board review- part 1: benign...
TRANSCRIPT
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Board Review- Part 1:
Benign HemePath
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Peripheral Blood
Smear Examination
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Elevated MCV = Macrocytosis
MCV > 100um3
• B12/Folate deficiency, aplastic anemia, MDS
• Autoimmune hemolytic anemia
• Liver disease, hypothyroidism, alcoholism
• Cold agglutinin disease
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Decreased MCV = Microcytosis
MCV < 80um3
• Iron deficiency
• Thalassemias
• Anemia of chronic
disease
• Hemoglobinopathies
– C, E, S, D
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Iron Panel Interpretation
Cause of
anemia
Serum
iron
TIBC Percent
saturation
Iron
deficiency
↓ ↑ ↓
Thalassemias ↑ / N ↓ / N
↑ / N
Sideroblastic
anemia
↑ ↓ / N
↑
Chronic
disease
N/↓ ↓ N
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Pathologic Red Blood Cells in
Peripheral Blood Smears
Type of Cell Underlying Change Disease States
Acanthocyte (spur cell) Altered cell membrane lipids Abetalipoproteinemia, liver
disease, postsplenectomy,
McLeod phenotype
Bite Cell (degmacyte) Heinz body pitting by spleen G6PD deficiency, drug-induced
oxidant hemolysis
Ovalocyte (elliptocyte) Abnormal cytoskeletal proteins Hereditary elliptocytosis
Rouleaux Circulating paraprotein Paraproteinemia
Schistocyte (helmet cell) Mechanical destruction in
microvasculature
DIC, TTP, HUS, prosthetic heart
valves
Spherocyte Decreased membrane
redundancy
Hereditary sphereocytosis,
immunohemolytic anemia (warm
Ab)
Stomatocyte Membrane defect with
abnormal cation permeation
Hereditary stomatocytosis, liver
disease
Target Cell (codocyte) Increased redundancy of cell
membrane
Liver disease, beta thalassemia
postsplenectomy, Hgb C/D/E/S
Burr Cell (ecchinocyte) Altered membrane lipids Usually artifactual but maybe
uremia
Tear Drop Cell (dacrocyte) Myelofibrosis
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•Irregular, long, sharply pointed and
bent spicules
•Absence of central pallor
•Most commonly seen in liver disease
Acanthocytes (Spur cells)
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Abetalipoproteinemia: absence of apolipoprotein B results in inability to transport
triglycerides in the blood-> Altered cell membrane lipids-> Acanthocytes
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McLeod phenotype/syndrome
• Absence of erythrocyte surface Kx
antigen (part of Kell antigen group)
• Acanthocytes with chronic but well
compensated hemolytic anemia
• Disease processes include muscular
dystrophy, cardiomyopathy
• May be associated with chronic
granulomatous disease
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Tear Drop Cells (Dacrocytes)
Myelofibrosis or bone marrow infiltrate
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Bite Cells
• G6PD deficiency
G6PD deficiency
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STOMATOCYTES
RBC with slit-like or rectangular area of central pallor, a mouth
Most often seen in liver disease
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Burr Cells (Ecchinocytes)
Projections- smaller
more regular than
acanthocytes
Often artifactual but
may be seen in
UREMIA
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Spherocytes
-Hereditary sphereocytosis,
-Immunohemolytic anemia (warm Ab)
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Hereditary spherocytosis
• Northern European ancestry
• Spectrin, ankyrin, band 3 or band 4.1 deficiency
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Hereditary spherocytosis
• Defects in vertical stabilization of the phospholipid bilayer of the RBC membrane cause separation of the spectrin - phospholipid bilayer
• Normal biconcave red cell loses membrane fragments and adopts a spherical shape • Inflexible cells are trapped in the splenic cords, phagocytosed by macrophages
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Osmotic Fragility Test
• Equal volumes of blood are placed in a
series of hypotonic solutions
• Allowed to reach equilibrium (24 hr,
37 C); centrifuged
• The RBC swells and lysis occurs
• As the % saline decreases
further, the amount of lysis
increases (determined by
optical density )
Normal
HS
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Elliptocytes
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Hereditary elliptocytosis
• Autosomal dominant trait
• Spectrin abnormality or deficiency
of protein band 4.1
• Asymptomatic without anemia and
usually with no splenomegaly and
only mild hemolysis
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21
Hereditary Pyropoikilocytosis
• Same mutations as in HE
• Present in the neonatal
period with severe
hemolytic anemia, RBC
fragments, poikilocytes,
elliptocytes,
microspherocytes,
hyperbilirubinemia
