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Flashcards in Hematology Deck (373):
0

What are the sites of fetal hematopoiesis?

0-2 mos: yolk sac
2-7 mos: liver and spleen
5-9 mos: bone marrow

1

How do sites of hematopoiesis differ between infants and adults?

Infants: marrow in all bones
Adult: more limited: *vertebrae and pelvis*, ribs, sternum, skull, sacrum, proximal ends of femur

2

In bone marrow, how many cells are stem cells?

1 in 20x10^6 (20 million)
Beyond this: sign of potential leukemia

3

What are molecular markers for hematopoietic stem cells (HSCs)?

HSC: CD34+ and CD38-

Once committed to differentiation, become CD38+, but lack lineage specific markers.

4

What transcription factors regulate the survival of HSCs in bone marrow?

NOTCH-1
GATA-2

5

What transcription factors commit cells to the myeloid lineage in early hematopoiesis?

PU.1
CEPB family

6

What transcription factors commit cells to erythropoietic and megakaryopoietic lineages?

GATA-1
FOG-1

7

Where are Erythropoietin and Thrombopoietin produced?

EPO: 90% in kidney
Thrombopoietin: Liver

8

3 roles of growth factors in hematopoiesis

1. control of cell cycle
2. gene activation
3. inhibition of apoptosis

9

What is BCL-2?

Anti-apoptotic protein
Production stimulated by growth factor
Inhibits release of cytochrome C from mitochondria

10

3 families of adhesion molecules

Immunoglobin superfamily: antigen dependent surface receptors (TCR, etc) and antigen independent surface adhesion molecules
Selectins: leukocyte and platelet adhesion to endothelium
Integrins: cell adhesion to ECM

11

What is CFU-GEMM?

first step of erythropoiesis: commitment of pluripotent stem cells to non-lymphoid lineage
CFU-GEMM: Colony Forming Unit - Granulocyte, Erythrocyte, Megakaryocyte, Macrophage

12

What is BFU-E?

Erythrocyte Burst Forming Unit - first committed erythroid progenitor
divides -> CFU-E

13

Is there RNA in the cytoplasm of an RBC?

No

14

What is erythropoietin? Where is it produced?

Glycosylated polypeptide (165 AA)
90% produced by peritubular interstitial cells of kidney
10% in liver and elsewhere

15

What factors in the kidney stimulate erythropoietin production?

HIF-2a and B
hypoxia induced

16

What type of anemia results following kidney damage (failure, removal, etc.)

Normochromic, normocytic
Because of reduced production rather than Hb or structure problem.

17

What is normal adult hemoglobin and what are its subunits?

HbA
consists of 2a and 2B

18

What forms of Hb are normally found in adult blood?

HbA (a2B2): dominant
HbF (a2Y2): fetal
HbA2 (a2d2):

19

Where are the components of hemoglobin synthesized?

All in RBC precursor cells
protoporphyrin: in mitochondria
Fe2+: transported by Transferrin -> mito -> + protoporphyrin -> haem
Globin: ribosomes

20

What is the P50 of hemoglobin under normal conditions? How does it change?

P50: partial pressure of O2 at which Hb is 50% sat.
normal blood: 26.6
increased affinity: falls
decreased affinity (ex. 2,3-DPG): rises

21

4 factors that move Hb O2 dissociation curve to the right

Move to right (low O2 affinity)
high 2,3-DPG
high H+
high CO2
HbS

22

factors that move Hb O2 dissociation curve to the left

Move to left (high affinity)
low 2,3-DPG
low H+
HbF

23

What is methemoglobinemia? Causes?

Circulating Hb w/ Fe3+ rather than 2+ (patients often cyanotic)

Hereditary HbM: AA substitution affecting heme pocket
Hereditary deficiency of methemoglobin reductase
Toxic: drug or toxin induced oxidation of Fe2+ in Hb.

24

How do RBCs produce energy?

ATP and NADH: Embden-Meyerhof pathway (glycolytic)
NADPH: Hexose Monophosphate Shunt (PPP)

25

Important proteins in RBC membrane structure.

Band 3 (Cl- / HCO3- exchanger): binds ankyrin which binds protein 4.2 which together bind alpha spectrin

Glycophorin binds protein 4.1 and actin which bind spectrin

26

What is the relationship between anemia and 2,3-DPG?

2,3-DPG usually rises in setting of anemia -> rightward shift of Hb / O2 dissociation curve: Hb gives O2 to tissues more readily.

27

With what Hb concentration do symptoms of anemia usually become apparent?

9-10 g/dL

28

What are the criteria for microcytic, hypochromic anemia, and what are the causes?

MCV: <27pg
Iron deficiency, thalassemia, anemia of chronic disease (some), lead poisoning, sideroblastic anemia

29

What constitutes normocytic, normochromic anemia and what are the types / causes?

MCV: 80-95 fL
MCH: >27pg
may be hemolytic or non-hemolytic
Acute blood loss, chronic disease, renal disease, mixed deficiencies, bone marrow failure (post-chemo)

30

What constitutes macrocytic anemia and what are the causes?

MCV >95 fL
Megaloblastic: B12 or folate deficiency
Non-megaloblastic: ETOH, liver disease, myelodysplasia, aplastic anemia

31

What is a normal reticulocyte count (% and absolute) and how does it change with anemia?

Normal: 0.5-2.5%, absolute: 50-150x10^9 /L

should rise w/ anemia due to increase EPO

32

If anemia is suspected, what should the first step be toward making a diagnosis?

look at a blood film to count / characterize

33

What stain is used to visualize RNA and Heinz bodies in a blood smear?

Methylene Blue (supra-vital staining)

34

What are Pappenheimer bodies?

Iron containing RBC/reticulocyte inclusions - siderotic granules

35

What is a Howell-Jolly body?

DNA remnant seen in reticulocytes

36

What are Heinz bodies?

Reticulocyte/RBC inclusions of oxidized, denatured Hb

37

What is ineffective hemopoiesis?

Death of erythroblasts before production of mature cells
Normally, 10-15% of developing erythroblasts die in marrow.

38

What is seen in anemia w/ ineffective hemopoiesis?

If marked: elevated unconjugated bilirubin and lactate dehydrogenase
Low reticulocyte count relative to degree of anemia and number of erythroblasts in marrow.

39

How is total erythropoiesis assessed?

Marrow cellularity
myeloid : erythroid ratio (normally 2.5 : 1 to 12 : 1, smaller with increased erythropoiesis)

40

What are microscopic features of Iron deficiency anemia?

Central pallor in RBCs (>1/3 diameter)
Small RBCs (smaller than lymphocyte)
"pencil" cells

41

4 causes of iron deficiency anemia

1. dietary lack
2. impaired absorption
3. increased requirement
4. chronic blood loss (most importantly)

42

What is the gold standard test for iron deficiency anemia?

Prussian Blue staining of Bone Marrow
Reveals a lack of granular iron stores

43

Where in the GI tract is iron absorbed?

Duodenum (mostly proximal)

44

3 ways iron is absorbed in duodenum

1) complexed with mucin
2) complexed with ascorbate
3) complexed with heme (globin enzymatically removed)

45

How is iron transported from intestinal enterocytes into plasma?

