ANEMIAS: HA and Hemoglobinopathies by Y2038O

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									            ANEMIAS




7/19/2012    Dr. Alka Stoelinga   1
                            Hemolysis



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 Hemolysis
Evidences of hemolysis
High colored urine
High colored stool
Anemia maybe +/-
Jaundice may be +/-
Excess urobilinogen in urine
High reticulocyte and normoblastic count
High lDH
High uric acid
Low haptoglobulin
Low hemopexin
Chr- Hemosideronuria

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 Intravascular hemolysis
• Rapid cell destruction
1.  Free Hb released in plasma
• Haptoglobin produced by liver
• Binds with free Hb and is degraded in liver
• Once Haptoglobins (Are reduced) are saturated,
2.  Free Hb is oxidised
• Methemoglobin + Albumin
• Methemalbumin- degraded
3.  Any Free Hb is bound to Haemopexin
4.  If all of these mechanisms are saturated/ overloaded, Free Hb
    urine
• When fulminant black urine (Falci. malaria)
• In smaller amt Renal tubular cells absorb Hb, degrade it and store
  iron as hemosiderin
• Subsequently tubular cells- sloughed- urine- hemosideriuria

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 Extravascular hemolysis

• Physiological Red cell destruction in RE cells in
  liver, spleen
• Haptoglobulins are normal or slightly reduced




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                               Features of Hemolysis

                                   Blood film



 Spherocytosis                         No Spherocytosis          Fragmentation


                                               •Hereditary
DCT+                  DCT-                                          •Microangiopathic
                                               • Enzymopathies
                                                                    • Traumatic
•Autoimmune
hemolysis
               •H. spherocytosis      •Malaria
                                      •Clostridium




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Congenital hemolysis


• RBC membrane defects (hereditary spherocytosis/ Elliptocytosis)
• G6PD deficiency
• Hemoglobinopathies




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Red cell membrane defect
• Defect in cytoskeleton
• Usually due to quantitative or functional
  deficiency of one or more proteins in
  cytoskeleton
• Cells loose their normal elasticity
• Each time they pass through spleen, they lose
  membrane relative to their cell volume
   Raised MCHC
  Abnormal shape
  Reduced cell survival (EVH)
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Hereditary Spherocytosis
• Autosomal dominant trait
• 25% have no family history
• Abnormalities in Beta spectrin and ankyrin
   Hemolytic crisis- when severity of hemolysis
  increases
   Megaloblastic crisis- follows folate deficiency
   Aplastic crisis- Parvovirus infection
• Presents with severe anemia and low
  reticulocyte counts
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 Investigations
• Blood picture- presence of spherocytes
• DCT –ve
• Osmotic fragility test- Increased sensitivity to lysis in
  hypotonic saline solution

Treatment
• Folic acid prophylaxis 5mg once weekly
• Blood transfusion after cross matching
• Consider splenectomy
     –   Growth retardation in children
     –   Recurrent severe crisis
     –   Death of a family member from the disease
     –   Symptomatic cholecystitis

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G6PD deficiency
• HMP shunt
• NADPH – protects red cells against oxidative stress
• G6PD deficiency Impairs production of NADPH
• Affects male; females are carriers
Clinical Features:
• Acute drug induced hemolysis
• Chronic compensated hemolysis
• Infection or acute illnesses
• Neonatal jaundice
• Favism (Vicia fava/ broad beans)
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Investigations
• Evidence of nonspherocytic intravascular
  hemolysis
• Bite cells, blister cells, irregular small cells
• Polychromasia reflecting reticulocytosis
• If stained with methyl violet- denaturated Hb is
  visible as Heinz bodies within RBC cytoplasm
• G6PD levels- low
Treatment
• Stop precipitating drugs
• Acute transfusion support- life saver
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 Autoimmune Hemolytic Anemia
• Red cell autoantibodies RBC destruction
• IgG/ M, rarely IgE or A
CLASSIFICATION
• Optimal temperature at which the antibody is active is
  used to classify AHA
• 1. Warm antibodies
     –   bind best at 37⁰C
     –   Majority are IgG
     –   React against Rh antigens
     –   80% of cases
• 2. Cold antibodies
     – Bind best at 4⁰C but can bind upto 37⁰C
     – Majority are IgM and bind compliment
     – 20% of cases
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Warm autoimmune hemolysis

• Middle aged females
Causes
• Idiopathic (50%)
• Others
            Lymphoid neoplasia                    Lymphoma; CLL; Myeloma

            Solid tumors                          Lung; Colon; Kidney; Ovary;
                                                  thymoma

            Connective tissue disease             SLE; RA

            Drugs                                 Methyldopa; Mefenamic acid;
                                                  Penicillin; Quinine

            Miscellaneous                         UC; HIV


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Investigations
• Hemolysis and spherocytes
• DCT/ Antiglobulin test

