ANEMIA Masatoshi Kida, M.D. Dept. of Pathology University of Vermont
ANEMIA <ul><li>any condition in which the  number of red cells , the  amount of hemoglobin  or the  volume of packed red b...
Blood Reference Values WBC  4,800-10,800/mm 3 RBC  M: 4.7-6.1 mil/mm 3  F: 4.2-5.4 mil/mm 3  ( or x 10 6 /  L) Plt  130,0...
Erythrocyte Indices <ul><li>Hemoglobin (Hgb) </li></ul><ul><li>Hematocrit (Hct) </li></ul><ul><li>Mean Corpuscular Volume ...
RBC “rule of 3’s” <ul><li>For normal erythrocytes: </li></ul><ul><ul><li>hemoglobin (g/dL)    3 x RBC count (millions) </...
classification of anemia by color <ul><li>hypochromic (decreased color) </li></ul><ul><ul><li>increased central pallor </l...
anemia <ul><li>M: Hb <13.5 Hct <41 </li></ul><ul><li>F: Hb <12 Hct <36 </li></ul>
 
ANEMIA morphologic classification microcytic MCV <80 normocytic MCV 80-100 macrocytic MCV >100
ANEMIA  classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li...
ANEMIA  classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><ul><li>iron deficiency anemia </li></u...
ANEMIA  classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li...
ANEMIA  classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li...
ANEMIA  classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><ul><li>iron deficiency anemia </li></u...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>blood loss </li></ul></ul><ul><ul><ul><l...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
Hereditary Spherocytosis <ul><ul><li>intrinsic defect in the  membrane cytoskeleton </li></ul></ul><ul><ul><li>genetic: au...
Hereditary Spherocytosis
Hereditary Spherocytosis <ul><li>Sx: 1. mild to moderate hemolytic anemia </li></ul><ul><li>2. splenomegaly </li></ul><ul>...
Hereditary Elliptocytosis <ul><ul><li>intrinsic defect in the membrane  cytoskeleton </li></ul></ul><ul><ul><li>genetic:  ...
Embden-Meyerhof glycolytic pathway
Pyruvate Kinase Deficiency <ul><ul><li>autosomal recessive </li></ul></ul><ul><ul><li>most common red cell enzyme deficien...
X
fluorescent spot test <ul><li>Pyruvate kinase  catalyzes the phosphorylation of ADP to ATP with the formation of  pyruvate...
 
G6PD Deficiency <ul><ul><li>Pathophysiology: decreased half life of G6PD </li></ul></ul><ul><ul><li>increased vulnerabilit...
G6PD Deficiency bite cell Heinz bodies
ANEMIA  pathophysiologic classification <ul><li>I  RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li...
hemoglobin molecule two    chains two    chains four   -globin genes two   -globin genes
globin genes CH16 CH11
Thalassemia Syndromes <ul><ul><li>heterogeneous  hemolytic  disorders characterized by  quantitative  abnormalities of  he...
Thalassemia Syndromes pathophysiology <ul><ul><li>Two (2) pathological mechanisms to contribute to develop anemia </li></u...
Thalassemia Syndromes pathophysiology <ul><ul><li>ineffective erythropoiesis </li></ul></ul><ul><ul><li>  +    severe ery...
α -thalassemia  1  2  /   normal  1  2  /    + -thal heterozygote (mild)  1  2  /    0 -thal ...
α -thalassemia  1  2  /    + -thal homozygote (moderate)  1  2  /    0 -thal x   + -thal (severe)  1...
β -thalassemia <ul><li>clinical classification of  β  thal is based on the severity of the anemia (based on the type of  g...
β -thalassemia promoter gene mutation: 75-80% reduction of transcription rate (  +  thal) chain termination mutation: pre...
“ Thalassemia Major” <ul><ul><li>homozygous  β + / β +  or  β 0 / β 0 </li></ul></ul><ul><ul><li>severe anemia at 6 to 9 m...
“ Thalassemia Major”
“ Thalassemia Major” <ul><ul><li>Dx: </li></ul></ul><ul><ul><li>anemia work up </li></ul></ul><ul><ul><li>hemoglobin elect...
“ Thalassemia Minor” <ul><ul><li>much more common than Thalassemia major </li></ul></ul><ul><ul><li>heterozygous b + /b or...
 
 
 
 
 
 
Sickle Cell Disease <ul><ul><li>prototype of hereditary hemoglobinopathies </li></ul></ul><ul><ul><li>structurally abnorma...
Sickle Cell Disease <ul><ul><li>- severe anemia    generalized growth and developmental impairment </li></ul></ul><ul><ul...
Sickle Cell Trait <ul><ul><li>- heterozygous (Ss) Hb S -- 30-40% </li></ul></ul><ul><ul><li>- approx. 10% of American blac...
Paroxysmal Nocturnal Hemoglobinuria (PNH) <ul><ul><li>an  acquired clonal disorder of stem cells, and results from a somat...
Paroxysmal Nocturnal Hemoglobinuria (PNH) <ul><ul><li>clinical: </li></ul></ul><ul><ul><li>- chronic hemolysis without dra...
TTP / HUS <ul><ul><li>Thrombotic Thrombocytopenic Purpura (TTP) </li></ul></ul><ul><ul><li>Hemolytic Uremic Syndrome (HUS)...
TTP / HUS <ul><ul><li>TTP (Thrombotic Thrombocytopenic Purpura) </li></ul></ul><ul><ul><li>adult female with pentad </li><...
Disseminated Intravascular   Coagulation (DIC) <ul><ul><li>- an acute, subacute, or chronic thrombohemorrhagic disorder oc...
Disseminated Intravascular   Coagulation (DIC) <ul><ul><li>Pathology:- wide spread thrombi </li></ul></ul><ul><ul><li>  (b...
Lead Poisoning <ul><ul><li>- inhibition of 5’-nucleotidase and sodium-potassium pump </li></ul></ul><ul><ul><li>   decrea...
Malaria <ul><ul><li>- intracellular protozoan parasite ( Plasmodium ) </li></ul></ul><ul><ul><li>P.falciparum : worldwide ...
Immunohemolytic Anemia <ul><ul><li>several subtypes </li></ul></ul><ul><ul><li>(1) warm antibody type </li></ul></ul><ul><...
Immunohemolytic Anemia <ul><ul><li>(1) warm antibody type </li></ul></ul><ul><ul><li>- 80 to 90% of autoimmune hemolytic a...
Immunohemolytic Anemia <ul><ul><li>(2) cold agglutinin type </li></ul></ul><ul><ul><li>- 10 to 20% of autoimmune hemolytic...
