red blood cells by mary yvonnette c. nerves, md, fpsp
TRANSCRIPT
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RED BLOOD CELLS
by
Mary Yvonnette C. Nerves, MD, FPSP
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Erythropoiesis
A process by which early erythroid precursor cells differentiate to becomethe mature RBCs
Primary regulator: ERYTHROPOIETIN
- stimulates red cell precursors at all levels ofmaturation to hasten the maturation process
- responsible for stimulating the premature releaseof reticulocytes into the bloodstream.
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Erythropoiesis Total erythropoiesis:
- total number of red blood cells (RBCs) - measured by the myeloid-erythroid
(M:E) ratio from aspirate smears plus the estimate of cellularity from biopsy
sections
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Effective erythropoiesis: - number of viable and functional RBCs available for physiologic needs - reflects the balance between the number ofcells produced and their life span- measured by the reticulocyte count, which is normally 1% of the total RBC count
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Stages of Maturation1. Pronormoblast (Rubriblast)2. Basophilic Normoblast (Prorubriblast)3. Polychromatophilic Normoblast
(Rubricyte)4. Orthochromatic Normoblast
(Metarubricyte)5. Reticulocyte6. Erythrocyte
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Pronormoblast Earliest recognizable and largest cell of the
erythrocyte series Morphology: - Size: 12 – 20 um
- Nucleus: large round, oval, dark violet; finechromatin; 1 – 2 nucleoli
- Cytoplasm: deep blue spotty, basophilic w/ a perinuclear halo
- N/C Ratio: 8:1 - BM (%): 1
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Basophilic Normoblast
Hemoglobin synthesis begins at this stage
Morphology:
- Size: 10 – 15 um
- Nucleus: large round to sl oval; condensed,coarse chromatin; 0 – 1 nucleoli
- Cytoplasm: deeply basophilic; clusters of free ribosomes
- N/C Ratio: 6:1
- BM (%): 1-4
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Polychromatic Normoblast Increased production of hemoglobin pigmentation and decreasing amounts of RNA
Last stage in which the cell is capable of mitoses
Morphology:
- Size: 10 - 15 um
- Nucleus: round nucleus, deep staining, may be centrally or eccentrically located; coarse & clumped chromatin
- Nucleoli: 0
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Morphology:
- Cytoplasm: abundant blue-gray (RNA) to pink-gray (hemoglobin)
- N/C Ratio: 4:1
- BM (%): 10-20
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Orthochromatic Normoblast
The last nucleated stage
Cannot synthesize DNA and cannot undergo cellular division
The NRBC sometimes seen in the peripheralcirculation
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Morphology:
- Size: 8 - 10 um
- Nucleus: small pyknotic nucleus; dense chromatin; 0 nucleoli
- Cytoplasm: abundant red-orange cytoplasmuniform in color
- N/C Ratio: 1:2
- BM (%): 5-10
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Reticulocyte Slightly larger than the mature RBC with residual amts of RNA Reticulocyte count: an index of bone marrow
activity or effective erythropoiesi Morphology: - Size: 8 - 10 um - Nucleus: anucleate cell containing small
amt of basophilic reticulum (RNA) - Nucleoli: 0 - Cytoplasm: large amt of blue-pink staining
hemoglobin cytoplasm
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Erythrocyte
A biconcave 6 – 8 um disc
Life span: 120 days
Main function: to transport hemoglobin, aprotein that delivers oxygen from the
lungs to tissues and cells
Contains 90% hemoglobin and 10% H2O
normal conc of RBCs varies w/ age, sex &geographic distribution
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Morphology:
- Size: 7 - 8 um
- Nucleus: anucleated cell
- Nucleoli: 0