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Hereditary Pyropoikilocytosis
(HPP)
• Reminiscent of erthrocyte morphology seen
after thermal burns
• Rare cause of severe hemolytic anemia
• 1/3 of family members with HPP have HE
• Many HPP patients have severe hemolytic
anemia in childhood that evolves into typical
HE later in life
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Target Cells
Characteristic of: – Liver disease
– Post-splenectomy
– Hemoglobin disorders
• Beta thalassemia
• Hemoglobinopathies
Hb S, C, D and E
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Hgb SC disease with C crystals, Taco cells and sickle cells
“Washington Monument crystals”
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Schistocytes
Microangiopathic
hemolytic anemia
DIC, TTP, HUS
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Rouleoux and Clumping
Rouleaux:
monoclonal gammopathy
vs. polyclonal gammopathy
RBC Clumping:
cold agglutinin
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Hypochromic anemia
MCH < 27 pg
• Disorders of globin synthesis – Thalassemic syndromes
• α-Thalassemia
• ß-Thalassemia
• Disorders of heme synthesis – Sideroblastic anemias
• Hereditary (X-linked, auto. dominant)
• Acquired (lead poisoning, alcoholic, medication, MDS)
• Disorders of Fe metabolism – Fe deficiency
– Chronic disease
– Neoplasia
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Iron Deficiency
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Reticulocytes
• Decreased cell survival
– Blood loss
– Autoimmune hemolysis
– Nonimmune hemolysis
• TTP, HUS, DIC
• H. spherocytosis
• G6PD
• PNH
• Hemoglobinopathy
• Thalassemia
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Nucleated RBCs
• Not normally present in
adult patients PS
• Present in:
– Severe hemolysis
– Myelophthisic condition
– Leukoerythroblastic
smear
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Basophilic Stippling
Precipitated ribosomes (RNA)
Fine – variety of anemias:
Siderblastic, sickle cell,
megaloblastic
Coarse – Lead intoxication,
thalassemia
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Heinz Bodies
• Precipitated denatured Hgb
• Seen in G6PD deficiency
• Seen with supravital staining – Crystal violet
– Brilliant cresyl blue
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Howell Jolly Bodies
Dense,usually
single
Nuclear remnant
Seen in:
- Postsplenectomy
- Hemolytic anemia
- Megaloblastic
anemia
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Pappenheimer bodies
Small, dense basophilic granules
(mitochondrial remnant that contains Fe)
Seen in:
- Sideroblastic anemia
- Post-splenectomy
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The Malignant Mimicker:
Leukemoid Reaction
• Precursor granulocytes in the PBS
• WBC in the range up to 100K
• Response to severe stress or infection
• Other signs of malignancy not present (i.e. CML)
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Neutrophil Disorders with
Abnormal Morphology
• Pelger-Huet anomaly
– Bilobed or nonsegmented nucleus
– asymptomatic
• May-Hegglin anomaly
– Cytoplasmic inclusions resembling Dohle bodies
– Many asymptomatic
• Chediak-Higashi syndrome
– Giant cytoplasmic granules in all granulocytes
– Immunodeficiency
• Alder Reilley Anomaly: inclusion is mucopolysaccharide (PAS+)
• Hypersegmentation
– B12/Folate deficiency, myelodysplasia, chemotherapy, or renal failure
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Pelger-Huet Anomaly
• Inherited, AD
• Acquired =
“pseudo” Pelger-
Huet as in MDS
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Chediak-Higashi Syndrome
• Autosomal
recessive
• Giant granules
• Severe
immunodeficiency
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May Hegglin Anomaly
• Thrombocytopenia
• Enlarged platelets
• Variable neutropenia
• Inclusions also seen in
eosinophils, basophils, and
monocytes
• Autosomal dominant
• Many patients are
asymptomatic
• Non-muscle myosin heavy
chain A (MYH9) mutation
• No impairment on PMN
function
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Alder Reilley Anomaly
• Resemble the large
primary granules of
promyelocytes
• Large, purple to purplish-
black, coarse azurophilic
granules
• No impaired PMN function
• Inclusion is a
mucopolysaccharide
(PAS+)
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Alder Reilley Anomaly
• Autosomal recessive
• Associated with several
different types of genetic
mucopolysaccharide
disorders (Hurler, Hunter,
San Fillipo, Maroteaux-
Lamy)
• Affects connective tissues,
heart, bone, CNS
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Hypersegmentation
• More than 5 lobes
• Seen most commonly in B12/folate def
• Uremia
• Chemotherapy
• Also seen in MDS and other MPN/MDS neoplasms
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Eosinophilia
• Allergic/hypersensitivity reactions
