Clinical Correlations Flashcards
(260 cards)
1
Q
Hereditary spherocytosis
A
Deficiency in RBC structural proteins (usually spectrin)
1. Symptoms
A. Spherocytes w/ dec life span
B. Hemolytic anemia
C. Splenomegaly
2. Genetics
A. 1/5000 people of Northern European ancestry
2
Q
Hereditary elleptocytosis
A
RBCs elliptical shape
1. Usually spectrin abnormality
3
Q
Pyruvate kinase deficiency
A
Leads to hemolytic anemia (nonspherocytic) 1. Symptoms A. Fatigue B. Pallor C. SOB D. Jaundice E. Inc risk gallstones 2. Second most common single gene disorder after G6PD deficiency 3. No Heinz bodies (precipitated Hb)
4
Q
G6PD deficiency
A
- Episodic hemolytic anemia induced by oxidative stress
- RBCs have Heinz bodies (precipitated Hb)
- One of most common single gene disorders
- Genetics
A. X-linked
B. Inc pop specific polymorphism
C. 400 distinct variants Id
D. 200 mutations (most point missense)
E. Alter enzyme kinetics- Stability (majority)
- Active site
- Allosteric site
- Classes I-IV
- Prevalence
A. 10% black men in US
B. Middle Mediterranean
C. Sardinians
D. Sephardic jews
5
Q
G6PD deficiency type I
A
Very severe
1. Clinical symptoms
A. Chronic nonspherocytic hemolytic anemia
2. Residual enzyme activity: <10%
6
Q
G6PD deficiency type II
A
Severe
1. Clinical symptoms
A. Acute hemolytic anemia
2. Residual enzyme activity: <10%
7
Q
G6PD deficiency type III
A
Moderate
1. Residual enzyme activity: 10-60%
8
Q
G6PD deficiency type IV
A
No symptoms
1. Residual enzyme activity: >60%
9
Q
General anemia
A
Dec circulating RBCs
1. Causes hypoxia
2. Dx: dec hematocrit and Hb
A. Hb normal
1. Men: 13.6-17.2
2. Women: 12.0-15.0
B. Hematocrit normal
1. Men: 39-49
2. Women: 33-43
3. Classification
A. Blood loss
B. Hemolytic
C. Impaired RBC production
4. Clinical findings
A. Pale
B. Weakness, malaise, and easy fatigability
C. Dec O2 sat -> dyspnea
10
Q
Hemolytic anemia
A
Accelerated RBC destruction (hemolysis)
- Life span <120 days
- Inc EPO release from kidneys -> RBC production -> inc reticulocytes in marrow
- Hallmarks: erythropoietin hyperplasia and reticulocytes
- Extravascular hemolysis
- Intravascular hemolysis
11
Q
Extravascular hemolysis
A
1.in phagocytes -> splenomegaly if persistent
A. RBCs less deformable => get stack
B. Features
1. Splenomegaly - often splenectomy
2. Anemia
3. Jaundice
12
Q
Intravascular hemolysis
A
- RBCs burst in circulation
- Less common
- Cause:
A. Mechanical force - defective heart valve
B. Biochem agents damage membrane - Clinical findings
A. Hemoglobinemia
B. Hemoglobinuria
C. Hemosiderinuria
D. Dec serum haptoglobin
E. Iron loss
13
Q
Hereditary spherocytosis (HS)
A
- Inherited RBC membrane defect -> spherocytes
- Sequestration and destruction in spleen
- Genetics: AD (75%)
- Prevalence: N. Europe 1/5000
- Pathogenesis:
A. Spectrin = major membrane protein affected- Self-associates one end
- Binds short actin filaments
- Connect other network proteins
A. Band 3
B. Glycophorin
C. Ankyrin
D. Band 4.2
E. Band 4.1
- Dx: osmotic fragility test = gold standard
- Tx:
A. No specific
B. Splenectomy improves anemia- Weigh pros and cons
14
Q
Hereditary spherocytosis morphology
A
1. Smears A. Spherocytes B. Dark red C. No central pallor D. Dec MCV E. Inc MCHC 2. Marrow A. Hyperplasia RBC progenitors B. Reticulocytes 3. Splenomegaly from xs macrophages 4. Cholelithiasis (40-50%)
15
Q
Hereditary spherocytosis clinical features
A
- Anemia
- Splenomegaly
- Jaundice
- Cells inc osmotic fragility in hypotonic soln
- Generally stable w/ aplastic crises occasionally
- Parvovirus B19 -> most severe crises
A. Targets erythroblasts -> apoptosis
B. No RBC progenitors in marrow until infection controlled
C. Anemia rapidly worsens
16
Q
Hereditary spherocytosis in Peds
A
- Need for transfusion does not lead to more severe disease later
- Some transfusion dependent until 6-12 mo old
- Monitor growth
- Exercise tolerance and spleen size documented
- Keep vaccinations up to date
- Gallbladder screening begin ~4 y/o, then every 3-5 years
- Document
A. Parvovirus B19 susceptibility
B. HIV and hepatitis serology - Folic acid supplementation for moderate to severe
A. Inc demand of brisk erythopoiesis
17
Q
G6PD pathogenesis
A
Episodic hemolysis w/ exposure to oxidative stress
1. Drugs
A. Anti-malarial
B. Sulfonamides
1. Bactrim: trimethoprim-sulfamethoxazole (TMP-SMX)
C. Nitrofurantin
D. Phenacetin
E. Aspirin (large doses)
F. Vit K derivatives
1. Fava beans (G6PD-B)
A. Divicine
B. Isouramil
C. Convincine
2. Infection (more common) -> phagocytes inc ROS
A. Oxidants attack globin chains
B. Oxidized Hb -> Heinz bodies
C. Heinz bodies -> intravascular hemolysis
D. Splenic phagocytes “pluck out” Heinz bodies -> bite cells
E. Bite cells trapped in spleen -> extravascular hemolysis
18
Q
G6PD clinical features
A
- Hemolysis 2-3 days after drug exposure
- RBCs uniformly deficient and vulnerable to oxidant injury
- Marrow -> new RBCs w/ adequate G6PD => hemolysis ends even if drug exposure continues
- Transient jaundice
- Dark urine
- Back and/or abdominal pain
- Severe
A. Hemoglobinuria
B. Acute kidney failure - Hemolytic anemia (congenital)
19
Q
Paroxysmal Nocturnal Hemoglobinuria (PNH)
A
- Acquired PIGA mutation
A. PIGA needed for glycosylphosphatidylinositol (GPI)
B. GPI = membrane anchor for proteins - Rare: 2-5/million in US
- PIGA X-linked => one mutated gene -> dec GPI
- Mutations in hematopoietic stem cells => all clinal progeny affected
- Thrombosis = leading COD
- 5-10% dev AML or myelodysplastic syndrome
- Dx: flow cytometry
- Tx: Eculizumab use to prove complement role
A. Prevents C5-C5a
B. Worked as tx
C. Dec hemolysis
D. Dec risk thrombsis 90%
E. Drawbacks- Very expensive
- Risk serious/fatal meningococcal infections
F. Hematopoietic stem cell transplant = only cure
20
Q
Paroxysmal Nocturnal Hemoglobinuria (PNH) Pathogenesis
A
- Blood deficient 3 GPI-linked proteins that reg complement activity
A. Decay-accelerating factor (CD55)
B. Membrane inhibitor reactive lysis (CD59)- Most important
- C3 convertase inhibitor
C. C8 binding protein
- RBC inc susceptible lysis/injury by complement
- Intravascular hemolysis by C5b-C9 membrane attack complex
- Complement fixation inc by dec pH in sleep
- Present w/ anemia and iron deficiency
- Thrombosis = leading COD
7.
21
Q
Immunohemolytic anemia (IHA)
A
- Antibodies (Ab) bind determinants on RBC membranes
A. Arise spontaneously or induced by exogenous agents - Uncommon
- Classified
A. Nature of AB
B. Presence predisposing conditions - Dx: detect Ab and/or complement on RBCs
A. Direct Coombs test
B. (+) = RBCs agglutinate w/ Abs - Warm Ab IHA
- Cold Ab IHA
22
Q
Warm antibody immunohemolytic anemia (IHA)
A
AutoAb bind RBCs and phagocytosed (spleen)
1. Incomplete -> spherocytes -> extravascular hemolysis
2. IgG (rarely IgA) active at 37C
3. Etiology
A. 60% idiopathic (primary)
B. 25% secondary to immunologic disorder or drugs
4. Presentation
A. Chronic mild anemia
B. Moderate splenomegaly
5. Usually don’t require tx
23
Q
Cold Ab IHA
A
Distal parts of body
1. Low-affinity IgM bind RBCs at temps <30C
A. Cross link RBCs -> agglutinate -> Raynaud phenomenon
2. Bind C3b in cold
3. Warmer: lose IgM, keep C3b coating
4. C3b coating -> extravascular hemolysis
5. Episodes
A. Recovery mycoplasma pneumonia and infectious mononucleosis
6. Chronic
A. B cell neoplasms
B. Idiopathic condition
24
Q
Microangiopathic hemolytic anemia
A
Small vessels narrowed/obstructed -> RBC damage 1. Disseminated intravascular coagulation (DIC): vessels narrowed w/ fibrin A. Most common 2. Other causes A. Malignant HTN B. Thrombotic thrombocytopenia purpura (TTP) C. SLE D. Hemolytic uremic syndrome (HUS) E. Disseminated cancer 3. Peripheral smear A. Burr cells B. Helmet cells C. Triangle cells
25
Sickle cell anemia
Prototypic hemoglibinopathy
1. Mutation in beta-globin -> sickle Hb (HbS)
2. Most common familial hemolytic anemia
3. Prevalence
A. 30% in Africa- protects against malaria
B. U.S. - 8% blacks heterozygous (1/600 affected)
26
Sickle cell pathogenesis
1. Single aa substitution in beta-globin -> deoxy HbS -> polymers -> sickle shape
A. Glu -> Val at position 6
2. Sickling initially reversible w/ reoxygenation
3. Over time -> irreversible -> rapid hemolysis
4. Sickling consequences
A. Chronic moderate to severe hemolytic anemia
1. RBC life span ~20 days
2. Severity proportional to irreversibility of sickled RBCs
B. Vascular obstructions -> ischemia and pain crises
27
Sickle cell morphology
```
1. Anatomic changes from
A. Severe chronic HA
B. Ischemia and infarction
C. Inc breakdown heme -> bilirubin
2. Peripheral smear: sickled RBCs
3. Bone marrow: reticulocyte hyperplasia
4. Prominent cheekbones
5. “Crew cut” skull changes
6. Splenomegaly in kids -> nubbin fibrous tissue w/ time = autosplenectomy
7. Hemosiderosis and pigment gallstone common
8. Usually presents after 6 mo old when HbF -> HbS
9. Avg. hematocrit = 18-30%
```
28
Sickle cells clinical features
1. Hyperbilirubinemia
2. Reticulocytosis
3. Vasoocclusive crises: pain and tissue damage
A. Hand-foot syndrome: most common in kids
B. Acute chest syndrome: slugging blood flow in inflamed lung
C. Stroke
D. Proliferation retinopathy -> blindness/vision damage
4. Aplastic crisis: sudden dec RBC production
A. Triggered by parvovirus B19
B. Self-limited
5. Prone to infection
A. Functionally asplenic
B. Encapsulated bacteria (pneumococci)
C. Salmonella osteomyelitis
29
Sickle cell dx and tx
1. Dx: electrophoresis
2. Clinical course highly variable
3. Supportive care -> inc survival to adulthood
A. 50% live >50 yrs
4. Prophylactic tx w/ penicillin (usually <5 y/o)
5. Tx: hydroxyurea - “gentle” DNA synthesis inhibitor
A. Allosteric bone marrow transplant
30
Thalassemia
```
Inherited mutation in globin -> dec synthesis of alpha or beta globin -> precipitates
1. Prevalence - prevents malaria
A. Mediterranean
B. African
C. Asian
```
31
Beta-Thalassemia pathogenesis
1. Genetics: Autosomal codominant
A. 2 alpha-globin genes on chromosome 16
B. One beta-globin gene on chromosome 11
2. Types
A. Beta0: no beta-globin chains
