BLOOD: Hematopoietic System Pathology 1

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Hematopoiesis Fetal: stem cells migrate to liver, bone marrow, spleen,lymph nodes Postnatal: extramedullary production subsides and bone marrow is site of blood formation Adult: blood formation only in flat bones 3

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5 Normal Erythrocyte Color – hemoglobin Biconcave shape - determined by cytoskeleton Deformability - easily deform (bend)

Hemoglobin (Hb) pyrrole ring Fe 2+ binds O 2 4 heme groups - 4 pyrrole rings each with 1 ferrous ion 4 globin polypeptide chains 2 alpha + 2 beta = HbA 2 alpha + 2 delta = HbA2 2 alpha + 2 gamma = HbF

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Anemia a reduction of hemoglobin in the blood: May be associated with: -Appearance of abnormal hemoglobin -Reduced numbers of RBCs -Structural abnormalities of RBCs Results in decreased oxygen to tissues (hypoxia): –decreased metabolism generally –somnolence, shortness of breath, fatigue, pallor

9 Classifying Anemias –Morphologically and biochemically (size, shape, protein (e.g., hemoglobin) analysis) –Etiologically (what caused it?)

Anemias – characterized by RBC color, size and shape Variation in color –Normochromic – normal levels of hb but insufficient number of rbcs –Hypochromic Variation in size (anisocytosis) –Small RBC: microcytic –Large RBC: macrocytic Variation in shape (poikilocytosis) 10

Anemia Morphology 11

Anemias - morphology, types Normocytic, normochromic anemia –dilutional anemia Microcytic, hypochromic anemia –RBC is small & pale –Examples (iron deficiency, thalassemia) Macrocytic, normochromic anemia –RBC is large and normal color –Examples (B12 and/or folic acid deficiency, chronic liver disease) Abnormal shape anemias –eliptocytosis, spherocytosis –sickle cell anemia is a classic example 12

Etiology and Pathogenesis of Anemias May be a consequence of: a)Decreased hematopoiesis b) Abnormal hematopoiesis c) Increased loss of RBCs 13

Decreased Hematopoiesis: Aplastic anemia –Decreased production of RBCs due to bone marrow failure (fails to regenerate) –Rare and usually accompanied by leukopenia and thrombocytopenia (i.e., pancytopenia) –Two forms exist: 1) Idiopathic (unknown cause) predominates Prognosis is poor without BM transplant 2) Secondary (caused by reversible BM suppression) cytotoxic drugs, radiation therapy, viral infection BM reduced to fibroblasts, fat cells, some lymphocytes 14

Aplastic anemia - clinical features Bleeding tendencies uncontrolled infections fatigue, weakness RBC symptoms show up late. Why? 15

Decreased hematopoiesis: Other types –Myelophthisic Anemia: Bone marrow stem cells replaced with metastatic tumor cells –Nutrient deficiency Iron (hemoglobin) B12 and folic acid (DNA synthesis) → megaloblastic anemia Protein (necessary for hematopoiesis) 16

Hemoglobin Synthesis requires –iron –vitamin B12 –vitamin B6 –folic acid anemia results from poor diet, malabsorption, or loss of nutrients 17

Recycling and reutilization are the primary means by which Fe levels are maintained – diet provides only small (1-2%) amounts of Fe Made in the liver 18

Decreased Hematopoiesis- iron deficiency anemia Most common anemia Typical causes: –chronic blood loss –inadequate iron intake or absorption (GI disease) –increased requirement - pregnancy, childhood growth Low iron = low hemoglobin synthesis Microcytic, hypochromic RBCs Responds well to supplementary iron, but may only be symptom of serious disease (marked by chronic bleeding or intestinal malabsorption) which can be masked by treatment 19

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Decreased Hematopoiesis: Megaloblastic anemia Deficiency of Vitamin B 12 or Folic acid –Hematopoietic cell maturation is delayed –DNA synthesis is impaired –Nucleus does not mature (remains large) –Prior to maturation, many megaloblasts are destroyed –Slowdown of erythropoiesis & loss of megaloblastic cells combine to cause reduction in RBCs (anemia) 21

22 Megaloblastic anemia

Megaloblastic anemia (cont’d) Folic acid deficiency –Inadequate intake or malabsorption due to intestinal disease –Pregnancy, lactation and infancy require more folic acid –Certain drugs (e.g., the anti-cancer drug, methotrexate) antagonize folic acid uptake –treated with oral intake of folic acid 23

Abnormal hematopoiesis Typically a genetic abnormality: Sickle Cell Anemia Thalassemia Hereditary Spherocytosis 24

Abnormal Hematopoiesis: Sickle cell HbA is replaced by HbS HbS has abnormal beta chain which still combines with normal alpha chains Autosomal recessive trait 25

26 HbS undergoes polymerization at low oxygen tension which causes “sickling”

Sickle cell Most prevalent among Black African Americans 50,000 persons in USA have sickle cell anemia about 1% of all black Americans have disease symptoms 27

Sickle cell Complication: multiple infarcts –brain : neurologic deficits –bones, spleen (autosplenectomy where the spleen becomes fibrotic, shrinks due to blood stasis, hypoxia and infarcts) & extremities: pain – retina: decreased vision, hemorrhage, neovascularization –bile stones: increased RBC destruction leads to increased bilirubin excretion 28 Treatment: hydration, analgesics, blood transfusions

Abnormal Hematopoiesis: Thalassemia Mediterranean anemia (“thalassa” is Greek for sea; most prevalent around Mediterranean sea) Autosomal recessive defect in synthesis of HbA –reduced rate of globin chain synthesis (alpha or beta) Defect is quantitative (decreased amount of globin), not qualitative (no abnormal globin produced as occurs in sickle cell) 29

Thalassemia minor mild symptoms microcytic, hypochromic anemia which does not respond to Fe supplemention (unlike iron deficiency anemia) protects against malaria. Smaller RBCs, and more of them, help withstand malaria attack where 50% of RBCs can be lysed 30

Thalassemia major high mortality insufficient number of RBC’s and cells prone to hemolysis die in childhood without transfusion 31

Abnormal Hematopoiesis: Hereditary spherocytosis cytoskeletal defect leads to destabilization of RBC membrane autosomal dominant, 1:5000 in US spherical cells, anisocytosis (unequal size) fragile cells, rupture easily in hypotonic media don’t deform, increased rigidity leads to splenic sequestration preferred treatment: splenectomy 32

33 Small or absent central pale zone

Increased loss of RBC’s Hemorrhage –dilution as body mobilizes fluid from interstitial space results in temporary dilutional anemia Intrasplenic sequestration –Idiopathic (unknown origin) hypersplenism (increased rate of RBC destruction) Immune hemolysis Infections –Malaria (Plasmodium parasite infection invades RBC and causes lysis) 34

Immune hemolytic anemia Antibodies that destroy RBCs (via complement activation) –Autoantigen autoimmune hemolytic anemia –Alloantigen blood transfusion hemolytic disease of the newborn –Neoantigen drug induced hemolysis where non-immunogenic chemical transforms self-protein into an immunogen (neoantigen) 35

AAA or AOanti-B BBB or BOanti-A ABABno antibodies OOOanti-A and anti-B phenotype genotype natural IgM antibody expressed Major Blood types (ABO) 36

Hemolytic disease of the newborn 37 IgG antibody