• Drug allergies
• Parasitic infections
• Connective tissue/collagen vascular disease
• Neoplasms
– T-cell lymphoma
– Hodgkin lymphoma
• Sarcoidosis
• Hypereosinophilic syndrome/Chronic eosinophilic leukemia
• Chronic/acute leukemia a/w PDGFRRA or PDGFRB mutations
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Basophilia
• Much more common in
malignancies like CML
vs. reactive
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Reactive Lymphocytosis
• Diseases with nonreactive morphology
– Infectious lymphocytosis (Whooping cough)
– Transient stress lymphocytosis
• Diseases with reactive morphology
– EBV,CMV, Toxo, adenovirus, HHV-6, viral
hepatitis
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Atypical/reactive lymphocytes
Plasmacytoid
lymphocyte
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Ehrlichiosis
• Found in the SE and S. Central US
• Rickettsial organism
• Transmitted by ticks
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Histoplasma
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Babesiosis
• Protozoa
• Endemic in the NE US
• Transmitted by the Ixodidae tick
• Morphology similar to malaria
• Tetrad form is diagnostic
• Risk Factors: – Post-splenectomy
– Immunocompromised
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Malaria
• Ringed stage
(trophozoite)
• Can see other
stages within
RBCs
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Gametocytes
Trophozoites (rings)
Plasmodium falciparum
Multiple rings/cell
Appliqué forms
1-2 chromatin dots
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Plasmodium vivax
Early Trophozoites (rings)
Enlarged RBCs
Schuffner’s Dots
Ameoboid rings
Mature trophozoite ->schizont
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Giant Platelets
• Size of an RBC
• Usually indicates a hyperreactive bone marrow 2o to underlying condition – ITP, TTP, DIC
• Can be inherited in the form of Bernard-Soulier syndrome, May-Heglin anomaly
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Platelet Clumping and
Satellitelosis
• Causes artificially low platelet
counts
• 2o to EDTA used in collection tubes
Solution is to use
sodium citrate instead
of EDTA
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Aplastic Anemia
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Aplastic Anemia
• Reduction of erythroid,
granulocytic/monocytic, and
megakaryocytic cell lines in the
bone marrow and their progeny in
the peripheral blood.
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Hypocellular Bone Marrow
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Aplastic Anemia- Causes
• Constitutional- including Fanconi’s
• Idiopathic
• Secondary
– Chemical/drug
– Radiation
– Infection
– Immune disorders
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Fanconi’s Anemia
• 2/3 of constitutional aplastic
anemia
• Autosomal recessive
– DNA repair defect (diagnosis:
chromosome breakage analysis)
• Phenotypic abnormalities- bone,
skin, mental retardation
• Aplasia develops by mid childhood
• Progression to AML
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Chemical/Drug
• Dose-dependant
– Chemotherapy
– Benzene
• Idiosyncratic
– Chloramphenicol, anticonvulsants,
sulfonamides, gold, NSAIDs
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Ionizing Radiation
• Aplastic anemia- acute
• Long-term effects are
myelofibrosis and acute leukemia
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Infections
• Hepatitis
– Rare, often fatal
– Non-A, non-B, non-C, non-G
– Usually 6 wks after clinical
symptoms
– No relation to severity of illness
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Parvovirus B19
• Usually red cell aplasia
– Selective cytotoxic invasion of
erthryoblasts
• Mild reduction in granulocyte and
megakaryocyte production
• Chronic hemolytic anemia pts. at risk
– Sensitive to cessation in RBC production
– Transient aplastic crisis
• Self limited
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Parvovirus B19
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Treatment
• Treat the underlying conditions:
infection, d/c meds
• For immune disorders: androgens,
immune modulation, cytokine therapy
• Transfusions
• Bone marrow transplant
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Deficiencies of Glycolytic Pathway
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-Mature RBCs have the capacity for a limited number of enzymatic reactions
-No mitochondria in RBC, so it depends entirely on anaerobic glycolysis to produce
energy.
-The mature RBC is completely dependent on glucose as a source of energy. Glucose
usually (90%) is catabolized to pyruvate and lactate in the major anaerobic
glycolytic pathway (Embden-Myerhof Pathway). In the process, ATP is generated to
play its major role in maintaining a cation gradient in the RBC, thus protecting it
from premature death.