B. Beta+: dec beta-globin chains
3. >100 single-base mutations
A. Abnormal DNA splicing
4. Beta-thalassemia minor (trait): heterozygous
A. Asymptomatic/mildly symptomatic
5. Beta-thalassemia major: homozygous
6. Beta-thalassemia intermedia: at least one beta+
A. Milder disease
7. Anemia mechanisms
A. Dec HbA formation -> Microcytic and hypochromic RBCs
B. Accumulation unpaired alpha-globin chains -> toxic precipitation damage precursors and RBC membranes
1. Ineffective erythropoiesis: precursors -> apoptosis
2. RBCs produced dec life span
8. Ineffective hematopoiesis-> inc absorption dietary Fe -> overload
A. Caused by dec hepcidic (- regulators)
32
Alpha-thalassemia pathogenesis
1. Deletions 1< or = or 4 alpha-globin genes
2. Severity depends on # deletions
A. Single = silent-carrier
B. All 4 = fatal in utero (hydros fetalis)
C. 3= xs beta globin-> HbH and Hb Bart -> dec damage => less ineffective erythropoiesis
1. Inc affinity O2 => dec delivery
33
Beta-minor and alpha-trait thalassemia morphology
Abnormalities only in peripheral blood
1. Microcytic and hypochromic
2. Target cells
34
Beta-thalassemia major morphology
```
1. Peripheral smear
A. Microcytosis
B. Hypochromia
C. Poikilocytosis
D. Anisocytosis
E. Nucleated RBCs (normocytic)
2. Bone marrow
A. Progenitor hyperplasia
B. Shift toward early forms
3. Skeletal deformities from marrow filling intramedullary space
4. Splenomegaly
5. Hepatomegaly
6. Lymphadenopathy
7. Ineffective precursors -> growth retardation an cachexia
8. Iron overload -> severe hemosiderosis if not treated
```
35
Beta-minor and alpha-trait thalassemia clinical features
1. Asymptomatic
2. Mild Microcytic hypochromic anemia
3. Normal life expectancy
36
Beta-thalassemia major clinical features
1. Presents as HbF deficiency
2. Growth retardation
3. Sustained w/ blood transfusions
A. Life span 20s to 30s
B. Iron overload
4. Treated w/ iron chelators
A. Prevent cardiac dysfunction
5. Hematopoietic stem cell transplant young = best tx
37
HbH and beta-intermedia clinical features
1. Moderate anemia - don’t usually need transfusions
| 2. Iron overload rare
38
HbC disease
Hb structural defect
1. Homozygosity = rare
2. Mild, chronic hemolytic anemia w/o infarction crisis
3. No specific therapy
39
HbSC disease
Hb structural defect
1. Hb = 1/2 HbC + 1/2 HbS
2. Compound heterozygotes = double hetrozygotes
3. Crises less frequent and severe than sickle cell
40
Methomoglobinemias
```
1. [O] result of
A. Acquired: drugs/chem
1. Nitrates
2. Nitrites
3. Sulfone drugs
4. Sulfonamides
5. Lidocaine
6. ROS
B. Congenital defects: mutations
1. NADH-cytochrome b5 reductase (NADH-methemoglobin reductase)
2. Alpha or beta-globin chain -> HbM = resistance to reductase
2. Babies more sensitive to oxidants
3. Presentation
A. “Chocolate cyanosis” - blue skin and mucous membranes
1. Brown blood from HbM
B. Symptoms related to degree tissue hypoxia
1. Anxiety
2. Headache
3. Dyspnea
4. Coma and death rare
4. Tx: methylene blue - [O] as reduces Fe3+ -> Fe2+
5. Kentucky blue people
```
41
Adenoiditis
Chronic inflammation and hyperplasia of pharyngeal tonsils
| 1. Can lead to middle ear infections
42
MALT lymphomas
Usually in stomach
43
Lymphadenopathy
Swelling, enlargement
1. Disrupt architecture
2. Pain/tenderness varies
3. Lymphoma = one cause
44
Lymphogenous spread (metastasis)
Metastasis via lymph nodes
1. Sentinel lymph nodes: 1st set lymph nodes downstream of tumor
2. Staging systems: evaluate progression and prognosis
45
IPEX syndrome
```
Immunodysregulatory polyendocrinopathy enteropathy X-linked
1. X-linked defect FoxP3
2. Severe autoimmunity
3. Presentation
A. Early onset diarrhea
B. Type I DM
C. Failure to thrive
D. Classic triad
1. Enteropathy
2. Endocrinopathy
3. Dermatitis
4. Tx: tried BMT w/ mixed results
```
46
Microcytic anemias
1. Caused by disorders of Hb synthesis
2. Normal production requires
A. Iron
B. Protoporphyrin (heme)
C. Globin
3. Iron deficiency anemia
4. Anemia of chronic disease
47
Iron deficiency anemia
```
1. Most common nutritional deficiency in the world
A. 10% people developed countries
B. 25-50% developing countries
2. Causes
A. Dietary lack
B. Dec absorption
C. Chronic blood loss
3. Etiology
A. Maintain normal need 1 mg Fe absorbed
B. Only 10-15% absorbed
1. 7-10 mg adult men
2. 7-10 mg adult female
C. Western world
1. Men eat enough
2. Women marginal
D. Animal sources better absorbed than plant
E. Impaired absorption
1. Sprue
2. Chronic diarrhea and gastrectomy
F. Inc requirements
1. Growing infants
2. Kids/adolescents
3. Premenopausal women
4. Pregnant
G. Chronic blood loss
1. Most common in western world
2. External or GI bleed
```
48
Iron deficiency anemia pathogenesis
1. Causes hypochromatic Microcytic anemia
2. Initially ferritin and hemosiderin reserves maintain normal Hb and hematocrit
3. Depletion -> dec serum Fe and transferrin saturation levels
A. Still no anemia
4. Anemia= complete depletion
A. Dec serum iron
B. Dec ferritin
C. Dec transferrin sat levels => inc free transferrin
49
Iron deficiency anemia morphology
1. Disappearance stainable iron from macrophages in bone marrow
2. Peripheral smear
A. Microcytic
B. Hypochromic
C. Pencil cells
50
Iron deficiency anemia clinical features
1. Pale
2. Weakness, malaise, fatigue
3. Dyspnea w/ mild exertion
4. Chronic
A. Koilonychia (finger nails)
B. Alopecia
C. Atropic change in tongue and gastric mucosa
D. Intestinal malabsorption
5. Dx criteria
A. Anemia
B. Hypochromic and Microcytic RBCs
C. Dec serum ferritin and Fe
D. Dec transferrin sat
E. Inc total iron-binding capacity
F. Respond to iron therapy
6. Inc platelet count common
51
Anemia of chronic disease
```
Microcytic anemia
1. Associated w/ chronic inflammation
2. Most common in hospitalized pts
3. Erythopoiesis suppressed by systemic inflammation
4. Causative disorders
A. Chronic microbial infections
B. Chronic immune disorders
C. Neoplasms
```
52
Anemia of chronic disease pathogenesis
1. Inc plasma hepcidin: blocks Fe transfer to precursors by downregulating ferroportin in macrophages
A. Caused by Il-6
53
Anemia of chronic disease clinical features
1. Dec serum FE
2. RBCs hypochromic and Microcytic
3. Fe storage in marrow inc
4. Inc serum ferritin
5. Dec total iron binding capacity
6. Other causes
A. Thalassemia
B. Sideroblastic anemias
C. Dec heme synthesis
54
Macrocytic anemias
1. Stem cell abnormalities impair RBC maturation
2. Main causes
A. Folate deficiency
B. Vit B12 deficiency
3. Pathogenesis
A. Dec thymidine biosynthesis -> abnormal rapidly dividing cells
B. RNA and cytoplasmic elements preceded normal rate -> hematopoietic precursors show nuclear-cytoplasmic asynchrony -> apoptosis (ineffective hematopoiesis)
C. Granulocytes and platelet precursors affected -> pancytopenia
4. Morphology
A. Marrow
1. Hypercellular w/ megablastic eerythroid progenitors
2. Reticulocytes
3. Nuclear-cytoplasmic asynchrony
B. Peripheral
1. Hypersegmented neutrophils = earliest stage
2. RBCs large, egg shaped macroovalocytes
3. MCV > 110 fL
55
Folate deficiency anemia
```
1. Causes
A. Dec intake
1. Alcoholics
2. Elderly
3. Poor
4. Most destroyed by cooking in 10-15 min
B. Impaired absorption
1. Phenytoin
2. Oral contraceptives
3. Acidic foods
4. Beans/legumes
5. Celiac
6. Tropical sprue
C. Inc loss: hemodialysis
D. Inc requirements
1. Pregnancy
2. Infancy
3. Inc hematopoiesis
E. Drugs: methotrexate (antagonist)
```
56
Folate deficiency anemia pathogenesis
1. Dihydrofolate -> tetrahydrofolate
A. Dihydrofolate reductase
2. Tetrahydrofolate needed dTMP synthesis
3. Dec dTMP -> dec DNA synthesis -> megaloblastic anemia
57
Folate deficiency anemia clinical features
1. Insidious onset
2. Nonspecific symptoms
A. Weakness
B. Easy fatiguability
3. Can coexist w/ othe deficiencies
4. GI tract problems (sore tongue)
5. No neurologic defects
6. Different from Vit B12 deficiency
A. Serum levels
B. RBC folate
C. Vit B12 levels
58
Vitamin B12 (cobalamin) deficiency
```
1. Causes
A. Vegan diet
B. Dec absorption
1. H+ pump inhibitors
2. GI tract probs
3. Gastrectomy
4. Ileal resection
5. Disorders fxn distal ileum
6. Gastric atrophy
C. Inc requirement
1. Pregnancy
2. Hyperthyroidism
2. After absorption
A. Stored in lever (sufficient supply 5-20 yrs)
```
59
Vitamin B12 (cobalamin) deficiency pathogenesis
1. Pernicious anemia: autoimmune attack gastric mucosa -> dec intrinsic factor
A. Chronic strophic gastritis
1. Dec parietal cells
2. Inc immune cells
3. Megaloblastic change in mucosal cells
2. Neurologic lesions = demyelination
60
Vitamin B12 (cobalamin) deficiency clinical features
1. Nonspecific symptoms
A. Pallor
B. Easy fatiguability
C. Dyspnea
2. Megaloblastic change oropharyngeal epithelium -> beefy red tongue
3. Neurologic symptoms
A. Don’t always resolve if deficiency corrected
4. Inc risk gastric cancer
5. Dx:
A. Dec serum Vit B12
B. Normal/inc folate serum
C. Moderate to severe Macrocytic anemia
D. Leukopenia w/ hypersegmented granulocytes
E. Dramatic reticulocyte response to Vit B12 tx
61
Normocytic anemias
1. Diverse etiologies
2. RBC shape clue to Dx
3. Categories
A. Hemolytic anemias: inc reticulocytes
B. Aplastic anemias: dec reticulocytes
62
Aplastic anemias
```
Normocytic anemia
1. Multipotent myeloid stem cells suppressed -> marrow failure and pancytopenia
A. Marrow: no recognizable hematopoietic elements (mostly fat)
2. Etiology
A. No initiating factor ID’d in most cases
B. 65% idiopathic
C. Most known = chem/drugs
1. Chemo
2. Benzene
3. Causes marrow suppression
A. Dose related
B. Reversible
4. Other not usually associated
A. Chloramphinicol
B. Gold salts
D. Viral infections -> persistent marrow aplasia (hepatitis 5-10% cases)
E. Specific inherited abnormalities
1. Fancoi anemia
2. Telomerase defects
```
63
Aplastic anemias pathogenesis
Not fully understood
1. 2 mechanisms
A. “Extrinsic” immune-mediated marrow progenitor suppression
1. Cells antigenically altered by drugs, infectious agents, environmental factors
2. Immune response
A. Th1 -> IFN-gamma and TNF -> suppress and kill progenitors
3. Supported by trials w/ immunosuppressants (effective 60-70% pts)