Immunohemolytic Anemia <ul><ul><li>(3) cold hemolysis </li></ul></ul><ul><ul><li>paroxysmal cold hemoglobinuria </li></ul>...
Drug-Mediated Injury <ul><ul><li>(1) autoantibody induction </li></ul></ul><ul><ul><li>α -methyldopa    Ig G antibody </l...
Aplastic Anemia <ul><ul><li>- pancytopenia characterized by </li></ul></ul><ul><ul><li>(1) anemia </li></ul></ul><ul><ul><...
Aplastic Anemia <ul><ul><li>Pathology:  markedly hypoplastic bone marrow </li></ul></ul><ul><ul><li>Clinical: - may occur ...
Megaloblastic Anemia <ul><ul><li>A group of disorders characterized by a reduced rate of DNA synthesis </li></ul></ul><ul>...
Vitamin B12 / Folate Deficiency <ul><li>Vitamin B12 (cobalamin) -- a vital ingredient for DNA synthesis and Krebs cycle </...
Vitamin B12 Absorption Vit B12:   absorbed in ileum   (with intrinsic factor) Intrinsic factor
Vitamin B12 / Folate Deficiency <ul><ul><li>Lab: </li></ul></ul><ul><ul><li>Blood: - macro-ovalocytes, giant hypersegmente...
Vitamin B12 Deficiency <ul><li>etiology: </li></ul><ul><li>dietary deficiency ---- rare </li></ul><ul><ul><ul><li>strict v...
Vitamin B12 Deficiency <ul><li>Sx: </li></ul><ul><li>weakness  ← anemia (megaloblastic anemia) </li></ul><ul><li>sore (“be...
Vitamin B12 Deficiency <ul><li>Lab: </li></ul><ul><li>low serum B12 level </li></ul><ul><li>increased serum homocysteine <...
folate deficiency <ul><li>etiology: </li></ul><ul><li>dietary deficiency (folate def. takes only months to develop) </li><...
folate deficiency <ul><li>Sx: </li></ul><ul><li>megaloblastic anemia </li></ul><ul><li>no neurologic degeneration </li></u...
Iron Deficiency Anemia <ul><li>Iron: absorbed in duodenum </li></ul><ul><li>When iron loss exceeds its intake for a long t...
Iron Deficiency Anemia <ul><li>Clinical: </li></ul><ul><li>- general fatigue </li></ul><ul><li>- SOB </li></ul><ul><li>- s...
Iron Deficiency Anemia <ul><ul><li>Lab: </li></ul></ul><ul><ul><li>Blood: - normochromic-normocytic </li></ul></ul><ul><ul...
Iron Deficiency Anemia <ul><ul><li>Serum iron (nl = 50-160 mg/dL) : low </li></ul></ul><ul><ul><li>Serum iron-binding capa...
sideroblastic anemia <ul><li>due to altered production of heme (defect in protoporphyrin production) </li></ul><ul><li>ass...
Sideroblastic Anemia <ul><ul><li>a heterogeneous group of disorders associated with various defects in the porphyrin biosy...
Sideroblastic Anemia <ul><ul><li>Sub-types: </li></ul></ul><ul><ul><li>Hereditary Sideroblastic Anemias </li></ul></ul><ul...
Sideroblastic Anemia
Sideroblastic Anemia <ul><ul><li>clinical: characterized by hypochromic, often microcytic, red  cells in the blood usually...
anemia work-up <ul><li>M: Hb <13.5 Hct <41 </li></ul><ul><li>F: Hb <12 Hct <36 </li></ul><ul><li>[check MCV] </li></ul><ul...
anemia work-up <ul><li>MCV >100 = macrocytic </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul><ul><ul><ul><li>Vit...
anemia work-up <ul><li>low reticulocyte: </li></ul><ul><ul><li>-  marrow failure -  leukemia/metastasis </li></ul></ul><ul...
 
 
 
 
 
 
 
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  1. 1. ANEMIA Masatoshi Kida, M.D. Dept. of Pathology University of Vermont
  2. 2. ANEMIA <ul><li>any condition in which the number of red cells , the amount of hemoglobin or the volume of packed red blood cells per unit volume is less than normal. </li></ul><ul><li>a pathophysiological condition in which the body cannot meet its demands for oxygen. </li></ul>
  3. 3. Blood Reference Values WBC 4,800-10,800/mm 3 RBC M: 4.7-6.1 mil/mm 3 F: 4.2-5.4 mil/mm 3 ( or x 10 6 /  L) Plt 130,000-400,000/mm 3 Hgb M: 14.0-18.0 g/dL F: 12.0-16.0 g/dL Hct M: 42-52% F: 37-47% MCV [= Hct(%) / RBC count(x10 6 /  L)/10] 80-100  3 (or fL) MCH [= Hgb(g/dL) / RBC count(x10 6 /  L)/10] 27-33 pg MCHC [= Hgb(g/dL) / Hct(%)/100] 32-36 g/dL RDW 8.5-11.5 % reticulocyte (absolute number) 40,000-100,000 /  L
  4. 4. Erythrocyte Indices <ul><li>Hemoglobin (Hgb) </li></ul><ul><li>Hematocrit (Hct) </li></ul><ul><li>Mean Corpuscular Volume (MCV) </li></ul><ul><li>Mean Corpuscular Hemoglobin (MCH) </li></ul><ul><li>Mean Corpuscular Hemoglobin Concentration (MCHC) </li></ul><ul><li>Red Cell Distribution Width (RDW) </li></ul><ul><li>[Packed Cell Volume (PCV)] </li></ul>
  5. 5. RBC “rule of 3’s” <ul><li>For normal erythrocytes: </li></ul><ul><ul><li>hemoglobin (g/dL)  3 x RBC count (millions) </li></ul></ul><ul><ul><li>hematocrit (%)  3 x hemoblobin (g/dL)  3% </li></ul></ul><ul><li>Failure to obey this “rule of 3’s” suggests an abnormality in erythrocytes (sickle cells, etc) </li></ul>
  6. 6. classification of anemia by color <ul><li>hypochromic (decreased color) </li></ul><ul><ul><li>increased central pallor </li></ul></ul><ul><li>normochromic (normal color) </li></ul><ul><ul><li>central pallor ~1/3 of the RBC diameter </li></ul></ul><ul><li>hyperchromic (increased color) </li></ul><ul><ul><li>(~spherocytosis) </li></ul></ul><ul><ul><li>loss of central pallor </li></ul></ul>
  7. 7. anemia <ul><li>M: Hb <13.5 Hct <41 </li></ul><ul><li>F: Hb <12 Hct <36 </li></ul>
  8. 9. ANEMIA morphologic classification microcytic MCV <80 normocytic MCV 80-100 macrocytic MCV >100
  9. 10. ANEMIA classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li></ul><ul><li>macrocytic anemia (MCV >100) </li></ul>
  10. 11. ANEMIA classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><ul><li>iron deficiency anemia </li></ul></ul><ul><ul><li>thalassemia syndromes </li></ul></ul><ul><ul><li>anemia of chronic disease </li></ul></ul><ul><ul><li>sideroblastic anemia </li></ul></ul>
