3 Erythrocyte Development EPO: 90% from kidney10% from liverThe hemoglobin concentration in adults has a Gaussian distribution. The mean hematocrit value for adult males is 47% (± SD 7) and that for adult females is 42% (± 5). Any individual hematocrit or hemoglobin value carries with it a likelihood of associated anemia. Thus, a hematocrit of 39% in an adult male or <35% in an adult female has only about a 25% chance of being normal.
5 Two main approaches for anemia that are not mutually exclusive: 1. Kinetic approach2. Morphological approach
6 Kinetic approach of Anemia Production?Survival/ Destruction?The key test is the …..
7 Reticulocyte Production Index— an estimate of marrow production relative to normal HctCorrected Ret= Ret(%) *45Corrected RetRPI=Maturation index
8 RPI (kinetic approach) RPI are the most helpful:extremely low (<0.1%)AA/ PRCA are the first considerationsextremely high (>3%)Blood loss/ hemorrhageHemolytic anemia (although 25% AIHA have normal RPI)
13 Distribution of Iron in Adults In the balanced state, 1 to 2 mg of iron enters and leaves the body each day. Dietary iron is absorbed by duodenal enterocytes. It circulates in plasma bound to transferrin. Most of the iron in the body is incorporated into hemoglobin in erythroid precursors and mature red cells. Approximately 10 to 15 percent is present in muscle fibers (in myoglobin) and other tissues (in enzymes and cytochromes). Iron is stored in parenchymal cells of the liver and reticuloendothelial macrophages. These macrophages provide most of the usable iron by degrading hemoglobin in senescent erythrocytes and reloading ferric iron onto transferrin for delivery to cells.
14 Storage iron Circulating iron RBC iron Tissue iron Figure 105-2: Laboratory studies in the evolution of iron deficiency. Measurements of marrow iron stores, serum ferritin, and total iron-binding capacity (TIBC) are sensitive to early iron-store depletion. Iron-deficient erythropoiesis is recognized from additional abnormalities in the serum iron (SI), percent transferrin saturation, the pattern of marrow sideroblasts, and the red cell protoporphyrin level. Patients with iron deficiency anemia demonstrate all the same abnormalities plus hypochromic microcytic anemia.
15 IDA Presentation Presentation Diagnosis Progressive MCV ↘ Progressive RBC ↘Typically high RDWTypically high MCV/RBCTypically mild PLT ↑Ferritin: low (N=20-300)Iron/TIBC <16% (N=~33%)BM iron stain
16 Causes of IDA Increased iron requirement Inadequate iron supply HypermenorrheaGI blood loss– hemorrhoid, PUD, GI cancer, angiodysplasiaFactitious removalHemolysisHemodialysisHookworm infestationRapid growth of teenagePregnancy and lactationPoor nutritional intakeMalabsorptionGastrectomy (may also has Vit B12 deficiency)
17 Iron Supply Oral: usually 3 months to restore iron storage IV Ferrum chewable (Fe 3+) 100mg/tabHematonic (Fe 2+) 50mg/tabIVAtofen (!! Risk of allergy and anaphylaxis—0.6%)
20 Hb Gene Harrison’s Principles of Internal Medicine 15th Ed. 2001 Figure 106-1: The globin genes. The -like genes ( , ) are encoded on chromosome 16; the -like genes ( , , , ) are encoded on chromosome 11. The and genes encode embryonic globins.
21 Thalassemia Presentation DiagnosisExclude IDAHb electrophoreis:Hb A2>3.5% or HbF>2% β-thalassemiaHbH(+) α-thalassemia with ¾ defect (HbH dz)HbA2 and HbF: N α-thalassemia with ¼ or 2/4 defectGene diagnosisConstant low MCVConstant high RBCTypically low RDWTypically low MCV/RBCTypically iron storage ↗
22 Gene Level of Thalassemia in Taiwan α-thalassemia: Prevalence 4%--SEAα0 deletion-α3.7 deletion-α4.2 deletionHbQS or HbCSβ-thalassemia: Prevalence 2%Codon 41/42 TCTT deletion β0IVS II 654 C-> T point-mutation β0Codon 17 A-> T β0Promoter 28 A-> G β+HbE (Codon 26 G-> A) β+??% α + β-thalassemia (Severity?)