Fe2+ is transported across basolateral membrane by ferroportin, oxidized to Fe3+ by hephaestin and released into plasma where it binds Transferrin

46

What is hephaestin?

ferricoxicase enzyme in basolateral enterocyte membrane. Oxidizes iron to Fe3+

47

How is iron transported into enterocytes?

Fe3+ -> Fe2+ in lumen by dcytb on brush border (ferric reductase)
Transported across by DMT-1

48

What is dcytb?

Ferric reductase found on apical brush border of duodenal enterocytes.
Fe3+ -> Fe2+ for transport into cell by DMT-1

49

What is DMT-1?

transporter on apical brush border of enterocytes. Transports Fe2+ into cell

50

How is iron transported in the blood?

Solubilized by Transferrin, which carries 80% to bone marrow and most of the rest to liver and kidney

51

Where is Transferrin produced?

liver

52

What is ferritin?

Iron storage protein found in many cell types
Hepatic parenchymal cells, macrophages

53

What is ferrochelatase?

heme synthetase
found in mitochondria. inserts iron into protoporphyrin

54

How much of absorbed iron is incorporated into Hb?

80%
rest in storage

55

What are and how do IRE and IRPs work?

IRE: iron responsive element - found in iron metabolism mRNA
IRP: iron responsive protein - IRE affinity modulated by iron levels

In high iron levels: IRP binds iron and has low affinity for IRE
Iron deficiency: IRP affinity for IRE is enhanced:
IRP binding in 3' region ->up-regulation of transferrin receptor
and DMT-1
IRP binding in 5' region -> down-regulation of ferritin and ALA
synthetase

56

What is the function of hepcidin?

Central regulator of iron metabolism
High levels of hepatic iron uptake -> Hepcidin production
Hepcidin binds ferroportin -> internalization and degradation -> DECREASED IRON ABSORPTION

57

What is TfR2?

Hepatic trasnferrin receptor - hepatocellular iron uptake.

58

What is the effect of inflammation on iron metabolsim?

Inflammation -> cytokine production, esp IL-6 -> increased hepcidin -> decreased iron absorption; increased hemophagocytosis, decreased erythropoietin production -> inhibited erythroid proliferation

59

What is ceruloplasmin?

ferricoxidase enzyme in plasma, oxidezes iron (Fe2+ -> Fe3+)

60

How much iron is in 1g of Hb?

3.5 mg

61

How much iron is absorbed / lost daily?

1-2 mg absorbed
1-2 mg lost (desquamation, sweat, no pathway)

62

How much iron is lost in a pregnancy?

500 mg total

63

How much iron is lost in a menstrual period?

4-100 mg

64

Physical signs of iron deficiency

Glossitis
Angular chelosis
Concave nails

65

What is TIBC?

Total Iron Binding Capacity

66

What happens to TIBC in Iron Deficiency Anemia?

Increased due to increased hepatic production of Transferrin

67

What lab tests are ordered in iron deficiency anemia and what are the usual findings?

Serum Transferrin: elevated
Serum Iron: low
Serum Ferritin: low

68

What is the preferred oral iron suppliment?

Ferrous Sulfate 324 mg (65mg iron) 3x daily

69

Is dietary intervention appropriate for iron deficiency anemia?

No - 3oz steak contains 3mg iron
adults need 150-200 mg = 10lbs steak

70

What are benefits of IV iron therapy?

Correction of nonhematologic effects of iron deficiency
Enhanced erythropoiesis

71

What is the #1 reason for failure to respond to oral iron supplimentation?

Failure to take pill

72

What is hereditary hemochromatosis and what kind of anemia does it produce?

#1 single gene inherited disease in US
Not anemic - iron overload
Iron deposits in organs -> dysfunction

73

What is the most common mutation found in heredetary hemochromatosis?

C282Y in HFE gene (6p21.3)
Mutation results in low levels of hepcidin -> elevated levels of ferroportin and increased iron absorption

74

How is iron toxic (as in hemochromatosis)?

Direct tissue toxicity
1. lipid peroxidation via iron-catalyzed free radical rxns
2. stimulation of collagen formation by stimulation of hepatic stellate cells
3. interaction of reactive oxygen species and of iron itself w/ DNA

75

How many blood transfusions does it take for signs of iron overload to become apparent?

10-20 transfusions
200mg iron / unit blood

76

How is iron overload (hemochromatosis) treated?

phlebotomy goals: ferritin <50

77

Conditions associated w/ anemia of chronic disease

Rheumatoid Arthritis
Chronic infections (osteomyelitis)
Inflammatory Bowel Disease
Cancer

78

What is the primary mechanism underlying anemia of chronic disease?

IL-6 produces an increase in hepcidin -> decreased iron absorption, decreased iron release from macrophages
Erythropoietin depression (production in kidney and decreased sensitivity in bone marrow)

79

Features of anemia of chronic disease

Low serum iron
Low serum transferrin
Low transferrin saturation
Decreased TIBC
Normal to High serum ferritin

80

What defines a finding of hypersegmented PMNs?

>5% PMNs w/ 5 nuclear lobes or more

81

What causes megaloblastic anemia?

Vitamin B12 or folate deficiency or metabolic impairment-> impairment of DNA synthesis (impaired thymidine and purine synth)

82

What are some causes of non-megaloblastic macrocytic anemia?

Liver disease, hemolysis, splenectomy, Myelodysplastic syndromes, hypothyroid, hemorrhage, etoh, pregnancy

83

What abnormal RBCs are seen in non-megaloblastic anemia assoc. w/ liver disease?

target cells, stomatocytes

84

What is a schistocyte?

Fragmented RBC - seen in hemolysis that may be associated with macrocytosis

85

Are patients who have undergone splenectomy typically anemic?

No, though they may display macrocytosis with Howell-Jolley bodies

86

What are Pelger-Huet cells?

bilobed PMNs seen in myelodysplastic syndrome

87

What is the association between hypothyroidism and macrocytosis?

May be due to nutrient malabsorption or menorrhagia

88

What is a normal serum B12 level

>400 pg/mL

89

What are 2 important biochemical roles of vitamin B12?

serves as a cofactor
1: Methylcobalamin: cofactor for methinonine synthase (methyltransferase): Homocysteine + mTHF -> methionine + THF
2: Adenosylcobalamin: cofactor for methylmalonyl CoA mutase: Methylmalonyl CoA -> Succinyl CoA

90

B12 deficiency results in the elevated levels of what substances?

Precursors in reactions in which B12 is a cofactor:
homocysteine and methylmalonyl CoA

91

How is B12 absorbed?

in food -> stomach where R-protein binds -> duodenum -> pancreatic enzymes degrade R-protein -> IF binds -> enterocyte -> IF degradation -> transcobalamin II binding and absorption to blood

92

What antibodies are associated with pernicious anemia?

Intrinsic Factor Autoantibodies (IFA): 100% specific for atrophic body gastritis
Gastric Parietal Cell Autoantibodies (PCA): non-specific for atrophic body gastritis

93

What are gastric parietal cell autoantibodies associated with?

autoimmune gastritis

94

What does a positive IFA titer indicate?

IFA: Intrinsic Factor Autoantibody
Indicates atrophic damage in gastric body mucosa (contributes to pernicious anemia)

95

Where is folic acid absorbed?

proximal jejunum

96

What is the daily intake requirement for B12 and folate?

B12: 7-30 mcg
Folate: 50-100 mcg

97

What are body stores of B12 and Folate?

