1. Hematology
Reference: Pathophysiology by Kathryn McCance
Mindy Milton, MPA, PA-C
July 1, 2010
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2. Components of the Blood
 Plasma: 55-65% of blood
 Formed elements:
 Plasma proteins
 Albumin
 Globulin
 Immune globulins
 Clotting factors
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3. Composition of the Blood: Plasma
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4. Composition of Blood: Formed Elements
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5. Structure of the RBC
 Stroma: innermost layer of lipids and proteins
 Biconcave Disc - navigation and diffusion
 Reversible deformability
 120 days life span
 42-48% of the blood volume
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6. RBCs
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7. RBCs
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8. Peripheral Blood Smear
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9. RBC
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10. Hemoglobin
 Structure
 Two Alpha chains
 Two Beta chains
 Single molecule of Heme connected to iron
which then can interact with oxygen
 Iron-oxygen binding is weak and reversible
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11. Structure of Hemoglobin
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12. Red Blood Cell Formation
 Myeloid stem cells in the red bone marrow produce
RBCs
 Takes 5-7 days to mature and form reticulocyte and
erythrocyte
 Nutrients needed for normal red blood cell
formation:
 Vitamin B12 see in anemias have issue
here
 Folic Acid
 Iron
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13. Stages of RBC Formation
See reticulocyte have
remnants of nucleus.
May see more in anemia.
<------
Use retic index to see if
responding to bone
marry tx.
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14. Maturation of Formed Elements
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15. Regulation of Erythropoesis
 Erythropoietin is secreted by the kidney in response
to tissue hypoxia
 Increased erythropoietin will increase oxygen
carrying capability of the blood
 Functions:
 Stimulates increased cell division rates in erythroblasts
 It accelerates Hgb concentration
ptsn with chronic
hypoxemia - adaptation
with increased Epo and
RBC’s.
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16. Erythropoesis
HYPOXIA
Erythropoetin
< RBC’S <Arterial PO2
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17. increased Hb will change
size and color of RBC’s
Hgb Formation
 Iron absorbed in duodenum
 Small amount of absorbed iron is bound to
transferrin, a protein transport molecule
 Remainder is stored in the intestinal epithelial cells
and bone marrow as ferritin
 In the bone marrow the transferrin/iron complex
binds with receptor site on erythroblasts
 Releases iron into erythroblasts and transferrin
returned to blood stream Pernicious anemia - loss
of intrinsic factor, need
B12 from stomach to
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absorb in duodenum.

18. Iron Cycle
Duodenum
Iron/transferrin
Storage Spleen Storage Liver
Storage intestine Storage Macrophages
Bone Marrow
Increased RBC’S 18
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19. Bilirubin conjugated by
Iron Cycle the liver to help
excretion in the bile.
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20. Red Blood Cell Turnover
KNOW THIS PICT
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21. Definitions
 NORMOCYTIC  MEGALOBLASTIC
 NORMOCHROMIC  POIKILOCYTOSIS
 MICROCYTIC  ANISOCYTOSIS
 MACROCYTIC Megaloblastic
microcytic = B12 defic
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22. Peripheral Smear
The RBC’s are smaller than normal, increased pallor
Increased variation in size (anisocytosis)
Increased variation in shape (poikilocytosis)
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23. Important Values
 MCV  87-103
 MCH  27-32
 MCHC  32-36
 RETICULOCYTE
 1%
COUNT  RETICULOCYTE
COUNT x Hct
 RETICULOCYTE  >3%=bleeding
INDEX
 <3%=decreased
formation
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24. Microcytic Hypochromic Anemia
 Iron Deficiency
 ETIOLOGY
 Dietary deficiencies of iron
 Infants need 1mg/kg/day
 Breast fed receive .4mg of iron per quart
 Cows milk less than .1mg per quart
 Bleeding with increased need
 Gastrointestinal and gynecological cancers
 Peptic ulcer disease
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25. Microcytic Hypochromic Anemia
 Iron Deficiency
 Etiology:
 Maternal needs for iron in pregnancy is about 800mg:
300mg for fetus and placenta, and 500mg needed for
maternal blood expansion
 Rapid expansion of blood volume during second
trimester is often manifested by drop in Hgb
 Diagnostic data
 Microcytosis: decreased MCV , microcytosis
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26. Microcytic Hypochromic Anemia
 Iron Deficiency
 Diagnostic data
 Hypochromia:
 Reduced to very low serum iron
 Reduced to very low serum ferritin
 High TIBC
 In pregnant women the microcytosis and hypochromia
may not be as clear but serum ferritin is low
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27. Microcytic Hypochromic Anemia
The RBCs here are smaller than normal and have an increased zone of central
pallor. This is indicative of a hypochromic (less hemoglobin in each RBC)
microcytic (smaller size of each RBC) anemia. There is also increased
anisocytosis (variation in size) and poikilocytosis (variation in shape).
