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HemOnc Flashcards

1
Q

[Anemia]

  1. Define anemia and normal levels
  2. Define hematocrit and normal values
A
  1. Anemia - decrease in RBCs, commonly due to iron deficiency or chronic disease
    Men: Hb < 13 g/dL
    Women: Hb < 12 g/dL in non-pregnant women (lower for pregnant women who have more plasma volume)
  2. Hematocrit - ratio of RBCs : total volume of blood (RBCs, plasma, and WBCs)
    Men: 47%
    Women: 42%
    *less reliable indicator of anemia than hemoglobin e.g. Hematocrit can increase due to loss of plasma during dehydration
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2
Q

[Anemia]

  1. Define reticulocytes and normal range
  2. Response to anemia intact vs inadequate
  3. Corrections for reticulocyte count
A
  1. Reticulocyte - immature RBC without a nucleus and with residual RNA, IDed via methylene blue stain (supravital staining)
    Normal: 1-2%
  2. Response to anemia via erythropoietin (EPO) and bone marrow –> reticulocytosis (increase in reticulocytes)
    - levels 3x normal when response intact
    - less than 3x normal with inadequate marrow response

3A. Correct for degree of anemia
Reticulocyte % x (Hgb/Normal Hgb) = Y
B. Correct for longer life of premature reticulocytes
Reticulocyte production index RPI = Y/2

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3
Q

[Anemia]

  1. Classify RBCs based on size in terms of MCV
  2. Classify RBCs based on measure of hemoglobin
A
  1. MCV = mean corpuscular volume
    Microcyte: MCV < 80 fL (femtoliter = 10^-15) *associated with poor cytoplasmic maturation –> low Hb
    Normocyte: MCV: 80-100 fL
    Macrocyte: >100 fL *associated with poor nuclear maturation –> lots of Hb synthesis
  2. Amount of Hb judged visually based on color of the cell
    Hyperchromic: more Hb in their RBCs
    Normochromic: normal amount of Hb
    Hypochromic: less Hb
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4
Q 
[Anemia] 
Define the following classifications of anemia including RBC size and possible causes: 
1. Hypoproliferative
2. Ineffective  
3. Blood loss / hemolysis
A
  1. Hypoproliferative - normocytic, bone marrow hypoplasia of erythroid lineage; RPI <2.5
    - causes: iron deficiency (early), inflammation i.e. anemia of chronic disease ACD (early), marrow damage, decreased EPO from kidney damage
  2. Ineffective - bone marrow hyperplasia of erythroid lineage; RPI <2.5
    A. macrocytic due to nuclear maturation defect e.g. folate deficiency, drugs
    B. microcytic due to cytoplasmic maturation defect e.g. TAILS
  3. Blood loss / hemolysis - RPI >2.5; bone marrow hyperplasia of erythroid lineage, normocytic
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5
Q

[Anemia] -
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment

  1. Iron deficiency
  2. Anemia of chronic disease
A

Microcytic anemia - problem producing hemoglobin
Normal HbA - 2 alpha and 2 beta globins

  1. Iron deficiency (late) - due to ineffective erythropoiesis; leads to microcytic, hypochromic anemia (pale cells with central pallor)
    A. Causes - late in iron deficiency –> bone marrow goes crazy, producing small cells (ineffective erythropoiesis); iron deficiency due to:
    - chronic bleeding (GI loss!!, menorrhagia)
    - malnutrition, pregnancy (increased demand), hookworm
    - gastrectomy (↓ acids –> ↓ Fe2+ form –> iron less readily absorbed)
    B. Findings - ↓ serum iron, ↓ ferritin, ↑ transferrin TIBC, ↓ transferrin saturation (iron/TIBC, ~33%) when ferritin (iron storage) decreases in liver, transferrin (iron transfer) increases in attempt to replenish iron stores
    - fatigue, conjunctival pallor, ↑RDW (anisocytosis)
    - pica, spoon nails (koilonychia)
    - can manifest as Plummer-Vinson syndrome (iron deficiency anemia, esophageal webs, atrophic glossitis)
  2. Anemia of chronic disease - inflammation
    A. Causes - late stage due to high hepcidin –> decreased gut absorption, iron release –> cannot make heme
    B. Findings - ↓ serum iron, ↓ TIBC, ↑ ferritin (trapped in cells), normal transferrin saturation (both iron and TIBC decreased)
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6
Q

[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
3. Thalassemias
A. Alpha thalassemia incl types

