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    Add as Friendhaemolytic anaemia peripheral smear erythropoieses

    by: pankaj

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    2 : Normal Red Cells No nucleus Biconcave discs Center 1/3 pallor Pink cytoplasm (Hb filled) Cell size 7- 8 µ - capill. Negative charge 100-120 days life span
    3 : The Factory – Bone Marrow Sternum, pelvis, vertebrae, long bones, skull bones, Tibia (paed) From stem cells (pleuripotent) 75% of marrow for WBC 25% of BM for Red cells Erythrod / Granulocyte Ratio 1:3 Large white areas are marrow fat
    4 : Hemoglobin (Hb)
    6 : HEMOPOIESIS Hemo: Referring to blood cells Poiesis: “The development or production of” The word Hemopoiesis refers to the production & development of all the blood cells: Erythrocytes: Erythropoiesis Leucocytes: Leucopoiesis Thrombocytes: Thrombopoiesis. Begins in the 20th week of life in the fetal liver & spleen, continues in the bone marrow till young adulthood & beyond!
    7 : Sites of erythropoiesis Mesoblastic stage- in the yolk sac Starts at 2 weeks of intrauterine life Hepatic stage- 2-7 months Both liver and spleen Myeloid stage
    8 : Myeloid stage Occurs in bone marrow Starts at 5 months of fetal life and takes over completely at birth Red bone marrow of all bone. Late adult life, red marrow of flat bones
    9 : SITES OF HEMOPOIESIS Active Hemopoietic marrow is found, in children throughout the: Axial skeleton: Cranium Ribs. Sternum Vertebrae Pelvis Appendicular skeleton: Bones of the Upper & Lower limbs In Adults active hemopoietic marrow is found only in: The axial skeleton The proximal ends of the appendicular skeleton.
    10 : In adults extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes destroyed or fibrosed In children, blood cells are actively produced in the marrow cavities of all the bones. By age 20, the marrow in the cavities of the long bones, except for the upper humerus and femur, has become inactive . Active cellular marrow is called red marrow; inactive marrow that is infiltrated with fat is called yellow marrow.
    11 : The bone marrow is actually one of the largest organs in the body, approaching the size and weight of the liver. It is also one of the most active. Normally, 75% of the cells in the marrow belong to the white blood cell-producing myeloid series and only 25% are maturing red cells, even though there are over 500 times as many red cells in the circulation as there are white cells. This difference in the marrow reflects the fact that the average life span of white cells is short, whereas that of red cells is long.
    12 : STEM CELLS These cells have extensive proliferative capacity and also the: Ability to give rise to new stem cells (Self Renewal) Ability to differentiate into any blood cells lines (Pluripotency) They grow and develop in the bone marrow. The bone marrow & spleen form a supporting system, called the “hemopoietic microenvironment”
    13 : Stem cells Totipotential stem cells- convert into any tissue type Pluripotent stem cell- Pluripotent hematopoeitic stem cell Committed stem cells- CFU E, CFU G, CFU M, etc
    15 : Hematopoietic stem cells (HSCs) are bone marrow cells that are capable of producing all types of blood cells. They differentiate into one or another type of committed stem cells (progenitor cells). These in turn form the various differentiated types of blood cells. There are separate pools of progenitor cells for megakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils; neutrophils and monocytes arise from a common precursor.
    16 :
    17 : PROGENITOR CELLS Committed stem cells lose their capacity for self-renewal. They become irreversibly committed. These cells are termed as “Progenitor cells” They are regulated by certain hormones or substances so that they can: Proliferate Undergo Maturation.
    18 :
    19 : ERYTHROPOIESIS 15-20µm- basophilic cytoplasm, nucleus with nucleoli. 14-17µm-mitosis, basophilic cytoplasm, nucleoli disappears. 10-15µm-’POLYCHROMASIA’ Hb appears, nucleus condenses. 7-10µm- PYKNOTIC Nucleus. Extrusion, Hb is maximum. 7.3µm- Reticulum of basophilic material in the cytoplasm. 7.2µm- Mature red cell with Hb.