-Hereditary deficiency of some of the glycolytic enzymes have been documented,
and several cause a hereditary nonspherocytic hemolytic anemia (HNSHA), whereas
others cause multisystem disease
-Most are rare
-Pyruvate kinase deficiency is the most common and comprises 90% of affected
patients
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-Hexokinase (AR) Mild-severe
-Glucose-6-isomerase (AR) Mod-severe
-Phosphofructokinase (AR) Mild myopathy
-Aldolase (AR) Mild-mod
-Phosphoglucerate Mild-severe
kinase (X-linked) retardation
-***Pyruvate kinase (AR) Mod-severe
Deficiencies of Glycolytic pathway
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Pyruvate Kinase Deficiency
-AR, patient must be homozygous for the trait to be
expressed fully
-Detected in infancy or childhood due to anemia, jaundice, splenomegaly , gall
stones. The severity of the condition is widely variable, even among patients with
the same level of deficiency.
Lab studies
-Norchromic normocytic, or macrocytic anemia with reticulocytosis in the absence
of blood loss, is suggestive of hemolysis.
-Enzyme assay and, more recently, DNA analysis by PCR or single-strand
polymorphism are available to confirm the diagnosis and to identify the carrier
state if the need arises.
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Fluorescent Screening test for Pyruvate kinase deficiency:
Principle: Reduced pyridine nucleotide (NADH) fluoresces when illuminated with
long-wave UV light.
Phosphoenolpyruvate (PEP) + ADP--------------> Pyruvate + ATP
Pyruvate + NADH + H+ ----------------------------> Lactate + NAD+
LDH is present in excess of PK, NAD production is limited by PK levels. Thus,
there should be a time dependent loss of fluorescence as NADH is oxidized to
NAD when PK is normal.
In PK-deficiency, fluoresence by NADH fails to disappear.
Pyruvate
kinase (PK)
Lactate dehydogenase
(LDH)
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RBC enzyme activity assays
-Spectrophotometric techniques that depend on the absorption of light of the
reduced pyridine nucleotide, NADPH, or NADH at 340nm.
-Reduction results in formation of NADPH or NADH, with increase in
absorbance at 340 nm, and oxidation results in formation of NADP or NAD with
a decrease in absorbance.
-The change in absorbance may be used to calculate enzyme activity.
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Deficiencies of Hexose Monophosphate
Shunt Pathway
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Hexose monophosphate Shunt (HMP)
G6PD deficiency Common
Gamma-Glutamylcysteine synthase Rare
GSH synthetase Rare
Glutathione reductase Rare
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G6PD Deficiency:
-G6PD enzyme located on X chromosome
-> 30 different mutations give rise to a variety of clinical diseases
-Normally 2 isotypes of G6PD: A and B. Can be differentiated based on
electrophoretic mobility
-B isoform most common type of enzyme found in all population groups
-A isoform, found in 20% black men in US, migrates more rapidly on
electrophoretic gels than B. It has similar enzyme activity as B, and does not cause
disease
-11% of US black men have G6PD variant (G6PD A-). It has same electrophoretic
mobility as A, but is unstable, resulting in enzyme loss and ultimate enzyme
deficiency. Older RBC have only 5-15% enzyme
-G6PD A- most clinically significant type of abnormal G6PD among US Blacks
-Other G6PD variants predominate in other racial groups: G6PDMED in Sicilians,
Greeks, Sepharic Jews, Arabs. G6PDCANTON or G6PDMAHIDOL in Asian population
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-X linked, so sex-linked inheritance pattern.
-Effect fully seen in affected men
-Carrier women are variable affected depending X chromosome inactivation
Clinical findings
-Episode of hemolysis following infection or ingestion of an oxidant drug
-In G6PD A- def, the hemolytic anemia is self-limited as the young RBC produced in
response to hemolysis have nearly normal enzyme.
-Five classes of G-6-PD deficiency exist based on enzyme activity levels, as follows:
1.Enzyme deficiency with chronic hemolytic anemia
2.Severe enzyme deficiency (enzyme level <10%)
3.Moderate-to-mild enzyme deficiency (enzyme level 10-60%)
4.Very mild-to-no enzyme deficiency (enzyme level > 60%)
5.Increased enzyme activity
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Laboratory Tests:
-Acute hemolysis is associated with formation of Heinz bodies (denatured Hgb).
-Bite cells (eccentrocytes) may be seen
-Fluorescent Screening test for G6PD Deficiency:
In the presence of NADP+, G6PD is oxidized to form 6-phosphogluconate and
NADPH. Then
6-Phophogluconate + NADP+ ----------------------- > Ribulose-5-P + NADPH + H+
NADPH can be detected by fluorescence
When G6PD is low, less NADPH is formed.
Normal sample shows a bright fluorescence after 5-10 minutes of incubation,
whereas deficient sample shows no fluorescence.
