYTIC (MCVgt94 or MCV100), and
that not only are the RBCs BIG and
hyperplastic/hypercellular, but so are the
neutrophils, and neutrophilic precursors in the
bone marrow too, and even more so,
HYPERSEGMENTED!!!
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PERNICIOUS ANEMIA

• MEGALOBLASTIC anemia
• LEUKOPENIA and HYPERSEGS
• JAUNDICE
• NEUROLOGIC posterolateral spinal tracts
• ACHLORHYDRIA
• Cant absorb B12
• LOW serum B12
• Flunk Schilling test, i.e., cant absorb B12,
  using a radioactive tracer

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FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS

• Decreased Intake diet, etoh-ism, infancy
• Impaired Absorption intestinal disease
• DRUGS anticonvulsants, BCPs, CHEMO
• Increased Loss Hemodialysis
• Increased Requirement Pregnancy, infancy
• Impaired Usage

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APLASTIC ANEMIAS

• ALMOST ALWAYS involve platelet and WBC
  suppression as well
• Some are idiopathic, but MOST are related to
  drugs, radiation
• FANCONIs ANEMIA is the only one that is
  inherited, and NOT acquired
• Act at STEM CELL level, except for pure red
  cell aplasia

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APLASTIC ANEMIAS
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APLASTIC ANEMIAS

• CHLORAMPHENICOL
• OTHER ANTIBIOTICS
• CHEMO
• INSECTICIDES
• VIRUSES
• EBV
• HEPATITIS
• VZ

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MYELOPHTHISIC ANEMIAS

• Are anemias caused by metastatic tumor cells
  replacing the bone marrow extensively

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Fe Deficiency Anemia

• Due to increased loss or decreased ingestion,
  almost always, in USA, nowadays, increased loss
  is the reason
• Microcytic (low MCV), Hypochromic (low MCHC)
• THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD,
  because FE is recycled!

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Fe Transferrin Ferritin (GREAT test) Hemosiderin
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Regulation of iron absorption
Gut lumen
Heme Fe
DMT1
Enterocyte
Ferritin


Fe
Fe
MTP1
Enterocyte precursor
Plasma transferrin
Transferrin Receptor
HFE
Hepcidin
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Gastrointestinal absorption 1 mg/day
Functional iron Blood, marrow, myoglobin 2 grams
Storage iron Liver, RES 1 gram
Plasma transferrin 2 mg
Daily physiologic loss 1 mg
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Clinical Fe-Defic-Anemia

• Adult men GI Blood Loss
• PRE menopausal women menorrhagia
• POST menopausal women GI Blood Loss

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2 BEST lab tests

• Serum Ferritin
• Prussian blue hemosiderin stain of marrow (also
  called an iron stain)

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Iron stores
Erythron iron
Marrow iron stores 1 - 3 0 - 1 0 0
Ferritin 50 - 200 lt20 lt15 0
TIBC 300 - 360 gt360 gt380 gt400
Serum iron 50 - 150 50 - 150 lt50 lt30
Red cells normal normal normal microcytic, hypochromic
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Serum transferrin receptor
Storage iron 107 mg
Storage iron 335 mg
Storage iron 1,102 mg
Serial measurement of sTfr during phlebotomy in 3
individuals
Goodnough, Skikne, Brugnara. Blood, 2000 96 823
- 833
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Ratio of serum transferrin receptor to ferritin
as a measure of total body iron
Cook, Flowers, Skikne. Blood 2003 101 3359 - 64
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Serum ferritin and total body iron
Kaltwasser, Gottschalk. Kidney Int. 1999
55(suppl) S49 - S56
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Treatment of iron def anemia

• Oral iron is the preferred initial treatment
• Recommended daily dose is 150-200mg/day of
  elemental iron
• 325 mg of ferrous sulfate contains 65 mg of
  elemental iron
• One table three times a day
• Administer iron on an empty stomach with half a
  glass of OJ or 250mg ascorbic acid

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Serum iron after oral iron in patients with iron
deficiency
80
60
Serum iron
40
20
1
2
3
4
Hours
WH Crosby, Arch Int Med circa 1970
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Safety of intravenous iron
Sodium ferric gluconate in sucrose
(Ferrlecit) Available in Europe gt 30 years 2.7 x
106 doses/year in Germany Italy in 1995 Iron
dextran (Imferon until 1992, InFed since 1992) 3
x 106 doses/year in US in 1996
Faich, Strobos. Am J Kidney Dis 1999 33(3)464-70
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Safety of intravenous iron
Reported severe adverse reactions (1976 -
1996) SFGS 3.3 severe allergic reactions/106
doses, no fatalities ID 8.7 severe allergic
reactions/106 doses, 31 fatalities
Faich, Strobos. Am J Kidney Dis 1999 33(3)464-70
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Safety of intravenous iron
Other theoretical risks iron overload sepsis a
cceleration of atherosclerosis
Faich, Strobos. Am J Kidney Dis 1999 33(3)464-70
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Medicare warning (
Recombinant human erythropoietin is approved only
for treatment of anemia caused by renal failure
or by cancer treatment and for certain
hematologic malignancies. Sodium ferric
gluconate in sucrose is approved only for
treatment of anemia in patients on hemodialysis
and for patients who have had a severe reaction
to iron dextran.
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Anemia of Chronic Disease

• CHRONIC INFECTIONS
• CHRONIC IMMUNE DISORDERS
• NEOPLASMS
• LIVER, KIDNEY failure

Please remember these patients may very very
much look like iron deficiency anemia, BUT, they
have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!
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Anemia of chronic disease
Typical lab findings Serum iron lt 50 TIBC lt
150 Normochromic or hypochromic red
cells Normal ferritin Normal serum transferrin
receptor
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Anemia of chronic disease
Mechanisms blunted erythropoietin
response diminished response of erythroid
precursors to erythropoietin decreased delivery
of iron from RES, increased intracellular
ferritin in macrophages decreased
gastrointestinal iron absorption
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Anemia of chronic disease
Mediators IL-1 IL-6 g-interferon TNF-a
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Anemia of chronic disease
Inflammation Tissue necrosis Infection Neoplasia C
ongestive heart failure Acute myocardial
infarction
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