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28. Microcytic Hypochromic Anemia
 Iron Deficiency
 Response with increased reticulocytosis within
one week
 Increased Hgb and Hct in one month
 Need to continue therapy to increase stores
 Serum Ferritin to 50ug/L
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29. Microcytic Hypochromic Anemia
 Thalassemia
 Etiology
 Hereditary anemias that result from a reduced or
absent synthesis of the alpha or beta globulin chains
 Occurs primarily in individuals of Mediterranean
descent or Asian origin
 Decrease in one or more of the globulin chains
 Decreased Hgb concentration and increased likelihood
of hemolysis
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30. Microcytic Hypochromic Anemia
 Thalassemia
 Beta Thalassemia (2 chains)
 Beta Thalassemia trait or minor
 Microcytosis, hypochromia, mild anemia, elevated Alpha
 Diagnosed by elevation of Hgb A2 levels on hemoglobin
electrophoresis
 Beta Thalassemia Major (Cooley’s)
 More severe anemia
 Increased cardiovascular burden
 Increased cardiac failure - high output cardiac failure. Heart
is having to work much harder, so may fail.
 Hyperplastic marrow
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31. Microcytic Hypochromic Anemia
 ALPHA Thalassemia
 Alpha trait: carrier state with one chain abnormal
 Alpha minor: two genes are defective
 Clinical Manifestations similar to Beta Thalassemia Minor
 Hemoglobin H disease
 Three traits are missing
 Clinical Manifestations similar to Beta Thalassemia Major
 Alpha Thalassemia Major
 Hydrops fetalis
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32. Microcytic Hypochromic Anemia
 Sideroblastic Anemia
 Insufficient uptake of iron
 Altered hemoglobin synthesis
 Characteristic ringed sideroblasts in bone marrow
 Dimorphism: characteristics of normal and
microcytic cells on smear
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33. Evaluation of Microcytosis
Microcytosis/Hypochromia
Fe, TIBC, Ferritin
< Fe
<Fe, <Ferritin, >TIBC
Normal
HgB Electrophoresis
Normal <HgBA2
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34. Macrocytic Anemia
 Etiology
 Vitamin B12 deficiency,  Chronic disease
due to lack of IF.  Hyperthyroidism
 Folic acid deficiency  Drug induced inhibition
 Pernicious anemia of folate absorption
 Alcoholics, lack of  Increased need with
minerals. pregnancy
 Gastric atrophy
 Dietary deficiency: short
gut syndrome, intestinal
surgery --> gasric
bypass
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35. Macrocytic Anemia
 Diagnostic Data
 Macrocytic, megaloblastic anemia
 Hyper-segmented PMNs (98%)
 Serum Folate
 Serum Cobalamin level
 Serum Homocysteine and Methylmalonic Acid
levels
look up some of this
stuff.
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36. Macrocytic Anemia
Hypersegmented PMNs
Macrocytosis
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37. Macrocytic Anemias
 Vitamin B12 and Folate Deficiency
 Treatment:
 1mg of Vitamin B12 per day week 1, 1 mg twice
weekly week 2, 1 mg per week for 4 weeks, then 1
mg per month for life.