B12: 2-3 mg (enough for 2-4 years)
Folate: 10-12 mg (enough for 4 months)

98

How is folic acid lost from the body?

bile and urine

99

What is methotrexate's role in folate deficiency?

inhibits folic acid -> THF rxn
decreased purine and pyrimidine production

100

What is compensated hemolysis?

Marrow produces more RBCs in face of hemolysis -> higher circulating reticulocyte numbers.

101

What is the effect of intravascular hemolysis? Cause?

severe and rapid process -> free Hb in circulation, renal toxicity
ex: mismatched blood transfusion

102

What happens in extravascular hemolysis? Cause?

Insidious process. RBCs in liver or spleen. Hb bound by serum proteins

ex: hereditary spherocytosis

103

Intracorpuscular vs extracorpuscular hemolytic anemia, inherited or acquired?

Intracorpuscular: inherited (except PNH)
extracorpuscular: acquired

104

Clinical findings in hemolysis

Pallor
Jaundice (elevated bilirubin)
Dark Urine (hemoglobin or urobilin)
Gallstones (elevated bilirubin)
Aplastic crises (exp Parvovirus B19 -> suppression of erythropoiesis)

105

What is the cause of Hereditary Spherocytosis?

RBC cytoskeletal defects: Band 3, ankyrin, and band 4.2 defects and spectrin deficiency (vertical interaction defect)

Autosomal dominant, poorly penetrant

106

How is hereditary spherocytosis diagnosed?

Osmotic fragility testing (hypotonic intolerance)
EMA fluorescence test (band 3 deficiency)

107

Clinical features of hereditary spherocytosis

often presents as neonatal jaundice
aplastic crisis (parvovirus implicated)
gallstones
may need transfusion

108

How is splenectomy helpful in hereditary spherocytosis and when is it warranted?

eliminates stressful microcirculatory environment, increases RBC lifespan.

warranted if Hb 9 gm% (gram solute / 100g solution)

109

What defect occurs in hereditary elliptocytosis?

Horizontal defect: spectrin and band 4.1 defect -> reduced RBC lifespan, but milder than spherocytosis

110

What is Southeast Asian Ovalocytosis?

Band 3 defect -> severe hemolysis

111

What is Paroxysmal Nocturnal Hemoglobinuria?

Acquired intrinsic RBC disorder
Mutation of PIG-A in stem cell progenitor in marrow -> lack of glycosyl phosphatidyl inositol (GPI) anchor results in loss of CD55 and CD59 -> no inhibition of compliment activation -> MAC induced lysis

112

What is a common progression of PNH?

Leukemia - premalignant condition
Myelodysplastic sydrome

113

What is the appearance of bone marrow in PNH?

Hypoplastic with low Fe stores
defective clone -> harm to normal marrow elements -> symptomatic state

114

What is Budd-Chiari?

Occlusion of IVC or Hepatic vein -> congestive liver disease
May be present in PNH due to platelet abnormality / hypercoagulability

115

What vessels are often affected in PNH?

Large veins: mesenteric, portal, hepatic

116

How is G6PD deficiency inherited?

X-linked recessive

117

What substances can trigger hemolysis in pts with G6PD deficiency?

Antimalarials (Primaquine)
Sulpha
Nitrofuratoin, chloramphenicol
Naphthalene (mothballs)
overwhelming infections

118

What population has the highest frequency of G6PD deficiency?

Blacks - 10% affected
Highest incidence in malarial areas
B-subtype affects caucasians - chronic hemolysis

119

2 types of autoimmune hemolytic anemia

Warm-reactive: idiopathic, involves IgG
Cold-reactive: associated with infection (mycoplasma, CMV, mono, lymphoma), involves IgM

120

What is Evan's Syndrome?

May occur with autoimmune hemolytic anemia
Ab coat platelets -> thrombocytopenia

121

How is AIHA diagnosed?

Coomb's tests (direct or indirect)

122

At what temperature are cold-reactive AIHA antibodies most active?

2-4 degrees C

123

How is AIHA treated?

Transfusion for low Hb
Protect kidney: alkalinize urine, maintain hydration
Steroids
plasmaphoresis (remove Ab from plasma, controversial)
Splenectomy (last resort)

124

What are causes of fragmentation hemolysis?

Microangiopathy: as in DIC - fibrin strands produce shear stress
Artificial valves
March hemoglobinuria: repeated trauma - runners, karate, soldiers
Heat denaturation: pre-trasfusion cell warmers

125

What subunit interface of Hb is particularly important for O2 binding?

a1B2 interface.
Mutations alter O2 affinity

126

What percent of delivered O2 are tissues able to extract?

25%

127

What is the P50 of Hb?

O2 tension at which Hb is 50% saturated
Normal ~26 torr

128

What chromosomes are Hb genes located on?

a: 16
B: 11

129

What are the forms of hemoglobins in normal adults?

HbA (a2B2) 96%
HbF (a2Y2) 1%
AbA2 (a2d2) 3%

130

What are the alpha thalassemias?

1 gene deletion: silent carrier
2 gene deletion (cis or trans, cis high risk to offspring): mild anemia
3 gene deletion: HbH disease: hypochromic microcytic anemia w/ splenomegaly (extramedullary hematopoiesis). Moderate anemia.
4 gene deletion: hydrops fetalis, intrauterine death

131

What Hb tetramers are seen in alpha thalassemia?

Insoluble tetramers formed due to inadequate alpha production
Bart's Hb: gamma Hb tetramers. only present in first few weeks of live
HbH: Beta tetramers in adults.
Both move faster than reg. Hb on electrophoresis.

132

What chelation agent is used for B-thalassemia major?

deferioxamine

133

What does management of B-thalassemia major consist of?

Blood transfusions
Chelation
Folic acid supplimentation
Splenectomy
Bone Marrow Transplant

134

What is Hb like in SC disorder?

2 abnormal B alleles:
HbS and HbC present
Patient produces no HbA

135

What is Sickle-B-Thalassemia?

Patient with HbS allele and either fully (SB0thal) or partially (SB+thal) suppressed 2nd B allele
Both have elevated HbA2
Both are microcytic

136

What is the inheritance pattern of sickling hemoglobins?

Codominant
Heterozygous individuals have discernable, but very mild clinical findings.

137

What is sickle cell Trait?

Heterozygousity for HbS
Rarely symptomatic: heat + dehydration + exercise, high altitude
Always: HbA > HbS

138

What bones are frequently involved in osteonecrosis in adults with SS disease?

Vertebrae and femur heads

139

What is acute chest syndrome in SS disease?

Pulmonary infarct or pneumonia caused by vascular occlusion

140

What is the result of co-inheritance of a-thalassemia with SS disease?

Helpful
Reduces severity of symptoms

141

What tests are used for diagnosis of Sickle Cell?

Solubility test: Cells lysed by saponin, deoxygenated by N-diathionite. HbS falls out of solution
Electrophoresis: F>S>C>A

142

What drug is given to Sickle Cell patients to stimulate HbF?

Hydroxyurea - iron chelator, anti-cancer - increases HbF

143

What occurs in combined HbE / B-thalassemia phenotype?

Transfusion dependent thalassemic phenotype

144

2 broad groups of WBCs

Phagocytes (granulocytes)
Immunocytes (lymphocytes, plasma cells)

145

Total number of leukocytes in peripheral blood

4-11x10^9 / L

146

2 classes of granules in PMN and when in development do they appear?