    20 : Pronormoblast 15-20 microns Mitosis present Nucleus with multiple nucleoli Basophilic cytoplasm with polyribosomes No hemoglobin
    21 : Basophilic erythroblast Large nucleus Basophilic cytoplasm Active mitosis Slight reduction in size
    22 : Polychromatophilic erythroblast Chromatin lumps Hb starts appearing Reduced mitoses
    23 : Orthochromatic erythroblast Small and pyknotic nucleus Eosinophilic cytoplasm Mitoses absent
    24 : Reticulocyte Reticular nuclear fragments Nucleus extruded Slightly larger than RBCs
    25 : Reticulocytes Young erythrocytes Contain a short network of clumped ribosomes and RER. Enter the blood stream Fully mature with in 2 days as their contents are degraded by intracellular enzymes. Count = 1-2% of red cells Provide an index of rate of RBC formation
    26 : Proerythroblast or pronormoblast Basophilic erythroblast or Early Normoblast Polychromatophilic (or intermediate) Erythroblast or Normoblast Dividing Polychromatophilic Erythroblast or Normoblast Orthochromatic (Acidophilic) erythroblast Or Late Erythroblast Orthochromatic erythroblast Extruding Nucleus Reticulocyte Reticulocyte (brilliant cresyl blue dye)
    27 : Duration Differentiation phase- from pronormoblast to reticulocyte phase- 5 days Maturation phase: from reticulocyte to RBC- 2 days
    28 : Factor needed of Erythropoiesis Erythropoietin ( Released in response to Hypoxia) Vitamin B 6 (Pyridoxine) Vitamin B 9 (Folic Acid) Vitamin B 12 (Cobolamin) Essential for DNA synthesis and RBC maturation Vitamin C ? Helps in iron absorption (Fe+++ ? Fe++) Proteins ? Amino Acids for globin synthesis Iron & copper ? Heme synthesis Intrinsic factor ? Absorption of Vit B 12 Hormones
    29 : Hormonal factors: Androgens: increase erythropoiesis by stimulating the production of erythropoietin from kidney. Thyroid hormones: Stimulate the metabolism of all body cells including the bone marrow cells, thus, increasing erythropoiesis. Hypothyroidism is associated with anemia while hyperthyroidism is associated with polycythaemia. Glucocorticoids: Stimulate the general metabolism and also stimulate the bone marrow to produce more RBCs. In Addison’s disease (hypofunction of adrenal cortex) anemia present, while in Cushing’s disease (hyperfunction of adrenal cortex) polycythaemia present. Factor needed of Erythropoiesis
    30 : Factor needed of Erythropoiesis Hormonal factors Pituitary gland: Affects erythropoiesis both directly and indirectly through the action of several hormone. Haematopoietic growth factors: Are secreted by lymphocytes, monocytes & macrophages to regulate the proliferation and differentiation of proginator stem cells to produce blood cells.
    31 : Factor needed of Erythropoiesis State of liver & bone marrow Liver - Healthy liver is essential for normal erythropoiesis because the liver is the main site for storage of vitamin B12 , folic acid, iron & copper. In chronic liver disease anemia occurs. Bone marrow - When bone marrow is destroyed by ionizing irradiation or drugs, aplastic anemia occurs.
    32 : Regulation of erythropoiesis Tissue Oxygenation
    33 : Erythropoietin Glycoprotein with 165 amino acids, 4 oligosaccharide chains and molecular weight of 34,000 Production- 85% by peritubular capillary bed interstitial cells(Kidney) and 15% by perivenous hepatocytes( Liver) Also seen in brain, salivary glands, uterus, oviducts Site of Action: BONE Marrow
    34 : Factors increasing erythropoietin secretion: Hypoxia Androgens Growth Hormone Catecholamines Prostaglandins Factors inhibiting erythropoietin secretion: Estrogen Theophylline
    35 : Action of Erythropoietin: Formation of Pronormoblast from stem cell Speeds up the differentiation through various stages of erythropoiesis Mechanism of Action: Formation of ALA synthetase Activation of Adenylyl Cyclase Synthesis of transferrin receptors
    36 : Maturation factors Vitamin B12 and Folic acid: Essential for DNA synthesis (Thymidine triphosphate) Abnormal and diminished DNA Failure of division and maturation Macrocytic / Megaloblastic anemia Other factors Cobalt Copper Vitamin C
    37 :
    38 : HEMOLYTIC ANEMIA Hemolytic anemia = reduced red-cell life span
    39 : HAEMOLYTIC ANAEMIAS The normal red cell life is 110-120 days after which the senile cells are removed by bone marrow and splenic macrophages. Reduced red cell survival leads to increased red cell production due to erythropoietin drive that can compensate for the reduced red cell life and maintain a normal Hb level. The mean red cell life is affected by molecular changes in either the red cell membrane or haemoglobin.