B. “Intrinsic” stem cell abnormality
1. Supported by 5-10% w/ telomerase defect -> shorter life span hematopoietic stem cells
3. Mechanisms not exclusive
A. Cells w/ telomerase defect could -> T cell attack
64
Aplastic anemias morphology
```
1. Marrow
A. Hypocellular
B. Mostly fat and fibrous stroma
C. Scattered lymphocytes and plasma cells
D. Aspirated often “dry tap”
```
65
Aplastic anemias clinical features
1. Any age, either sex
2. Insidious onset
3. Pancytopenia
A. Anemia
B. Thrombocytopenia
1. Petichae and ecchymosis
C. Neutropenia
1. Persistent infection
2. Sudden onset chills and fever
4. Dx: bone marrow biopsy
5. Prognosis: variable
6. Tx
A. BMT: 5 yr survival 75%
B. Immunosuppression if can’t do BMT
66
Pure red cell aplasia
Only RBC progenitors suppressed
1. Completely absent in marrow = severe
2. Associated w/ neoplasms
A. Thymoma
B. Large granular lymphocytic leukemia
3. Drug exposure
4. Autoimmune disorders
5. Parvovirus B19: only one w/o autoimmune basis
A. Usually cleared 1-2 wks
B. Hemolytic anemias -> aplastic crisis
C. Severe immunosuppression -> chronic aplasia and anemia
67
Myelophthistic anemia
Space occupying lesions replace marrow
1. Metastatic cancer = #1 cause
2. Inflitrative processes
3. Spent phase of myeloproliferative disorders
4. Immature granulocytes and nucleated RBCs in peripheral smears
5. Tear drop cells
68
Chronic renal failure
```
Associated w/ anemia
1. Severity proportional to uremia severity
2. Dec EPO synthesis
3. Tx: recombinant EPO
A. +/- iron replacement
```
69
Congenital hypoplastic anemia
```
“Diamond black fan anemia” (DBA)
1. Rare
2. Congenital bone marrow failure
3. Symptomatic early infancy
4. 7/million live births
5. Genetics: AD
A. Phenotype diversity
5. Morphology
A. Nomochromic
B. Macrocytic
C. Reticulocytopenia
```
70
Congenital hypoplastic anemia clinical features
1. Anemia appears 2-6 mo (25% at birth)
2. 92% dx by 1 yr old
3. 40-50% pts congenital anomalies
A. Craniofacial (50%)
1. Snub nose
2. High-arched palate
B. Skeletal (30%)
1. Upper limb and hand
2. Thumb
A. Flat thenar eminence
B. Triphalangeal thumb
C. Absent radial pulse
D. Genitourinary (38%)
E. Cardiac (30%)
F. Ophthalmic
G. Musculoskeletal
H. Short stature common
1. Unsure if result of disease, therapies, or both
4. Tx: limited response
A. Corticosteroids
1. 80% initially respond
2. Dec growth
3. Dec physical and cognitive dev
4. Often delay use until after 1 yr
B. Transfusion
C. Hematopoietic stem cell transplant - potentially curative
1. Sibling donors: HLA-matched
2. < or = 9 y/o to avoid iron overload
5. Cancer predisposition: solid tumor/leukemia 20% by 46 y/o
71
Fanconi anemia (FA)
```
Rare multi system hereditary disorder
1. Bone marrow failure
2. Predisposition cancers
A. MDS
B. AML
C. Epithelial cancer
3. Congenital malformations
4. 1/200,00 most populations
A. Ashkenazi Jews (1/30,000)
B. Afrikaners (1/22,000)
5. Carrier frequency: 1:200-300 most populations
6. Genetics: AR
7. All racial and ethnic groups
```
72
Fanconi anemia (FA) clinical features
```
1. Triad
A. Bone marrow failure
B. Congenital anomalies
C. Inc chromosome fragility
2. Pancytopenia
3. Short stature
4. Microcephaly (25-37%)
5. Microphthalmia (41%)
6. Hearing loss
7. Endocrine abnormalities
8. Absent radii and thumbs
9. Dev disabilities (27%)
10. Hyperpigmentation
11. Dx: hypocellular marrow
A. Check
1. Blood counts
2. Bone marrow fxn
3. Growth
4. Dev
5. Organ fxn
12. Tx:
A. Primarily supportive
B. Bone marrow transplant cures hematopoietic probs
C. Multidisciplinary team
```
73
Di George syndrome
1. Aka:
A. Velocardiofacial syndrome
B. Shprintzen syndrome
C. 22q11.2 microdeletion syndrome
74
Di George syndrome clinical features
```
1. Triad
A. Conotruncal cardiac abnormalities
B. Hypoblastic thymus -> dec T cells
C. Hypocalcemia -> tetany or seizures w/in days after birth
2. Performance
A. Normal dev/mild learning probs (62%)
B. Moderate to severe learning probs (18%)
C. IQ: 70-90
D. Psychiatric disorders (10%)
E. Dec motor tone and axial instability (walking 16-24 mo)
3. Growth: short stature (36%)
4. Ears and hearing: conductive hearing loss
5. Craniofacial
A. Cleft palate
B. Velopharyngeal incompetence
C. Small/absent adenoids
D. Prominent, squared nose
E. Narrow palpebral fissures
F. Abundant scalp hair
G. Deficient malar area
H. Vertical maxillary xs w/ long face
I. Returned mandible w/ dec chin
J. Microcephaly (40-50%)
6. Limbs
A. Slender and hypotonic
B. Hyperextensible hands and fingers (63%)
7. Cardiac defects (85%)
A. Ventricular septal defect (62%)
B. Right aortic arch (52%)
C. Tetralogy of fallot (21%)
D. Aberrant left subclavian a.
```
75
Kawasaki disease
```
“Musocutanieus Lymph node syndrome”
1. Most common cause acquired heart disease in kids
2. Dr. Tomisaku Kawasaki 1967
3. More Asians
4. Cause unknown: possibly viral/bacterial pathogens
5. Coronary a. Vasculitis -> MI
6. <5 y/o (80-90%)
7. M>F (1.5:1)
8. All racial and ethnic groups
9. Winter/spring seasonal predominance
10. DDX
A. Virus
B. Bacteria
C. Drug rxns
1. Serum sickness
2. Stevens-Johnson syndrome
D. Rheumatologist disease
E. Heavy metal toxicity: mercury
```
76
Kawasaki disease clinical findings
```
1. Dx criteria
A. Fever > or = 5 days +4:
1. Polymorphous exanthem: red rash w/ several different looking parts
2. Conjunctival injection w/o exudate: sclera bright red
3. Oropharyngeal erythema, lips cracking, “strawberry tongue”
4. Extremity erythema, edema, and periungual desquamation (skin peeling)
5. Cervical lymphadenopathy > 1.5 cm (unilateral)
2. Associated findings
A. Cardio (on echo)
1. Coronary a. Ectasia/aneurysms
2. Pericarditis
3. Myocarditis
4. Valvular regurgitation
5. Other aneurysms
B. CNS
1. Aseptic meningitis
2. Extreme irritability
C. GI
1. Hepatitis
2. Jaundice
3. Diarrhea
4. Gallbladder hydrops
5. Pancreatitis
D. GU
1. Urethritis
2. Hydrocele
E. MSK
1. Arthritis
2. Arthralgia
F. Derm
1. Erythema at site BCG vaccination
2. Erythema w/ desquamation of groin
G. Ocular: anterior uveitis
H. Resp
1. Radio graphic pneumonia
2. Antecedent resp illness
I. Labs
1. Anemia (normocytic, normochromatic)
2. Inc inflam markers
3. Leukocytosis w/ neutropenia and band form
4. Thrombocytosis (subacute phase)
5. Hypoalbuminemia
6. Inc serum transaminase
7. Hyperbilirubinemia
J. Urine: sterile pyuria
K. CSF: neutrophilic pleocytosis
```
77
Kawasaki disease tx
```
1. Acute
A. IVIG = mainstay
B. Inc dose aspirin 1-2 mo
C. Tx in 1st 10 days of fever
D. Delayed tx -> aneurysms
E. Start after 4 days of fever
2. Long term care
A. Cardiac care based on severity
B. Aneurysms resolves 50% cases
C. Persistent aneurysms -> stenosis -> occlusion and MI
```
78
Henoch-Schonlein Purpura (HSP)
1. Unknown definitive cause
2. Immune-mediated process induced by environmental factors
3. Aberrant glycosylation of IgA1
A. Can’t clear immune complexes -> deposited on organs
4. C3 deposited w/ IgA1 -> inflammation rxn
5. Risk factors
A. 90% <5 y/o
B. Peak incidence 6 y/o
C. 13-20/100,000 younger than 1 y/o
D. M > F (1.5:1)
6. Triggers
A. Infectious: usually URI
1. H. Influenzae
2. Strep
3. Staph
4. Varicella zoster
5. Epstein-Barr
6. Parvovirus B19
B. Meds
C. Insect bites
D. Cold weather
E. Foods
F. Trauma
79
Henoch-Schonlein Purpura (HSP) clinical features
1. Rash: first sign (75%)
2. Joint involvement
3. Glomerulonephritis
A. Hematuria
B. Proteinuria
C. Nephrotic syndrome
D. Acute nephrotic syndrome
E. HTN
F. Renal failure
G. Follow rash w/in 1-4 mo
4. Low grade fever
5. Local angiodema
6. Triad
A. Purpura
B. Arthralgia
C. Abdominal pain: w/in 1 wk cutaneous findings
1. Usually resolves in few days
7. Intussusception: complication
80
Henoch-Schonlein Purpura (HSP) dx and tx
```
1. DDx:
A. Child abuse
B. Meningococcemia
C. Rocky Mountain spotted fever
D. Papular-purpuric gloves and socks syndrome
E. SLE
F. Systemic juvenile idiopathic arthritis
G. Wegner granulomatosis
2. Dx:
A. Mostly clinical
B. Labs
1. CBC: platelet count and thrombocytopenia
2. Urinalysis: initial and follow up
3. Urine protein quantification
4. Serum creatinine: renal fxn
5. Serum albumin: hypoalbuminemia associated w/ nephrotic syndrome
3. Tx:
A. Supportive care
B. Fluid intake orally
C. IV fluids if needed
D. Rest
E. Avoid strenuous exercise
F. NSAIDs if no renal/GI probs
G. Acetaminophen
H. ACE inhibitors/angiotensin receptor blockers: persistent proteinuria
I. Corticosteroids: acute phase severe joint, GI, renal involvement (consult nephrologist)
4. Monitoring
A. Wks 1-4: weekly urinalysis and BP
B. Wks 5-12: every other wk
C. 6-12 mo: once/mo
D. Stop after 1 yr if okay
5. Prognosis
A. Recurrent disease: usually less bed subsequent times
B. Recur w/in 4 mo 33% kids
C. More common older kids and renal involvement
```
81
Intussuusception
Complication of HSP
1. One segment bowel invaginates into another -> obstruction
2. Bowel May “telescope”
3. Abdominal ultrasound
4. Mesentery compressed
5. Bowel wall obstructs lumen
6. Colicky abdominal pain and vomiting
7. Lymphatic and venous obstruction -> ischemia
8. Usually ileocecal in kids
82
Disorders due to vessel wall abnormalities
1. Relatively common
2. Mild bleeding problems
3. Presentation
A. Petichiae and purpura skin and mucous membrane (gingival)
B. PT and PTT usually normal => dx of exclusion
4. Infections -> petichiae and purpura
A. Meningococcemia
B. Septicemia
C. Infective endocarditis
D. Risckettsioses
E. Mechanisms
1. Microbial vasculitis
2. DIC
5. Drug rxns -> cutaneous petechiae and purpura w/o thrombocytopenia
A. Deposited immune complexes in vessel walls -> hypersensitivity vasculitis
6. Scurvy and Ehlers-Danilo’s syndrome
A. Inc bleeding from collagen defects -> weak vessel walls
83
Hereditary Hemorrhagic telangiectasia
“Weber-Osler-Rendu syndrome”
1. Genetics: AD
A. Mutations 5 < or + genes modulate TGF-beta signaling
2. Presentation
A. Dilated, tortuous blood vessels w/ thin walls - bleed easily
B. Bleeding most common mucous membranes
1. Nose
2. Tongue
3. Mouth
4. Eyes
5. GI tracts
84
Thrombocytopenia
1. Isolated thrombocytopenia: bleeding tendency w/ normal coag tests