- Cytoplasm: pink staining, zone of centralpallor is 1/3 of cell diameter devoid of hemoglobin
- N/C Ratio: NA
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Hemoglobin: Structure & Function
A conjugated protein that serves as the vehicle for the transportation of O2 and CO2
When fully saturated, each gram of Hgb can hold 1.34 mL of O2 A molecule of Hgb consists of 2 pairs of polypeptide chains (“globin”) and 4 prostheticheme grps each contg 1 atom of ferrous iron
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DESCRIPTION of TERMS
SIZE DESCRIPTORS
Anisocytosis: variation in the sizeof the RBCs due to a pathologic condition
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Normocytic: normal sized biconcave disc RBC- normal MCV
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Microcytic: Smaller RBCs less than 6 um- MCV < 80 fl- Defect / Change: abn size due to failure
of hgb synthesis- Dse: IDA, Thalassemia, Chronic dse
Macrocytic: Larger RBCs greater than 9um- MCV > 90 fl- Defect / Change: impaired DNA synthesis
/ stress erythropoiesis - Dse: Megaloblastic anemia / liver dse /
MDS / Alcoholism / Malaria
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Macrocytic Microcytic
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CHROMICITY DESCRIPTORS Normochromic: normal in color; pale central
area occupies less than 1/3
- Defect / Change: normal amt of Hgb
- Normal indices
Hypochromic: an RBC that has a decreasedHgb complement
- central pallor exceeds 1/3 of diameter ofcell
- Defect / Change: reduced Hgb content ( MCHC)
- Assoc conditions: IDA / Thalassemia
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“Hyperchromic”: no central pallor
- Defect / Change: greater than normal MCHC
- Assoc condition: Spherocytosis
“Hyperchromic” Hypochromic
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Polychromasia: blue-gray coloration
- Defect / Change: presence of RNA
- Assoc condition: increased erythropoietic activity / hemorrhage / hemolysis
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SHAPE DESCRIPTORS Poikilocytosis: variation in shape of the RBC
- Defect / Change: irreversible alteration of membrane
- Assoc conditions: Anemia / Hemolytic states
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Discocyte: normal biconcave erythrocyte - 6 – 8 um diameter; 0 – 2 um thickness
- Aka: Normocyte
Normal Red Cells (SEM)
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Acanthocyte: spheroid w/ 3 – 12 irreg spikesor spicules
- Aka: spur cell
- decreased cell volume
- Defect / Change: inc ratio of chole to lecithin
- Assoc conditions:
end-stage liver dse
Pyruvate kinase def
Hemolytic anemia
Abetalipoproteinemia
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Blister cell: contains 1 or more vacuoles
- Aka: Bite cells
- thinned periphery
- Defect / Change: formed by removal of Heinz bodies
- Assoc conditions:
Hemolytic episodes
G6PD def
Hemoglobinopathies
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Codocyte : peripheral rim of Hgb surr by clear area & central hemoglobinizedarea (bull’s eye)
- Aka: target cell
- Defect / Change: excess of surface to volume ratio
- Assoc conditions:
Hemoglobinopathies
Thalassemia
Liver dse
Postsplenectomy
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Dacryocyte: teardrop or pear-shaped w/single elongated point or tail
- Aka: tear drop cell- Defect / Change: squeezing &
fragmentation during splenicpassage
- Assoc conditions: Myeloid metaplasiaThalassemiaMegaloblastic anemiaHypersplenism
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Drepanocyte: crescent-shaped cell thatlacks zone of central pallor
- Aka: Sickle cell
- Defect / Change: polymerization ofdeoxygenated Hgb
- Assoc conditions:
Sickle cell anemia
SC disease
S-thalassemia