Primary: Promyelocyte
Secondary: Myelocyte: dominant in mature cells

147

What are the stages of PMN development and where are those stages found?

Marrow: Myeloblast -> Promyelocyte -> Myelocyte -> Metamyelocyte -> Band -> Neutrophil

Blood: Neutrophil only

148

Developmental process of monocyte / macrophage

Myeloblast -> Promonocyte -> monocyte (circulating) -> macrophage (tissue)

149

At what stage of development can Basophil, Eosinophil and PMN be differentiated?

Myelocyte

150

Do metamyelocytes divide?

NO. First stage that is non-dividing.

151

What is the typical ratio of myeloid: erythroid cells in bone marrow?

2:1 - 12:1

152

What is the lifespan of a granulocyte once released from the marrow?

6-10 hours circulating (2 pools of equal size, circulating and marginating. Marginating not counted in CBC)
4-5 days in tissue

153

What growth factors stimulate the myeloid line of cells?

IL-1, IL-3, IL-5 (eosinophil), IL-6, IL-11, GM-CSF, M-CSF, G-CSF

154

What is the difference between G-CSF and pegylated G-CSF? When are they used?

G-CSF: must be given daily
pegylated G-CSF (PEG): long acting, given 1x every 7-14 days

Used post chemo, AML, + EPO to improve marrow function, Peripheral blood stem cell harvesting ***

155

In peripheral blood stem cell harvesting what substance is given to increase the number of circulating stem cells?

G-CSF

156

After leaving the bone marrow what is the lifespan of a monocyte?

20-40 hours in circulation
months - years once in tissue as macrophage

157

What is a histiocyte?

macrophage in destination tissue

158

What receptors facilitate opsonization enhanced phagocytosis and what cells are involved?

Receptors: Fc and C3b on macrophages and neutrophils

159

2 classes of chemokines and cells responsive

CXC (alpha): neutrophils
CC: macrophage, basophil, eosinophil, NK

160

What disorders can lead to dysfunction of phagocyte chemotaxis?

Lazy leukocyte syndrome (congenital)
Corticosteroids
Myeloid leukemia, Myelodysplastic syndrome, Myeloproliferative syndrome

161

What can cause defect in phagocyte phagocytosis?

defective opsonization (hypogammaglobinemia)
complement deficiency

162

What can produce defective phagocyte killing?

Chronic Granulomatous disease (X-linked or AR - respiratory burst impaired)
Chediak-Higashi: phagosome-lysosome fusion defect

163

Pelger-Huet anomaly

AD, rare
bilobed or unsegmented neutrophils

164

May-Hegglin anomaly

AD
neutrophils have basophilic RNA inclusions
Associated with giant platelet thrombocytopenia

165

What is the appearance of PMNs in Chediak-Higashi syndrome?

Giant odd granules in phagocytic cells

166

Neutrophil Leukocytosis

Circulating neutrophils >7.5x10^9/L

167

What is Leukemoid Reaction?

reactive, excessive leukocytosis characterized by immature cells in circulation

Associated w/ severe / chronic infections, hemolysis, metastatic cancer.

168

What is Leukoerythroblastic Reaction?

Erythrocyte and Granulocyte precursors in blood
metastatic infiltration of the marrow, benign or neoplastic blood disorders

169

What constitutes neutropenia?

Neutrophil count <1.5*10^9 /L
below 0.2 is very serious

Blacks and middle eastern - typically low (benign ethnic neutropenia)

170

Kostman's Syndrome

AR
Neutrophil Elastase defect -> life-threatening infections in first year
-> marrow fibrosis and AML
G-CSF may help

171

Cyclical neutropenia

Neutrophil elastase defect (usually)
cyclical (3-4 week cycles) fall in neutrophils and usually corresponding rise in monocytes

172

Clinical features of neutropenia

Infections of mouth and throat -> ulceration and bleeding
Septicemia (s.epidermidis, gram - in gut)

173

What are treatments for autoimmune neutropenia?

Corticosteroids
Splenectomy
Rituximab (Anti-CD20 (Bcell marker))

174

Eosinophilic leukocytosis and Hypereosinophilic syndrome

Eosinophilic leukocytosis (eosinophilia): >0.4*10^9
Hypereosionophilic sydrome: >1.5*10^9 for over 6 mos w/ assoc. tissue damage
-heart valves, skin, lungs. treat w/ 'roids or cytotoxic drugs

175

What is basophil leukocytosis?

Basophils >0.1*10^9 /L
Usually myeloproliferative disorder such as chronic myeloid leukemia or polycythemia vera

176

3 causes of reactive basophil increases

Myxoedema
Smallpox or chickenpox
Ulcerative colitis

177

What is chronic eosinophilic leukemia?1

Eosinophils >1.5*10^9 with tissue dammage
Clonal cytogenetic or molecular abnormality is present.

178

Where are dendritic cells found?

Skin, lymph nodes, spleen, thymus

179

What are Birbeck granules characteristic of?

Langerhan's cells

180

What is Langerhan's Histiocytosis?

Clonal proliferation of CD1a + cells
Letterer-Siwe: before 2yoa. cutaneous eruptions, hepatosplenomegaly
Eosinophilic Granuloma: calvarium, ribs, femur. sometimes skin, lungs, stomach. Involvement of pituitary stalk -> DI
Hand-Schuller-Christian: calvarial defects, diabetes i., exophtalmos

181

Hemophagocytic Lymphohistiocytosis

AR, more frequenly acquired post infection (EBV, herpes, fung, bact, tumor. pt. may be immunocompromised)
Histiocytes in bone marrow destroy red cells, white cells and platelets
Fever, pancytopenia, multiorgan dysfunction, CNS involvement
Often fatal

182

Sinus Histiocytosis w/ massive lymphadenopathy

Rosai Dorfman
Painless, chronic cervical lymphadenopathy - normal histology
Fever and weight loss
Usually subsides over mos/ years

183

Gaucher Disease

Glucocerebrosidase deficiency -> glucocerebroside laden macrophages
Hepatosplenomegaly, bone deformity and fractures
Activated macs (Gaucher cells)-> IL1, IL6, TNF -> tissue damage

184

Niemann-Pick disease

Sphingomyelinase deficiency
Cherry-red spot, hepatosplenomegaly, CNS involvement - retardation
Sphingomyelin and cholesterol accumulation in tissues

185

Typical presentation of myeloproliferative neoplasm

hypercellular marrow
increased peripheral neutrophils, RBCs, and/or platelets
hepatosplenomegaly

186

What disease can myeloproliferative neoplasm progress to?

marrow fibrosis
acute leukemia

187

What is CML?

Chronic Myelogenous Leukemia (MPN disease)
t(9;22) -> fusion of BCR (C22) + ABL (C9) -> constitutively active TK -> proliferation of granulocytes and megakaryocytes

188

What is a myeloproliferative neoplasm?

Overpopulation of one or more of myeloid lineage
Granulocyte
Erythroid
Megakaryocytic
Mast

189

3 stages of CML

Chronic: leukocytosis w/ ~2% blasts, marrow fibrosis possible, no significant dysplasia
Accelerated: increased blasts 20% in blood or marrow
***70% are myeloid (AML), 20-30% lymphoid (ALL)***

190

What is Philadelphia Chromosome?

t(9;22) as seen in CML
Results in BCL + ABL fusion -> constitutively active TK

191

What is polycythemia vera?

