Hemoglobinopathies n n n n Hemoglobinopathies Thalassemia genetics Hb synthesis Hb A, A 2, F Hb ELP Hb Constant-Spring Hb Bart’s Hb H n n n Hb Lepore Hb E Hb S Hb C Hb SC disease HPFH
Hb structure
Hb dissociation curve
Anemia ? Production? Survival/Destruction? The key test is the …. .
The reticulocyte count (kinetic approach) n n Increased reticulocytes (greater than 2 -3% or 100, 000/mm 3 total) are seen in blood loss and hemolytic processes, although up to 25% of hemolytic anemias will present with a normal reticulocyte count due to immune destruction of red cell precursors. Retic counts are most helpful if extremely low (<0. 1%) or greater than 3% (100, 000/mm 3 total).
Causes of Anemia • Decreased erythrocyte production • Decreased erythropoietin production • Inadequate marrow response to erythropoietin • Erythrocyte loss • Hemorrhage • Hemolysis
Morphological Approach (big versus little) First, measure the size of the RBCs: • Use of volume-sensitive automated blood cell counters, such as the Coulter counter. The RBC’s pass through a small aperture and generate a signal directly proportional to their volume. • Other automated counters measure red blood cell volume by means of techniques that measure refracted, diffracted, or scattered light • By calculation
Underproduction macrocytic MCV>115 n B 12, Folate n Drugs that impair DNA synthesis (AZT, chemo) n MDS MCV 100 - 115 n Endocrinopathy (hypothyroidism) n Erythropoetin n Reticulocytosis
Underproduction Normocytic n Anemia of chronic disease n Mixed deficiencies n Renal failure n MM, Lymphoma Microcytic n Iron deficiency n Thalassemia n Anemia of chronic disease (30 -40%) n Sideroblastic anemias
Review red blood cell disorders Marrow production n Thalassemias n Myelodysplasia n Myelophthisic n Aplastic anemia n Nutritional deficiencies Red cell destruction n Hemoglobinopathies Enzymopathies n Membrane disorders n Autoimmune n
Review red blood cell disorders Marrow Production - Aplastic Anemia n n Acquired u Immunological u Toxins – Benzene u Drugs – methotrexate, chloramphenicol u Viruses – EBV, hepatitis Hereditary u Fanconi, u Diamond-Shwachman
Review red blood cell disorders Marrow Production - Myelodysplasia Preleukemia, most commonly in the elderly. n Supportive care that involves transfusion therapy is an option. n Poor response to growth factors n
Review red blood cell disorders Marrow Production - Myelophthisic Anemia associated with marrow infiltration n “teardrops” n Cancer, infections n Myelofibrosis n Treatment is aimed at the underlying disease n Supportive transfusions as needed. n
Review red blood cell disorders Red cell destruction Elevated reticulocyte count n Mechanical n Autoimmune n Drug n Congenital n
Hb Problems Heme production problem: porphyria n Fe incorporation into Heme: Sideroblastic anemia n Fe++ problems: IDA, hemochromatosis n n Globin problem: sickle cell disease, thalassemia
Hemoglobinopathies Decrease, lack of, or abnormal globin n May be severe hemolytic anemia n Abnormal Hb with low functionality n Mutation may be deletion, substitution, elongation n Hb electrophoresis may be helpful n
Hemoglobin Heme u Porphyrin ring and Fe n Globins u Alpha family on chromosome 16 ]--//--[ u Beta family on chromosome 11 ]--//--[ ]--[ [ n
Thalassemia n Genetic defect in hemoglobin synthesis u u u synthesis of one of the 2 globin chains ( or ) Imbalance of globin chain synthesis leads to depression of hemoglobin production and precipitation of excess globin (toxic) “Ineffective erythropoiesis” Ranges in severity from asymptomatic to incompatible with life (hydrops fetalis) Found in people of African, Asian, and Mediterranean heritage