A
  1. Thalassemia - microcytic anemia –> ineffective erythropoiesis (bone marrow cells are hyperplastic but not pushing out reticulocytes due to hemoglobin mutations)
    - carriers protected against Plasmodium falciparum malaria

A. Alpha thalassemia - deletions of alpha globin genes on chromosome 16 –> 2 genes on each chromosome –> 4 genes/alleles total
Cis-deletions in Asians, trans deletions in Africans

1 allele deletion: no anemia (asymptomatic carrier)
2 alleles: mild microcytic anemia (alpha thalassemia minor)
3 alleles: microcytic and hemolytic anemia with splenomegaly (HbH disease - excess beta globin forms HbH)
4 alleles: incompatible with life (no alpha globin –> excess gamma globin forms Hb Barts –> hydrops fetalis) *most likely in asians

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7
Q

[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
3. Thalassemias
A. Beta thalassemia

A
  1. Thalassemia - microcytic anemia

B. Beta thalassemia - due to point mutations of beta globin genes on chromosome 11 –> 1 gene on each –> 2 genes/alleles total; B+= mutated, B0=absent, B=normal
- seen in individuals of African, Mediterranean descent

i. Beta thal minor = B+/B –> increased HbA2 (alpha2delta2) and/or HbF (alpha2gamma2)

ii. Beta thal major =B0B0 (95% HbF) or B+/B+ (70% HbF)
- symptomatic after 6 mos (when HbF decreases)
- alpha chains precipitate and are toxic –> intramedullary hemolysis –> anemia
- bone marrow expansion (crew cut on skull xray, chipmunk facies), increased risk parvovirus B19 aplastic crisis
- blood smear: anisocytosis (all different shapes), poikilocytosis (all different sizes), target cells (represent poor spleen function and QC), schistocytes

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8
Q

[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
4. Sideroblastic anemia
5. Lead poisoning

A
  1. Sideroblastic anemia is result of interruption of the first step in the heme synthesis pathway (mt)
    A. Causes: mutation of delta-ALA synthase (X-linked recessive), alcohol (most common cause), vitamin B6 deficiency
    B. Findings: high iron, high ferritin and low transferrin TIBC, high saturation
    - basophilic stippling (retained rRNA fragments)
    - ring sideroblast due to ring of iron-laden mt (visualize via Prussian blue stain)
    C. Treatment: pyrodoxine B6 - cofactor for delta-ALA synthase –> only works for genetic cause
  2. Lead poisoning - type of sideroblastic anemia
    A. Cause - lead inhibits 2 enzymes: delta-ALA dehydratase (Step 2) and ferrochelatase (last step)
    B. Findings - LEAD
    Lead lines on gingivae and Long bones
    Encephalopathy and
    Abdominal colic
    Drops - wrist and foot
    - sideroblasts + basophilic stippling
    C. Treatment - chelation with dimercaprol and EDTA
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9
Q

[Anemia]
Describe the types of normocytic, nonhemolytic anemia incl causes, findings, and treatment

  1. Iron deficiency
  2. ACD
  3. Aplastic anemia
A

Normocytic, nonhemolytic anemia

  1. Iron deficiency (Early) - due to hypoproliferation - low levels of substrate so cells are normocytic but fewer are produced
  2. Anemia of chronic disease ACD (early) - inflammation leads to increased hepcidin from liver
    A. Cause - hepcidin blocks iron absorption into blood (by gut enterocyte) and iron release from liver (by hepatocyte) –> lower levels of substrate can be accessed in blood–> lower serum iron, increased ferritin and lower transferrin TIBC (bc perception is that iron stores are high)
    - associated with RA, SLE, neoplastic disorders, chronic kidney disease (treat with EPO)
  3. Aplastic anemia - affects hematopoietic stem cells in bone marrow
    A. Causes - stem cells damaged due to radiation, drugs (chloramphenicol), viruses (parvovirus B19, EBV, HIV, HCV), fanconi anemia (DNA repair defect), idiopathic
    B. Findings - pancytopenia - normal cell morphology but deficiency of RBC, WBC, and platelets; hypocellular bone marrow with fatty infiltrate
    - fatigue, malaise, pallor, mucosal bleeding (sign of infection)
    C. Treatment - immunosuppression, allogenic marrow transplant, RBC and platelet transfusion
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10
Q

[Anemia]
Describe the types of normocytic, hemolytic anemia incl causes, findings
1. Intravascular
2. Extravascular