 Oral preparations: 1 mg per day: poor absorption
 Folic Acid 200 ug/day (Young adults)
 Pregnancy 400ug/day
 Folate deficiency 0.5-1mg per day
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38. Hemolytic Anemia
 Spherocytosis
 Hereditary disease autosomal dominant trait in
individuals of northern European descent
 Red blood cells are spheroid in shape with
increased fragility
 Usually diagnosed before age 10.
 Anemia, splenomegaly, jaundice, spherocytes on
blood smear
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39. Spherocytosis
>Cell size
> fragility
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40. Hemolytic Anemia
 SICKLE CELL DISEASE
 Etiology
 Inherited autosomal recessive disease found
primarily in African Americans
 Abnormal Hemoglobin S (Hb S) in place of normal
Hb A due to replacement of glutamic acid with valine
on beta chain.
 HbS reacts to deoxygenation by stretching the
erythrocyte into an elongated sickle shape
 Increased hemolysis with ischemia and infarction
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41. Hemolytic Anemia
 Sickle Cell Anemia
 Percentage of HbS determines the degrees of sickling
with deoxygenation
 Sickled cells lose flexibility and cannot change shape as
they move through the vascular system
 Increased opportunity for obstruction, pain, and organ
infarction
 Abnormalities of membrane transport may be involved in
those with non reversible sickling
 Sickling will occur with hypoxia, acidosis, hypovolemia
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42. Pathophysiology of Sickle Cell Disease
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43. Hemolytic Anemia
 Sickle Cell Anemia
 Clinical Manifestations
 Four types of crisis
 Vaso-occlusive: sickled cells obstruct peripheral vessels
with increased pain, hand and feet swelling, infarction
 Aplastic crisis: normal sickled cells have a life span of
10-20 days so without an increase in erythropoesis of 5-8X
marked decrease in cells can occur after hemolysis
 Sequestration crisis: sequestering of blood in the spleen,
especially in young children can decrease blood volume and
cause cardiac collapse
 Hyper-hemolytic: increased hemolysis in those children
with more that one type of abnormality i.e. association of
G6PD
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44. Clinical Manifestations of Sickle Cell
Disease
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45. Sickle Cell Anemia
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46. Sickled RBC
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47. Sickle Cell Human Blood (sickle cells = green)
(SEM x 6,600)
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48. Sickle Cell Anemia
 Diagnostic Data
 Hemoglobin electrophoresis HbS
 Decreased Hct, normocytic, elevated platelet
count.
 Peripheral smear includes sickled cells, target
cells, and Howell-Jolly bodies
 Sickle cell test
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49. Howell-Jolly Bodies
The RBC in the center of the field contains several Howell-Jolly bodies,
or inclusions of nuclear chromatin remnants. There is also a nucleated
RBC just beneath this RBC. Abnormal and aged RBCs are typically
removed by the spleen. The appearance of increased poikilocytosis,
anisocytosis, and RBC inclusions suggests that a spleen is not present.
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50. Hemolytic Anemia
 G6PD DEFICIENCY
 ETIOLOGY:
 Deficiency of G6PD enzyme
 Genetic, X linked recessive disorder - comes from
mother, goes to son.
 Occurrence
 Blacks 10%
 Asians 5%
 Mediterranean 2-25%
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51. Hemolytic Anemias
 G6PD Deficiency
 G6Pd is an enzyme that normally enables RBC to respond
effectively to injury. In the absence oxidative stressors
damage the hemoglobin, interfere with normal enzymatic
activity, and damage plasma membranes. Damaged Hgb
precipitates in the cell forming Heinz bodies and causing
hemolysis
 Occurs in response to certain agents such as sulfonamides,
fava beans, infection, acidosis, hypoxemia.