Increased RBC production independent of normal regulatory mechanisms
Red cell mass >25% above mean normal (18.5 g/dL men, 16.5 g/dL women)
low rate of progression to AML
most deaths due to thrombosis or hemorrhage

192

What mutation is present in polycythemia vera?

Nothing specific
Most prevalent is JAK2 gain of function (>95% of cases, but non-specific)

193

What is the progression of polycythemia vera?

2 phases:
Polycythemic: increased red cell mass
Spent: marrow failure / fibrosis -> cytopenia and anemia

May present w/ HTN or thrombosis of mesenteric, portal, splenic veins

194

What is primary myelofibrosis?

Myeloproliferative Neoplasm
Early hypercellular marrow progresses to marrow fibrosis
Features: leukoerythroblastosis, tear shaped RBCs, extramedulary hematopoiesis
Progression to acute leukemia in 30%

195

What is the most common mutation seen in Primary Myelofibrosis?

JAK2 mutation in 50%

196

What is essential thrombocytopenia?

MPN involving megakaryocytic lineage
Sustained platelet count of >450*10^9 /L
Diagnosis of exclusion: rule out other MPN, MDS and causes of reactive thrombosis
Rare (<5%) progression to AML or MDS

197

What is the most frequent mutation seen in essential thrombocytopenia?

JAK2 - but non-specific. only 40-50% of cases

198

What marker is found on Mast cells involved in cutaneous mastocytosis?

CD117

199

What is a myelodysplastic syndrome?

secondary to cytopenia - clonal disorder of marrow stem cells
Hypercellular marrow, but failure to produce mature cells

200

What are non-clonal causes of myelodysplasia type changes?

B12 deficiency
Heavy metal poisoning
Parvovirus B19
ETOH
Drugs / chemo

201

What is seen in Refractory Anemia with Excess Blasts?

Type 1: <5% blasts in blood, 5-9% blasts in marrow. No Auer Rods.
25% progression to AML
Type 2: 5-19% blasts in blood, 10-19% in marrow. +/- Auer Rods
33% progression to AML

202

What are auer rods?

Seen in dysplastic myeloid blast cells (not always present, but markers of myeloid line in dysplastic conditions)
Granulocytic inclusions

203

What is Myelodysplastic Syndrome del(5q)

Single deletion -> megakaryocytic dysplasia, leukopenia, often refractory macrocytic anemia,
Usually middle-older females
Excellent prognosis

204

What is chronic myelomonocytic leukemia?

Peripheral monocytosis (>10%, >1x10^9 /L)
no philadelphia chrom
3mos with other causes ruled out.

205

What is Juvenile Myelomonocytic Leukemia?

Monocytic leukemia in kids 1,000/microL
Liver/spleen involvement
Death by organ failure 2ndary to leukemic infiltration
Bone Marrow Transpant needed

206

What are DAF and MIRL?

DAF: CD55
MIRL: CD59

Missing on RBC cell surface in PNH

207

What is Fanconi's anemia?

AR -> congenital aplastic anemia w/ skeletal abnormality, renal abnormality, growth tard
Due to chromosomal fragility
Treatment: support / BMT

208

2 classifications of acute leukemia

ALL: Acute Lymphatic Leukemia: >20% lymphoid blasts in blood or bone marrow
AML: Acute Myeloid Leukemia: >20% myeloid blasts in blood or bone marrow

209

What do the following stains indicate?
Myeloperoxidase (MPO)
Sudan Black
Non-specific Esterase (NSE)

MPO: specefic for myeloid differentiation
Sudan Black: Pos. in myeloid cells
NSE: Pos. for monocyte lineage

210

What is immunophenotyping?

Detection of surface markers by flow cytometery

211

What are cell surface markers for:
Myeloid line
Monocyte line
Immature (stem) cells

Myeloid: CD 13, 33, 177
Monocyte: CD 11c, 14
Immature: CD 34

212

Genetic anormalities associated with Acute Myelogenous Leukemia

t(15;17)
t(8;21)
Point mutations: NPM1 and FLT3

213

What is the result of t(8;21)(q22; q22)?

Fusion of AML1 (21) and ETO (8) -> chimeric protein that blocks core binding factor needed for transcription, blocking maturation

When detected, even if <20% blasts present, diagnosis is AML

214

What is inv(16) associated with?

AML w/ favorable prognosis
-> protein that interferes w/ core binding complex (sim to t(8;21))
Marked by myeloblasts, immature monocytes, and increased eosinophils

215

What is Acute Promyelocytic Leukemia?

AML usually associated with t(15;17)(q22;q12)
Also: FAB-M3
Increased promyelocytes
Many auer rods / cel
Surface markers: CD13 and 33 pos, CD 34 neg
Frequently associated w/ DIC

216

What oncogenes are involved in Acute Promyelocytic Anemia?

PML/RARA fusion -> retinoic acid insufficiency
Supplimentation is curative

217

What AML is especially associated with gingival hypertrophy?

11q23 mutation
Associated with DNA topoisomerase II inhibitors (leukemia treatment)
Often in infants
Monocytic (CD11c and CD14 pos)

218

What anti-cancer drugs are most often associated with AML?

Alkylating agents (cyclophosphamide)
Radiation
Topoisomerase II inhibitors (Etoposide)

219

7 types of AML not otherwise specified (M types)

M0: AML w/ minimal differentiation
M1: AML w/o maturation
M2: AML w/ maturation
M3: Promyelocytic Leukemia
M4: Promonocytic
M5: Monoblastic
M6: Erythroid
M7: Meakaryoblastic

220

Characteristics of acute megakaryobastic leukemia (FAB M7)

Extrememely rare. Down's predisposed, esp. before age 5)
Cytopenias
Large cells w/ pseudopods
Extensive marrow fibrosis -> "dry tap"

221

Characteristics of Acute Monoblastic Leukemia (FAB M5)

High number of circulating monoblasts (CD 11c, 14; NSE pos)
Gingival hypertrophy

222

2 presentations of Acute Lymphoblastic Leukemia/Lymphoma

Leukemia: Involves blood / bone marrow
Lymphoma: Involves lymph nodes and other tissues

Mostly children / young adults
May be T or B cell

223

How are the Cells of T lymphoblastic Leukemia/Lymphoma identifiec?

PAS positive nuclear ring
CD3 surface maker
MPO, Sudan Black neg

224

How are cells of B Lymphoblastic Leukemia/Lymphoma identified?

PAS dot like nuclear ring
CD10, 19, TdT

225

3 common mutations of B Lymphoblastic Leukemia Lymphoma

Philadelphia chromosome: t(9;22) poor prog
MLL gene: t(v;11q23) poor prog
TEL-AML1: t(12;21) good prog

226

What factors in the coagulation cascade are affected by Warfarin?

Vitamin K dependent: II, VII, IX, X

227

Why is Warfarin usually initially administered with UFH or LMWH?

Due to early depletion of proteins C and S -> prothrombotic state
C and S are depleted before coagulation factors

228

How is Warfarin therapy monitored?

PT and INR

INR = PT(patient) / PT( lab standard)

229

Other than Warfarin, what conditions can elevate PT and INR?