A. If platelets 20,000-50,000 -> inc risk post-traumatic bleeding
B. <5000 plots/uL -> spont bleeding
C. CNS hemorrhage = major hazard for severe
2. Causes
A. Dec production
B. Inc destruction
1. Marrow shows inc megakaryocytes
3. Immune thrombocytopenic purpura (ITP)
4. Thrombotic microangiopathies
85
Immune thrombocytopenic purpura (ITP)
1. Chronic = adults
| 2. Acute = kids
86
Chronic ITP
1. Relatively common
2. F>M
3. 20-40 y/o
4. AutoAb mediated platelet destruction
5. Secondary: predisposing conditions and exposures
A. SLE
B. HIV
C. B cell neoplasms (CLL)
6. Primary (idiopathic): only dx after secondary excluded
87
Chronic ITP pathogenesis
1. AutoAb directed at membrane glycoproteins IIb-IIIa of Ib
A. Most IgG
2. Spleen = major site opsonized platelet removal
3. Antiplatelet Ab recognized by IgG Fc receptor on phagocytes -> inc destruction
88
Chronic ITP morphology
```
1. Non-specific
A. Spleen normal size
1. Sinusoid congestion
2. Splenic follicle enlargement
3. Reactive germinal centers
B. Bone marrow
1. Megakaryocytes
2. Used to rule out thrombocytopenia from marrow failure or other primary marrow disorders
C. Peripheral smear
1. Megathrombocytes
```
89
Chronic ITP clinical features
1. Insidious onset
2. Petichiae
3. Epitaxis
4. Gum bleeding
5. Hemorrhages from minor trauma
6. Serious brain trauma
7. Labs
A. Dec platelets
B. Normal or inc megakaryocytes in marrow
C. Large platelets in smear
D. PT and PTT normal
8. Dx of exclusion
9. Tx: drugs
A. Dec Ab production
1. Splenectomy
2. Corticosteroids
3. Ritiximab
B. Dec platelet destruction
1. Splenectomy
2. Corticosteroids
3. IVIG
4. Anti-D immune globin
C. Inc platelet production
1. Thrombopoietin receptor agonists (eltrombopag)
90
Acute ITP
```
Children
1. Most common thrombocytopenia in kids (1:20,000)
2. Peak age: 1-4 yrs
3. Preceding viral infection 50-65% cases
4. Classification
A. No symptoms
B. Mild symptoms
1. Bruising/petichiae
2. Occasional minor epitaxis
3. Little interference w/ ADL
C. Moderate
1. More severe skin and mucosal lesions
2. Moderate epitaxis
3. Inc menorrhagia
D. Severe
1. Bleeding episodes
A. Menorrhagic
B. Epitaxis
C. Melena
2. Requires transfusion/hospitalization
3. Seriously interferes w/ ADL
```
91
Acute ITP pathogenesis
1. AutoAb directed at membrane glycoproteins IIb-IIIa of Ib
A. Most IgG
2. Spleen = major site opsonized platelet removal
3. Antiplatelet Ab recognized by IgG Fc receptor on phagocytes -> inc destruction
4. Common viruses
5. Epstein-Barr
6. HIV
92
Acute ITP clinical features
1. Sudden onset petichiae and purpura
A. “Fine yesterday”
2. Bleeding gums and mucous membranes (platelets <10x10^9)
3. Other abnormal findings on physical exam rare
A. Should look for other disorders if found
93
Acute ITP tx
1. Only education and counseling unless severe
A. Avoids therapeutic roller coster
B. Cheap
C. Min side effects
2. IVIG/corticosteroids if mucocutaneous bleeding
A. First line tx
B. Dec Fc-mediated phagocytosis
C. Expensive and time-consuming
D. ADRS
1. Headache
2. Vomiting
3. IVIG-induced aseptic meningitis
3. Corticosteroids used many years
A. Prednisone : more rapid inc platelets
B. Short course until platelets >20 x 10^9
94
Thrombotic microangiopathies
1. Widespread platelet -rich thrombi in microcirculation
2. Platelet consumption -> thrombocytopenia
3. Narrowing vessels -> microangiopathic hemolytic anemia
4. Thrombotic thrombocytopenia purpura (TTP)
5. Hemolytic uremic syndrome (HUS)
95
Thrombotic thrombocytopenia purpura (TTP)
1. Deficiency ADAMTS13 (vWF metalloprotease)
A. Degrades high-MW multiverses of vWF
B. Dec => multiverses accumulate -> platelets activation and aggregation
C. Inherited or acquired
96
Hemolytic uremic syndrome (HUS)
1. Normal ADAMTS13
2. Associated w/ infectious gastroenteritis
A. E. Coli strain 0157: H7
3. Toxin changes endothelial cell fxn -> platelet activation and aggregation
4. Children and older adults highest risk
5. Presentation
A. Bloody diarrhea first
B. HUS presents a few days later
6. Supportive care -> complete recovery
7. Irreversible renal damage and death in severe cases
97
Bleedining disorders related to defective platelet fxns
1. Several rare, inherited disorders
2. Classification
A. Adhesion defects
B. Aggregation defects
C. Platelet secretion disorders
1. Defective release mediators platelet activation (thromboxane and granule-bound ADP)
3. Bernard-Soulier syndrome
4. Glanzmann thrombashenia
5. Acquired defects
A. Aspirin/NSAIDs
B. Uremia
98
Bernard-Soulier syndrome
1. Defective platelet adhesion to subendothelial matrix
2. Genetics: AR
3. Deficiency platelet membrane glycoprotein complex Ib (GpIb)
A. VWF receptor
4. Pts variable, often severe, bleeding tendency
99
Glanzmann thrombashenia
1. Defective platelet aggregation
2. Genetics: AR
3. Platelets fail to aggregate in response to ADP, collagen, epinephrine, or thrombin
4. Deficiency/dysfunction glycoproteins IIb-IIIa
A. Used in bridge-formation between platelets by binding fibrinogen
5. Bleeding other severe
100
Acquired coagulation disorders
1. Most common
2. Several factors
A. Vit K required for factors VII, IX, X, and prothrombin => deficiency -> coag defect
B. Hepatic parenchymal disease -> hemorrhagic diatheses
3. Disseminated intravascular coagulation (DIC)
101
Disseminated intravascular coagulation (DIC)
Acquired coagulation disorder
1. Complication of many disorders
2. Systemic coag activation -> thrombi throughout microcirculation
3. Platelets and coag factors consumed -> fibrinolysis activated
4. Can cause
A. Tissue hypoxia from thrombi
B. Bleeding disorder
C. Depends on
1. Fibrinolysis
2. Consumption coagulopathy: depletion elements required for homeostasis
102
Disseminated intravascular coagulation (DIC) pathogenesis
1. Clotting
A. Intrinsic pathway: factor XII activation by surface contact, collagen, other (-) substances
B. Extrinsic: release tissue factor
C. Both -> thrombin
D. Normally limited by rapid clearance of clotting factors
1. Macrophages
2. Liver
3. Endogenous anti-coags (protein C)
4. Activation fibrinolysis
2. Triggered by
A. Release tissue factor or thromboplastic substances
1. Placenta
2. Cancers (APL, adenocarcinomas)
3. Gram +/- sepsis
B. Widespread endothelial damage -> release tissue factor
1. Expose subendothelial collagen and vWF
2. Antigen-Ab complexes
3. Temp extremes
4. Infections
3. Results
A. Inc thrombin
B. Dec inhibitory pathways that limit coag
4. Can result from acute intravascular hemolytic transfusion rxn
103
Disseminated intravascular coagulation (DIC) clinical features
1. Acute = bleeding disorder
2. Chronic = thrombosis
3. Severity ranges
A. Minimal
B. Shock
C. Acute renal failure
D. Dyspnea
E. Cyanosis
F. Convulsions
G. Coma
4. Labs
A. Thrombocytopenia
B. Inc PT and PTT
C. Inc fibrin split products
5. Prognosis varies
6. Tx: directed at underlying cause
104
Hereditary coagulation disorders
1. Von Willebrand disease
2. Hemophilia A
3. Hemophilia B
105
Von Willebrand disease
1. VWF carries factor VII in platelet granules in endothelial cells w/in Weibel-Palade bodies and subendothelium (binds collagen)
2. Endothelial cells stripped by trauma/injury -> exposes
A. Sub endothelial vWF -> binds platelets w/ glycoprotein Ib
1. Facilitate platelet adhesion to blood vessel walls
3. Genetics : AD
4. Prevalence : N. European descent
A. 1% in US = most common inherited bleeding disorder
5. Type 1 = classic and most common
A. Dec quantity vWF
6. Type 2 = several subtypes
A. Loss high-MW multiverses vWF => functional vWF deficiency
106
Von Willebrand disease clinical features
1. Spontaneous bleeding mucous membranes
2. Xs bleeding from sounds
3. Menorrhagia
4. Dx requires sophisticated tests
A. Quantity
B. Size
C. Fxn
1. Ristocetin platelet agglutination test
A. Ristocetin activate vWF and platelet glycoprotein Ib binding -> interplatelet bridges -> agglutination
D. Dec platelet fxn w/ normal #
E. Dec factor VIII
1. Inc PTT types 1-3
107
Hemophilia A
Deficiency factor VIII
1. Genetics: X-linked recessive
A. 30% caused by new mutation
B. Many causative mutations => variable severity
2. Severe: <1% normal factor VIII
3. Mild: only apparent w/ trauma/hemostatic stresses
4. 1/5000 males
108
Hemophilia A clinical features
1. Easy bruising
2. Hemorrhage w/ trauma/operation
3. Spontaneous bleeding in joints
4. No petichiae
5. Labs
A. inc PTT
B. Dec factor VIII
6. Tx:
A. Mixing pt plasma w/ normal -> dec PTT
B. Factor VIII infusions
109
Hemophilia B
Deficiency factor IX
1. Genetics: x-linked
2. Indistinguishable clinically from hemophilia A
3. Much less common
4. Inc PTT
5. Dx: specific factor IX assays
6. tx: infusion recombinant factor IX
110
Hemostasis
1. Arteriolar vasoconstriction
2. Primary hemostasis: platelet plug formation
3. Secondary hemostasis : fibrin deposition
4. Clot stabilization and resorption
111
Thrombosis
1. Primary causes (Virchow triad)
A. Endothelial injury
B. Stasis/turbulent flow
C. Hypercoagulability
112
Endothelial injury
1. Causes platelet activation -> thrombus formation in heart and arterial circulation
2. Severe : exposing vWF and tissue factor -> clot formation
3. Inflam/noxious stimuli -> shift gene expression to “prothrombotic”
4. Causes
A. Physical injury
B. Infectious agents
C. Abnormal blood flow
D. Inflam mediators
E. Metabolic abnormalities
1. hypercholesterolemia
2. Homocystinemia
3. Toxins from smoking
5. Prothrombic changes
A. Procoagulant changes: cytokines -> dec protein C and thrombomodulin
B. Anti-fibrinolytic effects
113
Stasis/turbulent flow
1. Leads to endothelial injury/dysfunction and pockets of stasis
2. Stasis -> venous thrombi
3. Effects :
A. Turbulence and stasis -> endothelial cell activation
B. Stasis: platelets contact endothelium
C. Stasis slows washout activated clotting factors
114
Stasis/turbulent flow clinical settings
1. Ulcerated artherosclerotic plaques -> turbulence
2. Aortic and arterial aneurysms -> stasis
3. Acute MIs -> stasis and turbulence -> cardiac thrombi
4. Rheumatic mitral valve stenosis -> lt atrial dilation and a fib -> stasis and thrombosis