  11. 12. ANEMIA classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li></ul><ul><ul><li>anemia of blood loss </li></ul></ul><ul><ul><li>hemolytic anemia </li></ul></ul>
  12. 13. ANEMIA classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><li>normocytic anemia (MCV 80-100) </li></ul><ul><li>macrocytic anemia (MCV >100) </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul>
  13. 14. ANEMIA classification by volume <ul><li>microcytic anemia (MCV <80) </li></ul><ul><ul><li>iron deficiency anemia </li></ul></ul><ul><ul><li>thalassemia syndromes </li></ul></ul><ul><ul><li>anemia of chronic disease </li></ul></ul><ul><ul><li>sideroblastic anemia </li></ul></ul><ul><li>normocytic anemia (MCV 80-100) </li></ul><ul><ul><li>anemia of blood loss </li></ul></ul><ul><ul><li>hemolytic anemia </li></ul></ul><ul><li>macrocytic anemia (MCV >100) </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul>
  14. 15. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>a. intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>b. extrinsic abnormality </li></ul></ul></ul><ul><li>II ↓ RBC production </li></ul><ul><ul><li>1. stem cell abnormality </li></ul></ul><ul><ul><li>2. erythroblast abnormality </li></ul></ul><ul><ul><li>3. unknown/multiple mechanism </li></ul></ul>
  15. 16. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>blood loss </li></ul></ul><ul><ul><ul><li>a. acute : trauma, massive hemorrhage </li></ul></ul></ul><ul><ul><ul><li>b. chronic : GI lesion, GYN lesion </li></ul></ul></ul>
  16. 17. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul>
  17. 18. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul>
  18. 19. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul>hereditary spherocytosis hereditary elliptocytosis
  19. 20. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>hereditary spherocytosis </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>hereditary elliptocytosis </li></ul></ul></ul></ul></ul>
  20. 21. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul>pyruvate kinase def. G6PD def.
  21. 22. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>pyruvate kinase def. </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>G6PD def. </li></ul></ul></ul></ul></ul>
  22. 23. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul>Thalassemia sickle cell disease Hb C disease
  23. 24. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Thalassemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>sickle cell disease </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hb C disease </li></ul></ul></ul></ul></ul>
  24. 25. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul>PNH
  25. 26. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>PNH </li></ul></ul></ul></ul></ul>
  26. 27. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chemical injury </li></ul></ul></ul></ul><ul><ul><ul><ul><li>infection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>immunologic injury </li></ul></ul></ul></ul>
  27. 28. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma (microangiopathic HA) </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>TTP/HUS, DIC </li></ul></ul></ul></ul></ul>
  28. 29. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chemical injury </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>lead poisoning </li></ul></ul></ul></ul></ul>
  29. 30. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chemical injury </li></ul></ul></ul></ul><ul><ul><ul><ul><li>infection </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>malaria </li></ul></ul></ul></ul></ul>
  30. 31. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chemical injury </li></ul></ul></ul></ul><ul><ul><ul><ul><li>infection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>immunologic injury </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>autoimmune hemolytic anemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>drug mediated injuries </li></ul></ul></ul></ul></ul>
  31. 32. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>acquired memb. defect </li></ul></ul></ul></ul><ul><ul><ul><li>extrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>mechanical trauma </li></ul></ul></ul></ul><ul><ul><ul><ul><li>chemical injury </li></ul></ul></ul></ul><ul><ul><ul><ul><li>infection </li></ul></ul></ul></ul><ul><ul><ul><ul><li>immunologic injury </li></ul></ul></ul></ul>
  32. 33. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><li>II ↓ RBC production </li></ul><ul><ul><li>1. stem cell abnormality </li></ul></ul><ul><ul><li>2. erythroblast abnormality </li></ul></ul><ul><ul><li>3. unknown/multiple mechanism </li></ul></ul>
  33. 34. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><li>II ↓ RBC production </li></ul><ul><ul><li>stem cell abnormality </li></ul></ul><ul><ul><ul><li>aplastic anemia </li></ul></ul></ul>
  34. 35. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><li>II ↓ RBC production </li></ul><ul><ul><li>1. stem cell abnormality </li></ul></ul><ul><ul><li>2. erythroblast abnormality </li></ul></ul><ul><ul><ul><li>megaloblastic anemia </li></ul></ul></ul><ul><ul><ul><li>iron deficiency anemia (defective Hb synthesis) </li></ul></ul></ul>
  35. 36. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><li>II ↓ RBC production </li></ul><ul><ul><li>1. stem cell abnormality </li></ul></ul><ul><ul><li>2. erythroblast abnormality </li></ul></ul><ul><ul><li>3. unknown/multiple mechanism </li></ul></ul><ul><ul><ul><li>sideroblastic anemia </li></ul></ul></ul>