Liver Disease
Prolonged Antibiotic treatment
DIC

230

What is target INR for most warfarin patients? What is the outcome of higher or lower values? What is normal INR for a healthy person?

2-3 on Warfarin. Normal person: <1.3
Higher: over anti-coagulation
Lower: under anticoagulation

231

How long does it take for Warfarin to reach therapeutic levels?

3-5 days
t1/2 = 36 - 42 hrs
Steady state: 4-5 * t1/2

232

Warfarin major drug interactions

CYP2C9 metabolism
Inducers (decrease anticoag effect): Rifampin
Inhibitor (increase anticoag effect): Amiodarone, Quinalones, TMP-SMX, Metronidazole

233

What is the INR "cut-off" for patients undergoing surgery? How long should patients be off Warfarin before surgery?

Cut off: 1.6 - below this patients should be ok for Sx.
Stop 5 days prior to procedure (2x factor II half-life)

234

What is Dabigatran?

Direct Thrombin inhibitor
No INR monitoring needed
No antidote - FFP is not useful!
Use in patients who are not controlled or non-compliant w/ warfarin

235

What is the timeframe for Dabigatran discontinuation before surgery?

Dependent on renal clearance:
CrCl >50mL/ min: 1-2 days prior
CrCl <50mL/min: 3-5 days

236

Can Dabigatran be used in patients undergoing valve replacement surgery?

No! Apparent increased likelihood of thrombotic event!

237

What are Rivaroxaban and Apixaban?

Direct Xa inhibitors
Renal elim
More GI bleeds than warfarin
Less GI intolerance than dabigatran

238

Heparin mechanism

binds AT III, exposes catalytic site, binds thrombin and factor X -> inactivation
-> 1000x increased activity of AT III

239

heparin antidote

protamine: binds and neutralizes heparin

240

Fondaparinux

indirect factor X inhibitor
does not bind Thrombin

241

Indications for Heparin / LMWH

ACS
Initial treatment of DVT and PE
Post surgery prophylaxis (abdominal or orthopedic sx)

242

What is heparin induced thrombocytopenia?

Ab formed against Heparin + Platelet Factor 4 -> prothrombotic state (Ab activates platelets)
Onset >7-10 days after initiation of heparin therapy
Life threatening
Once developed, no more heparin ever.

243

Can Fondaparinux be used in HIT patients?

Yes! Not officially approved, but safe.

244

What is first line treatment for heparin induced thrombocytopenia?

Parenteral Direct Thrombin Inhibitor
Bivalirudin
Lepirudin
Argatroban

**no antidote, but short half-life (0.5 - 1.5 hrs), so ok

245

Primary use for Factor VII administration

Hemophilia A and B
May be used off-label for severe bleeding
Difficult to monitor
Arterial thromboembolism more common than venous

246

How is the effectiveness of antiplatelet therapy monitored?

Bleeding Time: cut and time to stop bleeding. 1-9 min is normal. (rarely done)
Aggregometery: >50% aggregation is unacceptable - target <50%

247

Aspirin dosing and side effects

75-325 mg / day (no value in larger dose)
Bleeding
Dyspepsia, GI bleed
Tinnitus in overexposure

248

How long before surgery should aspirin be witheld?

>5 days
Aspirin is irreversible COX inhibitor
Platelet t1/2 is 7-10 days - need time to replenish

249

Dipyridamole mechanism

increases cAMP production and inhibits PDE -> decreased degradation
Inhibits adenosine uptake
Inhibits platelet activity

250

Dipyridamole use

Sub-par antiplatelet
Used in stroke treatment w/ aspirin
Immediate release formulation rarely used (poor absorption, short t1/2)

251

Clopidogrel mechanism and indication

Irreversible inhibition of PG2Y12 receptor - blocking Adenosine mediated platelet activation
indications: ACS, MI, stroke, peripheral arterial disease

252

What genetic polymporphisms affect clopidogrel activity?

CYP2C19 is required for prodrug activation
*2 and *3 -> complete loss of enzymatic activity -> ineffectiveness of drug
*17 -> higher rate of activity -> patients may experience exaggerated effect (elevated bleeding risk)

253

Side effects of ticagrelor and mechanism

Reversible P2Y12 receptor
may cause dyspnea and ventricular pauses
Due to increased ATP release from RBCs -> elevated levels of Adenosine
**Avoid in pts w/ asthma/COPD, sick sinus syndrome, AV block, bradycardia related syncope

254

What effect does aspirin have on ticagrelor?

ASA doses over 100mg reduce effectiveness of ticagrelor
mechanism unknown

255

3 iron chelators

deferoxamine, deferiprone, defirasirox

256

How long does it take for iron chelation therapy to take effect? What is the goal of therapy?

Onset in 3-6 mos
Goal: < 500mcg/L circulating ferritin

257

What drug targets the product of t(9;22)?

Philadelphia chromosome -> Bcr-Abl fusion protein - constitutively active TK
Imatinib, Dasatinib, Nilotinib - TK inhibitors

258

What is azacytidine

Hypomethylating agent -> tumor cell apoptosis
**Only drug to show survival benefit in MDS**

259

Overall effect of rituximab

Depleted Bcells
Long lasting effect. Vaccines given after admin are not effective. Takes months to replenish Bcells

260

1 in what number of bone marrow cells is a true hematopoietic stem cell?

1 in 10,000

261

How is stem cell harvesting from peripheral blood done?

G-CSF is administered -> efflux of marrow stem cells into circulation
Harvest stem cells on day 4-5 post administration

262

What is the mechanism of cure in autologous stem cell transplantation?

High-dose chemo
Transplant is essentially a support device facilitating the high dose of chemo.

263

3 diseases treated by autologous stem cell transplantation

multiple myeloma
Non-Hodgkin's and Hodgkins Lymphoma

264

What is the mechanism of cure in allogenic stem cell transplantation?

Complex: high dose therapy
complete replacement of patient's stem cell compartment
Graft vs. Tumor action

265

What are drawbacks of allogenic stem cell transplantation

difficulty finding donor
Toxicity: 20-30% mortality, 30-40% cure rate

266

What diseases are treated by allogenic stem cell transplantation?

Hematologic malignancy: ALL, AML, NHL, MDS
Stem cell disorders, hemoglobinopathies

267

What HLA antigens must be matched for transplantation?

A, B, C, DR

encode glycoproteins - transmembrane receptors that present antigen to immune cells
A,B,C: MHC I
DR: MHC II

268

After stem cell transplant, how long does it take for the cells to assume function?

2 weeks.
Timeframe until function requires intensive hospital care - need for platelet and blood transfusions

269

What organs are initially targeted in GVHD?

Skin, Liver, GI

270

What infections are stem cell transplant recipients susceptible to?

Normal flora - damaged mucosal barrier
HSV, CMV, EBV - reactivation - if hx, prophylactic antivirals given
RSV - acquired
fungal - candida, aspergillus

271

Rate of GVHD on stem cell transplants

50% in allogenic
70% in unrelated

272

What is c-MPL?

receptor for thrombopoietin

273

2 platelet granules and their contents

alpha granules: 50-70/platelet. Adhesion, growth, coagulation factors: fibrinogen, fibronectin, VWF, PDGF, PF4, factor V, factor XI, HMWK, PAI-1
delta (electron dense): 2-7/platelet. ADP, ATP, serotonin, Ca2+

274

What platelet receptors bind VWF?