5. Hyper viscosity -> stasis
6. Sickle cell -> thrombosis
115
Hypercoagulability
1. Caused by coag factor defects
2. Venous thrombosis
3. Inherited (primary)
A. Factor V Leiden mutation/G1691A mutation
4. Acquired (secondary)
116
Factor V Leiden mutation/G1691A mutation
Inherited hypercoagulability
1. 2-15% Caucasian carriers
2. 60% in pts w/ DVT
3. Glu -> arg substitution at residue 506
4. Factor V resistant to cleavage and inactivation by protein C
5. Carriers 5x risk venous thrombosis
6. Affected 50x risk venous thrombosis
117
Nucleotide substitution (G->A) in untranslated region of prothrombin gene
Inherited hypercoagulability
1. 1-2% general pop
2. Inc prothrombin transcription
3. 3x risk venous thrombosis
118
Anticoagulant deficiency
```
Inherited hypercoagulability
1. Less common
2. Antithrombin III
3. Protein C
4. Protein S
5. Present w/ venous thrombosis and recurrent thromboembolism
A. Adolescence/early adult life
```
119
Inc homocysteine
Inherited hypercoagulability
1. Arterial and venous thrombosis
2. Atherosclerosis
3. Thioester linkages between homocysteine metabolites and proteins (fibrinogen)
4. Dec cystathione beta-synthase
120
Acquired hypercoagulability
1. Oral contraceptives and inc estrogen in pregnancy -> hepatic coag factors and dec anti-thrombin III
2. Disseminated cancers -> procoag tumor products -> predisposes to thrombosis
3. Aging -> inc platelet aggregation and dec release PG12 from endothelium
4. Smoking and obesity -> hypercoag
A. Unknown mech
5. Heparin-induced thrombocytopenia (HIT) syndrome
6. Anti-phospholipid Ab syndrome
121
Heparin-induced thrombocytopenia (HIT) syndrome
Acquired hypercoagulability
1. 5% pts treated w/ unfractioned heparin
2. AutoAb bind heparin-platelet membrane proteins complex (platelet factor-4)
3. Can bind othe complexes
4. Effects
A. Platelet activation
B. Aggregation
C. Consumption
D. Venous and arterial thrombosis
5. Tx: stop heparin therapy to break cycle
6. Dec risk complication w/ low-MW heparin
122
Anti-phospholipid Ab syndrome
Acquired hypercoagulability
1. Old name: lupus anti-coagulant syndrome
2. Primary form: hypercoagulable state w/o other autoimmune disease
3. Secondary form: well-defined autoimmune disease
4. Tx
A. Anti-coagulation
B. Immunosuppression
123
Anti-phospholipid Ab syndrome clinical features
1. Recurrent thrombosis
2. Repeated miscarriages
3. Cardiac valve vegetations
4. Thrombocytopenia
5. More variable
A. Pulmonary embolism
B. Pulmonary HTN
C. Stroke
D. Bowel infarction
E. Renovascular HTN
124
Anti-phospholipid Ab syndrome pathogenesis
1. Ab bind epitomes on proteins unveiled by phospholipids
A. Beta-2-glycoprotein I
1. Associated w/ endothelial cells, trophoblasts, and prothrombin
2. In vivo -> hypercoagulable state (uncertain mech)
3. In vitro: Ab interfere w/ phospholipids and inhibit coagulation
4. Ab show false (+) for syphilis because syphilis antigen embedded in cardiolipin
125
Blue baby
Hemolytic disease of fetus/newborn
1. Maternal Ab attack blood antigen on fetus/new born -> hemolysis
A. Can be fatal
2. Prevention Rh-related HDFN “immune hydrops fatalis”
A. RhoGAM: anti-D Ab coats Rh antigen before mother starts making own -I maternal attack on fetus cells
126
Transfusion-related immunomodulation (TRIM)
1. Like mild graft-vs-host disease
2. Leads to post-transfusion inc risk infections
3. Transfused WBCS and other factors regulate pts immune system
127
Acute intravascular hemolytic transfusion rxn
1. Complement proteins -> massive inflammatory event
2. MAC: hemolysis ->
A. Hemoglobinemia (red plasma)
B. Hemoglobinuria (red/dark urine)
3. Cytokines
A. Inflammatory: IL-1, IL-6, TNF-alpha
1. Fever
2. Renal vasoconstriction
3. Inc thrombomodulin -> DIC
B. IL-8: neutrophil chemotaxis and activations
1. Dec BP and tissue edema -> shock
4. Can be fatal w/ as little as 30 cc of blood
128
Acute extravascular hemolytic transfusion rxn
```
1. Clinical
A. Fever/chills
B. Jaundice
C. Clinically stable
D. Complications very rare
2. Labs
A. Hemoglobinemia/uria- rare
B. Inc bilirubin
C. Inc LDH
D. +DAT - IgG
```
129
Delayed hemolytic transfusion rxns
1. 3-10 days post transfusion
2. Less severe than acute
A. Fever
B. Dec hematocrit
C. New RBC alloantibody
3. Renal monitoring
4. More severe in sickle cell pts
A. Vasocclusive crises
B. Hyperhemolysis
5. Usually in pts w/ previous exposure to RBC antigens
A. Previous transfusion
B. Pregnancy
C. Hematopoietic stem cell transplant
130
Febrile nonhemolytic transfusion rxn
1. Presentation
A. Fever
1. Rise of 1C or over 38C during transfusion w/o other reason for fever
B. Chills
C. Rigors
2. Possibly from inc cytokines in donor unit
3. LRRCs prevent it
131
Transfusion related acute lung injury (TRALI)
1. Onset w/in 6 hrs start of transfusion (usually w/in 2 hrs)
2. Frequency: 1:10,000 transfusions
3. Presentation
A. Hypoxemia
B. Fever
C. Hypotension
D. Tachypnea
E. Dyspnea
F. Diffuse pulmonary edema
4. Dx:
A. Chest X-ray
B. Blood gas
C. Post/pretransfusion NT-BNP ratio <1.5
D. Blood for HLA or antineutrophil Abs
5. DDx:
A. Fluid overload
B. Septic transfusion
C. Anaphylaxis
D. Unrelated acute lung injury
6. Tx
A. Stop transfusion
B. Resp support
C. BP support
132
Transfusion related acute lung injury (TRALI) pathogenesis
1. HLA/granulocyte specific Ab react w/ leukocytes or endothelium
2. Activate neutrophils
133
Transfusion-transmitted disease
```
1. Serratia marcescens
A. Gram (-) bacillus
B. Red at room temp
C. Very mild
2. S. Aureus
3. S. Epidermidis
4. E. Coli
A. Gram (-) bacillus -> shock
5. Strep species
6. Propionibacterium acnes
A. Gram (+) bacillus
B. Common contaminant
C. Rarely causes symptoms
```
134
Bruton (x-linked) agammaglobinemia
1. No functional B cells => no Abs
2. Mutation in Bruton’s tyrosine kinase
A. Needed for BCR signaling
3. Presentation
A. Often no tonsils
B. Recurrent/unusual infections early childhood
4. Genetics: x-linked recessive
5. Tx: weekly IVIG
135
Transient hypogammaglobinemia of infancy
1. Infant unprotected by maternal Abs
2. From 6-24 mo
3. Presentation: recurrent infections
4. Proposed causes
A. Maternal Ab suppresses fetal Ig production
B. Abnormal T cells don’t help B cells
C. Abnormal/immature B cells
136
Selective IgA deficiency
1. Most common primary immunodeficiency
2. Normal amounts other isotypes
3. 85-90% pts asymptomatic
4. Recurrent infections
A. GI
B. Resp
5. Problems w/ blood transfusions: might have IgA sensitive WBCS
137
X-linked hyper IgM syndrome
1. Inc IgM
2. Dec other isotypes
3. Life expectancy <30 yrs
A. Inc w/ bone marrow transplant
4. Presentation
A. Children
B. Recurrent resp infections
C. Pneumocystis jirovecii
1. Tx: bactrim
2. Fungus that survives phagocytes w/o T cell help
138
Common variable immunodeficiency
1. Dec IgG, IgA, and IgM
2. Normal IgE
3. Dec T cell proliferation
4. Inc susceptibility chronic lung disease
5. Often dx in vaccine non-responders
6. Difficult to dx bc variety of presentations
139
Farmer’s lung
```
Hypersensitivity pneumonitis
1. Immune-complex mediated
A. Deposited in airway
2. Delayed-type hypersensitivity
3. Inc IL-1 and TNF-alpha
4. Allergy to inhaled mold
```
140
Immune reconstitution inflammatory syndrome
1. Inflam rxn assoc w/ immune reconstitution when treating HIV
2. Possibly from rapid inc CD4+ count
3. Presentation
A. Fevers
B. Sweats
C. Malaise
D. +/- localized manifestation
4. Common illnesses
A. TB: paradoxic (worsening) symptoms
B. Mycobacterium Avium complex: suppurative lymphadenitis
C. Meningitis
5. Only use corticosteroids in severe rxns
7. ART continued unless life-threatening
141
Combined immunodeficiencies (CID)
1. Impaired dev/fxn T cells -> dec Ab response
2. SCID (most severe forms)
A. Lack fxnal T cells
B. 1:50,000 births
3. Presentation in infancy
A. Pneumonia (pneumocystis and viruses)
B. Diarrhea
C. Failure to thrive
D. Skin rash (GVHD from maternal T cells)
4. Types
A. Adenosine delaminates deficiency (ADA)
B. X-linked SCID (SCIDX1)
C. Recombinase-activating gene 1 and 2 (RAG1/2) defect
142
Adenosine delaminates deficiency (ADA)
```
Type of CID
1. Phosphorylated metabolites -> apoptosis lymphoid precursors in marrow and thymus
2. 10-15% AR
3. Housekeeping enzyme
A. Deafness
B. Behavioral problems
C. Liver toxicity
```
143
X-linked SCID (SCIDX1)
```
Type of CID
1. Aka: common gamma chain defect (IL2RG)
1. 40% of SCID
2. IL2RG encodes gamma-chain for
A. IL-2
B. IL-4
C. IL-7 -> T cell proliferation
D. IL-9
E. IL-15 -> NK dev
F. IL-21
3. Lack T and NK cells
4. Normal # B cells
```
144
Recombinase-activating gene 1 and 2 (RAG1/2) defect
1. Needed for VDJ recombination
2. 20% SCID
3. AR
4. Lack T and B cells
5. NK cells normal
145
CD40L deficiency - Hyper IgM syndrome
1. CD40/CD40L needed for B cell activation and immunoglobulin class switching
146
Antibody deficiencies
1. Inc susceptibility bacterial infections upper and lower airways
A. Otitis
B. Sinusitis
C. Pneumonia
D. Skin abscesses
E. Meningitis
F. Arthritis
G. Viral infection
H. Giardia
2. Interfere w/ B cell dev, maturation, and fxn
3. Types
A. X-linked agammaglobinemia (XLA or Bruton’s)
B. Common variable immunodeficiency (CVID)
C. IgA deficiency
D. Specific Ab deficiency
147
X-linked agammaglobulinemia (XLA or Bruton’s)
1. Very young
2. No B cells
3. Defective Briton tyrosine kinase
A. X-linked
B. 85% early onset agammaglobulinemia
4. Block at pro-B to pre-B stage
148
Common variable immunodeficiency (CVID)
1. Most common primary immunodeficiency = wastebasket term
2. Dec levels at least one Ig isotype AND dec Ab production w/ exposure to antigens
3. Recurrent infections - adulthood
A. Resp tract
B. Common bacteria
4. Autoimmune manifestations
5. Granulomatous lesions
6. Lymphoid hyperplasia
7. Tumors (esp lymphoma)
8. Genetics: heterogenous (mostly sporadic)
9. Normal # B cells
10. Defective TACI
149
IgA deficiency
1. 1:700 people
2. 2/3 asymptomatic
A. Others recurrent infections and autoimmunity
3. Pathophysiology not well understood
A. Assoc w/ MHC alleles
150
Specific Ab deficiency
1. Dec Ab to specific antigen
| 2. Total Ig and B cell levels normal
151
Severe congenital neutropenia