  36. 37. Hereditary Spherocytosis <ul><ul><li>intrinsic defect in the membrane cytoskeleton </li></ul></ul><ul><ul><li>genetic: autosomal dominant </li></ul></ul><ul><ul><li>pathoetiology: spectrin deficiency -> decreased RBC surface memb. -> loss of biconcavity </li></ul></ul><ul><ul><li>anemia: moderate anemia </li></ul></ul><ul><ul><li>normocytic </li></ul></ul><ul><ul><li>hyperchromic </li></ul></ul><ul><ul><li>reticulocytosis </li></ul></ul><ul><ul><li>entrapment of spherocytes in the spleen ( splenomegaly ) ( extravascular hemolysis ) </li></ul></ul><ul><ul><li>increased erythrocyte osmotic fragility </li></ul></ul>
  37. 38. Hereditary Spherocytosis
  38. 39. Hereditary Spherocytosis <ul><li>Sx: 1. mild to moderate hemolytic anemia </li></ul><ul><li>2. splenomegaly </li></ul><ul><li>3. marked compensatory erythroid hyperplasia in BM </li></ul><ul><li>4. jaundice, pigment cholelithiasis ← ( ↑ bilirubin ) </li></ul><ul><li>5. increased risk for acute red-cell aplasia due to parvovirus B19 infection </li></ul><ul><li>Lab: 1. increased osmotic fragility </li></ul><ul><li>2. normal MCV with increased MCHC </li></ul><ul><li>Tx: splenectomy </li></ul>
  39. 40. Hereditary Elliptocytosis <ul><ul><li>intrinsic defect in the membrane cytoskeleton </li></ul></ul><ul><ul><li>genetic: autosomal dominant </li></ul></ul><ul><ul><li>pathoetiology: impaired aggregation of spectrin </li></ul></ul><ul><ul><li>anemia: 90% of pt. are non-anemic </li></ul></ul><ul><ul><li>non-hypochromic elliptocytes >25% (nl=<15%) </li></ul></ul><ul><ul><li>Sx: splenomegaly </li></ul></ul>
  40. 41. Embden-Meyerhof glycolytic pathway
  41. 42. Pyruvate Kinase Deficiency <ul><ul><li>autosomal recessive </li></ul></ul><ul><ul><li>most common red cell enzyme deficiency involving Embden-Meyerhof glycolytic pathway </li></ul></ul><ul><ul><li>inability to maintain normal ATP levels </li></ul></ul><ul><ul><li>mild to moderate hemolysis </li></ul></ul><ul><ul><li>splenomegaly </li></ul></ul><ul><ul><li>patients tolerate anemia rather well (  high levels of 2,3-DPG ) </li></ul></ul><ul><ul><li>Dx: - fluorescent spot test </li></ul></ul><ul><ul><li>- enzyme assay </li></ul></ul>
  42. 43. X
  43. 44. fluorescent spot test <ul><li>Pyruvate kinase catalyzes the phosphorylation of ADP to ATP with the formation of pyruvate . Pyruvate then reduces any NADH present to NAD with formation of lactate. Loss of florescence of NADH under ultra-violet light is observed as evidence of the presence of pyruvate kinase. </li></ul>phosphoenol pyruvate pyruvate lactate PK ADP ATP *NADH NAD
  44. 46. G6PD Deficiency <ul><ul><li>Pathophysiology: decreased half life of G6PD </li></ul></ul><ul><ul><li>increased vulnerability to oxidative denaturation due to limited </li></ul></ul><ul><ul><li>generation of NADPH (older RBCs are preferentially destroyed) </li></ul></ul><ul><ul><li>Genetics: </li></ul></ul><ul><ul><li>high genetic heterogeneity </li></ul></ul><ul><ul><li>x-linked recessive (  full expression in male hemizygote) </li></ul></ul><ul><ul><li>Sx: </li></ul></ul><ul><ul><li>hemolysis after exposure to oxidant stress </li></ul></ul><ul><ul><li> - drugs: primaquine, chloroquine, sulfonamides, nitrofurantoins </li></ul></ul><ul><ul><li> - infections: viral hepatitis, pneumonia, typhoid fever </li></ul></ul><ul><ul><li>“ favism” : hemolysis after ingestion of fava beans (Mediterranean type) </li></ul></ul><ul><ul><li>Lab: </li></ul></ul><ul><ul><li>- poikilocytes, some spherocytes </li></ul></ul><ul><ul><li>- Heinz bodies : precipitates of denatured hemoglobin material </li></ul></ul><ul><ul><li>- “bite cells” </li></ul></ul>
  45. 47. G6PD Deficiency bite cell Heinz bodies
  46. 48. ANEMIA pathophysiologic classification <ul><li>I RBC loss </li></ul><ul><ul><li>1. blood loss </li></ul></ul><ul><ul><li>2. ↑ RBC destruction </li></ul></ul><ul><ul><ul><li>intrinsic abnormality </li></ul></ul></ul><ul><ul><ul><ul><li>membrane disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>enzyme disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hgb synthesis disorder </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Thalassemia </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>sickle cell disease </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Hb C disease </li></ul></ul></ul></ul></ul>
  47. 49. hemoglobin molecule two  chains two  chains four  -globin genes two  -globin genes
  48. 50. globin genes CH16 CH11
  49. 51. Thalassemia Syndromes <ul><ul><li>heterogeneous hemolytic disorders characterized by quantitative abnormalities of hemoglobin synthesis </li></ul></ul><ul><ul><li>genetic defect in globin production </li></ul></ul><ul><ul><li>selective depression or absence of a- or b- chain of hemoglobin </li></ul></ul><ul><ul><li>broad spectrum of presentation </li></ul></ul><ul><ul><li>predominantly seen in persons of Mediterranean , African and Asian ancestry </li></ul></ul><ul><ul><li>α -thalassemia : α -chain deficiency due to gene deletion </li></ul></ul><ul><ul><li>β -thalassemia : β -chain deficiency due to point mutation (Cooley’s anemia) </li></ul></ul>
  50. 52. Thalassemia Syndromes pathophysiology <ul><ul><li>Two (2) pathological mechanisms to contribute to develop anemia </li></ul></ul><ul><ul><li>1. inadequate Hgb formation  low MCHC, hypochromasia </li></ul></ul><ul><ul><li>2. relative excess of unaffected Hgb chain </li></ul></ul><ul><ul><li>  aggregation and precipitation of excess chain </li></ul></ul><ul><ul><li>  damage to the cell membrane </li></ul></ul><ul><ul><li>  loss of K+ and impaired DNA synthesis </li></ul></ul><ul><ul><li>  apoptosis of RBCs in BM (“ ineffective erythropoiesis ”) </li></ul></ul>