6-phosphogluconate
dehydrogenase
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Quantitative G6PD assay:
-Formation of NADPH from NADP+ from G6P is measurable by a change in
absorbance created by NADPH at 340 nm in a spectrophotometer
Heinz body test:
Crystal violet or neutral red is added to blood
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Paroxysmal Nocturnal
Hemoglobinuria (PNH)
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Introduction
• Recurrent, episodic
– Intravascular hemolysis
– Hemoglobinuria
– Venous thrombosis
• May not always be
– Paroxysmal (acute)
– Nocturnal
– hemoglobinuric
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Additional Points
• Clonal disorder
– Not a malignant clone
• Deficiency of complement-control proteins
– On all affected hematopoietic cells
• Increased susceptibility to complement lysis
– Erythrocytes not able to endocytose
membrane attack compex (MAC: end product
of complement cascade) as opposed to
nucleated cells
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Complement Control Proteins
•CD55 (decay accelerating
factor: DAF)
–Regulates C3 convertase
•CD59 (membrane inhibitor of
reactive lysis: MIRL)
–Modulates complement-
mediated lysis
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Complement Control Proteins
Regulation of C3 Convertase
•CD55 (DAF)
–Inhibits association of
C4b and C2
–Promotes dissociation
of C4bC2a complex
(C3 Convertase)
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Complement Control Proteins
• CD59 (MIRL) prevents formation of Membrane Attack Complex and lytic action
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Clinical
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Nocturnal Hemoglobinuria
•Classical
description
–Dark urine in morning
that clears through
the day
–Sleep decreases pH,
increases
complement activity
-Accumulation of
urine
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Flow Cytometry •Preferred
confirmatory test
•Decreased
expression of CD55
and/or CD59
PNH
Normal
PNH
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AUTOIMMUNE
HEMOLYTIC
ANEMIAS
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WARM TYPE
-Abrupt onset
-May be severe
-Slight female preponderance
-IgG antibodies
-Extravascular hemolysis
-Antibodies commonly against broad Rh
antigens
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WARM AIHA
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COLD TYPE
-Acute or insidious onset
-Mild to severe anemia
-Female preponderance
-IgM antibodies
-Agglutination of red cells at low temperatures
-Complement activation
-Intravascular and extravascular hemolysis
-Antibodies commonly against I or I antigens
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COLD TYPE
• Acute: postinfectious, self limited, younger patients
• Chronic: idiopathic, older patients
• Cold agglutinin disease (CAD): insidious, elderly women,
associated with lymphoproliferative disorders
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COLD AIHA
•
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LAB PARAMETERS
WARM COLD
DAT 2+ TO 4+ 2+ TO 4+
ANTI IgG + -
ANTI C3 RARE +
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TREATMENT
WARM AIHA
-Corticosteroid therapy
-Intravenous IVIG
-Immunosuppressants
-Splenectomy
COLD AIHA
-Immunosuppressants and splenectomy: no role
-Keeping patient warm
-Treatment of underlying disease
-Plasmapheresis
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Hemophagocytic syndrome
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Syndrome Definition • “Hemophagocytosis” – Process by which
macrophages engulf RBCs, WBCs,
platelets and their precursors
• Hemophagocytic syndrome =
Hemophagocytic lymphohistiocytosis
(HLH)
– Two main groups: Genetic and acquired
– Mechanism: highly active yet ineffective
immune response that is life-threatening
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Bone marrow aspirate
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HLH - Pathophysiology
• Theory: Inappropriate immune reaction caused by proliferating, active T cells and macrophages with inadequate apoptosis of immunogenic cells
• Impaired cytotoxic function of NK cells
– Decreased NK activity with persistent T-cell activation
• Cytokine hypersecretion, inflammatory response
– IFN-gamma, TNF-alpha, IL-6, IL-10, M-CSF
– Responsible for clinical signs, cytopenias, coagulopathy, high triglycerides
– Infiltrate tissues and lead to necrosis and organ failure
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HLH – Criteria
• sCD25 (alpha chain of soluble IL-2 receptor)
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HLH and Infection
• Viruses (esp. EBV), bacteria, parasites, spirochetes,
mycobacteria, fungi
• Difficulty distinguishing acquired from familial
– Familial cases may be precipitated by infection
– May mimic an infectious illness
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HLH and Infection
• Impractical to exclude all possible infectious causes
• If HLH criteria are met, then screen for EBV, CMV,
parvovirus B19, HIV
• History should guide testing
– HIV infection: Pneumococcus, Pneumocystis,
Histoplasma, Penicillium marneffei
– Animal exposure: Brucella, Rickettsia
– Travel exposure: Leishmania, malaria
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HLH and other Associations