1. Absolute neutrophil count <500
2. Defect elastase gene (ELA2) -I promyelocyte stage
A. Destroys bacteria during inflammation
3. Genetics: AD
152
Cyclic neutropenia
1. Different ELA2 mutation -> shorter neutrophil lifespan -> nadir every 21 days
2. Periodic infections
153
Chronic granulomatous disease
1. Defective NADPH oxidase complex in phagosome
2. Genetics
A. 75% x-linked
B. 25% AR
3. Unusual infections
A. Nocardia
B. Aspergillus
C. Mycobacteria
4. Chronic inflammation -> granulomatous manifestations
A. Colitis
B. Hydronephrosis
154
Leukocyte adhesion deficiency
1. Impaired trafficking
2. LAD1: defect beta-2-integrin (CD18)
A. Mediates adhesion LFA-1 and ICAM -> transendothelial passage
3. LAD2: defect sialyl-Lewis-X on leukocytes (E-selectin)
4. All AR
5. Present young
A. Severe infections
B. No pus
C. Inc WBC
D. Dec wound healing
E. Periodontitis
F. Delayed separation umbilical cord
155
TLR defects
1. Pathway includes: MyD88, IL-1, IL-6, TNF-alpha, and IL-12
2. MyD88 and IRAK defects
A. AR
B. Severe, invasive pyogenic infections early in life -> dec w/ age
156
Complement defects
1. Many
2. Dec Ci, C2, C3 of classic complement -> autoimmune similar to SLE
3. Dec C2 and C3 -> inc encapsulated bacteria infections
4. Dec C5-C9 -> recurrent/invasive neisserial infections
157
Wiskott-Aldrich syndrome (WAS)
1. X-linked
2. Triad
A. Eczema
B. Few/small platelets
C. Immunodeficiency
3. WAS protein only in hematopoietic cells
A. Actin cytoskeleton
B. Immune cell interactions
158
Ataxia-telangiectasia
1. AR
2. Triad
A. Ataxia
B. Ocular telangiectasias
C. Infections
3. ATM gene defect
A. DNA repair
4. Dec T cell # and fxn
5. Hypogammaglobulinemia
159
Hyper-IgE syndrome (HIES)
```
1. Triad
A. Eczema
B. Very high IgE
C. Infections
1. Pulmonary and skin
A. S. Aureus
B. Candida/Aspergillus
2. AD version: STAT3 deficiency (Janus kinase)
A. Differentiation CD4+
B. Maintenance CD8+ memory cells
3. AR version: DOCK8 mutation
A. Involved actin cytoskeleton
B. Viral skin infections
C. Inc food allergy and anaphylaxis
```
160
Cheddar-Higashi syndrome (CHS)
1. AR
2. Triad
A. Gray hair
B. Peripheral neuropathy
C. Dec cell-mediated cytotoxicity
3. Defect lysosomal trafficking
161
Diagnostic approach primary immunodeficiencies
```
1. HX
A. Recurrent strep and UTI not immunodeficiency
2. Physical
A. Lack lymphoid tissues in agammaglobulinemia
B. Eczema
C. Petichiae
D. Telangiectasias
E. Pigment change
3. Labs
A. CIDs
1. T cell/NK panel
2. Mitogen stimulation
3. TRECS
B. Ab deficiency
1. B cell panel
2. Quantitative immunoglobulins
3. Ab response to vaccines
C. Neutrophil ct: weekly for 6 wks
D. CGD
E. LAD: flow cytometry CD18
F. TLR defects
G. Complement defects
H. Protein specific flow cytometry
I. Genetics testing
```
162
Plasma cell dyscrasias
1. Neoplastic plasma cells -> monoclonal immunoglobin/fragment
A. Serve as markers
B. Pathological consequences
2. Plasma cell neoplasms 15% deaths by lymphoid neoplasms
3. Most common and deadly = multiple myeloma
4. M protein = monoclonal immunoglobin in blood
A. Complete = 160,000 Da => restricted to plasma and extracellular fluid
1. Not in urine
B. Immunoglobin light chains
5. Abnormal Igs assoc w/ plasma cell neoplasms
A. Monoclonal gammopathy
B. Dysproteinemia
C. Paraproteinemia
6. M proteins assoc w/
A. Multiple myeloma (plasma cell myeloma)
B. Monoclonal gammopathy of undetermined significance (MGUS)
C. Primary amyloidosis
D. Waldenstrom macroglobinemia
163
Multiple myeloma
1. One of most common lymphoid cancers
A. 20,000 new cases/yr in US
2. Median age = 70 yrs
3. M>F
4. Africans most common
5. Usually involves bone marrow, lytic lesions throughout skeletal system
6. M proteins
A. IgG 60%
B. IgA 20-25%
C. IgM, IgD, IgE rare
D. Remaining cases only kappa or gamma light chains
1. Excreted in urine = Bence Jones proteins
7. Often produce both M proteins and Bence Jones proteins
164
Multiple myeloma pathogenesis
1. Translocation IgH (chromosome 14) and oncogenes = cyclin D1 and D3
2. Dysregulation D cyclins common -> inc cell proliferation
3. Factors mediate bone destruction = major pathological feature
4. Defective humoral immunity
A. Inc risk bacterial infections
5. Renal dysfunction from several effects
A. Alone or in combo
165
Multiple myeloma morphology
1. Multifocal destructive skeletal lesions
A. Vertebral column
B. Ribs
C. Skull
D. Pelvis
E. Femur
F. Clavicle
G. Scapula
H. Arise medullary cavity -> cancellous bone -> destroy cortex -> pathological fxs
I. Punched-out defects 1-4cm
2. Marrow
A. Inc plasma cells >30% cellularity
B. Abnormal cytoplasmic inclusion containing Ig
C. Leukemic picture = myeloma cells spread to viscera
166
Multiple myeloma clinical features
1. Pathologic fx and chronic pain from bone resorption
2. Hypercalcemia -> neurologic manifestations
A. Confusion
B. Weakness
C. Lethargy
D. Renal dysfxn
3. Recurrent bacterial infections
4. Renal failure (50% pts)
A. Assoc w/ Bence Jones proteinuria
5. Amyloidosis -> inc renal dysfxn and deposit on other tissue
6. Inc Igs in blood and/or Bence Jones proteins in urine
A. Free light chains and M proteins together 60-70% cases
B. 20% cases only light chains
167
Multiple myeloma Dx and prognosis
1. Dx on radiology and labs
A. Suspect w/ bone lesions on imaging
B. Requires bone marrow exam
C. Marrow -> normocytic normochromic anemia
1. Sometimes w/ moderate leukopenia and thrombocytopenia
2. Prognosis variable
A. Multiple bony lesions untreated ~6-12 mo
B. Medial survival 4-7 yrs
168
Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL)
Only differ in peripheral blood involvement
1. >5000 cells/uL = CLL
2. Most cases fit CLL
3. CLL most common leukemia in adults in Western world
169
CLL and SLL pathogenesis
1. Indolent, slow growing
2. Inc tumor cell survival more imp than tumor proliferation
A. Inc BCL2 -I apoptosis
B. Signals generated by BCR
C. BCR signals flow thru Bruton tyrosine kinase -> genes promote survival CLL/SLL cells
D. Cause dysregulation normal B cells
1. Accumulation CLL/SLL cells -> hypogammaglobulinemia
2. ~15% pts dev autoantibodies against own RBCs/platelets (from normal B cells)
170
CLL and SLL morphology
1. Absolute lymphocytosis
2. Circulating cells fragile -> smudge cells
3. Involved lymph nodes effaced sheet of small lymphocytes
A. Scattered ill-defined foci
B. Actively dividing cells
4. Predominant cells small, resting lymphocytes w/ dark, round nuclei and scanty cytoplasm
5. Proliferation centers = mitotically active
A. Pathognomonic for CLL/SLL
6. Lymph nodes, bone marrow, spleen, and liver involved
171
CLL and SLL immunophenotype and genetics
1. Mature B cells expressing CD20s and surface Igs and CD5
2. 50% tumors have karyotypic abnormalities
A. Trisomy 12
B. Deletions portions 11, 13, and 17
C. Translocations rare
172
CLL and SLL clinical features
1. Often symptomatic when detected
2. Common signs/symptoms nonspecific
A. Fatiguability
B. Wt loss
C. Anorexia
3. Generalized lymphadenopathy and HSM 50-60% pts
4. WBC count inc
A. Slightly = SLL or
B. >200,000 cells/uL
5. Hypogammaglobulinemia 50% pts -> bacterial infections
6. Less commonly
A. Autoimmune hemolytic anemia
B. Thrombocytopenia
173
CLL and SLL prognosis and tx
1. Course and prognosis highly variable and depend on disease stage and genetic findings
A. TP53 tumor suppressor gene assoc w/ survival <30% at 10 yrs
B. Isolated abnormalities chromosome 13q assoc w/ overall survival about = to matched population
2. Hematopoietic stem cell transplant
A. Only young pts who fail conventional therapy
3. Few tumors -> aggressive tumors resembling DLBCL (Richter transformation)
A. Median survival <1ys after transformation
174
Hairy cell leukemia
1. Uncommon
2. Indolent B cell neoplasm
3. Fine, hairlike cytoplasmic projections
4. Activation mutations in serine/threonine kinase BRAF
5. Express B cell markers, surface Ig, CD11c and CD103
A. CD11c and CD103 diagnostic
6. Older males
7. Infiltration bone marrow and spleen
A. Splenomegaly = massive
1. Most common, sometimes only physical finding
2. Pancytopenia (50% cases)
3. Leukocytosis = uncommon
4. Scattered “hairy cells” in peripheral smear
8. Indolent but progressive w/o tx
A. Pancytopenia and infections = major clinical probs
9. Extremely sensitive to chemo (purine nucleosides)
10. Excellent prognosis w/ tx
11. Great response to BRAF inhibitors if fail conventional therapy
175
Myeloproliferative disorders
```
1. In adults
A. Trilineage hematopoiesis flat bones
1. Erythrocytes
2. Leukocytes
3. Platelets
2. Myeloid neoplasms
A. Acute myeloid leukemia (AML)
B. Myelodysplastic syndromes (MDS)
C. Myeloproliferative neoplasms
3. Myeloproliferative disorders
4. Chronic myeloid leukemia (CML)
5. Polycythemia Vera
6. Primary myelofibrosis
7. Essential thrombocytosis
```
176
Acute myeloid leukemia (AML)
1. Neoplastic cells stopped at early stage myelopoiesis
2. Blasts accumulate in marrow
A. Replace normal elements
B. Circulation in peripheral blood
177
Myelodysplastic syndromes (MDS)
1. Disordered and ineffective terminal differentiation -> dysplastic marrow precursors and peripheral blood cytopenias
178
Myeloproliferative neoplasms
1. Inc/dysregulated growth neoplastic clones
| 2. Assoc w/ inc 1+ formed elements in peripheral blood
179
Myeloproliferative disorders
1. Mutated, constitutively activated tyrosine kinase or other lesions -> GF independence
2. 4 major entities
A. CML
B. Polycythemia Vera
C. Primary myelofibrosis
D. Essential thrombocytosis
180
Chronic myeloid leukemia (CML)
1. 25-60 y/o
A. Peak incidence 40s-50s
2. 4500 new cases/yr in US
181
Chronic myeloid leukemia (CML) pathogenesis
1. BCR-ABL t(9:22)
A. 95% cases
B. Granulocytic cells
C. Erythroid cells
D. Megakaryocytes
E. B cell precursors
F. T cell precursors - sometimes
2. Arises from transformed hematopoietic stem cells
3. GF dependence of CML progenitors dec by BCR-ABL
4. Early disease: xs normal blood cells (granulocytes and platelets)
182
Chronic myeloid leukemia (CML) morphology
```
1. Characteristic peripheral findings
A. Leukocyte count >100,000 cells/uL
B. Circulating cells