GPIIbIIIa: VWF, fibronectin, thrombospondin, fibrinogen
GP1b/v/ix: insoluble VWF

275

What cells produce VWF and where is it stored?

Endothelial cells and megakaryocyte
stored in Weibel-Palade bodies (W-P bodies)

276

How do cAMP and Ca++ impact platelet adhesion and activation?

low cAMP and high Ca++ -> activation and adhesion

277

substances that stimulate and inhibit platelet activation and adhesion

stimulate: ADP, TXA2
inhibit: ASA, Prostaglandin, Prostacyclin

278

What is glanzmann's thrombasthenia?

Deficiency of GpIIaIIIb -> platelet aggregation defect

279

What is Bernard-Solier syndrome?

Deficiency of GP1b -> platelet aggregation defect

280

3 defects in platelet aggregation

GPIIaIIIb: glanzmans thrombasthenia
P1b: Bernard Solier
VWF: VW disease

281

Platelet counts indicating thrombocytopenia and thrombocytosis

450,000/mL: thrombocytosis

282

What is the importance of MNSsU glycoproteins?

Sialic acids impart negative charge to RBCs which draws Na+ -> zeta potential which repels other cells.

283

What differentiates ABO antigens?

H antigen: O blood group: terminal sugar is single fucose
B antigen: terminal sugar is fuc + galactose
A antigen: terminal sugar is fuc + N-acetylgalactosamein (galnac)

284

What kind of antibodies are formed against the major blood groups?

anti A and B: IgM
Rh: IgG

285

What is coomb's reagent?

Anti Human Immunoglobin

286

5 blood groupings that may result in transfusion reactoins

ABO
Rh
Kell
Duffy
Kidd
All may -> HTR and HDFN

287

How are red blood cell units stored? What is HCT?

HCT 50-70%
Store at 4 +-2 deg C for 35 days

288

What are the major Rh antigens?

D, C, c, E, e

>50 Rh antigens, these are most clinically relevant

289

What are the cellular functions of Rh antigens?

cation transport and membrane integrity

290

What is Rh null?

complete lack of Rh antigens -> abnormal membrane and decreased RBC lifespan (hemolytic anemia)

291

What is the most common cause of HDFN?

ABO antibodies, though Rh is more severe

292

What is anti-A,B and in whom is it found?

IgG that reacts to both A and B blood groups
Type O people have anti-A,B

293

What is the survival rate for hydrops fetalis?

14%

294

What is the cause of edema seen in hydrops fetalis?

Anemia -> tissue anoxia -> increased CO -> HF
Tissue Anoxia -> endothelial permeability -> decreased osmotic pressure -> edema

295

What enzyme underlies infant jaundice?

Glucuronosyltransferase
begins working ~ 3 days after birth

296

At what level of bilirubin does kernicterus develop?

Indirect bilirubin (unconjugated) 20mg/dL or higher

297

What is weak D procedure?

If test for D Ag is negative, Weak D procedure with antiglobulin serum. If +2 to +4 agglutination, consider Rh positive

298

What should be done in the case of a pregnant woman with a positve Ab screening?

Identify Ab
Any IgG Ab must be titered at 2-4 week intervals after 20 wks gestation

299

What is the L:S ratio?

Lecithin : Sphingomyelin
Indicates degree of fetal lung maturity
>2:1 indicates mature enough to function after birth
1.5-2:1 40% will develop RDS
<1.5:1 70% will develop RDS

300

Can a mother already producing anti-D receive RhIg?

No

301

What is the best practice for administration of RhIg?

300mcg of anti-D w/in 72 hours of delivery

300mcg neutralizes 15mL packed RBC or 30 mL whole blood

302

What cord blood studies are required after birth?

ABO typing: If mom is type O and baby is A or B - worry about HDN
Rh typing: if baby is Rh+ and mom is Rh-, RhIg candidate
Direct Antiglobulin Testing: If positive, eluate to ID Ab coating baby's RBCs

303

What is definitive therapy for HDN? What is accomplished?

Exchange transfusion:
-removes Ab coated RBCs
-removes maternal Ab
-removal of bilirubin
-replacement of RBCs (treats anemia)

304

What antibody can be formed in mycoplasma pneumonia infection?

Auto anti-I

305

What antibody can be formed during infectious mononucleosis?

Anti-I

306

What is the McLeod Phenotype?

Lacks Kx Ag
Assoc. w/ chronic granulomatous disease with acanthrocytes

307

What is Fy(a-b-) phenotype?

Lacks Duffy Ag
Malaria (P. vivax) resistance
68% in african americans, more in africa
Fyb present in other tissues, absent in RBC

308

What are "nuisance antibodies"?

Lewis, M, N
cause discrepancies in reverse typing
no clinical significance

309

What is cryoprecipitate?

Blood product: concentrated fibrinogen, "antihemophiliac factor"

310

How are platelets stored and how long can they be kept?

Stored at room temp with agitation
Keep for 5 days

311

Weight and Hb cutoffs for blood donation. Age and timing.

110 lbs
12.5
17yo
56 days between donations

312

What diseases are screened for in blood donations?

Chagas
Hep B and C
HIV 1 and 2
HTLV
Syphilis
WNV

313

What is TRALI?

Transfusion Related Lung Injury - ARDS like
Usually blood donation from multiparous female
Anti-granulocyte of anti-HLA
Chills, fever, dyspnea 4-8 hrs. post transfusion

314

What incompatibility is most prevalent in Acute Transfusion Reaction?

ABO

315

What is TACO?

Transfusion Associated Circulatory Overload
Fluids administered faster than patient can accomodate volume

316

What transfusion reaction is responsible for most fatalities?

TRALI

317

Describe the composition of the B-cell receptor

2 heavy chains, 2 light chains, CD79 heterodimer (a + b) (signal transducer)

318

4 pan-B cell markers

CD19, CD20, PAX5, CD79

319

Order of Immunoglobin gene rearrangement

Heavy chain then kappa followed by lambda if kappa is deleted

320

Describe the composition of Tcell Receptor

a and B antigen binding chains
gamma, delta, epsilon, zeta signal transduction chains
CD8 (interacts with a3 domain of MHC-1 of APC)

321

Earliest Tcell marker

CD7 - present through life of cell

322

Where is CD3 found in Tcells

Early: cytoplasmic
At onset of negative selection, before transitioning from cortex to medulla transitions to surface

323

What are NK cells?

CD8+ Tcells that lack TCR
Large Granular Lymphocytes (LGL)
CD16,56,57
Kill cells w/ low HLA-I

324

What cancer is caused by transformation of NK cells?

LGLL
Large Granular Lymphocyte Leukemia

325

What are major functions of lymph?

Maintain fluid balance (interstitial fluid and protein -> blood)
Absorb lipid from intestine and transport -> blood
Defend against infectious agents

326

Define hypersplenism

Splenic enlargement
Reduction of at least one cell line in blood w/ normal bone marrow function

--large spleen sequesters more cells w/ growth

327

vaccination in asplenic individual

Pneumococcal 2wks prior to splenectomy
Annual influenza
H.flu and meningococcal

328

2 classifications of lymphocyte disorders

Reactive / benign
-lymphadenopathy / lymphocytosis
-lymphocyte deficiency or dysfunction
Malignant / neoplastic
-lymphatic leukemia
-lymphomas
-immunoproliferative disorders

329

define lymphadenopathy and generalized lymphadenopathy

lymphadenopathy: >1cm or >2cm inguinal
Generalized: 3+ non-contiguous areas of lymphadenopathy

330

What is a normal lymphocyte count for adults and infants?

birth - 6 mo: 5500-7300/mcL
adult: 2500/mcL

331

Relative lymphocytosis

Total count is normal, but % is increased

332

4 causes of relative lymphocytosis

Exanthem (mumps/ german measels)
Convalescence phase of acute infection
Thyrotoxicosis
Neutropenia (low neutrophil -> relative increase in lymphocytes)

333

What causes infectious mononucleosis?