A

Hemolytic anemia - high RPI
Location of hemolysis: Intravascular vs extravascular

  1. Intravascular hemolysis - breakdown of RBCs in the blood vessels
    A. Causes: paroxysmal nocturnal hemoglobinuria, others

B. Findings - decreased haptoglobin (RBCs lyse in the circulation and are bound to haptoglobin for clearance), increased LDH, hemoglobinuria (when haptoglobin capacity exceeded), hemosiderinuria (tubular renal cells get sloughed - dark urine presents 3 days late)

  1. Extravascular hemolysis - RBCs phagocytosed in liver and spleen
    A. Causes - RBC membrane defect, RBC enzyme defect, hemoglobinopathies S and C, autoimmune

B. Findings - macrophages in spleen clear RBCs –> increased LDH, large increase in unconjugated bilirubin (from heme breakdown) –> jaundice but NO hemoglobinuria or hemosiderinuria (no free Hb in circulation)

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11
Q 
[Anemia]
Describe the differences between intravascular and extravascular normocytic, hemolytic anemia in terms of: 
1. serum haptoglobin
2. urine hemoglobin
3. urine hemosiderin
4. unconjugated bilirubin
5. serum LDH
A
  1. serum haptoglobin - absent in intra, mildly reduced in extra
  2. urine hemoglobin - present in intra, absent in extra
  3. urine hemosiderin - present in intra, absent in extra
  4. unconjugated bilirubin - mildly elevated in intra, very elevated in extra
  5. serum LDH (marker of RBC breakdown) - elevated in both
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12
Q

[Anemia]
Describe causes of intrinsic hemolytic anemia
1. Hereditary spherocytosis
2. G6PD deficiency

A

Cause of hemolysis related to the RBC: Intrinsic (e.g. RBC defect) vs extrinsic (e.g. autoimmune)

  1. Hereditary spherocytosis - inherited defect (AD) in membrane protein (ankyrin, spectrin) –> RBCs become spherical –> cannot pass through spleen so prematurely removed (extravascular hemolysis) –> splenomegaly and aplastic crisis (esp with parvovirus B19)–> need to remove spleen but could lead to Howell-Jolly bodies (DNA remnants normally removed by splenic macrophages)
    - also jaundice, anemia present at birth
    - osmotic fragility test (cells are more fragile)
  2. G6PD deficiency - X-linked recessive; G6PD needed to make NADPH, which is needed to reduce GSSG to GSH; no reduced glutathione GSH –> inability to turn H202 into H20 –> increased susceptibility to oxidant stress when exposed to sulfa drugs, antimalarials, fava beans
    - Heinz bodies of oxidized, denatured hemoglobin; bite cells where macrophages have removed Heinz bodies (visualize via methylene blue supravital staining)
    - both intravascular (pink serum) and extravascular hemolysis (back pain) + dark urine
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13
Q

[Anemia]
Describe causes of intrinsic hemolytic anemia
4. Sickle cell disease

  1. Variants
    A. HbSC
    B. HbS/Beta thalassemia
A
  1. Sickle cell: Glu -> Val at position 6 on chromosome 11 (beta globin gene)–> HbS (SS is disease, AS is trait); AR inheritance
    - crew cut on skull X-ray bc of marrow expansion
    - sickled cells on smear
    - can lead to vaso-occlusive crisis (due to low hypoxemia, dehydration, acidosis), aplastic crisis, autosplenectomy, dactylitism (pain crisis in hands), bone pain, pigmented black gallstones, priapism (persistent, painful erection)
    - acute chest syndrome with pulmonary infiltrate (death in adults)
    - infection by encapsulated organisms e.g. H. influenzae, S. pneumoniae (death in children)
    - treat with hydroxyurea to increase HbF, hydration

5A. HbC disease: Glu –> Lys mutation
- can have HbSC (1 of each mutant gene)
- mild sickle cell disease
- HbC crystals and target cells on smear
B. HbS/Beta thalassemia - mild sickle cell disease

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14
Q

[Anemia]
Describe causes of intrinsic hemolytic anemia
6. Paroxysmal nocturnal hemoglobinuria