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Echinocyte: regular 10-30 scalloped shortprojections evenly distributed / spiny-like
- Aka: Burr cell / crenated RBC- Defect / Change: Depletion of ATP Exposure to hypertonic soln Artifact in air drying- Assoc conditions:
UremiaCirrhosis / HepatitisChronic renal dse
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Ovalocyte: egglike or oval-shaped cell
- Defect / Change:
Hgb has bipolar arrangement
Reduction in membrane chole
- Assoc conditions:
Megaloblastic BM
Myelodysplasia
Sickle cell anemia
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Elliptocyte: rod or cigar shape, generallynarrower than ovalocytes
- Defect / Change: polarization of Hgb
- Assoc conditions:
Thalassemia
Iron def
Hereditary elliptocytosis
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Schistocyte: Fragmented RBCs varying in size & shape
- Aka: Helmet cells- Defect / Change: extreme fragmentation
produced by damage of RBC by fibrin, altered vessel walls, prosthetic heart
valves- Assoc conditions:
DIC / TTP / BurnsMicroangiopathic hemolytic anemia
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Spherocyte: smaller in diameter than normal RBC w/ concentrated Hgb content; no visible central pallor- Defect / Change:
lowest surface area to volume ratiodefect of loss of membrane
- Assoc conditions: Hereditary spherocytosisIso- & autoimmune hemolytic anemiaSevere burnsHemoglobinopathies
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Stomatocyte: normal sized cell w/ slitlike area in center
- Defect / Change:
artifact of slow drying
known to have inc permeability to Na+
- Assoc conditions:
Hereditary stomatocytosis
Acute alcoholism
Liver dse
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RED CELL INCLUSIONS
Basophilic Stippling - cytoplasmic remnants of RNA- Fine: thin round dark blue granules
uniformly distributed- Defect/Change: represents
polychromasia (reticulocyte)- Coarse: medium sized uniformly
distributed- Defect/Change: represents
impaired erythropoiesis
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Basophilic Stippling - Assoc conditions:
Thalassemia
Lead Poisoning
Increased reticulocytosis
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Cabot Ring - rings, loops, or figure eights; red to
purple- Defect / Change: remnants of
microtubules of mitotic spindle
- Assoc conditions:Megaloblastic anemiaDyserythropoiesis
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Heinz bodies - deep purple irregularly shaped inclusions
found on RBC inner surface of membrane - Defect / Change: represent precipitated,
denatured Hgb due to oxidative injury - Assoc conditions:
Hereditary defects in HMSG6PD defUnstable HgbsSplenectomized ptsThalassemia
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Howell-Jolly bodies: coarse round denselystained purple 1-2 um granules
eccentrically located on periphery of membrane
- Defect / Change: nuclear remnants; contain DNA
- Assoc conditions:Megaloblastic anemiaSevere hemolytic processThalassemiaAccelerated erythropoiesis
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Pappenheimer bodies: small, 2-3 um irregular basophilic inclusions that aggregate in small clusters near periphery w/ Wright’s stain
- Defect / Change: unused iron (nonheme) deposits
- Assoc conditions:Sideroblastic anemiaDefective erythropoiesisMDSHemolytic anemiaThalassemia
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Ringed Sideroblasts- Nucleated RBC that contains nonheme
iron particles (siderotic granules) arranged in ring form
- Defect / Change: excessive iron overload in mitochondria of normoblasts
- due to defective heme synthesis- Assoc conditions:
Sideroblastic anemiaMDS
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Ringed SideroblastsPrussian blue iron stain showing excess accumulation of iron as ferritin in mitochondria ringing nucleus.
