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Blood and Lymph- Hemoglobinopathies by Turnicky
Blood and Lymph- Hemoglobinopathies by Turnicky
Hemoglobinopathies are....
Qualitative vs Quantitative
Abnormalities in hemoglobin synthesis leading to impaired binding or transport of oxygen

Qualitative: defect in formation of the Hb molecule. Properties of that Hb may lead to pre-mature hemolysis.

Quantitative: Decreased synthesis of globin with resultant decrease in hemoglobin formation.
Anemia due to abnormal globin synthesis...structural vs synthesis... name conditions for each
Abnormality in the structure or synthesis of the globin chains: the heme portion is normal

Structural: mutations involving amino acid deletions or substitutions
-Sickle cell anemia as an example

Synthesis: genetic defect that cause reduced synthesis of structurally normal globin chains
-The thalassemias
Name the types of hemoglobins, and when you have them...
-At birth Hb F (alpha2;gamma2) is predominant
-At six months of age Hb F gene becomes inactive and by one year of age Hb A (alpha2; beta2) becomes the major Hb

-A (alpha2 beta2); A2 (alpha2 delta2); F(alpha2 gamma2)
-A is major (95-95%), A2 minor (2-3), Fetal (.8-2.0)
-no S or C

-Clinical manifestations are determined by the amount of variant Hb present
-Frequently not manifest until after 6 mo when the HB F gene becomes inactive.
What do you see in diabetics that's used to monitor glucose control?
-Hb A1c is a minor Hb formed by post-translational addition of glucose to the beta chain.

-Increased levels produced in diabetics with increased blood glucose levels

-Tool for monitoring glucose control
Altered Solubility
amino acid substitution results in a molecules that polymerizes into insoluble, rigid aggregates of Hb resulting in hemolytic anemia.
-Hb S; Hb C
Altered Stability
amino acid substitutions/deletions can disrupt normal conformation disturbing binding of heme to globin or disrupt the stability of the globin subunit resulting in an unstable hemoglobin
Altered Function
aa substitutions of the globin chain may affect O2 affinity

-High affinity: Decreased O2 delivery to tissue producing erythrocytosis
-Low affinity: Premature O2 release
-No affinity: Hb in reduced state (fe+3), Cyanosis, HbM.
How do you identify the varieties of hemoglobin?
Hb electophoresis:
Each Hb has an electric charge of a different degree. Subjecting dissolved blood to an E- field, components move at different rates forming bands, each band is then quantitated as a %, which indicates the severity of any abnormality
hemoglobin S aka sickle cell anemia...

what is the scientific designation, what does it mean?
Scientific designation for hemoglobin S:
-B6 Glu>Val
-The mutation is the beta chain affecting the amino acid in the sixth position. The amino acid glutamic acid is replaced by valine
-Change in net charge; hence altered electrophoretic mobility

Solubility of HbS in the doxy state is markedly reduced:
-S molecules polymerized into rigid aggregates.
-After polymerization the cells assume a crescent shape.
What factors contribute to sickling?
-Hypoxia, acidosis, hypertonicity and temperatures>37o promote deoxygenation and the formation of HBS polymers
-The spleen, kidney retina and BM provide the above microenvironment
-Sickling also depends on HbS concentration within the red cell (MCHC) and
-Intracellular Hb composition of normal Hb (%A, %A2, %F)
-Sickled cells may return to normal biconcave shape upon reoxygenation. With repeated sickling the red cell membrane becomes leaky and rigid leading to irreversible sickled cells (Removed by spleen,liver, BM)
-May initiate vaso-occlusive crises (Impaired cell deformability;
Increased cell adherence to endothelium)
Most common worldwide hemoglobinopathy
-Africa certain regions 40% (Increased in regions with P. falciparum)
What does the bone marrow look like with sickle cell anemia? What accounts for the majority of clinical signs?
Anemia: chronic extravascular hemolysis resulting in hyperplastic BM; thinning of cortex, to compensate for increased red cell turnover

Vaso-occlusive crisis:
-Blockage of microvasculature by rigid sickled cells
-Spontaneous event resulting in hospitalization
-Triggered by infection, decreased O2 pressure, dehydration, or reduced blood flow
What else happens in vaso-occlusive crisis?
Pain, low grade fever, tissue necrosis.
-Infarction of tissue: GI, liver, bone, lung, spleen
-Aseptic necrosis of femoral head
-Dactylitis: infarction of metacarpals/tarsals (swelling of hands and feet)
-Recurrent priapism

Slowing of blood flow in occlusive areas may result in thrombosis
-Stroke (subclinical infarction in 30% of children)
-Blindness
-Chronic leg ulcers
-Placental infarctions
What is a common cause of death in the young patients of sickle cell?