    40 : A haemolytic state exists when the in vivo survival of the RBC is shortened. Anaemia occurs if the onset of haemolysis is sudden with no time for marrow compensation or in severe chronic haemolysis when the mean red cell life is very short. The usual marrow response in acute hemolytic anemia is reflected by a reticulocyte index of 2–3, whereas in long-standing chronic hemolysis, the increase in erythropoiesis is approximately 6-fold.
    41 : Correcting Retic Count Retic Index = Retic % x Patient Hct Normal Hct Absolute Retic = Retic % x RBC/mm3 Retic Production Index = Retic Index Days in circulation
    42 : CLINICAL FEATURES Jaundice: generally mild and often not noticed by the patient. Anaemia: recent onset = acquired long-standing = possibly congenital. Haemoglobinuria: intravascular haemolysis. Urobilinogenuria: increased Hb catabolism. Splenic pain: spenomegaly or splenic infarction. Leg ulcers: intrinsic red cell disorders, e.g. sickle cell disease. Skeletal hypertrophy: severe congenital haemolytic anaemias and thalassaemias.
    44 : Haemolytic anaemia Intravascular vs. Extravascular Intravascular red cells lyse in the circulation and release their products into the plasma fraction. Anemia Decreased Haptoglobin Hemoglobinemia Hemoglobinuria Urine hemosiderin Increased LDH Extravascular ingestion of red cells by macrophages in the liver, spleen and bone marrow Little or no hemoglobin escapes into the circulation Anemia Decreased Haptoglobin Normal plasma hemoglobin Increased LDH
    45 :
    46 :
    47 : Evidence of Hemolysis Low RBC survival with chromium tagging study Unconjugated bilirubin Plasma Hb Decreased serum haptoglobin
    48 : Evidence of Erythropoiesis Polychromasia Increased reticulocyte “Shift” macrocytosis Hypercelluar BM
    49 : HEMOLYTIC ANEMIA INTRACORPUSCULAR HEMOLYSIS Membrane Abnormalities Metabolic Abnormalities Hemoglobinopathies EXTRACORPUSCULAR HEMOLYSIS Nonimmune Immune
    50 : Membrane Defect Hereditary spherocytosis Hereditary elliptocytosis Hereditary pyropoikilocytosis PNH (sensitivity to complement lysis -- sugar water test, Ham’s test) Hereditary stomatocytosis (possibly Rh null)
    51 : Metabolic Defect(enzyme deficiency) G6PD deficiency Hexose monophosphate shunt Most common RBC enzyme defect, >50 variants X-linked Low glutathione due to low NADPH Oxidative lysis, Heinz bodies, spherocytic Primaquine, fava beans Pyruvate kinase deficiency Glycolysis Low RBC ATP level Non-spherocytic B12 and folate deficiency Macrocytic HJ bodies Hemoglobinopathies Poikilocytosis Abnormal Hb
    52 : Hemoglobin Abnormalities Unstable hemoglobin disease Sickle cell anemia Other homozygous hemoglobinopathies (CC, DD, EE; Chapter 52) Thalassemia major Hemoglobin H disease Doubly heterozygous disorders (such as hemoglobin SC disease and sickle thalassemia)
    53 : HEMOLYTIC ANEMIA - IMMUNE Drug-Related Hemolysis PENICILLIN,CEFTRIAXONE,CEFOTETAN,QUINIDINE,ALPHA-METHYLDOPA,LEVODOPA,PROCAINAMIDE,SULFA DRUGS Alloimmune Hemolysis Hemolytic Transfusion Reaction Hemolytic Disease of the Newborn Autoimmune Hemolysis Warm Autoimmune (WAIHA)70-80% Cold Autoimmune (CAIHA) 20-30% Mixed 7-8% Paroxysmal Cold Hemoglobinuria - rare