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Siderocyte: non-nucleated cell containing iron granules
- Defect / Change: excessive iron overload in mitochondria of normoblasts- due to defective heme synthesis
- Assoc conditions:Sideroblastic anemiaMDS
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Autoagglutination: clumping of RBCs- Defect / Change: presence of antibody- Assoc conditions:
Cold agglutininAHA
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Rouleaux Formation: alignment of RBCslinear appearing as stacks of coins
- Defect / Change: concentration of fibrinogen &
immunoglobulin- Assoc conditions:
MM / Waldenstrom’s macroglobulinemia
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Red Cell Studies
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Hematologic tests used to measure several important parameters that reflect rbc
structure and function: 1) Hemoglobin determination2) Erythrocyte count3) Hematocrit4) Erythrocyte Indices: MCH, MCHC,
MCV 5) Reticulocyte Count6) Osmotic Fragility Test7) Erythrocyte Sedimentation Rate (ESR)
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Measurement (units) Men Women
Hemoglobin (gm/dL) 13.6-17.2 12.0-15.0
Hematocrit (%) 39-49 33-43
Red cell count (106/μL) 4.3-5.9 3.5-5.0
Reticulocyte count (%) 0.5-1.5
Mean cell volume (μm3) 82-96
Mean corpuscular hemoglobin (pg) 27-33
Mean corpuscular hemoglobin concentration (gm/dL) 33-37
RBC distribution width 11.5-14.5
Adult Reference Ranges for Red Blood Cells
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Hemoglobin
- involves lysing the erythrocytes, thus producingan evenly distributed solution of
hemoglobin in the sample
- Hemiglobincyanide Mtd: blood is diluted in a soln of K3Fe(CN6). The K3Fe(CN6) oxidizes Hgbs to hemiglobin (metHgb) and K cyanide provides cyanide ions to form HiCN, w/c has a broad absorption max at a wl of 540 nm
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Erythrocyte Count- involves counting the number of rbcs per unitvolume of whole blood. - expressed as number of cells per unit volume,
specifically cells/µL- NV: Female = 4.2 - 5.4 x 106/µL
Males = 4.7 - 6.1 x 106/µL
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Hematocrit- sometimes referred to as the Packed CellVolume (PCV) or volume of packed red cells - is the ratio of the volume of RBCs to that of the
whole blood- varies with age and sex- expressed as a percentage or as adecimal fraction
Plasma
Buffy coat
Red cells
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Erythrocyte Indices1) Mean Cell Volume (MCV)
- average volume of red cells- calculated from the Hct and RBC count
MCV = Hct x 1000 RBC (in millions/uL)
- expressed in femtoliters (fl) or cubic micrometers
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2) Mean Cell Hemoglobin (MCH)- content (weight) of Hgb of the average red cell- calculated from the Hgb and RBC
count
MCH = Hgb (in g/L) RBC (/L)
- value is expressed in picograms (pg)
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3) Mean Cell Hemoglobin Concentration (MCHC)- the average conc of Hgb in a given
volume of packed red cells- calculated from the Hgb conc & the Hct
MCHC = Hgb (in g/dL)
Hct
- expressed in g/dL
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Morphologic Classification of Anemias
Type of Anemia Blood Constants
MCV (mm3 or fl)
MCHC (g.Hb/dl.RBC or
mmol/l)
Microcytic hypochromic 60-87 20-30
Macrocytic normochromic 103-160 32-36
Normocytic normochromic 87-103 32-36
Microcytic normochromic 60-87 32-36
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Reticulocyte Count- Principle: Reticulocytes are immature non-nucleated red cells that contain RNA andcontinue to synthesize Hgb after the loss ofthe nucleus- Supravital staining: blood is briefly incubated
in a soln of new MB or BCB, the RNA isprecipitated as a dye-ribonucleoproteincomplex dark blue network (reticulum or
filamentous strand) - NV: 0.5 – 1.5% or 24 – 84 x 109/L
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Osmotic Fragility Test (OFT)- a measure of the ability of red cells to take up
fluid without lysing- Red cells are suspended in a series of tubes
contg hypotonic solns of NaCl solns varying from 0.9% to 0.0%, incubated at room temp for 30 mins and centrifuged - the percent hemolysis in the supernatant solns
is measured & plotted for each NaCl conc.