1. Neutrophils
2. Metamyelocytes
3. Myelocytes
4. Basophils
5. Eosinophils
6. Inc platelets
2. Marrow = hypercellular
A. Inc maturing granulocytic and medakaryocytic precursors
3. Red pulp of enlarges spleen looks like marrow because xs extramedullary hematopoiesis -> splenic infarcts
```
183
Chronic myeloid leukemia (CML) clinical features
1. Insidious onset
2. Initial symptoms nonspecific
3. Sometimes splenomegaly -> dragging sensation in abd = 1st symptom
4. Dramatic inc granulocytes w/ infection, stress, chronic inflammation, and certain neoplasms
5. Test BCR-ABL fusion
A. Karyotyping
B. FISH
C. PCR assay
6. Hx = slow progression
A. W/o tx median survival = 3 yrs
B. Variable (unpredictable) period
C. Accelerated phase (50%)
1. Anemia
2. New thrombocytopenia
3. Additional cytogenetic abnormalities
D. Final transformation -> resembles acute leukemia (Blast crisis)
E. Other 50% cases -> blast crisis w/o accelerating phase
7. 30% cases blast crisis resembles precursor B cell ALL
8. 70% cases blast crisis resembles AML
184
Chronic myeloid leukemia (CML) Tx
Tyrosine kinase inhibitors (imatinib) -> sustained remission w/ manageable toxicity
1. Prevents progression to blast crisis
185
Polycythemia Vera
1. Activating point mutation in JAK2
A. Normally signals EPO receptor and other GF receptors
B. Mutation dec GF dependence of hematopoietic cells -> xs proliferation (panmyelosis)
C. Most signs/symptoms from inc red cell mass
2. Must be distinguished from relative polycythemia
3. Low serum EPO => GF independence
186
Polycythemia Vera Morphology
```
1. Inc blood volume and viscosity from polycythemia
A. Congestion in tissues
1. Hepatomegaly w/ foci of extramedullary hematopoiesis
2. Splenomegaly
B. Thrombosis and infarctions common
1. Heart
2. Spleen
3. Kidneys
2. Bone marrow hypercellular
A. Fibrosis 10% pts at dx
1. Leads to spent phase in fraction
A. Marrow replaced by fibroblasts and collagen
```
187
Polycythemia Vera clinical features
1. Insidious onset
2. Late Middle Ages
3. Pts plethoric and cyanotic
4. Other complaints from thrombotic and hemorrhagic tendencies and HTN
A. Headache
B. Dizziness
C. GI symptoms
D. Hematemesis
E. Melena
5. 30% pts thrombotic complications brain and heart
6. Hemorrhages
A. Minor common
B. Life-threatening 5-10% pts
7. Vascular comp death w/in months w/o tx
188
Polycythemia Vera dx
In lab
1. RBCs range 6-10 mill/uL and Hct often 60%<
2. Granulocytes 50,000 cells/uL
3. Platelet count >400,000/uL
4. Basophilia common
5. Platelets functionally abnormal
A. Giant platelets and megakaryocyte fragment in blood
189
Polycythemia Vera tx
1. Phlebotomy inc survival 10 yrs by keeping RBC levels normal
2. JAK2 inhibitors approved for tax of spent phase
190
Primary myelofibrosis
1. Hallmark
A. Obliterative marrow fibrosis -> dec bone marrow hematopoiesis-> cytopeniass and extramedullary hematopoiesis
2. JAK-STAT driving force
3. Inappropriate release fibrogenic factors from neoplastic megakaryocytes
4. Displaced hematopoietic stem cells -> secondary hematopoietic organs
A. Spleen
B. Liver
C. Lymph nodes
D. Leads to extramedullary hematopoiesis
191
Primary myelofibrosis morphology
1. Peripheral abnormal
A. RBCs bizzare shapes
B. Immature WBCs
C. Large platelets
192
Primary myelofibrosis clinical features
1. 60< y/o
2. Present progressive anemia and splenomegaly
3. Nonspecific symptoms
A. Night sweats
4. Severe normochromic normocytic anemia
5. Leukoerythroblastosis
6. More difficult to treat than PV and CML
7. Median survival 4-5 yrs
193
Essential thrombocytosis
```
1. Activating point mutations
A. JAK2 50%
B. MPL 5-10%
2. Progenitors TPO-independent -> hyperproliferation
3. Inc platelets
4. Absence polycythemia and marrow fibrosis
5. Smears
A. Large platelets
B. Mild leukocytosis
6. 1-3/10,000 per yr
7. Usually 60+ y/o
A. Sometimes young adults
8. Indolent
```
194
Essential thrombocytosis clinical features and tx
1. Indolent
A. Long asymptomatic periods
B. Occasional thrombotic or hemorrhagic crises
2. Medial survival 12-15 yrs
3. Tx = gentle chemo to suppress throbopoiesis
195
White cell neoplasms
```
1. Lymphoid neoplasms
A. Hodgkin lymphoma
B. Non-Hodgkin lymphomas
C. Certain leukemias
D. Plasma cell dyscrisias
2. Myeloid neoplasms
A. Certain leukemias
B. Myelodysplastic syndromes (MDS)
C. Myeloproliferative neoplasms
3. Histiocytic neoplasms
A. Langerhans cell histiocytic
```
196
Lymphoid neoplasms
```
1. Plasma cell tumors
A. Arise in bone
B. Symptoms from complete or partial monoclonal immunoglobulin
2. Two groups
A. Hodgkin lymphoma
B. Non-Hodgkin lymphomas
3. B and T cell tumors from cells arrested at specific stage of normal differentiation
A. Hints at specific stage seen in morphology
4. WHO classification considers
A. Morphology
B. Cell of origin
C. Genotype
D. Clinical features
```
197
Lymphoid neoplasms dx
Lab tests
1. Immunochemistry
2. Flow cytometry
3. Used to detect lineage-specific antigens
4. ID’d by CDs
198
Non-Hodgkin lymphomas
1. Acute lymphoblastic leukemia/lymphoma (ALL)
2. Peripheral B-cell neoplasms
A. Mantle cell lymphoma (MCL)
B. Extranodal marginal zone lymphoma
C. Diffuse large B cell lymphoma
D. Burkitt lymphoma
3. Follicular lymphoma
199
Follicular lymphoma (FCCL)
1. Most common indolent NHL in US
A. 40% adult NHLs in US
2. 85% t(14:18)
A. Fuses BCL2 and IgH -> overexpression BCL2 -I apoptosis
200
Follicular lymphoma (FCCL) morphology
1. Lymph nodes have nodular proliferation
2. Centrocytes: larger lymphocytes
A. Cleaves nuclei w/ indentations
B. Condensed chromatin
C. Indistinct nucleoli
3. Centroblasts: large
A. Vesicular chromatin
B. Several nuclei
C. Minor component
201
Follicular lymphoma (FCCL) immunophenotype
1. FCCL B cell markers (CD20)
2. Germinal center B cells CD10 and BCL 6
3. 85% cases BCL2 expressed
202
Follicular lymphoma (FCCL) clinical features
1. 50+ y/o
2. M=F
3. Painless, generalized lymphadenopathy
4. Bone marrow involved 80% cases
5. Slow growing
6. Median survival 10 yrs
7. Not curable
8. Tx for bulky, symptomatic disease
A. Cytotoxic drugs
B. Rituximab (anti-CD20 Ab)
9. Progresses -> diffuse large B cell lymphoma 30-40%
A. Median survival <1 yrs after transformation
203
Mantle cell lymphoma (MCL)
NHL - peripheral B cell neoplasm
1. Naive B cells in mantle zone of normal lymphoid follicles
2. 6% NHLs
3. M>F
4. 50+ y/o
204
Mantle cell lymphoma (MCL) pathogenesis
T(11:14) fused cyclin C1 and IgH -> overexpression cyclin D1 -> growth by -> cells G1 to S phase
205
Mantle cell lymphoma (MCL) morphology
1. Lymph nodes diffuse or vaguely nodular pattern
2. Cells larger than normal lymphocyte
A. Irregular nucleus
B. Inconspicuous nucleoli
3. Marrow involved most cases
4. Peripheral blood 20% cases
5. Sometimes in GI tract
206
Mantle cell lymphoma (MCL) immunophenotype
1. IgM
2. IgD
3. CD20
4. CD5
5. Cyclin D1
207
Mantle cell lymphoma (MCL) clinical features
1. Fatigue
2. Lymphadenopathy
3. Marrow
4. Spleen
5. Liver
6. GI
7. Moderately aggressive and incurable
8. Median survival 4-6 yrs
208
Extranodal marginal zone lymphoma
```
NHL - peripheral B cell neoplasm
1. Indolent B cell tumor in epithelial cells
A. Stomach
B. Salivary
C. Small and large bowel
D. Lungs
E. Orbit
F. Breast
```
209
Extranodal marginal zone lymphoma pathogenesis
1. Arise w/in
2. Sustained by chronic inflammation from autoimmune or chronic infection
3. H. Pylori assoc can dec tumor cells w/ H. Pylori antibiotic tx
A. Initiated by polyconal immune rxn
B. More clonal evolution -> inc tumor independence
4. Lymphoepithelial lesions = aggregates of infiltration
210
Extranodal marginal zone lymphoma immunophenotype
Mature B cells CD20 and IgM
211
Extranodal marginal zone lymphoma clinical features
1. Swelling salivary glands, thyroid, or orbit or H. Pylori discovery
2. Localized cured by excision and radiation
212
Diffuse large B cell lymphoma
NHL - peripheral B cell lymphoma
1. 30% NHLs
2. Most common adult lymphoma
3. Aggressive
213
Diffuse large B cell lymphoma pathogenesis
1. 1/3 cases DLBCL rearrangements on BCL 6 gene on 3q27
2. Other activating point mutation BCL6 promotor
3. Inc BLC6 protein = transcriptional regulator of gene expression in germinal center B cells
4. 30% t(14:18) -> overexpression BCL2
A. Some transformed follicular lymphoma
B. Usually lack BCL6 mutations => 2 molecular classes
214
Diffuse large B cell lymphoma morphology
1. Diffuse growth pattern
| 2. B cells large and vary in appearance
215
Diffuse large B cell lymphoma immunophenotype
1. CD20
2. +/- IgM/IgG
3. +/- CD10, BCL6
216
Diffuse large B cell lymphoma special subtypes
1. EBV-associated
2. Kaposi sarcoma herpesvirus
3. Mediastinal large B cell lymphomas
217
EBV-associated DLBCL
Arise in AIDS iatrogenic immunosuppression
1. Transplant recipients
2. Elderly
218
Kaposi sarcoma herpesvirus DLBCL
HHV-8 - assoc w/ rare primary effusion lymphomas
1. Pleural cavity
2. Pericardium
3. Peritoneum
219
Mediastinal DLBCL
1. Young women
| 2. Spread abdominal viscera and CNS
220
Diffuse large B cell lymphoma clinical features
1. Usually 60+ y/o, can happen at any age
2. Rapidly growing mass at one or several sites
3. Extranodal presentation common
A. GI tract most common
4. Uncommon involvement
A. Liver
B. Spleen
C. Bone marrow
5. W/o tx = aggressive and rapidly fatal
221
Diffuse large B cell lymphoma Tx
1. Intensive chemo
2. Anti-CD20 immunotherapy
3. 60-80% -> remission w/ tx
A. 50% remain NED => cured
4. Refractory tx
A. High dose chemo
B. Hematopoietic stem cell transplant
222
Burkitt lymphoma
```
NHL - peripheral B cell lymphoma
1. Endemic in Africa
2. African vs non-endemic disease
A. Histologically the same
B. Clinical and virologist differences
```
223
Burkitt lymphoma pathogenesis
1. Translocation MYC gene on chromosome 8 -> overexpression MYC transcription factor
A. Most fuse MYC and IgH (chrom 14)
B. Variant translocations w/ kappa or lambda light chain loci
2. MYC = master regulator Warburg metabolism (aerobic glycolysis)
A. Rapid cell growth
3. Fastest growing human tumor
4. Latently infected w/ EBV
A. Most endemic cases
1. Co-infections dec immune competence -> B cell proliferation