  51. 53. Thalassemia Syndromes pathophysiology <ul><ul><li>ineffective erythropoiesis </li></ul></ul><ul><ul><li> +  severe erythroid hyperplasia </li></ul></ul><ul><ul><li> hemolysis excess absorption of iron </li></ul></ul><ul><ul><li>  </li></ul></ul><ul><ul><li> severe iron overload </li></ul></ul>
  52. 54. α -thalassemia  1  2  /  normal  1  2  /   + -thal heterozygote (mild)  1  2  /   0 -thal heterozygote (moderate)
  53. 55. α -thalassemia  1  2  /   + -thal homozygote (moderate)  1  2  /   0 -thal x  + -thal (severe)  1  2  /   0 -thal homozygote (lethal)
  54. 56. β -thalassemia <ul><li>clinical classification of β thal is based on the severity of the anemia (based on the type of genetic defect and gene dosage ) </li></ul><ul><li>β + -> some β chain production </li></ul><ul><li>β 0 -> no β chain production </li></ul><ul><li>clinical manifestation </li></ul><ul><li>homozygous ( β + / β + or β 0 / β 0 ) severe </li></ul><ul><li>heterozygous ( β + / β or β 0 / β ) mild </li></ul>
  55. 57. β -thalassemia promoter gene mutation: 75-80% reduction of transcription rate (  + thal) chain termination mutation: premature termination of mRNA translation (  0 thal) splicing mutation: aberrant splicing (  0 &  + thal) most common cause of thal
  56. 58. “ Thalassemia Major” <ul><ul><li>homozygous β + / β + or β 0 / β 0 </li></ul></ul><ul><ul><li>severe anemia at 6 to 9 months of age requiring blood transfusion </li></ul></ul><ul><ul><ul><ul><li>death at early age, if not transfused </li></ul></ul></ul></ul><ul><ul><li>severe erythrophagocytosis and extramedullary hematopoiesis </li></ul></ul><ul><ul><li>  hepatosplenomegaly </li></ul></ul><ul><ul><li>marked red marrow expansion  “Crew-Cut” sign </li></ul></ul><ul><ul><li>hemosiderosis </li></ul></ul><ul><ul><li>heart disease 2º to hemochromatosis is the major cause of death in older patients </li></ul></ul>
  57. 59. “ Thalassemia Major”
  58. 60. “ Thalassemia Major” <ul><ul><li>Dx: </li></ul></ul><ul><ul><li>anemia work up </li></ul></ul><ul><ul><li>hemoglobin electrophoresis  no or very low HbA </li></ul></ul><ul><ul><li> markedly elevated HbF </li></ul></ul><ul><ul><li>DNA analysis </li></ul></ul><ul><ul><li>Rx: </li></ul></ul><ul><ul><li>blood transfusion with iron chelators </li></ul></ul><ul><ul><ul><li>improvement of anemia </li></ul></ul></ul><ul><ul><ul><li>suppression of secondary features related to excessive erythropoiesis </li></ul></ul></ul><ul><ul><li>BM transplantation </li></ul></ul>
  59. 61. “ Thalassemia Minor” <ul><ul><li>much more common than Thalassemia major </li></ul></ul><ul><ul><li>heterozygous b + /b or b 0 /b </li></ul></ul><ul><ul><li>peripheral smear: hypochromia, microcytosis, basophilic stippling, target cells </li></ul></ul><ul><ul><li>may be resistant against falciparum malaria </li></ul></ul><ul><ul><li>usually asymptomatic or mild anemia (microcytic anemia) </li></ul></ul><ul><ul><li>DDx: iron deficiency anemia </li></ul></ul><ul><ul><ul><ul><ul><li>serum iron </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>total iron binding capacity </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>serum ferritin </li></ul></ul></ul></ul></ul>
  60. 68. Sickle Cell Disease <ul><ul><li>prototype of hereditary hemoglobinopathies </li></ul></ul><ul><ul><li>structurally abnormal hemoglobin from a point mutation </li></ul></ul>
  61. 69. Sickle Cell Disease <ul><ul><li>- severe anemia  generalized growth and developmental impairment </li></ul></ul><ul><ul><li>- vaso-occlusive complications </li></ul></ul><ul><ul><li>- painful crisis: bones, lungs, liver, brain, spleen, penis </li></ul></ul><ul><ul><li>- acute chest syndrome </li></ul></ul><ul><ul><li>- aplastic crisis </li></ul></ul><ul><ul><li>- sequestration crisis (splenic hyperplasia  pooling of blood) </li></ul></ul><ul><ul><li>- chronic hyperbilirubinemia </li></ul></ul><ul><ul><li>- increased susceptibility to infection  septicemia, meningitis </li></ul></ul><ul><ul><li> (encapsulated bacteria) </li></ul></ul><ul><ul><li>Dx: clinical findings </li></ul></ul><ul><ul><li>peripheral blood smear </li></ul></ul><ul><ul><li>hemoglobin analysis </li></ul></ul>
  62. 70. Sickle Cell Trait <ul><ul><li>- heterozygous (Ss) Hb S -- 30-40% </li></ul></ul><ul><ul><li>- approx. 10% of American blacks </li></ul></ul><ul><ul><li>- normal peripheral blood count and RBC life span </li></ul></ul><ul><ul><li>- rare sickling with low oxygen tension, low pH </li></ul></ul><ul><ul><li>(local ischemia, high altitude, pneumonia, etc.) </li></ul></ul>
  63. 71. Paroxysmal Nocturnal Hemoglobinuria (PNH) <ul><ul><li>an acquired clonal disorder of stem cells, and results from a somatic mutation in phosphatidylinositol glycan A (PIGA) gene that is essential for the synthesis of the glycosylphosphatidylinositol (GPI) anchor protein of the membrane, and makes RBCs very sensitive to complement-mediated cell lysis due to the deficiency of proteins that regulate complement activity </li></ul></ul>GPI-linked complement reg. Proteins CD55 (DAF) CD59 CD8 binding protein
  64. 72. Paroxysmal Nocturnal Hemoglobinuria (PNH) <ul><ul><li>clinical: </li></ul></ul><ul><ul><li>- chronic hemolysis without dramatic hemoglobinuria (75%) </li></ul></ul><ul><ul><li>- paroxysmal and nocturnal intravascular hemolysis (25%) </li></ul></ul><ul><ul><li>- venous thromboses in hepatic, portal or cerebral veins </li></ul></ul>
