General Principles

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					Minimal Requirement for
 Concepts of Anemia
       Dec 12, 2009
Erythrocyte Development

         EPO: 90% from kidney
              10% from liver

Fe + protoporphyrin    α2β2
    ↓                  ↓
      heme +       globin
Two main approaches for anemia that are
  not mutually exclusive:

         1. Kinetic approach
         2. Morphological approach
Kinetic approach of Anemia

  Production?   Survival/ Destruction?

       The key test is the …..
   Reticulocyte Production Index—
    an estimate of marrow production relative to normal

Corrected   Ret= Ret(%) *
        Corrected Ret
        Maturation index
         RPI (kinetic approach)

• RPI are the most helpful:
  – extremely low (<0.1%)
     • AA/ PRCA are the first considerations

  – extremely high (>3%)
     • Blood loss/ hemorrhage
     • Hemolytic anemia (although 25% AIHA have normal RPI)
  Morphological Approach-1
MCV>115                   MCV 100 - 115
• Vit B12, Folate         • Ditto
• Drugs that impair DNA   • Reticulocytosis
  synthesis (AZT,         • Hypothyroidism
  chemotherapy,           • Alcoholism/ liver dz
 Morphological Approach-2
Normocytic (MCV 80-100)   Microcytic (MCV<80)
• Anemia of chronic       • Iron deficiency anemia
  disease (ACD)           • Thalassemia
• Mixed deficiencies      • Anemia of chronic
• Renal failure             disease (ACD, 30-40%)
• BM dz (ex AA, MDS,      • Sideroblastic anemia
  MM…)                    • Pb intoxification
Iron and IDA
 of Iron in
Storage iron Circulating iron  RBC iron  Tissue iron
Harrison’s Principles of Internal Medicine 15th Ed. 2001
             IDA Presentation
Presentation               Diagnosis
• Progressive MCV ↘        • Ferritin: low (N=20-300)
• Progressive RBC ↘        • Iron/TIBC <16% (N=~33%)
• Typically high RDW
• Typically high MCV/RBC   • BM iron stain
• Typically mild PLT ↑
                         Causes of IDA
Increased iron requirement               Inadequate iron supply
•   Hypermenorrhea                       •   Poor nutritional intake
•   GI blood loss– hemorrhoid, PUD, GI   •   Malabsorption
    cancer, angiodysplasia
                                         •   Gastrectomy (may also has Vit B12
•   Factitious removal                       deficiency)
•   Hemolysis
•   Hemodialysis
•   Hookworm infestation

•   Rapid growth of teenage
•   Pregnancy and lactation
                Iron Supply
• Oral: usually 3 months to restore iron storage
  – Ferrum chewable (Fe 3+) 100mg/tab
  – Hematonic (Fe 2+) 50mg/tab

• IV
  – Atofen (!! Risk of allergy and anaphylaxis—0.6%)
Hb Gene

   Harrison’s Principles of Internal Medicine 15th Ed. 2001
        Thalassemia Presentation
Presentation                  Diagnosis
• Constant low MCV           • Exclude IDA
• Constant high RBC
• Typically low RDW          • Hb electrophoreis:
• Typically low MCV/RBC         – Hb A2>3.5% or HbF>2%  β-
• Typically iron storage ↗
                                – HbH(+)  α-thalassemia with ¾
                                  defect (HbH dz)
                                – HbA2 and HbF: N 
                                  α-thalassemia with ¼ or 2/4 defect

                             • Gene diagnosis
  Gene Level of Thalassemia in Taiwan
• α-thalassemia: Prevalence 4%
   –   --SEAα0 deletion
   –   -α3.7 deletion
   –   -α4.2 deletion
   –   HbQS or HbCS

• β-thalassemia: Prevalence 2%
   –   Codon 41/42 TCTT deletion β0
   –   IVS II 654 C-> T point-mutation β0
   –   Codon 17 A-> T β0
   –   Promoter 28 A-> G β+
   –   HbE (Codon 26 G-> A) β+

• ??% α + β-thalassemia (Severity?)
   β –Major (終身輸血)

           Hb H disease (黃疸)

           Hydrops fetalis (死胎)
         Thalassemia Treatment
• Mild: None

• Severe:
   – Folic acid
   – RBC transfusions + iron chelators
   – Allo-SCT
Comparison of Iron Chelators
          Deferasirox (Exjade)
• Common adverse effect:
   –   Cre elevation (40%), (ref. 14% in DFO)
   –   Proteinuria (18%)
   –   GI (abd pain, N/V, diarrhea, 10-15%)
   –   Hepatitis (8%)
   –   Headache (15%), skin rash (11%)
   –   No agranulocytosis, neutropenia or arthralgia