Treatment
• Manage underlying condition
• Stop offending drugs
• Prednisolone 1mg/kg
• Blood transfusion after cross matching
• Splenectomy to be considered
• Immunosuppressive therapy- Azathioprim/
  Cyclophosphamide
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Cold Agglutinin disease
• IgM binds red cells at 4⁰C and cause them to
  agglutinate
• Low grade intravascular hemolysis- cold, painful,
  blue fingers, toes, ears, nose (acrocyanosis)
• Blood film- red cell agglutination
• MCV- raised
• IgM
Treatment
• Keep extremities warm during winter
• Steroids
• Cross matching and blood transfusion
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• The Direct Coombs test, is used to test for autoimmune hemolytic
  anemia.
• In certain diseases or conditions an individual's blood may contain IgG
  antibodies that can specifically bind to antigens on the red blood cell
  (RBC) surface membrane, and their circulating red blood cells (RBCs)
  can become coated with IgG alloantibodies and/or IgG autoantibodies
• Complement proteins may subsequently bind to the bound
  antibodies.
• The direct Coombs test is used to detect these antibodies or
  complement proteins that are bound to the surface of red blood cells
• Procedure:
• A blood sample is taken and the RBCs are washed (removing the
  patient's own plasma) and then incubated with antihuman globulin
  (also known as "Coombs reagent"). If this produces agglutination of
  RBCs, the direct Coombs test is positive, a visual indication that
  antibodies (and/or complement proteins) are bound to the surface of
  red blood cells



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            Hemoglobinopathies-
             Sickle cell anemia

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Hemoglobin
• Hb has 4 globin chains
• Each containing an iron containing porphyrin
  pigment called haem
• Globin chains- 2α + 2non α chains
• Hb A ααββ (90-97%)
• HbF ααγγ (Fetus, 1%)
• HbA2 ααδδ (2%)



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Abnormalities
1. Alteration in the amino acid structure of
   polypeptide chains of globin fraction of Hb
    – E.g.: Hb S
2. Amino acid sequence is normal but
   polypeptide chain production is impaired or
   absent
    – E.g. Thalassaemias




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Sickle cell anemia
• Single glutamic acid Valine substitution at
  position 6 of beta globin polypeptide chain
• Inherited as autosomal recessive trait
• Homozygotes produce abnormal beta chains
  that make HbS/ SS
    – Results in clinical syndrome called Sickle cell disease
• Heterozygotes produce a mixture of normal and
  abnormal beta chains that make HbA and HbS/
  AS
    – Clinically asymptomatic sickle cell disease
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Pathogenesis
• When Hb S is deoxygenated, molecules of Hb
  polymerize to form pseudocrystalline structures
  called Tactoids
• These distort the RC membrane and produce
  characteristic sickle-shaped cells
• Polymerization is reversible when reoxygenated
• Permanent Distortion leads to Irreversibly
  Sickled red cells


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Note
• Sickling is precipitated by:
    – Hypoxia
    – Acidosis
    – Dehydration
    – Infection
• Irreversibly sickled cells have shortened survival
• Plugs the vessels in microcirculation
• This results in a no. of acute syndromes called
  crisis and chronic organ damage

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Clinical Features
1. Vaso Occlusive crisis (Most common)
• Acute severe bony pain
    – Affects areas of active marrow
    – Hands and feet in children
    – Femora, humeri, ribs, pelvis and vertebrae in adults
• Systemic response:
    – Tachycardia
    – Sweating
    – Fever

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Clinical Features
2. Sickle chest syndrome:
• Follow vaso-occlusive crisis
• Most common cause of death in Adult sickle
   cell disease
a) Bone marrow infarction leads to fat emboli to
   lungs
b) Ventilatory failure



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    Clinical Features
3.      Sequestration crisis
•       Thrombosis of venous outflow from organ
•       Loss of function
•       Acute pain
•       Spleen (Children)
•       Massive Splenomegaly severe anemia
        circulatory collapse death
•       Recurrent Sickling in spleen in children
        infarction
•       In adults No functional spleen
•       Capsular stretching Liver sequestration
        Severe pain
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Clinical Features
4. Aplastic crisis
• Infection in adult sicklers with Parvovirus B19
• Results in severe but self limiting red cell
   aplasia
   – Very low Hb
   – Heart failure
   – Reticulocytes- “low”




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    Investigations
•     Hb- low (6-8g/dl)
•     Blood film- sickled cells with target cells
•     Features of hyposplenism
•     Reticulocytosis
•     HbS (Na dithionite)
•     Hb electrophoresis
        – No Hb A
        – 2-20% Hb F
        – Predominance of Hb S
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    Treatment
•     Prophylactic folic acid supplementation
•     Penicillin V
•     Pneumococcal, Haemophilus, hep B vaccination
•     Vaso-occlusive crisis
•     Aggressive rehydration
•     O2
•     Analgesics
•     Antibiotics
•     Blood transfusion- full genotyped
•     Hydroxyurea
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            Hemoglobinopathies-
               Thalassaemia



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  Thalassaemias
• Thalassaemia is an inherited impairment of hemoglobin production, in
  which there is partial or complete failure to synthesize a specific type
  of globin chain
• In Thalassaemia the genetic defect, which could be either mutation or
  deletion, results in reduced rate of synthesis or no synthesis of one of
  the globin chains that make up hemoglobin.
• This can cause the formation of abnormal hemoglobin molecules, thus
  causing anemia, the characteristic presenting symptom of the
  Thalassaemias.