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- The larger the amount of red cell membrane(surface area) in relation to the size of thecell, the more fluid the cell is capable ofabsorbing before rupturing- Cells that are more spherical, w/ a decreased
surface/volume ratio, have a limited capacity to expand in hypotonic solns & lyse at a higher conc of NaCl than do normal biconcave cells OFT
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- Cells that are hypochromic & flatter have a greater capacity to expand in hypotonic solns, lyse at a lower conc than do normal cells, & are said to have decreased osmotic fragility
- Cells with increased surface/volume ratio are osmotic resistant IDA, thalassemia, liver dse, & reticulocytosis
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Erythrocyte Sedimentation Rate (ESR)- detect and monitor an inflammatory response
to tissue injury (an acute phase response) in which there is a change in the plasma conc of several proteins
- Principle: When well-mixed venous blood is placed in a vertical tube, RBCs will tend to fall toward the bottom. The length of the
fall of the top of the column of RBCs in a given interval of time is called the ESR
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- ESR is affected by (3) FACTORS:a) erythrocytesb) plasma compositionc) mechanical / technical factors
- Red Cell Factors: Anemia increases ESR (change in RBC plasma ratio
favors rouleaux fotn) ESR is directly proportional to the weight of thecell
aggregate & inversely proportional to the surface area
Microcytes sediment slower than macrocytes Rouleaux accelerate the ESR Red cells w/an abnormal or irregular shape hinder
rouleaux fotn & lower the ESR
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- Plasma Factors: Elevated levels of fibrinogen accelerate ESR Albumin & lecithin retard ESR Cholesterol accelerate ESR
- Mechanical / Technical Factors: A tilt of 3o can cause errors up to 30% ESR ESR increases as the temp increases ESR tubes with a narrower than standard bore will
generally yield lower ESR ESR stands fro > 60 mins falsely elevated ESR Greater conc of EDTA falsely low ESR
- Methods: Westergren Mtd / Wintrobe Mtd
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ERYTHROCYTE DISORDERS
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Two main disorders affecting RBCs:
1. Polycythemia (Erythrocytosis)
- an elevated Hct level above the normal range
2. Anemia
- a reduction below normal limits of the total circulating red cell mass
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Relative Reduced plasma volume (hemoconcentration)
Absolute
Primary Polycythemia vera, rare erythropoietin receptor mutations (low erythropoietin)
Secondary High erythropoietin
Appropriate: lung disease, high-altitude living, cyanotic heart disease
Inappropriate: erythropoietin-secreting tumors (e.g., renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma)
Pathophysiologic Classification of Polycythemia
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POLYCYTHEMIAMay be classified into (2) major conditions:
1) Relative Polycythemia
- an increase in the Hct or red cell count as a result of decreased plasma volume
- total red cell mass is NOT increased
- Assoc conditions: acute dehydration or hemoconcentration / pts on diuretic
therapy / Gaisbock’s syndrome (psedopolycythemia or stress erythrocytosis)
- BM: Normal
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2) Absolute (or Secondary) Polycythemia- an erythropoietin mediated increase in
RBCs and Hgb due primarily to ahypoxic situation
- increase in the total red cell mass in the body assoc w/ normal or sl increased plasma volume
- Assoc conditions: tumors / anabolic steroids / & renal dso such as cystic dse, hydronephrosis / & adrenal cortical hyperplasia
- BM: Erythroid hyperplasia
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3) Polycythemia rubra vera (Primary Erythrocytosis)- an absolute increase in all cell types,
RBCs, WBCs and platelets- not dependent on erythropoietin levels- BM: all three cell lines increased
(panhyperplasia)
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ANEMIA
Decreased oxygen carrying capacity of the blood
Anemia may also be "defined" in terms of the Hb content
Hb < 12 g/dL in an adult male
Hb < 11 g/dL in an adult female
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AnemiaMales: Hb < 13.5 Hct < 41Female: Hb < 12 Hct < 36
MCV
MicrocyticMCV < 80
NormocyticMCV 80-100
MacrocyticMCV > 100
Reticulocyte Count
Low
High
Marrow FailureAplastic anemiaMyelofibrosisLeukemia /MetastasisRenal failureAnemia of Chronic disease
Iron deficiency anemiaThalassemiaAnemia of Chronic diseaseSideroblastic anemia
Megaloblastic anemiaAlcoholic liver disease
Sickle cell anemiaG6PD def anemiaHereditary spherocytosisAIHAPNH
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ANEMIAS SECONDARY TO BLOOD LOSS
Acute: e.g., hemorrhage due to trauma, massive GI bleeding,
or child delivery. Usually the iron stores remain normal.
Chronic: e.g., bleeding peptic ulcer or excessive menstrual
bleeding.