• Malignancy
– T-cell lymphoma
• Autoimmune diseases
– Juvenile RA, Still’s disease (systemic-onset juvenile
idiopathic arthritis), SLE
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HLH - Laboratory
• CBC, AST/ALT, bilirubin, triglycerides, ferritin, fibrinogen
• Bone marrow: Insensitive
– May be negative in 2/3 of initial aspirates
• sCD25 >2400 U/ml
– Highly specific serum parameter
• NK cell perforin expression
• Genetic testing
– PRF1, Munc13-4 (available at Cincinnati Children's Hospital)
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HLH - Treatment
• Immediate goal: Immune suppression
– Corticosteroids
– Cyclosporin A: prevents T cell activation
– Etoposide: Critical for EBV-infected pts, inhibits
EBNA synthesis in EBV-infected cells
• Genetic HLH: Bone marrow transplant
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CRYOGLOBULINAEMIA
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CRYOGLOBULINS
• Cryoglobulins are plasma proteins that
precipitate at low temperature ( 0 to 4 degree
Celsius ) and dissolve at higher temperature
• They were first described in 1933 by Wintrobe
and Buell (at John Hopkins Hosp)
• In 1962, Lospaluto et al. showed that
cryoglobulins contains more than one
immunoglobulin ( Am J Med 1962;32:142-7 )
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Peripheral blood smear with clumps of
precipitated cryoglobulin
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CLASSIFICATION( Brouet et al.’s )
• TYPE I:- Single Monoclonal Immunoglobulins
– Type I CGB consists of a single monoclonal Ig, usually IgG or IgM,
infrequently IgA, and very rarely monoclonal light chain protein
• TYPE II :- Mixed Monoclonal/ polyclonal IG
– Type II CGB are mixed CGB consist of two or more IG of different
classes. One component of the complex is a monoclonal protein
(with a high proportion being IgM), that has rheumatology factor
activity, in association with polyclonal IG component
• TYPE III :- Mixed polyclonal IG
– Type III CGB are also mixed CGB, consisting of two or more IG of
different classes, however, each component is a polyclonal IG
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CRYOGLOBULIN TYPES &
ASSOCIATED DISEASES
Types of CGB Immunochemical
composition Associated diseases Comments
Type I : Single
Monoclonal IG
IgG
IgA
Monoclonal
L-Chain
IgM
B-cell dyscrasis:
Myeloma
W. Macroglobulinemia
CLL
Hairy Cell Leukaemia
Cryoglobulin
concentratio
n is usually
HIGH (>
5mg/ml )
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CRYOGLOBULIN TYPES &
ASSOCIATED DISEASES
Type of CGB Immunochemical
composition
Associated Diseases Comments
Type II: Mixed
Monoclonal
/Polyclonal IG
IgM-IgG
IgG-IgG
IgA-IgG
B- Cell dyscasias:
Myeloma
W. Macroglobulinaemia
CLL
HCV
Circulating
immune
complexes
CGB con.
usually(5mg/ml)
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CRYOGLOBULIN TYPES & ASSOCIATED DISEASES
Type of CGB Immunochemical
composition
Associated Diseases Comments
Type III : Mixed
Polyclonal IG
IgM-IgG
IgM-IgG-IgA
Autoimmune disease:
Rheumatoid arthritis
SLE
Sjogren’s syndrome
Hepatitis
Vasculitis
Circulating
immune complexes
in response to Ig
challenge in
Rheumatoid disease
and chronic
infections
CGB conc. is
usually < 1mg/ml )
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CLINICAL ASSOCIATION
• Type I cryoglobulinemia are more likely to be symtomatic and are usually associated with acrocyanosis, retinal haemorrhage, Raynaud’s phenomenon, and arterial thrombosis
• High levels of type I cryoglobulins are associated with symptoms of hyperviscosity
• Mixed CG, are less commonly symptomatic and are usually associated with vascular purpura and arthritis/ arthalgia; this is secondary to deposition within tissue (immune complexes ) which activate complement and induce localized inflammation
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HEPATITIS C VIRUS-ASSOCIATED
CRYOGLOBULINEMIA
• When no underlying disease is present, this is referred
to as essential mixed cryoglobulinaemia ( EMC )
• In EMC, the possible role of hepatotropic viruses has
been suggested by the high frequency of co-existing
liver abnormalities
• The prevalence of anti-hepatitis C virus (HCV )
antibodies and the correlation with clinical and
serological parameters of EMC have been
investigated
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ANALYSIS PROCEDURE
• A white precipitate (cryoglobulin) appears in the
serum after 24-72 hours of storage at 37oC
• The cryoglobulins can be quatitated by:
Measuring the cryoglobulin protein
spectrophotometrically by absorbance at 280mm
• Ig component of cryoglobulins can be determine by:
– Immunoelectrophoresis
– Isoelectric focusing in asociation with
immunofaxition
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THERAPEUTIC MODALITIES FOR
SYMPTOMATIC PATIENTS
• Corticosteriods
• Subcutaneous interferon alpha ( IFN ), with or without plasma
exchange
• Care must be given to ensure blood components are warmed
before infusion
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Bone Marrow Disorders
of Nonhematopoietic
Elements
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Lipid Storage Disorders
• Hereditary lysosomal
enzyme deficiency
– Autosomal recessive
• Partially degraded
lipids accumulate in
macrophages
– Liver, spleen, bone
marrow, etc.