• Pregnancy safety:
   – FDA category B

Megaloblastic Anemia
    Megaloblastic Anemia Presentation
    Presentation                      Diagnosis
•    High high MCV                   • ??Schilling test
•    Pancytopenia
•    Hypersegmented PMN
                                     • Low Vit B12 or folic acid
•    Typically high RPI, hemolysis
     (LDH ↗), indirect                  – Vit B12: 270~400: empirical try
     hyperbilirubinemia                 – Vit B12< 270: definite deficiency

• Tinnitus or other neurological
• Vegetarism (奶, 蛋, 維他命)
• Gastrectomy or Pernicious anemia
        Remember Pancytopenia
•   P: PNH
•   A: Asplatic anemia
•   N: Neoplasm/ Near neoplasm (including MDS)
•   C: Cirrhosis/ Connective tissue disease
•   Y: Vit B12/ Folic acid
•   T: Toxin/ Drug
•   O: Overwhelming sepsis (Hemophagocytic
    syndrome)/ Others

Vit B12/Folate Deficiency Anemia
• Vit B12 deficiency:
   – Vit B12 1 mg im qd *5 q1wk *4  q1m*3  q6m
   – R/I pernicious anemia
     (Anti-parietal Ab, anti-IF Ab and PES)
      • Thyroid dz
      • Gastric cancer

• Folate deficiency: Improved diet, folic acid
   Usually rapid response
Most important F/U Reticulocyte, LDH

                  Harrison’s Principles of Internal Medicine 15th Ed. 200
Hemolytic Anemia
             Is there hemolysis?
• Damaged RBCs on smear
     • spherocytes (immune hemolysis, HS)
     • RBCs fragments (microangiopathic anemias)

• Marrow response to hemolysis
     • polychromasia on smear
     • reticulocytosis
     • erythroid hyperplasia in marrow

• Biochemical evidence of RBCs destruction
     • Indirect hyperbilirubinemia
     • increased LDH
     • decreased/absent haptoglobin
Extravascular vs Intravascular hemolysis
                    Extravascular   Intravascular
Test                Hemolysis       Hemolysis

LD                                   

bilirubin                            

haptoglobin         N to absent     absent

hemoglobinuria        absent        present

free Hb in plasma     absent        present

urine hemosiderin     absent        present
An approach to hemolytic anemia
        Hemolytic anemia

Immune                      Non-immune

                 Congenital                  Acquired
• Autoimmune     Defects of:                 • PNH
                 •Membrane/ skeleton         • Infections
• Alloimmune     (eg. Hereditary spherocytosis) sepsis
• Drug-induced   •Enzymes
                 (eg. G6PD deficiency)       • Mechanical
                                               Prosthetic heart valve
                 • Hemoglobinopathy            Microangiopathic HA
                                                (TTP, HUS, DIC)

                  AIHA and DAT reactions
           Anti-IgG    Anti-C3d   %    Note
I          +           -          35   因RBC上的Ag不夠多,無法接上補體
II         +           +          56   Typical case
III        -           +          9    1.可能因為Ab不是IgG,如IgM or IgA
                                       2.Ab可能是cold-reacting, ex. DL Ab (PCH)
                                       3.Low affinity Ab
IV         -           -          <1

                IgM                               IgG
    Cold        CAD (第二常見)                        PCH (DL-Ab)
                infection, WM, AILD,
                lymphoma, CLL, malignancy
    Warm        Rare                              最常見, 分為Idopathic及
                                                  secondary –lymphoma,
                                                  autoimmune, viral, other
                                                  malignancy, HIV
                                  D/D of AIHA
                  Warm AIHA                                          Cold AIHA
  RBC’s coated with IgG, Fix complement poorly     RBC’s coated with IgM which fixes complement
(usually C3 only)

Younger age                                      Older age

extravascular hemolysis                          Intravascular hemolysis
(Spleen is primary site of destruction)          (Liver is primary site of destruction)

Spherocytes on PB smear                          Agglutination on PB smear

 70% associated with other illnesses               90% associated with other illnesses

 Treatment: steroids, Splenectomy                  Treatment: avoidance of cold
 Rituximab                                         Poor response to steroids, splenectomy
 Immunosuppressants                                Rituximab
                                                   Plasmapheresis in refractory cases
     Hepcidin and
Anemia of Chronic Disease
       D/D of ACD and IDA
  Lab measure               ACD              IDA

   Plasma Fe         Reduced (normal)      Reduced

Plasma transferrin   Reduced (normal)      Increased

 Transferrin sat.    Reduced (normal)      Reduced

 Plasma ferritin     Increased (normal)*   Reduced

   Plasma TfR              Normal          Increased

  TfR/log ferritin        Low (<1)         High (>4)

ACD may concurrently coexist
with true iron deficiency
(In this situation, iron/TIBC is
more reliable than ferritin)
ACD Treatment