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HYPOPROLIFERATIVE ANEMIAS (Impaired Production)
reduced production of red cells can be subdivided into: deficiency of haematinics
iron deficiency B12 and folate deficiency
dyserythropoiesis (production of defective cells) anaemia of chronic disorders (AOCD) myelodysplasia sideroblastic anaemia
marrow infiltration (myelophthisic anemia) aplasia (failure of production of cells)
aplastic anaemia red cell aplasia
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Normal forms of iron (Fe) and iron metabolism Functional iron is found in Hb, myoglobin, and
enzymes (catalase & cytochromes) Ferritin: physiological storage form Hemosiderin: degraded ferritin + lysosomal
debris (Prussian blue positive) Iron is transported by transferrin
Iron Deficiency Anemia
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causes: Dietary deficiency: elderly, children and poor Increased demand: children & pregnant women Decreased absoprtion:
generalized malabsorption
after gastrectomy Chronic blood loss:
GI bleeding (e.g. peptic ulceration, carcinoma of stomach or colon)
menorrhagia
urinary tract bleeding
Hook worm (Ancylostoma duodenale adult worm sucks 0.2 ml blood/day)
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Lab Findings: Microcytic, hypochromic anemia. Low serum iron BM: show absence of iron Ferritin: Low serum ferritin indicates low body stores
of iron Transferrin: These carrier proteins will be
unsaturated and available to bind iron, hence the Total Iron Binding Capacity (TIBC) is increased with anemia.
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Char by iron being trapped in BM macrophages
Can be grouped in 3 categories:
- chronic microbial infections (eg. Osteomyelitis)
- chronic immune disorders (eg. RA)
- Neoplasms (eg. lymphoma, breast/lung CA)
Chronic inflamm dso inc IL-1, TNF, IF-Gamma - reduction in renal erythropoietin marrow erythroid
precursors do notproliferate
- hepcidin synthesis in liver inhibits release of iron
Anemia of Chronic Disease (AOCD)
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Labs: low serum iron
increased serum ferritin
decreased TIBC
normochromic, normocytic anemia or hypochromic, microcytic anemia
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A group of dso in which the blood and BM hematopoietic cells display changes
Pathogenesis: impaired DNA synthesis (delayed mitoses) while RNA is not impaired; this produces nuclear-cytoplasmic asynchrony
Megaloblastic anemias can be divided into groups:
- anemia caused by B12 deficiency
- anemia caused by folate deficiency
- anemias nonresponsive to either therapy
Megaloblastic Anemia
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important background knowledge: B12:
vitamin B12 is required for DNA replication and inhibition of transcription of DNA to RNA
B12 is normally absorbed from gut by the following mechanism:
- secretion of intrinsic factor by parietal cells in stomach
- binding of intrinsic factor and vitamin B12 in lumen
- intrinsic factor- B12 complex is absorbed in terminal ileum through pinocytotic vesicles
Folate: - folate is required for DNA replication and inhibition of
transcription of DNA to RNA
lack of B12 or folate means that RNA builds up and the cells become too large
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Causes: causes of vitamin B12 deficiency (pernicious
anaemia) lack of intrinsic factor
- atrophic gastritis - parietal cells are destroyed - gastrectomy
malabsorption of B12 not related to lack of intrinsic factor
- tropical sprue or bacterial overgrowth of terminal ileum - ileal disease (e.g. Crohn's disease affecting the terminal
ileum) - fish tape-worm (these attach to intestinal wall, and
therefore in large enough numbers, may prevent B12-intrinsic factor complex absorption in terminal ileum)
- poor diet - rare
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causes of folate deficiency poor diet - especially in alcoholics malabsorption - coeliac disease increased cell turnover (e.g. leukaemia, chronic
haemolysis, pregnancy) antifolate drugs (e.g. phenytoin)
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Peripheral Blood Findings:
WBCs Normal or decreased
RBCs Decreased
Hgb Decreased
MCV Increased (usualy > 100 fl)
MCH Increased
MCHC Normalor slightly decreased
Platelet count Normal or decreased
Reticulocyte count Decreased
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Reticulocyte Count
Normal or decreased Increased
Macrocyte normal, no hyersegmented
neutrophils
Macro-ovalocytes,Hypersegmented
neutrophils
BM not megaloblastic
R/O Refractory anemia,Sideroblastic anemia,
Myelodysplasia, drug induction,
liver disease,Aplastic anemia
HemolyticHemorrhagic
deficiency
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Morphologic Abnormalities: Large RBC's with nuclear-cytoplasmic dyssynchrony Ovalocytes: The large RBC's tend to have an oval-shape.