TYPES
• α Thalassaemia

• β Thalassaemia
     – Homozygous- Beta Thalassaemia major
              • β⁰- no β gene
              • β⁺- few β gene
     – Heterozygous- Beta Thalassaemia minor

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 Pathophysiology
• Normal hemoglobin is composed of two chains each of α and β
  globin.
• Thalassemia patients produce a deficiency of either α or β globin,
  unlike sickle-cell disease which produces a specific mutant form of β
  globin.
• The thalassemias are classified according to which chain of the
  hemoglobin molecule is affected.
• In α thalassemias, production of the α globin chain is affected
• In β thalassemia production of the β globin chain is affected.
• β globin chains are encoded by a single gene on chromosome 11
• α globin chains are encoded by two closely linked genes on
  chromosome 16.
• Thus in a normal person with two copies of each chromosome, there
  are two loci encoding the β chain, and four loci encoding the α chain.
• Deletion of one of the α loci has a high prevalence in people of
  African or Asian descent, making them more likely to develop α
  thalassemias.
• β thalassemias are common in Africans, but also in Greeks and
  Italians.
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α Thalassaemia
• α thalassemias result in decreased alpha-globin production,
  therefore fewer alpha-globin chains are produced
• Resulting in an excess of β chains in adults and excess γ chains in
  newborns.
• The excess β chains form unstable tetramers (called Hemoglobin H
  or HbH of 4 beta chains)
SUMMARY
• Reduced or absent production of alpha chain
• Chromosome 16
• 2 alpha gene loci
• Hence, 4 alpha genes
• If 1 is deleted- No clinical effect
• If 2 are deleted- mild hypochromic anemia
• If 3 are deleted- Hb H disease
• If all 4 are deleted- Stillborn (Hydropfetalis)


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Alpha Thalassaemia
CAUSE
• Failure of production of hemoglobin alpha chains due to gene deletion
AGE AND SEX
• Both sexes from birth
GENETICS
• 2 alpha genes from each parent
PRESENTATION
• Hydrops fetalis if all gene are deleted
• Hb H disease if 3 genes are deleted
• Mild hypochromic microcytic anemia if 2 genes are deleted
TREATMENT
• Hydrops fetalis- none
• Hb H- No specific therapy required; Avoid iron therapy; Folic acid if necessary


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Complications
1. Hypersplenism
2. Iron overload
• Due to transfusion therapy
•       Iron overload
•              Deposition in liver (Cirrhosis)
•              In Pancreas (Diabetes)
•              In skin (Bronze diabetes)
•              In gonads (Gonadal failure)
•              In heart (Cardiomyopathy Heart failure)
3. HBV/ HCV
4. HIV




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β Thalassaemia
• Mutations are characterized as (βo or β thalassemia major) if they
  prevent any formation of β chains (which is the most severe form of
  β thalassemia)
• They are characterized as (β+ or β thalassemia intermedia) if they
  allow some β chain formation to occur.
• In either case there is a relative excess of α chains, but these do not
  form tetramers: rather, they bind to the red blood cell membranes,
  producing membrane damage, and at high concentrations they
  form toxic aggregates
SUMMARY
• β Thalassaemia
      – Homozygous- Beta Thalassaemia major
                – Either unable to synthesize Hb A OR
                – Profound hypochromic anemia
            • β⁰- no β gene
            • β⁺- few β gene
      – Heterozygous- Beta Thalassaemia minor
                – Mild anemia
                – Little or no clinical disability


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Diagnostic features of Beta Thalassaemia
MAJOR
• Profound hypochromic anemia
• Evidence of severe red cell dysplasia
• Erythroblastosis
• Absence or gross reduction of amount of Hb A
• Raised levels of Hb F
• Evidence that both parents have Thalassaemia minor

MINOR
• Mild anemia
• Microcytic hypochromic erythrocytes
• Target cells
• Punctate basophilia
• Raised resistance of erythrocytes to osmotic lysis
• Raised Hb A2 fraction
• Evidence that one parent has Thalassaemia minor


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Treatment of Beta Thalassaemia
PROBLEM                                      TREATMENT
• Erythropoietic failure                     • Allogenic bone marrow transplantation
                                             from HLA compatible antigen
                                             • Transfusion to maintain Hb> 10g/dl
                                             • Folic acid 5mg daily
• Iron overload                              • Iron therapy is forbidden
                                             • Desferrioxamine therapy
• Splenomegaly with mechanical               • Splenectomy
problems, with increased requirement of
transfusion




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Delta (δ) thalassemia
• As well as alpha and beta chains being present
  in hemoglobin about 3% of adult hemoglobin
  is made of alpha and delta chains.
• As with beta thalassemia, mutations can occur
  which affect the ability of this gene to produce
  delta chains.




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Functions of spleen

Red pulp
• Mechanical filtration of red blood cells
• Reserve monocytes
White pulp
• Active immune response through humoral and cell-
  mediated pathways.




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            • Hematological
              malignancies


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