23 優生學的理由β –Major (終身輸血)Hb H disease (黃疸)Hydrops fetalis (死胎)
24 Thalassemia Treatment Mild: NoneSevere:Folic acidRBC transfusions + iron chelatorsAllo-SCT
26 Figure 107-2: The assimilation of cobalamin Figure 107-2: The assimilation of cobalamin. On entering the stomach, dietary cobalamin (Cbl) forms a complex with R binding protein. As this protein is digested in the small intestine, cobalamin is transferred to intrinsic factor (IF). This complex passes through the intestine until it reaches specific receptors on the mucosa of the distal ileum. The internalized Cbl is then transferred to transcobalamin II (TC II), which circulates in the plasma until it binds to receptors on cells throughout the body and is internalized.
27 Megaloblastic Anemia Presentation DiagnosisHigh high MCVPancytopeniaHypersegmented PMNTypically high RPI, hemolysis (LDH ↗), indirect hyperbilirubinemiaTinnitus or other neurological presentationVegetarism (奶, 蛋, 維他命)Gastrectomy or Pernicious anemia??Schilling testLow Vit B12 or folic acidVit B12: 270~400: empirical tryVit B12< 270: definite deficiency
29 Vit B12/Folate Deficiency Anemia Treatment Vit B12 deficiency:Vit B12 1 mg im qd *5 q1wk *4 q1m*3 q6mR/I pernicious anemia (Anti-parietal Ab, anti-IF Ab and PES)Thyroid dzGastric cancerFolate deficiency: Improved diet, folic acid
30 Usually rapid response Most important F/U Reticulocyte, LDH Harrison’s Principles of Internal Medicine 15th Ed. 2001Figure 107-3: Hematologic response of a patient with pernicious anemia to an intramuscular injection of 100 g cobalamin on day 0.
32 Is there hemolysis? Damaged RBCs on smear Marrow response to hemolysis spherocytes (immune hemolysis, HS)RBCs fragments (microangiopathic anemias)Marrow response to hemolysispolychromasia on smearreticulocytosiserythroid hyperplasia in marrowBiochemical evidence of RBCs destructionIndirect hyperbilirubinemiaincreased LDHdecreased/absent haptoglobin
33 Extravascular vs Intravascular hemolysis Extravascular IntravascularTest Hemolysis HemolysisLD á áábilirubin á áhaptoglobin N to absent absenthemoglobinuria absent presentfree Hb in plasma absent presenturine hemosiderin absent present
34 An approach to hemolytic anemia ImmuneNon-immuneCongenitalAcquiredAutoimmuneAlloimmuneDrug-inducedDefects of:Membrane/ skeleton(eg. Hereditary spherocytosis)Enzymes(eg. G6PD deficiency)HemoglobinopathyPNHInfectionssepsismalariaMechanicalProsthetic heart valveMicroangiopathic HA (TTP, HUS, DIC)Hypersplenism
35 D/D of AIHA Warm AIHA Cold AIHA RBC’s coated with IgG, Fix complement poorly (usually C3 only)RBC’s coated with IgM which fixes complementYounger ageOlder ageextravascular hemolysis(Spleen is primary site of destruction)Intravascular hemolysis(Liver is primary site of destruction)Spherocytes on PB smearAgglutination on PB smear70% associated with other illnesses90% associated with other illnessesTreatment: steroids, SplenectomyRituximabImmunosuppressantsTreatment: avoidance of coldPoor response to steroids, splenectomyPlasmapheresis in refractory cases
36 D/D of ACD and IDAACD may concurrently coexist with true iron deficiency(In this situation, iron/TIBC is more reliable than ferritin)
66 Leukoerythroblastosis Immature RBC (nucleated RBC) and myeloid cells in peripheral bloodCausesBone morrow disorders：Infiltrative disorders or hematologic malignancyPeripheral disorders：Severe infection, major stress or operation, acute blood loss
67 Thrombocytosis Primary: Bone marrow disease Secondary (Reactive) Myeloproliferative diseaseSecondary (Reactive)MalignancyInflammation or infectionConnective tissue disorderBlood loss or anemiaSplenectomy