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Hypersegmented Neutrophils: One of the earliest signs of disease. 5 or 6 lobes
Howell-Jolly Bodies: Nuclear fragments seen in Megaloblastic anemia.
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pancytopenia associated w/ a severe reduction in the amt of hematopoietic tissue that results in deficient production of blood cells
Etiology: Acquired
idiopathic Chemical agents Physical agents Viral infections
Inherited Fanconi’s anemia
Aplastic Anemia
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Pure red cell aplasia: erythrocyte stem cells are suppressed, but the other formed elements of blood are unaffected
Anemia due to isolated depletion of erythroid precursors in the marrow, and may be acute or chronic.
Lab Findings:
- Normochromic, normocytic or macrocytic anemia
- Reticulocytes are decreased or absent because it is hypoproliferative.
- BM: hypocellular or dry tap
reduction in all cell lines
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HEMOLYTIC ANEMIAS (Increased Destruction)
Grp of dso that can be inherited, acquired,or drug-induced
Char by an increased red cell destruction or shortened survival of the RBC
Char by increased BM activity, polychromasia, nucleated RBCs and an increased reticulocyte count w/ stress reticulocytes
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Hemolytic anemias share the ff. features:
1. shortened red cell life span, that is, premature destruction of red cells
2. elevated erythropoietin levels and increased erythropoiesis in the marrow & other sites
3. accumulation of products of Hgb catabolism,due to an increased rate of red celldestruction
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HEMOLYTIC ANEMIAS Acquired
Immune-mediated- Autoimmune- Alloimmune (Transfusion)- Drug-induced
Microangiopathic Infection
Hereditary Enzymopathies Membranopathies Hemoglobinopathies
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INTRINSIC DEFECTSHereditary Spherocytosis
abnormal cell membrane assoc cytoskeletoncausing red cells to be spherical and
fragile
principle defect is an abnormality of the membrane protein ankyrin
Lab findings: Normocytic, hyperchromic anemia (normal MCV and increased
MCHC)
- increased pigment catabolism, erythroid hyperplasia, & reticulocytosis
- red cells with increased OFT
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Glucose-6-Phosphate Dehydrogenase Deficiency
Normal: G6PD metabolises glucose, and formssmall amounts of ATP (which
maintains the cell cytoskeleton and membrane) and NADPH (which mops up free radicals) G6PD def renders the cell susceptible to damage
by free radicals an X-linked recessive condition, in which haemolytic crises are precipitated by infections or certain drugs Lab findings: poikilocytes & spherocytes, & Heinz
bodies (stain w/ methyl violet)
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HEMOGLOBINOPATHIES Normal Hgb:
HbA / HbF / HbA2 (adult)
Hb Gower-1 and 2 / Hb-Portland (embryonic)
Hemoglobin-A alpha2, beta2 Predominant hemoglobin in adults
Hemoglobin-A2
alpha2, delta2
Found in normal adults
Hemoglobin-F alpha2, gamma2
Fetal (cord) hemoglobin, with higher O2-binding affinity
Hemoglobin-S alpha2, beta2 (beta: Glu-6
---> Val)
Sickle-Cell Hemoglobin. Sickle crisis can result from low O2-tension.
Hemoglobin-C alpha2, beta2 (beta: Glu-6
---> Lys)
Hemoglobin-C Disease. Second most common hemoglobinopathy.