EBV

334

complications of infectious mono

peripheral neuropathy
hemolytic anemia: IgM cold auto-antibody, i blood group
thrombocytopenia

335

What is the treatment for lymphopenia?

Monthly IV immunoglobulins

336

What is curative for chronic lymphoid leukemia

nothing - incurable

337

What is the most common adult leukemia in the Western Hemisphere?

Chronic Lymphocytic Leukemia
rare in Middle East

338

Describe staging and treatment for chronic lymphocytic leukemia

0: absolute lymphocytosis >15 x 10^9/L : observe
I: + enlarged lymph nodes : treat select cases
II: + ellarged liver and/or spleen : treat select cases
III: + anemia (marrow failure): Treat
IV: +thrombocytopenia: Treat

339

What cytologic markers contribute to a poor prognosis in chronic lymphocytic leukemia?

CD38
ZAP70

high is bad in both cases

340

Best treatment strategy for Chronic Lymphocytic Leukemia

Rituximab + chemotherapy

341

What drugs are used to treat chronic lymphocytic leukemia?

Chlorambucil (alkylating agent, nitrogen mustard)
Fludarabine (purine analog)
Rituximab (anti-cd20)
Campath H1 (anti-CD52)

342

What is Richter's Syndrome?

Transformation of chronic lymphocytic leukemia to diffuse large cel (Bcell) lymphoma
-sudden (w/in 6mos) increase in size of a lymph node out of proportion to others in pt.

343

What is Evan's Syndrome?

Complication of chronic lymphocytic leukemia
Autoimmune Hemolytic Anemia + Autoimmune Thrombocytopenia

344

Features of prolymphocytic leukemia

Massive splenomegaly w/o lymphadenopathy
Lymphocytosis (high and rising)
Lymphocytes w/ prominent nucleoli
Bcell > Tcell 3:1

345

Features of Hairy Cell Leukemia

Older men affected
Splenomegaly w/o lymphadenopathy
Pancytopenia
Dry BM tap
CD19, 20 Bcell markers) Plus CD11c, 25, 103

346

What is treatment of choice for hairy cell leukemia (HCL)?

2-chlorodeoxyadenosine (cladribine)
90% complete remission

347

Features of Large Granular Lymphocytic Leukemia (LGLL)

Splenomegaly, arthralgia, positive RA serology
Neutropenia + infections
Tcell or NK cells
Treatment often not needed, but: MTX, cyclophosphamide, 'roids, G-CSF (for neutropenia)

348

Features of Adult Tcell Lymphoma

HTLV-1 virus (esp. Japan and Carribbean)
clover-leaf lymphocytes
Poor prognosis - aggressive chemo needed
hypercalcemia, skin lesions, hepatosplenomegaly, lymphadenopathy

349

What is the characteristic cell of Hodgkin's Lymphoma?

Reed-Sternberg cell (seen in cHL, not NLPHL)
CD15 and 13 positive
Large bi-nuclear "owls eye" appearance

350

Features of Hodgkin's Lymphoma

large rubbery lymphadenopathy
bimodal age
normocytic, normochromic anemia
Neutrophilia, Eosinophilia
Lymphopenia
Thrombocytosis
ESR and CRP elevation

351

What are "B" symptoms

fever, night sweats, weight loss
worse prognosis (Hodgkins)

352

What is treatment for Hodgkin's Lymphoma

Early stages (I and II): 2-4 cycles AVBD chemo (adriamycin, bleomycin, vinblastine, dacarbazine) followed by radiation therapy
Late stages: AVBD alone

353

Features of Non-Hodgkin's Lymphoma

lymphadenopathy: painless, firm
B symptoms (fever, night sweats, weight loss)
Organ specific presentation: SOB, early satiety, marrow failure, CNS involvement (headache, focal deficits), rash

354

What genetic abnormalities are most common in follicular lymphoma?

t(14;18)
BCL2 overexpression

355

What is treatment for follicular lymphoma?

No cure
Rituximab
Mean survival is 6-9 years

356

Grades of follicular lymphoma

I: small, cleaved cells predominate
II: mix of small and larger cells
III: large cells predominate

357

What is small lymphocytic lymphoma?

Counterpart to chronic lymphocytic leukemia w/ lymph node presentation rather than blood/ bone marrow.

358

What is the differential diagnosis for a pt. w/ massive splenomegaly and no lymphadenopathy?

Hairy Cell Leukemia
Prolymphocytic Leukemia
Marginal Zone Lymphoma

359

What is the characteristic karyotype of marginal zone lymphoma?

t(11;14)(q13;32) -> overexpression of cyclin D1 / BCL1

360

What is the most common Non-Hodgkins Lymphoma?

Diffuse Large Cell Lymphoma (aggressive tumor)

361

Is Diffuse Large Cell Lymphoma curable?

Yes!
treat with R-CHOP (Rituximab, cyclophosphamide, hydroxydoxorubicin, oncovin, prednisone)

362

What is Burkitt's Lymphoma?

Very aggressive lymphoma
2 forms: endemic: EBV +, Africa, children's jaws
sporadic: 20% EBV+, nodal or extranodal
starry-sky histology, vacuolated cells

363

What genetic abnormality is associated with Burkitt's Lymphoma?

t(8;14) and myc overexpressoin

364

What is mycosis fungoides?

Chronic cutaneous Tcell lymphoma
Incurable
Looks like psoriasis
CD4+
progresses to deeper organs

365

What are Sezary cells?

Seen in Sezary syndrome - Tcells (CD4+) with cerebreform nuclei
subform of Mycosis Fungoides

366

What is multiple myeloma?

Plasma Cell malignancy that homes to bone marrow
Production of monoclonal protein
>10% plasma cells in BM (<4% normal)
In symptomatic: CRAB (hyperCalcemia, Renal impairment, Anemia, Bone disease)

367

What is MGUS?

Monoclonal Gammopathy of Uncertain Significance
Similar to multiple myeloma but no CRAB and <10% plasma cells in marrow

368

What markers are expressed on cells in multiple myeloma?

CD38 and 138

369

What is Rouleaux Formation?

Stacking of RBCs due to excess Ig (as in multiple myeloma) -> disturbance of surface charge

370

What is the pathogenesis of bone disease in multiple myeloma?

IL6 -> plasma cell growth factor
MIP1a -> activation of osteoclasts
Other tumor factors suppress osteoblast activity

371

6 clinical features of multiple myeloma

anemia
recurrent infections
hypercalcemia
amyloidosis (5%)
hyperviscosity syndrome (2%)

372

Is multiple myeloma curable?

No
Palliative care
steroids, autologous (usually) bone marrow transplant
Thalidomide, lenalidomide, proteasome inhibitors
radiation to bone lesions