A
  1. Paroxysmal nocturnal hemoglobinuria - acquired somatic mutation in hematopoietic stem cells –> increased complement-mediated RBC lysis –> hemolysis triggered by mild respiratory acidosis at night
    A. Cause - PIGA mutation on X chromosome –> no GPI –> can no longer attach CD55/59 to RBC –> abnormal complement activation
    B. Findings - triad:
    i. Coombs (-) hemolytic anemia (direct coombs neg bc non immune mediated)
    ii. pancytopenia (↓ RBC, WBC, platelets)
    iii. venous thrombosis (due to platelets)
    - can lead to AML
    - hemaglobinuria (pink serum) –> intravascular hemolysis
    - free Hb inactivates NO –> smooth muscle contraction –> abdominal pain
    *ONLY pure cause of intravascular hemolysis; all other intrinsic causes can lead to extravascular or intravascular hemolysis
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15
Q 
[Anemia]
Describe causes of extrinsic hemolytic normocytic anemia 
1. Autoimmune hemolytic anemia 
2. Microangiopathic hemolytic anemia 
3. Macroangiopathic hemolytic  anemia
4. Infections
A
  1. Autoimmune hemolytic anemia - Ab against RBCs (confirm via Direct Coomb’s test)
    A. Warm - IgG - chronic anemia, seen in SLE, CLL, penicillin use –> extravascular hemolysis with spherocytes
    B. Cold - IgM - acute anemia, seen in mycoplasma, mono –> painful, blue fingers and toes –> intravascular hemolysis with RBC clumps
  2. Microangiopathic anemia - RBCs damaged when passing by platelet microthrombi in narrow vessel –> schistocytes hallmark sign; also platelet destruction (thrombocytopenia); this anemia is seen in DIC, lupus, malignant HTN, hemolytic-uremic syndrome HUS, and thrombotic thrombocytopenic purpura TTP
  3. Macroangiopathic anemia - anemia secondary to prosthetic heart valves, aortic stenosis
  4. Infections - malaria, babesia (maltese cross)
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16
Q 
[Anemia]
Describe causes of macrocytic anemia
1. Megaloblastic  
A. Folate deficiency
B. B12 deficiency
A
  1. Megaloblastic anemia - due to ineffective erythropoiesis (RPI <2.5, marrow hyperplasia); macrocytic because of poor nuclear maturation

A. Folate THF deficiency - acts as methyl donor with B12 to form methionine from homocysteine, used in nucleotide synthesis; takes months to develop

  • trouble maturing nucleus in RBC precursor
  • causes: malnutrition (alcoholics), antifolates (methotrexate, phenytoin), increased requirement (hemolytic anemia, pregnancy)
  • findings: low folate, normal B12, high homocysteine

B. B12 deficiency - cofactor for methionine synthase (with THF) and methylmalonylCoA mutase; takes years to develop

  • folate trap with B12 deficiency
  • causes: vegans, malabsorption in ileum (Crohn’s), pernicious anemia (no intrinsic factor), pancreatic disease (decreased enzymes to release B12 to bind IF)
  • diagnose with Schilling test
  • findings: normal folate, low B12, high homocysteine and methylmalonyl coA accumulates –> CNS damage (subacute combined degeneration of myelin; vibration and proprioception problems)
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17
Q 
[Anemia]
Describe causes of macrocytic anemia
1. Megaloblastic  
C. Orotic aciduria 
2. Non-megaloblastic
A

1C. Orotic aciduria - AR disease; cannot convert orotic acid to UMP (de novo pyrimidine synthesis)
- cannot be cured by folate or B12; give UMP to bypass the mutated enzyme

  1. Non-megaloblastic - macrocytic anemia in which DNA synthesis unimpaired
    - caused by liver disease, alcoholism
    - macrocytes without hypersegmented neutrophils
    - can convert into megaloblastic if deficiency persists
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18
Q

[Molecular Basis, Hematologic Malignancy]
Describe how sustained growth signals occur by the various ways to cause myeloproliferative disorders

  1. Receptor activation
  2. Non-receptor tyrosine kinases
    A. Bcr-Abl
  3. Downstream signal-transducing proteins
    A. BRAF V600E
A
  1. Receptor activation - receptor can dimerize without ligand, can translocate to be ubiquitously expressed (balanced translocations most common chromosomal changes)
  2. Non-receptor tyrosine kinases
    A. Bcr-Abl - result of balanced translocation between BCR (chromosome 22) and ABL (chromosome 9; tyrosine kinase that promotes survival) –> Philadelphia chromosome –> BCR domain facilitates dimerization –> Bcr-Abl chimeric protein constitutively active and trapped in cytoplasm (cannot perform genome surveillance) –> chronic myelogenous leukemia CML
  3. Downstream signal-transducing proteins
    A. BRAF V600E gain of function mutation –> constitutively active –> sends signals to MAPK –> enhances cell survival and proliferation –> hairy cell leukemia (100% have the mutation; proliferation of maure B cells with hairy cytoplasmic processes)
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19
Q