What can follow?
Bacterial infection:
-Encapsulated microorganisms (strep. Pneumoniae and -Hemophilus influenzae)
Pneumonia common, meningitis prevalent

Aplastic crisis: temporary cessation of erythropoiesis in the setting of chronic hemolysis leading to worsening of anemia
-Follows viral, bacterial infections
What is the MOST common cause of death in children?
Chest syndrome: resembles pneumonia
-Fever, chest pain, pulmonary infiltrates from:
-Pulmonary edema
-Fat embolism from infarcted BM
-Infection
-Unknown causes
Older children/adults with splenic hypofunction present with what?
-Basophilic stippling
-Howell-Jolly bodies
-siderocytes
What are the diagnostic tests for sickle cell anemia? What's the therapy?
-Hb electrophoresis (usually done to dx)
-Solubility test (rapid test)
-Sickling test (confimatory)
-DNA PCR testing for mutation
-Beta chain position #6: substitution of Glutamic acid to Valine

Aimed at suppressing formation of Hbs polymerization (nothing effective long term)
-Transfusion
-In aplastic crisis; Splenic sequestration
-Decreasing vaso-occlusion:
-Hydration; prophylaxsis for infection
Hydroxyurea
-Reduces sickling by reactivating fetal genes and elevating levels of HbF
-Fewer vaso-occlusive events

Side effects: cytopenias
Sickle cell Trait. Symptoms? Why is it important to diagnose?
-Heterozyous condition (one normal gene)
-The one normal gene confers enough normal Hb to prevent symptoms or anemia

Important to diagnosis because of genetic complications:
-One of four children born to parents who each have the trait will have sickle cell disease
-Two of four will have the trait
What is the second most prevalent hemoglobinopathy?
Hemoglobin C
Beta (6) Glu>Lys
usually asymptomatic
-The danger is the combination of C trait with another abnormal hemoglobin
What do you see intracellularly in hemoglobin C disease?
Disease (homozygous)
-.02% of US blacks

Many target cells

>90% Hb C

Often asymptomatic; variable hemolysis

Intracellular Hb crystals found
What heterozygous state is almost as severe as homozygous sickle cell disease?
Hemoglobin S/C:
-Both beta chains are abnormal and no HbA is formed
-Both sickling and HbC crystal formation leading to vaso-occulsive crisis.
Hemoglobin E... who gets it, what is the change? what happens to o2 affinity?
-Most prevalent amongst SE Asians
-Beta (26) Glu to Lys
-Target cells/microcytosis
-Heteroz: no anemia; microcytosis only
-Homoz: mild anemia
-Decreased O2 affinity (shift to the right);
-Danger is combination with other abnormal hemoglobins
Thalassemia is what. and the variants.
Decreased globin chain synthesis
-Structural gene delections or
-Mutations in controlling sites preventing gene expression.

Alpha thalassemia:
-Impaired alpha chain synthesis

Beta thalassemia:
Impaired beta chain synthesis
Beta Variant
HPFH: failure in the switch of the gamma chain to the beta chain after birth. Only HbF produced.
What do you always see in alpha and beta thalassemia? what else is there?
-Hypochromic microcytosis (ALWAYS SEE THIS)
-Basophilic stippling
-Increased Hb A2
-Increased RBC mass with low Hb conc.
What do you see in the CBC?
-RBC count elevated
-MCH and MCHC decreased
-MCV decreased (<67 fl think thal.)
-Normal RDW (IDA is large RDW)
-All the cells are similar sized
-Peripheral smear: Target cells

Still in doubt?
Erythrocyte Proto-phorphyrin test:
Normal (abnormal in all anemias)
-(elevated in IDA)
Why is there an elevated RBC count?
Diminished synthesis of a globin chain:
-Too few cells with normal hemoglobin
-Marked tissue hypoxia

Compensatory erythropoietin driving marked marrow hyperplasia and even greater ineffective erythropoiesis releasing increased numbers of red cells into the circulation
-Cells with excess alpha or beta chains.
-There is a relative excess of globin chains from the chain not effected resulting in production of red cells with abnormal hemoglobin containing an excess of a particular globin chain. These Hbs are unstable and precipitate resulting in extravascular removal in the spleen (continuous chronic hemolysis)
Beta Thalassemia: Homozygous Thalassemia Major (Cooley’s Anemia)
-Infant protected until 6mo when HbA replaces HbF as the major Hb
-Severe anemia: cardiac failure in 1st decade
-Chronic hemolysis with gallstones, gout and icterus
-Splenomegally
-Extramedullary hematopoiesis
-BM hyperplasia with facial deformities
-Lack of Beta chain production
-Compensatory production of excess free alpha chains precipitate in the red cells resulting in chronic hemolysis and significant anemia.
-Dramatic reduction in HbA with reduced O2 carrying capacity
-Marked ineffective erythroid hyperplasia
What is stimulated because of the erythroid hyperplasia? what can this cause? how do you treat?
-The erythoroid hyperplasia stimulates iron absorption in the gut leading to iron toxicity.
-Transfusion therapy prolonging life to 3rd decade
-Secondary Hemochromatosis
-Cardiac siderosis
-Pancreatic iron overload with DM
-Hepatic cirrhosis