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52. Hemolytic Anemia
 G6PD Deficiency
 Clinical Manifestations
 Pallor
 Icterus
 Dark urine
 Back Pain
 All si/sx occur after acute exposure and will clear
when exposure is terminated
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53. Normocytic Normochromic Anemia
 Aplastic Anemia
 Pancytopenia: reduction or absence of all three
types of blood cells
 Failure of bone marrow to produce adequate
number of blood cells
 Etiology
 Acquired
 Hereditary
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54. Normocytic Normochromic Anemia
 Aplastic Anemia
 Hereditary:
 Fanconi’s Anemia: characterized by defect in DNA repair
 Pancytopenic
 Acquired
 Idiopathic
 Secondary:
 Drugs and chemicals
 Infections
 Radiation
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55. Normocytic Normochromic Anemia
 Aplastic Anemia
 Pathophysiology
 Autoimmune with involvement of Interferon produced
by killer T cells and capable of inhibition
hematopoiesis and apoptosis of cells
 Clinical Manifestations
 Early depend upon which cell line is most
significantly involved
 Anemia, infections, bleeding
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56. Normocytic Normochromic Anemia
 Post Hemorrhagic Anemia
 Acute blood loss
 Cells that remain if normal before hemorrhage
remain normal in size and character
 Stabilization of vascular volume will cause
hemodilution
 See table 26-5 for clinical manifestations of acute
blood loss
 Based of severity
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57. Anemia of Chronic Disease most puzzling
 Etiology Not sure why this
happens.
 Decreased erythrocyte life span **Chronic renal failure
 Decreased bone marrow response
 Abnormal iron metabolism
 Increased production of lactoferrin and apoferritin which
compete with transferrin for binding with iron. These two
substances increase the storage form of iron but decrease the iron
available for erythrocyte formation
 Stimulation of cytokines such as interferon that decrease
hematopoiesis, decrease response of the bone marrow
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58. Anemia of Chronic Disease
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59. Clinical Manifestations of Anemia
 Tachycardia  Pallor
 Tachypnea  Systolic murmur
 Movement of fluid  Fatigue
from interstitial spaces  Weakness
to vascular volume  Dyspnea
 Increased turbulence of  Dizziness
blood flow  Syncope
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60. Progression and Manifestations of Anemia
review
look at co
mechanis
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61. Polycythemia
 Definition: increased number of erythrocytes
 Types
 Relative: increased hematocrit secondary to
hemo-concentration
 Absolute
 Secondary: increased RBCs secondary to hypoxia with
increased stimulus for release of erythropoietin
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62. Polycythemia
 Types
 Primary
 Polycythemia Vera
 Non malignant abnormal proliferation of bone marrow stem
cells
 Normal or below normal erythropoietin
 Genetic alterations of stem cells with alterations in all three
lines with elevation of red blood cells, white cells, and
platelets
 Abnormal cell populations develop in response to growth
factors, protein phosphorylation, interaction between tumor
suppression gene and multiple growth factors
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63. Polycythemia
 Types
 Primary: Polycythemia Vera
 Clinical Manifestations
 Increased absolute numbers of cells
 Increased risk of thrombi
 Slowed circulation can cause increased drowsiness,
delirium, rubor color to hands and feet, engorgement of
cerebral and retinal vessels
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64. Neutropenia
 Definition: decreased in circulating neutrophils with
clinical signs at less than 2000
 Etiology
 Infection
 Toxins form bacteria.
 Antibody mediated
 Bone marrow failure
 Immune disorders - autoimmune
 Anemia due to Folate and/or Vitamin B 12 deficiency
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65. Neutrophilia
 Definition
 Increased numbers of neutrophils
 Etiology
 Infection
 Leukemia
 Shift to the left:
 Release of immature neutrophils (bands)
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66. Neutrophilia
The RBCs in the background appear normal. The important finding here is the presence of many
PMNs. An elevated WBC count with mainly neutrophils suggests inflammation or infection. A
very high WBC count (>50,000) that is not a leukemia is known as a "leukemoid reaction". This
reaction can be distinguished from malignant WBCs by the presence of large amounts of leukocyte
alkaline phosphatase (LAP) in the normal neutrophils. 66
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67. Leukemia
 Most common form of childhood cancer
 80-85% are ALL
 (Acute Lymphoblastic Leukemia) - pretty curable.