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THALASSEMIACaused by impaired production of one of the polypeptide chains of the Hb moleculeEpidemiology: Mediterranean, African & Asian ancestryautosomal recessive disease Types according to clinical severity:thalassaemia major = homozygote;
thalassaemia minor = heterozygote Types according to molecular defect: beta thalassaemia alpha thalassaemia
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Beta-Thalassemia Major (Homozygous state):
- severe hypochromic, microcytic anaemia, hepato- splenomegaly, marrow hyperplasia causing
skeletal deformities, haemochromatosis develops with repeated transfusions
Minor (Heterozygous states):
- reduction in HbA, but increase in HbA2; mild anaemia with hypochromia
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Clinical Nomenclature
Genotype Disease Molecular Genetics
β-Thalassemias
Thalassemia major
Homozygous β0-thalassemia (β0/β0)
Severe; requires blood transfusions
Rare gene deletions in β0/β0
Defects in transcription, processing, or translation of β-globin mRNA
Homozygous β+-thalassemia (β+/β+)
Thalassemia intermedia
β0/ββ+/β+
Severe, but does not require regular blood transfusions
Thalassemia minor
β0/ββ+/β
Asymptomatic with mild or absent anemia; red cell abnormalities seen
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Alpha-Thalassemianote that there are 4 copies of the alpha globin gene (not 2), and therefore four possible degrees of alpha thalassaemia exist
3 good copies - silent carrier 2 good copies - mild anaemia with microcytosis 1 good copy - moderate haemolytic anaemia
with hypochromia and mycrocytosis; HbH (tetramer of beta)
0 good copies - lethal in utero (hydrops fetalis)
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α-Thalassemias
Hydrops fetails -/--/- Lethal in utero without transfusions
Mainly gene deletions
HbH disease -/--/α Severe; resembles β-thalassemia intermedia
α-Thalassemia trait
-/-α/α (Asian)-/α-/α (black African)
Asymptomatic, like β-thalassemia minor
Silent carrier -/αα/α Asymptomatic; no red cell abnormality
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Thalassemia MajorPatient with thalassemia major due to heterozygous hemoglobin E/B thalassemia. Note prominent target cells, anisopoikilocytosis, and three nucleated red cells (normoblasts)
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Sickle Cell Disease Endemic to Sub-saharan Africa, due to heterozygous advantage conferred against Falciparum Malaria (infected RBC's preferentially sickle and are thus taken to the spleen and sequestered, limiting the spread of infection) PATHOGENESIS: Point-mutation of Glu Val at 6th
position of beta-globin chain Pathophysio: abn Hgb polymerises at low O2
saturation causing abnormal rigidity and deformity of red cells and become
abnormality fragile (and undergo haemolysis and sludge in small vessels) autosomal recessive, with a point mutation in beta gene
forming an abnormal HbS; more common in Negroes
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Lab. Findings
Smear: normochromic, normocytic anemia, increased polychromasia, normoblasts are present, numerous target cells, Howell-Jolly and Pappenheimer bodies are present, sickle cells
OFT decreased
BM: normoblastic hyperplasia w/ increased iron storage
Electrophoresis: no HbA, 80% HbS (SCD)
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Sickle Cells (SEM)Scanning electron micrograph (SEM) showing sickle cells obstructing small vessel.
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EXTRINSIC DEFECTSImmune Hemolytic Anemias
Dso in w/c erythrocyte survival is reduced because of the deposition of Ig &/or `
complement on the red cell membrane
Classification:
1. Autoimmune Hemolytic Anemia
2. Isoimmune Hemolytic Anemia
3. Drug-induced Hemolytic Anemia
LAB: (+) direct & indirect antiglobulin tests
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Agglutination of erythrocytes is seen on this peripheral blood smear
Coomb’s Test
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Traumatic Hemolytic AnemiaChar by striking morphologic abn of the red cells,
w/c include fragments (schistocytes) & irregularly contracted cells (triangular cells, helmet cells)
MICROANGIOPATHIC HEMOLYSIS: RBC's being damaged by intravascular fibrin-clots, in small vessels. DIC, TTP, HUS.
MACROANGIOPATHIC HEMOLYSIS: Damage by artifical heart valves.
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Have a nice day!