  65. 73. TTP / HUS <ul><ul><li>Thrombotic Thrombocytopenic Purpura (TTP) </li></ul></ul><ul><ul><li>Hemolytic Uremic Syndrome (HUS) </li></ul></ul><ul><ul><li>- widespread formation of hyaline thrombi in microcirculation </li></ul></ul><ul><ul><li>- endothelial injury and activation of intravascular thrombosis seem to be the initiating mechanisms </li></ul></ul><ul><ul><li>- may have diverse causes </li></ul></ul><ul><ul><li>- verotoxins ( E.coli O157:H7) </li></ul></ul><ul><ul><li>- viral infection </li></ul></ul>
  66. 74. TTP / HUS <ul><ul><li>TTP (Thrombotic Thrombocytopenic Purpura) </li></ul></ul><ul><ul><li>adult female with pentad </li></ul></ul><ul><ul><li>1. Fever </li></ul></ul><ul><ul><li>2. Thrombocytopenia </li></ul></ul><ul><ul><li>3. Microangiopathic hemolytic anemia </li></ul></ul><ul><ul><li>4. Transient neurologic deficits </li></ul></ul><ul><ul><li>5. Renal failure </li></ul></ul><ul><ul><li>HUS (Hemolytic Uremic Syndrome) </li></ul></ul><ul><ul><li>child with acute renal failure </li></ul></ul><ul><ul><li>microangiopathic hemolytic anemia </li></ul></ul><ul><ul><li>thrombocytopenia </li></ul></ul><ul><ul><li>no neurologic symptoms </li></ul></ul>
  67. 75. Disseminated Intravascular Coagulation (DIC) <ul><ul><li>- an acute, subacute, or chronic thrombohemorrhagic disorder occurring as a secondary complication in a variety of diseases </li></ul></ul><ul><ul><li>- activation of clotting system resulting in wide spread formation of microthrombi throughout the microcirculation </li></ul></ul><ul><ul><li>- as a consequence, causing consumption of platelets, fibrin and coagulation factors, and activation of thrombolytic mechanism </li></ul></ul><ul><ul><li>Two major triggering mechanisms </li></ul></ul><ul><ul><li>1. release of tissue factor or thromboplastic substance </li></ul></ul><ul><ul><li>2. widespread endothelial injury </li></ul></ul>
  68. 76. Disseminated Intravascular Coagulation (DIC) <ul><ul><li>Pathology:- wide spread thrombi </li></ul></ul><ul><ul><li> (brain, heart, lungs, kidneys, adrenals, spleen , liver) </li></ul></ul><ul><ul><li>- microinfarcts </li></ul></ul><ul><ul><li>Clinical: - ~50% associated with obstetric complications </li></ul></ul><ul><ul><li>- ~30% with carcinomatosis </li></ul></ul><ul><ul><li>- microangiopathic anemia </li></ul></ul><ul><ul><li>- dyspnea, cyanosis </li></ul></ul><ul><ul><li>- convulsions, coma </li></ul></ul><ul><ul><li>- oliguria, acute renal failure </li></ul></ul><ul><ul><li>- shock, circulatory failure </li></ul></ul>
  69. 77. Lead Poisoning <ul><ul><li>- inhibition of 5’-nucleotidase and sodium-potassium pump </li></ul></ul><ul><ul><li> decreased RBC survival </li></ul></ul><ul><ul><li>- intestinal absorption of Pb is enhanced by def. of calcium, iron or zinc </li></ul></ul><ul><ul><li>- blood accumulates 5-10% of absorbed Pb </li></ul></ul><ul><ul><li>- Pb clearance: </li></ul></ul><ul><ul><li>from blood  rapidly cleared </li></ul></ul><ul><ul><li>from bone  slow (half-life = 30 yrs) </li></ul></ul><ul><ul><li>Lab: basophilic stippling </li></ul></ul>
  70. 78. Malaria <ul><ul><li>- intracellular protozoan parasite ( Plasmodium ) </li></ul></ul><ul><ul><li>P.falciparum : worldwide infection affecting 100 million people </li></ul></ul><ul><ul><li>1 to 1.5 million deaths each year </li></ul></ul><ul><ul><li>other malaria parasites: </li></ul></ul><ul><ul><li>P.vivax </li></ul></ul><ul><ul><li>P.ovale </li></ul></ul><ul><ul><li>P.malariae </li></ul></ul>
  71. 79. Immunohemolytic Anemia <ul><ul><li>several subtypes </li></ul></ul><ul><ul><li>(1) warm antibody type </li></ul></ul><ul><ul><li>(2) cold agglutinin type </li></ul></ul><ul><ul><li>(3) cold hemolysin </li></ul></ul>
  72. 80. Immunohemolytic Anemia <ul><ul><li>(1) warm antibody type </li></ul></ul><ul><ul><li>- 80 to 90% of autoimmune hemolytic anemia </li></ul></ul><ul><ul><li>- lg G antibody </li></ul></ul><ul><ul><li>- coating RBC with anti-Rh Ab and complement </li></ul></ul><ul><ul><li>- RBCs are ultimately destroyed by splenic macrophages </li></ul></ul><ul><ul><li>clinical: - intermittent hemolysis </li></ul></ul><ul><ul><li>- moderate splenomegaly </li></ul></ul><ul><ul><li>- unpredictable clinical course </li></ul></ul><ul><ul><li>etiology: </li></ul></ul><ul><ul><li> a. idiopathic disease </li></ul></ul><ul><ul><li> b. secondary disorder </li></ul></ul><ul><ul><li>- lymphoma (lymphocytic lymphoma) </li></ul></ul><ul><ul><li>- leukemia (chronic lymphocytic leukemia) </li></ul></ul><ul><ul><li>- autoimmune disorders (SLE, collagen vascular diseases) </li></ul></ul><ul><ul><li>- viral infections </li></ul></ul><ul><ul><li>- drugs: penicillin, cephalosporin (hapten) </li></ul></ul><ul><ul><li>α -methyldopa (autoantibody) </li></ul></ul>
  73. 81. Immunohemolytic Anemia <ul><ul><li>(2) cold agglutinin type </li></ul></ul><ul><ul><li>- 10 to 20% of autoimmune hemolytic anemia </li></ul></ul><ul><ul><li>- Ig M type antibody </li></ul></ul><ul><ul><li>- complement-coated RBC will be removed by liver Kupffer cells </li></ul></ul><ul><ul><li>etiology: </li></ul></ul><ul><ul><li>a. acute: - mycoplasma </li></ul></ul><ul><ul><li> - infectious mononucleosis </li></ul></ul><ul><ul><li>b. chronic: - idiopathic </li></ul></ul><ul><ul><li> - lymphoma </li></ul></ul>
  74. 82. Immunohemolytic Anemia <ul><ul><li>(3) cold hemolysis </li></ul></ul><ul><ul><li>paroxysmal cold hemoglobinuria </li></ul></ul><ul><ul><li>- caused by IgG bind to RBCs at low temp and fix complement </li></ul></ul><ul><ul><li>- acute intermittent massive hemolysis after exposure to cold </li></ul></ul><ul><ul><li>- complement dependent hemolysis </li></ul></ul><ul><ul><li>- caused by IgG against P blood group antigen </li></ul></ul><ul><ul><li>- IgG-Ab (Donath-Landsteiner Ab) binds to RBC and fix complement at cold temp and then complement activation when temp is elevated. </li></ul></ul><ul><ul><li>mostly seen after infection: mycoplasmal pneumonia </li></ul></ul><ul><ul><li>measles </li></ul></ul><ul><ul><li>mumps </li></ul></ul>
