Hematology Flashcards
0
Q
How do sites of hematopoiesis differ between infants and adults?
A
Infants: marrow in all bones
Adult: more limited: vertebrae and pelvis, ribs, sternum, skull, sacrum, proximal ends of femur
1
Q
What are the sites of fetal hematopoiesis?
A
0-2 mos: yolk sac
2-7 mos: liver and spleen
5-9 mos: bone marrow
2
Q
In bone marrow, how many cells are stem cells?
A
1 in 20x10^6 (20 million)
Beyond this: sign of potential leukemia
3
Q
What are molecular markers for hematopoietic stem cells (HSCs)?
A
HSC: CD34+ and CD38-
Once committed to differentiation, become CD38+, but lack lineage specific markers.
4
Q
What transcription factors regulate the survival of HSCs in bone marrow?
A
NOTCH-1
GATA-2
5
Q
What transcription factors commit cells to the myeloid lineage in early hematopoiesis?
A
PU.1
CEPB family
6
Q
What transcription factors commit cells to erythropoietic and megakaryopoietic lineages?
A
GATA-1
FOG-1
7
Q
Where are Erythropoietin and Thrombopoietin produced?
A
EPO: 90% in kidney
Thrombopoietin: Liver
8
Q
3 roles of growth factors in hematopoiesis
A
- control of cell cycle
- gene activation
- inhibition of apoptosis
9
Q
What is BCL-2?
A
Anti-apoptotic protein
Production stimulated by growth factor
Inhibits release of cytochrome C from mitochondria
10
Q
3 families of adhesion molecules
A
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
Q
What is CFU-GEMM?
A
first step of erythropoiesis: commitment of pluripotent stem cells to non-lymphoid lineage
CFU-GEMM: Colony Forming Unit - Granulocyte, Erythrocyte, Megakaryocyte, Macrophage
12
Q
What is BFU-E?
A
Erythrocyte Burst Forming Unit - first committed erythroid progenitor
divides -> CFU-E
13
Q
Is there RNA in the cytoplasm of an RBC?
A
No
14
Q
What is erythropoietin? Where is it produced?
A
Glycosylated polypeptide (165 AA) 90% produced by peritubular interstitial cells of kidney 10% in liver and elsewhere
15
Q
What factors in the kidney stimulate erythropoietin production?
A
HIF-2a and B
hypoxia induced
16
Q
What type of anemia results following kidney damage (failure, removal, etc.)
A
Normochromic, normocytic
Because of reduced production rather than Hb or structure problem.
17
Q
What is normal adult hemoglobin and what are its subunits?
A
HbA
consists of 2a and 2B
18
Q
What forms of Hb are normally found in adult blood?
A
HbA (a2B2): dominant
HbF (a2Y2): fetal
HbA2 (a2d2):
19
Q
Where are the components of hemoglobin synthesized?
A
All in RBC precursor cells
protoporphyrin: in mitochondria
Fe2+: transported by Transferrin -> mito -> + protoporphyrin -> haem
Globin: ribosomes
20
Q
What is the P50 of hemoglobin under normal conditions? How does it change?
A
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
Q
4 factors that move Hb O2 dissociation curve to the right
A
Move to right (low O2 affinity) high 2,3-DPG high H+ high CO2 HbS
22
Q
factors that move Hb O2 dissociation curve to the left
A
Move to left (high affinity)
low 2,3-DPG
low H+
HbF
23
Q
What is methemoglobinemia? Causes?
A
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)
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What is MGUS?
Monoclonal Gammopathy of Uncertain Significance
| Similar to multiple myeloma but no CRAB and <10% plasma cells in marrow
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What markers are expressed on cells in multiple myeloma?
CD38 and 138
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What is Rouleaux Formation?
Stacking of RBCs due to excess Ig (as in multiple myeloma) -> disturbance of surface charge
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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
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anemia
recurrent infections
hypercalcemia
amyloidosis (5%)
hyperviscosity syndrome (2%)
```
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Is multiple myeloma curable?
No
Palliative care
steroids, autologous (usually) bone marrow transplant
Thalidomide, lenalidomide, proteasome inhibitors
radiation to bone lesions