[Molecular Basis, Hematologic Malignancy]
Describe how sustained growth signals occur by the various ways to cause myeloproliferative disorders
4. Nuclear transcription factor
A. c-myc
B. BCL-6

A
  1. Nuclear transcription factor
    A. c-myc - important regulator of transcription and other molecular changes (mt function, RNA synthesis, glycolysis) and cellular changes (cell growth)
    - balanced translocation between chromosomes 8 and 14 –> c-myc on 8 translocated with IgH heavy chain gene on 14 –> c-myc constitutively on –> leads to Burkitt lymphoma (tumor of mature B cells)

B. BCL-6 - found in germinal center of lymph nodes, acts as transcriptional repressor (inhibits response to genotoxic stress, inhibits memory and plasma cell differentiation)
- aberrant BCL-6 expression due to point mutations in regulatory region (70%) OR balanced translocation next to IgH promoter (30%) –> downregulation of p53, cyclin D2 –> diffuse large B cell lymphoma DLBCL

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20
Q

[Molecular Basis, Hematologic Malignancy]
Describe how sustained growth signals occur by the various ways to cause myeloproliferative disorders
4. Nuclear transcription factor
C. PML-RARa

  1. Cell cycle regulators
    A. Cyclin D1
    B. CDK4
A

4C. RARa - regulates sequences where retinoic acid binds, acts as transcriptional repressor –> differentiation and maturation of cells

  • balanced translocation between PML gene on chromosome 15 and RARa gene on chromosome 17 –> t(15;17) chimeric PML-RARa protein sticks to site and blocks transcription of target genes –> blocks differentiation and maturation –> expansion of immature cell population (blasts) –> acute promyelocytic leukemia APML M3
  • treat with retinoic acid (ATRA, synthetic vitamin A) to replace chimeric protein and allow maturation to occur
  • DIC is complication of APML (due to increased tissue factor expression)
  1. Cell cycle regulators - gain of function mutations in oncogenes
    A. Cyclins - phosphorylate checkpoint regulation proteins –> liberates E2F transcription factors so DNA replication and transcription can occur
    - produced and degraded cyclically
    - balanced translocation of Cyclin D1 on chromosome 11 and IgH locus on chromosome 14 –> continuous overexpression of Cyclin D1 –> promotes G1 to S phase transition –> mantle cell lymphoma MCL

B. Cyclin-dependent Kinase CDK4 - activated by cyclins, work with them to form complex and phosphorylate proteins
- amplification leads to melanoma

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21
Q

[Molecular Basis, Hematologic Malignancy]
Describe how cells evade cell death to cause myeloproliferative disorders
1. General intrinsic apoptotic pathway
2. Bcl-2

A
  1. Sensors (Bid, Bad, Puma) bind and tie up Bcl-2; free Bcl-2 binds Bax/Bak and prevents pore formation (anti-apoptotic)
    - when Bcl-2 is tied up, Bax and Bak can promote pore formation; release of cytochrome c and APAF1 initiates apoptosis
  2. t(14; 18) balanced translocation (Bcl-2 on 18 and IgH promoter on 14) –> increased Bcl-2 protein (necessary but not sufficient, need another insult) –> lymphadenopathy and marrow infiltration –> follicular lymphoma
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22
Q

[Platelet Disorders]

Describe examples of non-hematologic bleeding disorders

A

Non-hematologic bleeding disorders
1. Hereditary hemorrhagic telangiectasia - AD, small clusters of abnormal arteriovenous malformations (blood vessel clusters) in the skin, GI tract, mucous membranes

  1. Ehlers-Danlos syndrome - collagen defect with defective platelet binding –> pulling on vessels can cause bleeding
  2. Primary vascular defects - defects of vessel walls e.g. Berry aneurysm
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23
Q