• Organomegaly,
cytopenias
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Gaucher’s Disease
• Enzyme deficiency: Glucocerebrosidase
• Accumulate Glucocerebroside
• 3 clinical forms, all AR
– Type I- adult
– Type II- acute infantile, neuronopathic
– Type III- subacute juvenile, neuronopathic
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Gaucher’s Disease
• Gaucher cell
– “Wrinkled
cigarette paper”
or “crepe paper”
– PAS positive
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Pseudo-Gaucher Cell
• Indistinguishable from true Gaucher
cell
• Conditions with high cell membrane
turnover
– CML, hemoglobinopathies, myeloma
– Increased burden of glucocerebroside
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Gaucher Cell Look-alike
• MAI infection
• Macrophages packed
with organisms
– Negatively staining
organisms mimics
striations of Gaucher
cells.
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Niemann-Pick Disease
• Enzyme deficiency: Sphingomyelinase
• Accumulate Sphingomyelin
• 3 clinical forms, all AR • Type A- early onset
• Type B- adult, no cerebral involvement
• Type C- late onset
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Niemann-Pick Disease
• Foamy macrophages
– “Bubbly” appearance
– Weak PAS+
– Oil Red O and Sudan
black positive
• May also present as
Sea blue histiocytes
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Sea Blue Histiocytes
• Macrophages contain ceroid
– Lipofuscin-like pigment
– H&E-> yellow-brown
– Wright/Geimsa-> bright blue green
– PAS positive
• High turnover states: CML, ITP
• Lipidoses and hyperlipidemia
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Sea Blue Histiocytes
H & E
Geimsa
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Sarcoidosis
• Epitheloid granulomas in lung and
other organs
– Bone marrow involvement 17%
– A/w lymphadenopathy, spleenomegaly,
lymphopenia
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Sarcoidosis
• Epitheloid histiocytes
– Small, noncaseating
granulomas
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Bone Marrow Infarction
• Coagulative necrosis
• Associated with neoplastic
process, vasocculsive disorders
and hemoglobinopathies
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Bone Marrow Infarction
• Homogenously
staining
• Ghost cells
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Serous Fat Atrophy
• AKA gelatinous
transformation
• Associated with
starvation and
wasting diseases
• Homogenous
extracellular
substance with
“gelantinous”
appearance
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Renal Osteodystrophy
• Chronic renal insufficiency
– 2o hyperparathyroidism
• Increased osteoclast activity- irregular
scalloping of bony trabeculae and
peritrabecular fibrosis
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Renal Osteodystrophy
• “Scalloping” of
bony trabeculae
• Peritrabecular
fibrosis
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Nonmalignant
Lymphadenopathy
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Reactive Lymphoid Hyperplasia
Follicular Pattern
• Numerous enlarged, oddly shaped follicles
• Prominent germinal centers
• Tingible body macrophages
• Nonhomogenous lymphoid population
• Frequent mitoses
• Polyclonal surface immunoglobulins
• Germinal centers negative for bcl-2
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Reactive Lymphoid Hyperplasia
Sinus Pattern
• Prominent sinuses
• Histiocyte hyperplasia
• Proliferation of plasma cells
• Polyclonal surface immunoglobulins
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Progressive Transformation of Germinal Center
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Progressive Transformation of Germinal Center: expanded
follicular center infiltrated by mantle cells. A benign process.