B. 20% sporadic cases
C. Most EBV-infected B cells killed by CD8 cells
D. Surviving infected cells -> lymphoma
224
Burkitt lymphoma morphology
1. Intermediate size
2. Round/oval nuclei
3. 2-5 distinct nucleoli
4. Inc rates proliferation and apoptosis
A. Macrophages surrounded by clear space = starry sky pattern
225
Burkitt lymphoma immunophenotype
1. IgM
2. CD20
3. Germinal center markers CD10 and BCL6
226
Burkitt lymphoma clinical features
1. Children and young adults
2. Extranodal sites
A. Endemic
1. Maxillary
2. Mandibular
B. N. America
1. Bowel retroperitoneum
2. Ovaries
3. Sometimes leukemic presentation => have to distinguish from ALL
4. Often cured w/ intensive chemo
227
Hodgkin lymphoma
1. Group of neoplasms w/ Reed-Sternburg (RS) tumor giant cells
2. Arise single lymph node or chain of lymph nodes
3. Spread stepwise fashion
4. Subtypes
A. Nodular sclerosis
B. Mixed cellularity
C. Lymphocyte rich
D. Lymphocyte depletion
E. Lymphocyte predominant
1. RS cells express germinal center B cell markers
228
Hodgkin lymphoma morphology
```
1. Reed-Sternburg (RS) cell
A. 2 mirror-image nuclei/nuclear lobes
B. “Owl eye”
2. Express CD15 and CD30
3. Lack CD45 (LCA), B and T cell markers
```
229
Nodular sclerosis
HL - most common form
1. M=F
2. Lower cervical, supraclavicular, and mediastinal lymph nodes
3. Adolescents and young adults
4. Excellent prognosis
230
Nodular sclerosis morphology
1. Lacunar cells
| 2. Collagen bands
231
Mixed-cellularity HL
Most common form in pts 50+ y/o
1. 25% all HL cases
2. M>F
3. More disseminated
4. Assoc w/ systemic manifestations
5. RA cells mixed w/ inflammatory infiltrate
232
Lymphocyte-Rich HL (LRHL)
Uncommon
1. Most cells reactive lymph nodes
2. Mononuclear variants
233
Lymphocyte depletion HL
Least common form (<5% cases)
1. Lymphocytes rare
2. Inc RS cells
234
Lymphocyte-predominant HL
1. 5% HL cases
2. Lymphohistiocytic (L and H) variant RS cells (popcorn cells)
A. CD20
B. (-) CD15 and CD30
3. Isolated cervical or axillary lymphadenopathy
235
Lymphocyte-predominant HL pathogenesis
1. Arises from germinal center B cells
2. EBV in 70% cases of mixed-cellularity and less in “classical” forms
A. One of steps contributing to dev
3. Cytokines -> nonneoplastic, inflam infiltrate
236
Lymphocyte-predominant HL clinical features
1. Painless lymphadenopathy
2. Staging guides therapy and prognosis
A. Younger pts + favorable subtype -> stage I/II
1. Usually no “B symptoms”
B. Stages III/IV -> “B symptoms”, pruritis, and anemia
3. Good outlook even if advanced
4. Long-term survivors w/ RT inc risk
A. Other cancers (lung and breast)
B. CV disease
237
Acute lymphoblastic leukemia/lymphoma (ALL)
```
1. 85% B-ALLs
A. Childhood acute leukemias
B. Most common childhood cancer
C. 2500 new cases/yr <15 y/o
D. Whites:blacks 3:1
E. M>F
F. Hispanics highest incidence
G. Peak incidence 3 y/o
2. Less common T-ALLs
A. Adolescent males thymus lymphomas
B. Peak incidence adolescence (thymus biggest)
```
238
Acute lymphoblastic leukemia/lymphoma (ALL) pathogenesis
1. Chromosal lesions dysregulate transcription factors for normal differentiation B and T cell proliferation
A. T-ALLs: gain-of-fxn mutation
1. 70% NOTCH1 mutation (T cell differentiation)
B. B-ALLs: loss-of-fxn mutation
1. PAX5 (B cell differentiation)
C. Mutations -> maturation arrest and inc self-renewal
2. Mutations in transcription factors not enough to cause ALL
A. Need lesions that drive cell growth
1. Inc tyrosine kinase activity
2. Inc RAS signaling
239
Acute lymphoblastic leukemia/lymphoma (ALL) morphology
```
1. T-ALLs
A. Mediastinal masses (50-70%)
1. Lymphadenopathy
2. Splenomegaly
B. High mitotic rate
2. Both: tumor cells
A. Basophilic cytoplasm
B. Nuclei w/ delicate, stippled chromatin and small nucleoli
3. Blast appearance B and T-ALLs => dx needs immunophenotype studies
4. Peripheral smears highly variable
A. WBCs >100,000 cells/uL
1. 50% pts <10,000 cells/uL
B. Few pts w/ no circulating blasts (aleukemic leukemia)
C. Anemia almost always
D. Platelet ct <100,000/uL
E. Neutropenia common
```
240
Acute lymphoblastic leukemia/lymphoma (ALL) genetics
1. 90% cases non random karyotypic abnormalities
A. B-ALL: hyperdiploidy (>50 chromosomes/cell) and t(12:21)
1. ETV6 and RUNX1 -> abberent transcription factor
B. 25% B-ALL t(9:22)
1. BCR-ABL
C. T-ALLs diverse chromosomal aberrations
241
Acute lymphoblastic leukemia/lymphoma (ALL) immunophenotype
Good for subtyping ALLs and distinguish from AML
1. Terminal deoxynucleotidyl transferase (TdT): specifically expressed in ALL (95% cases)
2. Subtyping uses surface markers
242
Acute lymphoblastic leukemia/lymphoma (ALL) clinical features
1. Very aggressive
2. Most pts present w/in few weeks on symptom onset
3. Symptoms related to dec marrow fxn
A. Fatigue from anemia
B. Fever from secondary infections from neutropenia
C. Bleeding: thrombocytopenia
4. Effects of neoplastic infiltration
A. Bone pain: marrow expansion and infiltration
B. Lymphadenopathy
C. Splenomegaly
D. Hepatomegaly
E. T-ALL
1. Compression large vessels and airways in mediastinum
5. CNS manifestations - meningeal spread
A. Headache
B. Vomiting
C. Nerve palsies
243
Acute lymphoblastic leukemia/lymphoma (ALL) prognosis
1. 95% remission in kids w/ tx
A. 75-85% cured
2. Still leading cancer COD in kids
3. Only 35-40% adults cured
4. Factors assoc w/ worse prognosis
A. <2 y/o becasue usually involve MLL gene in translocation
B. Present as adolescent or adult
C. Peripheral blast count >100,00 cells/uL
D. Molecular detection residual disease after tx
5. Favorable markers
A. 2-10 y/o
B. Low WBCs
C. Hyperdiploidy
6. Tx t(9:22) w/ BCR-ABL tyrosine kinase inhibitors + chemo -> better outcome kids and adults B-ALL
244
Acute Myeloid Leukemia (AML)
| Pathogenesis
1. Median age 50 y/o
2. Mutations in transcription factor genes for myeloid cell differentiation -> accumulate blasts in marrow
3. T(15:17) in acute promyelocytic leukemia (APL)
A. Fusion PML/RARA -I myeloid differentiation at promyelocytic stage
B. ATRA overcome block -> neoplastic cells -> neutrophils
1. Rapidly clears tumor
245
Acute lymphoblastic leukemia/lymphoma (ALL) morphology
```
1. Blasts >20% marrow cellularity
A. Delicate nuclear chromatin
B. 3-5 nucleoli
C. Azurophilic cytoplasmic granules
2. Auer rods
A. More numerous in APL
B. Specific for neoplastic myeloblasts
3. In some subtypes AML monoblasts, erythoblasts, or megakaryocytes predominate
```
246
Acute lymphoblastic leukemia/lymphoma (ALL) classification
1. AMLs assoc w/ specific genetic aberrations
2. AMLs w/ dysplasia, from MDS’s
3. AMLs occurring after genotoxic chemo
4. AMLs lacking above features
A. Subclassified based on predominant line of differentiation tumor exhibits
5. FAB classifications
247
Acute lymphoblastic leukemia/lymphoma (ALL) immunophenotype
1. Heterogenous expression of immunologic markers
2. Most express some combo
A. CD13
B. CD14
C. CD15
D. CD33
E. CD64
F. CD117
3. CD34 often present on myeloblasts
4. Used to distinguish AML from ALL
248
Acute lymphoblastic leukemia/lymphoma (ALL) clinical features
```
1. Most symptoms related to
A. Anemia
B. Neutropenia
C. Thrombocytopenia -> bleeding disorder
2. Symptoms
A. Fatigue
B. Fever
C. Spontaneous mucosal and cutaneous bleeding
3. Pro coag and fibrinolytic factors released by leukemic cells
4. Opportunistic infections frequent
A. Pseudomonas
5. Signs/symptoms less severe that ALL
6. CNS spread less common than ALL
```
249
Acute lymphoblastic leukemia/lymphoma (ALL) prognosis
1. “Good-risk” karyotype abnormalities assoc 50% chance long-term disease-free survival
A. T(8:21)
B. Inv(16)
2. Overall survival 15-30% w/ conventional chemo
3. TP53 mutations assoc w/ particularly poor prognosis
4. APL treated w/ ATRA and arsenic salts better prognosis
250
Myelodysplastic syndromes
1. Group of clonal stem cell disorders w/ maturation defects
A. Ineffective hematopoiesis
B. Inc risk transformation -> AML
2. Marrow replaced by transformed multipotent stem cells
A. Differentiation ineffective and disordered
B. Hypercellular or normocellular
3. Smear: one or more cytopenias
4. Cells genetically unstable => prone to more mutations -> AML
5. Causes
A. Most idiopathic
B. Alkylating agent chemo
C. Radiation
251
Myelodysplastic syndromes pathogenesis
```
1. Mutation categories
A. Epigenetic factors
B. RNA splicing factors
C. Transcription factors
2. 10% of MDS cases have loss-of-fxn mutations (TP53)
A. Complex karyotype
B. Poor clinical outcomes
3. Recurrent chromosomal abnormalities
A. Monopolies 5 and 7
B. Deletions 5q, 7q, 20q
C. Trisomy 8
```
252
Myelodysplastic syndromes morphology
1. Abnormal-appearing hematopoietic precursors
A. Megablastoid erythroid precursors
B. Granulocyte precursors w/ abnormal granules or nuclear maturation, and small megakaryocytes
253
Myelodysplastic syndromes clinical features
```
1. As comman as AML
A. 15,000 pts/yr in US
2. 50-70 y/o
3. Infections
4. Anemia
5. Hemorrhages
```
254
Myelodysplastic syndromes prognosis
Variable
1. Poor w/ conventional chemo
2. Worse case assoc w/ inc blasts, cytogenetic abnormalities, or TP53 mutations
3. Transformation -> AML 10-40% pts
4. Median survival time 9-29 mo
255
Iron deficiency anemia take home
1. Low MVC
2. Always assumed colorectal cancer in a man until proven otherwise
3. Pitfall: replete get Fe w/o referring to GI
256
MDS take home
1. Usually high MCV
2. More than one cell line affected
3. Heterogenous prognosis
4. Allogeneic stem cell transplant only cure
257
CLL take home
1. Often dx incidentally
2. Chronic disease
3. Immediate tx NOT necessary
4. Many good tx options
258
CML take home
1. Easy to dx
2. Chronic disease
3. Immediate tx necessary
4. On therapy indefinitely
259
AML take home
1. Harder to dx
2. Difficult to treat
3. Stem cell transplant often needed for cure
4. APL = imp subtype
A. Curable w/ ATRA and arsenic
260
ALL take home
```
1. More common in kids
A. 80% cure
2. Difficult to treat in adults
3. Lymphadenopathy
4. LOTS of chemo to get to remission
5. Stem cell transplant often needed for cure
```