 15-20% ANLL
 (Acute Non Lymphoblastic Leukemia)
 Most of these are involving the myeloid cells lines so
also AML (Acute Myelogenous Leukemia)
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68. Leukemia
 Classification
 Cell Line
 Acute and chronic
 Morphologic: FAB system (L1),L2, L3
 Immunologic: cell surface markers
 Etiology
 Genetic Risk
 Other inherited diseases such as Down’s Syndrome
and Fanconi’s Anemia
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69. All hemolysis will cause
an increase in uric acid
Leukemia
 Clinical Manifestations
 Pallor: decreased # of red blood cells
 Fatigue: decreased O2 carrying capability
 Bleeding: decreased platelet function - nose bleeds
 Fever: infection or increased metabolism secondary to
increased number and destruction of white blood cells
 Petechiae: decreased platelets
 Renal Failure: elevated uric acid levels from increased
cell breakdown
 Metastatic extramedullary invasion: CNS
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70. Acute Lymphocytic Lukemia
The WBCs seen here are lymphocytes, but they are blasts--very immature
cells with larger nuclei that contain nucleoli. Such lymphocytes are
indicative of acute lymphocytic leukemia (ALL). ALL is more common in
children than adults. Many cases of ALL in children respond well to
treatment, and many are curable.
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71. Acute Lymphoblastic Leukemia
Cytoplasmic
Vacoules
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72. Leukemia
 Types
 Chronic myelocytic
 Philadelphia chromosome is a diagnostic marker
 Not believed to be genetically transmitted but an error in mitosis
 Increased splenomegaly
 Chronic Lymphoblastic
 Abnormality of B cells
 Do not mature into plasma cells
 Decreased humoral immune system function
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73. Philadelphia Chromosome: CML
Myeloid cells of CML are also characterized by the Philadelphia
chromosome (Ph1) on karyotyping. This is a translocation of a
portion of the q arm of chromosome 22 to the q arm of chromosome 9,
designated t(9:22).
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74. Chronic Lymphocytic Leukemia
These mature lymphocytes are increased markedly in number. They are
indicative of chronic lymphocytic leukemia, a disease most often seen in
older adults. This disease responds poorly to treatment, but it is indolent.
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75. Cell Differentiation
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76. Hodgkin Lymphoma
 Definition
 Malignancy of a lymph node
 Arises in one or a chain of lymph nodes and spreads
in contiguous nodes
 Characterized by the presence of Reed Sternberg
cells
 Review the Cotswold Staging System Table 27-6
 Clinical manifestations
 Fever, wt loss, night sweats, pruritis
 Painless enlargement of lymph node most commonly
in cervical area
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77. Hodgkin Lymphoma
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78. Hodgkin Lymphoma
Note the large cells with large, pale nuclei containing large purple
nucleoli at the arrowheads. These are Reed-Sternberg cells that are
indicative of Hodgkin's disease.
Reed
Sternberg
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79. Non Hodgkin Lymphoma
 Definition
 Malignant changes within the lymphoid system
without the presence of Reed Sternberg cells
 Usually involves multiple peripheral nodes
 Swelling is painless with indolent growth
 Can have abdominal tumors, tumors of testes
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80. Multiple Myeloma
 Neoplastic proliferation of a single clone of a
plasma cell involved in production of a
specific immunoglobulin.
 Clinical manifestations: bone pain, weakness,
fatigue, anemia secondary to bone marrow
crowding with abnormal cells
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81. Multiple Myeloma
The rounded "punched out" lesions of multiple myeloma appear as lucent
areas with this skull radiograph.
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82. Multiple Myeloma
The skull demonstrates the characteristic rounded "punched out" lesions of
multiple myeloma.