  75. 83. Drug-Mediated Injury <ul><ul><li>(1) autoantibody induction </li></ul></ul><ul><ul><li>α -methyldopa  Ig G antibody </li></ul></ul><ul><ul><li>(2) immune complex formation (drug-Ab complex) </li></ul></ul><ul><ul><li>quinidine  Ig M complex </li></ul></ul><ul><ul><li> complement-mediated lysis </li></ul></ul><ul><ul><li>(3) hapten formation (drug-RBC membrane protein complex) </li></ul></ul><ul><ul><li>penicillin </li></ul></ul>
  76. 84. Aplastic Anemia <ul><ul><li>- pancytopenia characterized by </li></ul></ul><ul><ul><li>(1) anemia </li></ul></ul><ul><ul><li>(2) neutropenia </li></ul></ul><ul><ul><li>(3) thrombocytopenia </li></ul></ul><ul><ul><li>- failure or suppression of multipotent myeloid stem cells causes inadequate production or release of the differentiated cell lines </li></ul></ul><ul><ul><li>Etiology: </li></ul></ul><ul><ul><li>- 65% idiopathic </li></ul></ul><ul><ul><li>- chemicals/drugs </li></ul></ul><ul><ul><li>(benzene, chloramphenicol, alkylating agents, antimetabolite) </li></ul></ul><ul><ul><li>- whole body irradiation </li></ul></ul><ul><ul><li>- viral hepatitis </li></ul></ul>
  77. 85. Aplastic Anemia <ul><ul><li>Pathology: markedly hypoplastic bone marrow </li></ul></ul><ul><ul><li>Clinical: - may occur at any age </li></ul></ul><ul><ul><li>- variable initial manifestations </li></ul></ul><ul><ul><li> (depending on the affected cell line) </li></ul></ul><ul><ul><li>- no splenomegaly </li></ul></ul><ul><ul><li>- normocytic and normochromic RBCs </li></ul></ul><ul><ul><li>- no reticulocytosis </li></ul></ul><ul><ul><li>Dx: bone marrow biopsy </li></ul></ul><ul><ul><li>hypocellular due to stem cell failure </li></ul></ul>
  78. 86. Megaloblastic Anemia <ul><ul><li>A group of disorders characterized by a reduced rate of DNA synthesis </li></ul></ul><ul><ul><li>The dyssynchrony in nuclear (DNA) and cytoplasmic (RNA) development is the morphologic hallmark of this type of disorder, since RNA synthesis, RNA processing and protein synthesis are unaffected. </li></ul></ul>
  79. 87. Vitamin B12 / Folate Deficiency <ul><li>Vitamin B12 (cobalamin) -- a vital ingredient for DNA synthesis and Krebs cycle </li></ul>Methylcobalamin a coenzyme for tetrahydrofolate (FH 4 )
  80. 88. Vitamin B12 Absorption Vit B12: absorbed in ileum (with intrinsic factor) Intrinsic factor
  81. 89. Vitamin B12 / Folate Deficiency <ul><ul><li>Lab: </li></ul></ul><ul><ul><li>Blood: - macro-ovalocytes, giant hypersegmented PMNs (no giant platelets) </li></ul></ul><ul><ul><li>- pancytopenia </li></ul></ul><ul><ul><li>- elevated MCV </li></ul></ul><ul><ul><li>- anisocytosis </li></ul></ul><ul><ul><li>- poikilocytosis </li></ul></ul><ul><ul><li>BM: - hyperplastic </li></ul></ul><ul><ul><li>-  myeloid : erythroid ratio </li></ul></ul><ul><ul><li>- megaloblasts </li></ul></ul><ul><ul><li>- giant metamyelocytes </li></ul></ul><ul><ul><li>- autohemolysis ( -> ↑ serum bilirubin, ↑ LDH) </li></ul></ul>
  82. 90. Vitamin B12 Deficiency <ul><li>etiology: </li></ul><ul><li>dietary deficiency ---- rare </li></ul><ul><ul><ul><li>strict vegetarians) </li></ul></ul></ul><ul><li>decreased absorption </li></ul><ul><ul><li>decreased intrinsic factor </li></ul></ul><ul><ul><ul><li>gastrectomy </li></ul></ul></ul><ul><ul><ul><li>pernicious anemia </li></ul></ul></ul><ul><ul><li>pancreatic insufficiency </li></ul></ul><ul><ul><li>intestinal malabsorption </li></ul></ul><ul><ul><ul><li>parasites (fish tapeworm [ Diphyllobothrium latum ]) </li></ul></ul></ul><ul><ul><ul><li>bacteria (blind-loop syndrome) </li></ul></ul></ul><ul><ul><ul><li>ileal Crohn’s disease </li></ul></ul></ul>
  83. 91. Vitamin B12 Deficiency <ul><li>Sx: </li></ul><ul><li>weakness ← anemia (megaloblastic anemia) </li></ul><ul><li>sore (“beefy”) tongue ← generalized epithelial atrophy </li></ul><ul><li>demyelination of spinal cord (posterior and lateral portions) (subacute combined spinal degeneration) </li></ul><ul><ul><li>loss of vibration and position senses ← posterior tracts loss </li></ul></ul><ul><ul><li>arm and leg dystaxia ← dorsal spinocerebellar tracts loss </li></ul></ul><ul><ul><li>spastic paralysis ← corticospinal tracts loss </li></ul></ul>
  84. 92. Vitamin B12 Deficiency <ul><li>Lab: </li></ul><ul><li>low serum B12 level </li></ul><ul><li>increased serum homocysteine </li></ul><ul><li>increased methylmalonic acid in urine </li></ul><ul><li>Dx: Schilling test </li></ul><ul><li>oral radioactive B12 -> 2 hrs later -> parenteral large flushing dose of non-labeled B12 -> measure urine for radioactive B12 </li></ul><ul><li>nl: >7% of radio-labeled B12 excreted in 24-hr urine </li></ul><ul><li>abnormal (lacking IF): less than 7% of B12 excreted </li></ul><ul><li>Tx: intramuscular vitamin B12 </li></ul><ul><li>-> increase in reticulocytes in 5 days </li></ul>
  85. 93. folate deficiency <ul><li>etiology: </li></ul><ul><li>dietary deficiency (folate def. takes only months to develop) </li></ul><ul><ul><li>“ tea and toast” diet (elderly individuals) </li></ul></ul><ul><ul><li>chronic alcoholics </li></ul></ul><ul><li>decreased absorption </li></ul><ul><ul><li>intestinal malabsorption (folate is absorbed in upper intestine) </li></ul></ul><ul><li>increased requirement </li></ul><ul><ul><li>pregnancy (folate def in pregnancy -> neural tube defects) </li></ul></ul><ul><ul><li>infancy </li></ul></ul><ul><li>folate antagonists </li></ul><ul><ul><li>chemotherapy (i.e. methotrexate) </li></ul></ul>