Bone marrow Transplantation
Death in 2nd or 3rd decade
Beta Thalassemia:Heterozygous Beta Thalassemia Minor..always a problem?
-One normal beta gene is present directing nearly normal beta chain synthesis
-RBC survival near normal except in stress or pregnancy when moderate Hypo/micro anemia develops.
-Usually only a mild Hypo/micro anemia

CBC values still persist:
Elevated rbc number, decreased MCH, decreased MCV
-But to a lesser extent
-Target cells, Basophilic stippling
*Frequently confused with IDA.
Alpha Thalassemia -named according to how many mutations of the 4 alpha genes ...
Silent Carrier (1 of 4.. asx)
Alpha Thal Trait (2 of 4)
Hemoglobin H Disease (3 of 4)
Hydrops fetalis with Hb Bart’s (4 of 4)
Name the genotype, and findings for each:
Silent Carrier
Alpha Thal Trait
Hemoglobin H Disease
Hydrops fetalis with Hb Bart’s
Silent Carrier: genotype: aa/a-
findings: normal or slight microcytosis, no dz

Alpha Thal Trait: genotype -a/-a or --/aa
findings: mild hypo/micro anemia, target cells, baso stippling (mimicks IDA)

Hemoglobin H Disease: genotype: --/-a
-findings: mod to marked hypo/micro anemia, target cells, baso stippling, servere hemolytic anemia, Hb H.

Hydrops fetalis: genotype: --/-- (no alpha chains, only beta)
-findings: fatal; servere anemia, numberous NRBCs, Hb Bart's
Hb Bart’s has
very high O2 affinity with no release to tissues.
Hemoglobin Dissociation Curve
Shift left- increase affinity for oxygen from Hb (capillaries at lungs)
Shift right- decreased affinity for oxygen (capillaries at tissues)

At 60mmHg the curve is almost flat, indicting little change in sat. above this
-So, PaO2 of 60 or more provides >90% sat
-<60, curve is steep, small changes in PaO2 greatly reduce the SaO2

Steep mid-section results in additional delivery of large volume of O2 in response to tissue hypoxia
Hypoproliferative Anemia
-A heterogeneous group of acquired or hereditary disorders characterized by Bone Marrow HYPOCELLULARITY
-Much of the normal marrow is replaced by fat
-Defect is due to depletion, damage, or inhibition of stem cells
-Pleuripotent: Aplastic Anemia with decrease in all 3 cell lines with peripheral pancytopenia
-Unipotent: only one cell line affected, eg pure red cell aplasia
Aplastic Anemia
Pluipotential stem cell disorder with Peripheral pancytopenia
Variable etiology:
-Bone Marrow Matrix Defects (stromal)
-Immunologic Suppression
-Deficient Growth Factors
-Abnormal or deficient stem cells

mostly idiopathic (80%)
Aplastic Anemia: Lab
-Pancytopenia is typical
-NRBCs and teardrop cell NOT typical, if seen suggests marrow replacement (myelophthisic anemia); no architectural damage.
-Relative reticulocyte count maybe normal but corrected retic count is always low.
-Erythropoietin often increased

Therapy: Remove causative agent if known
-Hematopoietic growth factors are used, but do not result in sustained response.
-Immunosuppressive therapy
-Antilymphocyte globulin, cycloporine
Aplastic Anemia: Pure Red Cell Aplasia
-Selective decrease in erythroid precursor cells in BM and peripheral anemia
-No disturbance of granulopoiesis or thrombopoiesis.
-Corrected Reticulocyte count is low
Bone Marrow Replacement Disorders
Bone marrow failure with resultant peripheral cytopenias not the result of aplastic anemia or a stem cell defect
Myelophthisic Anemia
-BM infiltration by tumor, fibrosis or granulomas
-Release of immature cells in peripheral blood: NRBCs, tear drop cells & neutrophilic left shift:
-Called a leukoerythroblastic picture
-Anemia with normal, increased, or decreased leukocytes and platelets
-The abnormal replacement disrupts the normal marrow architecture allowing release of immature cells. Anemia, thrombocytopenia or pancytopenia may be seen
-In aplastic anemia, the marrow architecture is preserved and numerous immature cells are not observed in the peripheral circulation. Pancytopenia is characteristic.
Myelodysplastic Syndrome (MDS)... what is the most consistent finding?
-Clonal pluripotential stem cell disorder
-Previously call pre-leukemia
-BM maturation abnormalities characterized by BM hypercellularity with peripheral cytopenias, with anemia
-Frequent chromosomal abnormalities
-Anemia most consistent finding, often macrocytic by indices, but dimorphic on smear review.