Maybe a/w NLPHL
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Infectious Mononucleosis
• EBV virus
• Clinical information: febrile, exudative pharyngitis, cervical lymphadenopathy, splenomegaly, abnormal LFTs, common in adolescence/young adulthood, rare after 40 y/o
• Peripheral blood lymphocytosis with atypical lymphocytes
• Expanded paracortex (T-cell zone) by many immunoblasts & R-S like cells
• Mottled pattern, foci of necrosis
• Different from NHL: polymorphous background of transformed lymphocytes, persistent of reactive follicles, architecture preservation. Immuno for R-S like cells: (+) for CD45, CD30 and CD20; (-) for CD15. Also many large CD8-pos cells
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Measles Lymphadenitis
• Measles (rubeola) or history of recent vaccination
• Axillary, cervical, inguinal lymph nodes
• Mottled histologic pattern
• Follicular hyperplasia
• Proliferation of immunoblasts
• Warthin-Finkeldey giant cells (syncytia of lymphocytes)
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HIV Lymphadenitis (persistent generalized
lymphadenopathy)
• Pattern A (Acute): Enlarged lymph node with hyperplastic follicles and reactive germinal centers, naked follicular centers, folliculolysis by mantle-zone cells, monocytoid B cells in sinus, Warthin-Finkeldey giant cells
• Pattern B (Chronic): Involution of germinal centers, depletion of lymphocytes, increased plasma cells, vascular hyperplasia
• Pattern C (Burnout): Small or absent follicles with hyalinized germinal centers and collagen-ensheathed arterioles (“lollipop”), plasma cells, more severe lymphocyte depletion-> naked stroma
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Toxoplasma Lymphadenitis
• Most common parasitic infection in US
• Cat definitive host; Toxoplasma gondii
• Posterior cervical LN most often affected
• Triad: Reactive germinal centers; perifollicular and intrafollicular clusters of epithelioid histiocytes; patches of monocytoid cells in sinus
• Serologic tests for confirmation
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Kikuchi-Fujimoto
(Subacute necrotizing lymphadenitis)
• Affects predominantly young Asians
• Females more often than males
• Benign course, spontaneous remission
• Fever, cervical lymphadenapthy
• Patchy necrosis, marked apoptosis, nuclear debris
• Aggregates of histiocytes
• Neutrophils, eosinophils absent
• Kawasaki’s disease: infancy and childhood. Histology similar to Kikuchi + fibrin thrombi
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Systemic Lupus
Lymphadenopathy
• Architecture effaced
• Follicles inconspicuous
• Necrosis focal or confluent
• Nuclear debris and hematoxylin bodies (basophilic masses of
DNA)
• Presence of plasma cells, immunoblasts
• Vasculitis with fibrinoid necrosis
• Granulomas, neutrophils and eosinophils: absent
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SHML-Rosai-Dorfmann Disease
Histologic Features
• Effacement of follicles
• Dilatation of sinuses
• Proliferation of sinus histiocytes with emperipolesis (lymphocytes in histiocytes)
• Lipid-laden macrophages
• Absence of necrosis
• Lack of mitoses
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Castleman
Lymphadenopathy
• Hyaline-vascular type
• Plasma cell type
• Mixed type
• Multicentric
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Castleman Lymphadenopathy:
Hyaline-Vascular Type
• More common; younger patients
• Isolated lymph node mass; often mediastinal
• Frequently asymptomatic
• Hyaline deposits in atrophic germinal centers
• Collagen-ensheathed (“lollipop”) arterioles
• Concentric layering of lymphocytes (“target” follicles)
• Interfollicular vascular hyperplasia
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Castleman Lymphadenopathy:
Plasma Cell Type
• Older patients
• Systemic symptoms
• Possible associations: polyneuropathies,
organomegaly, endocrinopathy, monoclonal
gammopathy, skin changes (POEMS
syndrome)
• Hyperplastic lymphoid follicles with active
germinal centers
• Interfollicular sheets of plasma cells
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Castleman’s Disease, plasma cell type
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Castleman Lymphadenopathy
Multicentric Form
• Atypical lymphoproliferative disorder
• Most are plasma cell type or mixed type (features of both types)
• Older patients
• Severe systemic symptoms
• Multiple lymphoid organs involved
• High levels of IL-6 in lymph nodes & serum
• Kaposi sarcoma/HHV-8 often present
• HIV infection often associated
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Dermatopathic Lymphadenopathy
• LNs draining areas of dermatitis, also a/w cutaneous T cell lymphoma
• Pruritis, eosinophilia
• Axillary, inguinal lymphadenopathy
• Architecture preserved; follicular hyperplasia
• Paracortical, palely stained, confluent areas of histiocytes/interdigitating dendritic cells/ Langerhan’s cells. Histiocytes are the major component.
• Melanin pigment-laden macrophages
• Immuno: CD1a+ (LCs); and S100+ (IDCs and LCs)
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