    54 : Warm vs. Cold Auto WARM Reacts at 37 degC Insidious to acute Anemia severe Fever, jaundice frequent Intravascular not common Splenomegaly Hematomegaly Adenopathy None of these COLD Reacts at room temperature Often chronic anemia 9-12 g/dL (less severe) Autoagglutination Hemoglobinuria, acrocyanosis and raynaud’s with cold exposure No organomegaly
    55 : EXTRACELLULAR DEFECTS Fragmentation Hemolysis DIC, TTP, HUS Extracorporeal membrane oxygenation Prosthetic heart valve Burns—thermal injury Hypersplenism Venom - Snake, Spider, Bee
    56 : Plasma Factors Liver disease (Spur-cell ) Hypophosphatemia Vitamin E deficiency in newborns Abetalipoproteinemia Infections Malaria Babesia Clostridium Gram negative endotoxin Wilson Disease
    57 : Etiologic and Pathogenetic Classification of the Hemolytic Disorders I. Inherited Hemolytic Disorders A. Defects in the erythrocyte membrane 1. Hereditary spherocytosis D. Deficiencies of enzymes involved in the pentose phosphate pathway and in glutathione metabolism 1. Glucose-6-phosphate dehydrogenase (G6PD) E. Defects in globin structure and synthesis 1. Unstable hemoglobin disease 2. Sickle cell anemia 3. Other homozygous hemoglobinopathies (CC, DD, EE; Chapter 52) 4. Thalassemia major 5. Hemoglobin H disease 6. Doubly heterozygous disorders (such as hemoglobin SC disease and sickle thalassemia)
    58 : Etiologic and Pathogenetic Classification of the Hemolytic Disorders II. Acquired Hemoltyic Anemias A. Nonimmune: due to 1. Traumatic and microangiographic hemolytic anemias 2. Infectious agents 3.Chemicals, drugs, and venoms 4. Physical agents 5. Hypophosphatemia 6. Spur-cell anemia in liver disease 7. Vitamin E deficiency in newborns
    59 : Etiologic and Pathogenetic Classification of the Hemolytic Disorders II. Acquired Hemoltyic Anemias B. Immunohemolytic anemias Iso (allo) immune: transfusion of incompatible blood Hemolytic disease of the newborn 2. Heteroimmune: Virus, bacterial infections, chemical, Drug-induced 3. Autoimmune hemolytic anemia Idiopathic (the essential cause is unknown) Secondary or symptomatic (in case of lymphoma, chronic lymphocytic leukemia, Other malignant disease, Immune-deficiency states, Systemic lupus erythematosus and other autoimmune disorders, Virus and mycoplasma infections) Autoimmune hemolytic anemia caused by warm-reactive antibodies (Coomb’s positive). Autoimmune hemolytic anemia caused by cold-reactive antibodies Cold hemagglutinin disease Paroxysmal cold hemoglobinuria
    60 : Etiologic and Pathogenetic Classification of the Hemolytic Disorders II. Acquired Hemoltyic Anemias C. Paroxysmal nocturnal hemoglobinuria
    61 : The Three Primary Measures Measurement Normal Range RBC count (RCC) 4- 5.7 million Hemoglobin 12 to 17 Hematocrit (PCV) 38 to 50 A x 3 = B x 3 = C - This is the rule of thumb Check whether this holds good in a given result If not -indicates micro or macrocytosis or hypochro.