  86. 94. folate deficiency <ul><li>Sx: </li></ul><ul><li>megaloblastic anemia </li></ul><ul><li>no neurologic degeneration </li></ul><ul><li>Lab: </li></ul><ul><li>low serum folate level </li></ul><ul><li>increased serum homocysteine </li></ul><ul><li>Tx: folate </li></ul>
  87. 95. Iron Deficiency Anemia <ul><li>Iron: absorbed in duodenum </li></ul><ul><li>When iron loss exceeds its intake for a long time, iron storage decreases and insufficient amount of iron is available for hemoglobin production </li></ul><ul><li>Iron deficiency anemia develops in sequence of stages: </li></ul><ul><li>1. Iron Depletion </li></ul><ul><li>2. Iron Deficient Erythropoiesis </li></ul><ul><li>3. Iron Deficiency Anemia </li></ul>
  88. 96. Iron Deficiency Anemia <ul><li>Clinical: </li></ul><ul><li>- general fatigue </li></ul><ul><li>- SOB </li></ul><ul><li>- spoon nails (koilonychia) </li></ul><ul><li>- smooth, sore tongue </li></ul><ul><li>- epithelial atrophy </li></ul><ul><li>- pica (eating unusual things [e.g., dirt]) </li></ul>
  89. 97. Iron Deficiency Anemia <ul><ul><li>Lab: </li></ul></ul><ul><ul><li>Blood: - normochromic-normocytic </li></ul></ul><ul><ul><li> microcytosis, anisocytosis, poikilocytosis, hypochromia </li></ul></ul><ul><ul><li>- decreased reticulocytes </li></ul></ul><ul><ul><li>- low MCV </li></ul></ul><ul><ul><li>- relatively low Hgb, Hct </li></ul></ul><ul><ul><li>Marrow: no iron storage </li></ul></ul><ul><ul><li>normoblastic hyperplasia </li></ul></ul><ul><ul><li> smaller normoblast with deficient Hgb </li></ul></ul>
  90. 98. Iron Deficiency Anemia <ul><ul><li>Serum iron (nl = 50-160 mg/dL) : low </li></ul></ul><ul><ul><li>Serum iron-binding capacity (nl = 250-400 mg/L) : increased </li></ul></ul><ul><ul><li>% saturation of TIBC (nl = 20-55%) : <15% </li></ul></ul><ul><ul><li>Serum ferritin (nl = 12-300 mg/L) : low </li></ul></ul>
  91. 99. sideroblastic anemia <ul><li>due to altered production of heme (defect in protoporphyrin production) </li></ul><ul><li>associated with ring sideroblasts in bone marrow </li></ul><ul><li>peripheral blood: may show dismorphic RBCs </li></ul><ul><li>lab: increased serum iron ferritin free erythrocyte protoporphyrin (FEP) % saturation of TIBC decreased TIBC </li></ul>
  92. 100. Sideroblastic Anemia <ul><ul><li>a heterogeneous group of disorders associated with various defects in the porphyrin biosynthetic pathway </li></ul></ul><ul><ul><ul><ul><li>porphyrn biosynthesis defects </li></ul></ul></ul></ul><ul><ul><ul><ul><li>diminished heme synthesis </li></ul></ul></ul></ul><ul><ul><ul><ul><li>increased cellular iron uptake </li></ul></ul></ul></ul><ul><ul><li>characterized by the association of anemia with presence of ringed sideroblast (a normoblast containing excessive deposits of iron within mitochondria) in bone marrow </li></ul></ul>
  93. 101. Sideroblastic Anemia <ul><ul><li>Sub-types: </li></ul></ul><ul><ul><li>Hereditary Sideroblastic Anemias </li></ul></ul><ul><ul><li>hereditary sex-linked </li></ul></ul><ul><ul><li>inheritance undetermined </li></ul></ul><ul><ul><li>Acquired Sideroblastic Anemias </li></ul></ul><ul><ul><li>primary (idiopathic) sideroblastic anemia </li></ul></ul><ul><ul><li>secondary (drug- or toxin-induced) sideroblastic anemia </li></ul></ul><ul><ul><li> anti TB drugs (isoniazid, cycloserine, pyrazinamide) </li></ul></ul><ul><ul><li> lead poisoning </li></ul></ul><ul><ul><li> chloramphenicol </li></ul></ul><ul><ul><li> ethanol </li></ul></ul>
  94. 102. Sideroblastic Anemia
  95. 103. Sideroblastic Anemia <ul><ul><li>clinical: characterized by hypochromic, often microcytic, red cells in the blood usually mixed with normochromic cells </li></ul></ul><ul><ul><ul><li>hypochromic anemia </li></ul></ul></ul><ul><ul><ul><li>hyperferremia </li></ul></ul></ul><ul><ul><ul><li>increased transferrin saturation </li></ul></ul></ul><ul><ul><li>Lab: serum iron: increased </li></ul></ul><ul><ul><li>TIBC: decreased </li></ul></ul><ul><ul><li>% saturation: greatly elevated </li></ul></ul><ul><ul><li>bone marrow: - markedly increased iron storage </li></ul></ul><ul><ul><li>- erythroid hyperplasia </li></ul></ul><ul><ul><li>- increased sideroblasts </li></ul></ul>
  96. 104. anemia work-up <ul><li>M: Hb <13.5 Hct <41 </li></ul><ul><li>F: Hb <12 Hct <36 </li></ul><ul><li>[check MCV] </li></ul><ul><li>MCV <80 = microcytic </li></ul><ul><ul><li>Fe deficiency </li></ul></ul><ul><ul><li>thalassemia </li></ul></ul><ul><ul><li>anemia of chronic disease </li></ul></ul><ul><ul><li>sideroblastic anemia </li></ul></ul>
  97. 105. anemia work-up <ul><li>MCV >100 = macrocytic </li></ul><ul><ul><li>megaloblastic anemia </li></ul></ul><ul><ul><ul><li>VitB12 deficiency </li></ul></ul></ul><ul><ul><ul><li>folate deficiency </li></ul></ul></ul><ul><ul><li>alcoholic liver disease </li></ul></ul><ul><li>MCV 80-100 = normocytic </li></ul><ul><li>[chech reticulocyte count] </li></ul>
  98. 106. anemia work-up <ul><li>low reticulocyte: </li></ul><ul><ul><li>- marrow failure - leukemia/metastasis </li></ul></ul><ul><ul><li>- aplastic anemia - renal failure </li></ul></ul><ul><ul><li>myelofibrosis - anemia of chronic disease </li></ul></ul><ul><li>high reticulocyte: </li></ul><ul><ul><li>sickle cell anemia - autoimmune hemolytic anemia </li></ul></ul><ul><ul><li>G6PD deficiency - hereditary sphelocytosis </li></ul></ul><ul><ul><li>paroxysmal nocturnal hemoglobiuria </li></ul></ul>
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