Thalassemia n n n n 1925: Described by Dr. Thomas Cooley and Dr. Pearl Lee of Detroit 1920’s: Osmotic fragility test 1932: Dr. George Whipple of Rochester coined the name “thalassa anemia” from Greek story about Xenophon’s army returning from Persia 1930’s: Familial pattern recognized 1950’s: Alkali denaturation test for Hb F, Hb ELP 1956: Coulter model A 1960’s: RBC indices 1980’s: Histogram, DNA analysis, PCR
Thalassemia n Genetic defect in hemoglobin synthesis u u u synthesis of one of the 2 globin chains ( or ) Imbalance of globin chain synthesis leads to depression of hemoglobin production and precipitation of excess globin (toxic) “Ineffective erythropoiesis” Ranges in severity from asymptomatic to incompatible with life (hydrops fetalis) Found in people of African, Asian, and Mediterranean heritage
Signs and Symptoms Hemolytic n Bone changes (hair on end) n Ethnicity: Mediterranean, Africa, Southeast Asia n Hypo-Micro, Poikilocytosis n NRBC’s, reticulocytosis, basophilic stippling n Siderocytes (with repeated transfusions) n
Thalassemia Blood Smears
X-ray of scull in Thalassemia: “Hair-on-end”
Perl’s iron stain (Prussian blue) with potassium ferrocyanide Siderocyte Sideroblasts
Thalassemia n n n n Deletion of one or more alpha genes from chromosome 16 - / : silent career with little signs --/ : cis double deletion more common in SEA - /- : trans double deletion --/- : Hb H disease --/--: Hb Bart’s hydrops fetalis Hb Constant-Spring: elongation (discovered in Kingston, Jamaica; 2% of Thai have it)
Thalassemia Lab Changes High RBC n Low H&H and indices n High RDW n May need to rule out IDA n Hb ELP not useful except in Hb H n BCB prep for Hb H n
Hb H Prep with Brilliant cresyl blue thalassemia Hydrops fetalis
Peripheral blood smear: Hb H disease
Thalassemia n n n n Usually point mutation in the control region chr 11 + has minimal production o has no production +/ + or o/ o is thal major or Cooley’s anemia Often not apparent at birth until chain takes over chain production High Hb A 2, Hb F Related: Hb Lepore ( fusion), HPFH
Hb F preparation with Kleihauer-Betke Fetal Hb resists acid elution
Thalassemia The only treatments are stem cell transplant and simple transfusion. n Chelation therapy to avoid iron overload has to be started early. n
Sickle Cell Anemia Single base pair mutation results in a single amino acid change. n Under low oxygen, Hgb becomes insoluble forming long polymers n This leads to membrane changes (“sickling”) and vasoocclusion n
Red Blood Cells from Sickle Cell Anemia n Deoxygenation of SS erythrocytes leads to intracellular hemoglobin polymerization, loss of deformability and changes in cell morphology. OXY-STATE DEOXY-STATE
Hb S Sickling Hb n Autosomal n Sickle crisis in low oxygen condition n 6 glutamate to valine substitution n Prevalent in Eastern Africa n Solubility test n Sickling test (meta-bisulfite) n
Other Hemoglobinopathies n n n Hb C ( 6 Glu-Lys) in Western Africa u Cigar-like crystals u Billiard ball cells u Folded cells Hb SC disease u Washington monument cells u Mitten shape Hb E ( 26 Glu-Lys) in SEA u Moves with Hb A 2 in Hb ELP and A 2 column (ie, false elevated Hb A 2)
Hb C disease Hb SC disease
Unusual Hemoglobins in the World
Review red blood cell disorders Red cell destruction – membrane disorders Hereditary spherocytosis n Hereditary elliptocytosis n Hereditary pyropoikilocytosis n Southeast Asian ovalocytosis n
Review red blood cell disorders Red cell destruction – membrane disorders
Review red blood cell disorders Red cell destruction – enzymopathies G 6 PD deficiency n Pyruvate kinase deficiency n Other very rare deficiencies n
Thank you תודה רבה
Скачать презентацию Hemoglobinopathies n n n n Hemoglobinopathies Thalassemia genetics
Hbthy (1).ppt