    62 : The Three Derived Indicies Measurement Normal Range RCC 4 to 5.7 Hemoglobin 12 to 17 Hematocrit 38 to 50 MCV C ÷ A x 10 MCH B ÷ A x 10 MCHC (%) B ÷ C x 100
    63 : Hemolytic Anemia Anemia of increased RBC destruction – Normochromic, normocytic anemia – Shortened RBC survival – Reticulocytosis – due to ? RBC destruction Will not be symptomatic until the RBC life span is reduced to 20 days – BM compensates 6 times
    64 : Findings in Hemolytic Anemia
    65 : Tests to define the cause of hemolysis Hemoglobin electrophoresis Hemoglobin A2 (ßeta-Thalassemia trait) RBC enzymes (G6PD, PK, etc) Direct & indirect antiglobulin tests (immune) Cold agglutinins Osmotic fragility (spherocytosis) Acid hemolysis test (PNH) Clotting profile (DIC)
    66 : Peripheral smear
    67 : spherocytes - hereditary spherocytosis - acquired hemolytic anemia (e.g. AIHA) - physical or chemical injury - heat
    68 :
    69 : elliptocytes - heredirary elliptocytosis - iron def. anemia myelofibrosis with myeloid metaplasia - megaloblastic anemia - sickle cell anemia - normal (<10% of cells)
    70 :
    71 : Elliptocytosis
    72 : StomatocytesSlit like central pallor in RBC Liver Disease Acute Alcoholism H Stomatocyosis Malignancies
    73 : Stomatocytes
    74 : acanthocytes(irregular surface spicules) irregularly spiculated cells with bulbous/rounded ends of spicules - abetalipoproteinemia - liver disease
    75 : echinocytes(crenated cells, burr cells) regularly contracted cells with smooth surface undulation - uremia - artifact - hyperosmolarity - discocyte-echinocyte transformation (may be associated with reduced ATP of RBCs)
    76 : EchinocytesEvenly distributed spicules > 10 Uremia Peptic ulcer Gastric Ca PK-D Called Burr Cells
    77 : bite cells Removal (“bites”) of membrane by splenic macrophages - G6PD deficiency
    78 : Heinz bodies denatured hemoglobin - G6PD deficiency
    79 : Heinz body preparation with Crystal violet Unstable hemoglobin
    80 :
    81 : drepanocytes(sickle cells) - sickle cell anemia
    82 :
    83 : basophilic stippling irregular basophilic granules (remnants of RNA) fine stippling: increased production of RBCs (reticulocytosis) coarse stippling: lead poisoning impaired Hgb syntheisis megaloblastic anemia other sever anemias
    84 : dacrocytes(teardrop cells) - thalassemia - myelofibrosis
    85 : leptocytes(target cells) - liver disease (obstructive jaundice) - post splenectomy - hemoglobinopathies (hypochromic anemias) thalassemia Hgb C disease Hgb H disease beta thalassemia relative increase of cell membrane --> “target” formation
    86 :
    87 : rouleaux lined up RBCs in a row - multiple myeloma
    88 : sideroblast/siderocyte inorganic iron-containing granules (Pappenheimer bodies) - sideroblastic anemia abnormally trapped iron in mitochondria forming a ring around nucleus - post splenectomy ring sideroblasts intermediate sideroblast siderocyte
    89 : Howell-Jolly body remnant of nuclear chromatin single: megaloblastic anemia hemolytic anemia post splenectomy multiple: megaloblastic anemia other abnormal erythropoiesis
    90 : Acanthocytes5-8 spikes of varying length, irregular intervals Called Spur Cells, Occur in A H A
    91 : schistocytes(cell fragments) indication of hemolysis - megaloblastic anemia - severe burns - traumatic hemolysis - microangiopathic hemolytic anemia (helmet cells, triangular cells) “helmet cell”
    92 : Shistocytes MAHA Prosthetic valves Uremia Malignant HT Fragmented, Helmet or triangle shaped RBC
    93 :
    94 : MAHA Micro Angiopathic Hemolytic Anemia
    96 : Malaria Schistocytes
    97 : Normal BM High Power E : G = 1 : 3
    98 :
    99 : Bone marrow
    100 : Hyperactive BM – SkullHemolytic Anemia

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