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83. Hemostasis
 Vasoconstriction
 Formation of the platelet plug
 Vessel damage
 Platelet aggregation and attachment to vessel wall
in the presence of calcium
 In the presence of ADP released by erythrocytes
platelets attach to cell wall
 Release chemical mediators: histamine,
thromboxane A, and prostacyclin
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84. Platelet Plug Formation
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85. Platelet Aggregation
Adherence
Fibrin
Threads Fibrin Mesh
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86. Hemostasis Steps
 Activation of the clotting factors
 Prothrombin-PA-Thrombin
 Thrombin to Fibrinogen
 Platelets > Fibrin Stabilizing Factor > Cross
Linking Bonds
 Clot Retraction
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87. Hemostasis Steps
 Intrinsic Pathway
 Activated when Factor VIII (Hageman Factor)
contacts subendothelial tissue after vascular
injury
 Extrinsic pathway
 Tissue Thromboplastin is released by damaged
endothelial cells and comes into contact with
clotting factors
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88. Coagulation Cascade
review
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89. Lysis of Clot - fibrinolytic system
 Plasminogen activates Plasmin in the presence
of t-PA and thrombin
 Plasmin is a proteolytic enzyme
 Splits fibrin and fibrinogen into fibrin
degradation products - can be used as tx.
 Uses up clotting factors in the process: Factor V,
Factor VII
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90. Fibrinolytic System
know this
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91. Immune Thrombocytopenic Purpura
(ITP)
 Pathophysiology
 Autoimmune mediated platelet destruction
 Recurrent episodes
 Usually initially follows a viral infection
 Peak onset 20-40 years of age
 Platelets are the first line defense against bleeding
 Platelet counts below 100,000
 IgE attaches to platelet and causes destruction.
91
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92. Immune Thrombocytopenia Purpura
 Clinical Manifestations
 Bruising
 Petechiae
 Bleeding
 Counts below 50,000 with increase risk
 Counts below 10,000-15,000 frank bleeding
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93. Immune Thrombocytopenia Purpura
 Differential Diagnosis
 Leukemia
 Meningococcemia - cause petichei 2 toxic
 Drug Induced
 Von Willebrand’s Disease - hemophylia
 Diagnostic Data
 CBC with platelet count
 aPt, Ptt, INR, bleeding time
93
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94. Immune Thrombocytopenia Purpura
 Treatment
 Referral
 Prednisone Infusion
 Splenectomy
94
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95. Hemophilia
 Inherited Hemorrhagic Disease
 Types
 Hemophilia A: Classic - Factor VIII deficiency (most
common, X recessive)
 Hemophilia B: Christmas Disease - IX deficiency (x
linked)
 Hemophilia C: Factor XI deficiency (men and women)
 von Willebrand Disease: Factor VIII deficiency (Inherited
autosomal; will see increase for several days, vs classic).
 Pathophysiology: lack of the clotting factor impacts
the clotting cascade and formation of thrombin
95
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96. Hemophilia
 Clinical Manifestations
 Often not noted during first year of life
 Prolonged bleeding
 After minor trauma
 Hemarthrosis of the joints (can predispose to
degenerative disease)
 Deep muscle bruising
 Joint deformities with contractures (muscle
deformaties).
 Intracranial hemorrhage and abdominal bleeding
 the most feared complication - emergency 96
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97. Disseminated Intravascular Coagulation
(DIC)
 Etiology
 Associated with well defined clinical conditions that act
as a procoagulant (activates clotting cascade)
 Hypoxemia
 Acidosis
 Shock
 Sepsis
 Precipitated by
 Endothelial damage
 Tissue damage
 Direct activation of Factor X
97
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98. Disseminated Intravascular Coagulation
(DIC)
 Pathophysiology
 Wide spread clotting
 Utilization of clotting factors
 Increase in levels of thrombin
 Activation of the fibrinolytic pathway
 Elevation of Plasmin
 Increased Fibrin Degradation Products
98
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99. Blood Clot Formation (blood cells, platelets, fibrin clot)
(SEM x10,980)
99
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100. Human Red Blood Cells, T-lymphocytes, Platelets and Fibrin Threads
(SEM x7,700)
100
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