[Platelet Disorders]
1. Describe common reasons behind thrombocytopenia

  1. Describe genetic causes behind decreased platelet production:
    A. Thrombocytopenia absent radii (TAR) syndrome
    B. Wiskott Aldrich syndrome
    C. May-Hegglin anomaly
  2. Describe acquired causes behind decreased platelet production
A
  1. Thrombocytopenia - decreased platelet count; can be congenital or acquired (more common)
    A. decreased production –> bone marrow problem
    B. increased destruction –> decreased platelet half-life
    C. sequestration - stored or hidden
    all will be discussed in future cards
  2. Genetic causes behind A (Decreased platelet production due to abnormal bone marrow) –> rare, present early, associated with physical defects
    A. TAR - AR, bilateral radius aplasia
    B. Wiskott Aldrich - X-linked recessive, defect in WAS gene –> T-cell deficiency and increased risk of recurrent infections, eczema
    C. May-Hegglin anomaly - autosominal dominant mutation in MYH-9 –> big platelets and dohle bodies (big granules)
  3. Acquired causes: medications, infection, alcohol, bone marrow failure (aplastic anemia, myelodysplasia), bone marrow infiltration (leukemia, gaucher)
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24
Q 
[Platelet Disorders] 
1. Describe disorder of increased platelet destruction - Immune Thrombocytopenia Purpura (ITP) 
A. Causes
B. Lab findings
C. Clinical findings
D. Types
E. Treatment
A

Platelet destruction - low platelet count, high mean platelet volume MPV
ITP = immune platelet destruction; most common cause of thrombocytopenia in children and adults

  1. ITP
    A. Causes - immune-mediated destruction (most common cause is drugs)
    - most common type is production of autoimmune IgG against platelet antigens eg GPIIb/IIIa –> autoantibodies produced by plasma cells in spleen –> bind to platelets in spleen –> then consumed by splenic macrophages

B. Lab findings - low platelet number, normal WBC, Hb, RBCs on smear, normal PT/PTT; increased megakaryocytes in bone marrow; low thrombopoietin TPO

C. Clinical findings - easy bruising, petechiae

  • bleeding risk increases when platelet < 20,000
  • normally asymptomatic, no splenomegaly

D. Types

i. Acute - in kids, happens weeks after viral infections or immunization, spontaneous remission within weeks
ii. Chronic - in adults (women of child-bearing age 20-40), higher bleeding risk, chronic condition

E. Treatment - not curative

  • corticosteroids (suppress immune system and production of auto-antibody), IVIG (spleen eats that IgG instead of the platelet-bound IgG), TPO receptor agonist
  • cannot give recombinant TPO because auto-antibodies will develop
  • splenectomy (refractory cases)
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25
Q

[Platelet Disorders]
Immune mediated destruction of platelets
2. Causes of Secondary ITP
3. Causes of neonatal ITP

A
  1. Secondary ITP (non-idiopathic)
    - viral infections (HIV, CMV, EBV, parvoB19)
    - vaccinations (MMR, varicella)
    - immune (DiGeorge, CVID)
    - autoimmune (Lupus, Crohn’s)
  2. Neonatal
    A. Neonatal autoimmune - due to auto-antibodies transferred passively via maternal IgG (if mom has lupus, ITP); treat with IVIG
    B. mom and baby have different platelet antigens –> maternal antibodies made against fetus antigens and cross placenta; treat with maternal platelets, IVIG
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26
Q

[Platelet Disorders]
Describe types of non-autoimmune platelet destruction:
1. Thrombotic thrombocytopenia purpura TTP
2. Hemolytic-uremic syndrome HUS
3. HUS and TTP Lab findings
4. HUS and TTP Clinical findings
5. HUS and TTP treatment

A

Microangiopathic hemolytic anemia - damaged platelets and RBCs bc of damage to blood vessels

  1. TTP
    - (most commonly acquired) Ab against ADAMTS13, commonly seen in adult females
    - (AR inherited) deficiency of ADAMTS 13
    low ADAMTS13 –> vWF is not cleaved –> ultralarge ULvWF agglutinates leads to abnormal platelet adhesion –> platelet microthrombi
  2. HUS - seen in children with E. coli O157:H7 dysentery (Exposure to undercooked beef) –> E. coli verotoxin damages endothelial cells –> platelet microthrombi
    - also Campylobacter or Shigella
  3. Lab findings:
    - thrombocytopenia with increased bleeding time
    - normal PT/PTT
    - schistocytes
    - increased megakaryocytes on bone marrow biopsy
  4. Clinical findings Pentad
    i. skin and mucosal bleeding (due to thrombocytopenia)
    ii. microangiopathic hemolytic anemia
    iii. CNS problems - confusion, focal abnormalities more common in TTP
    iv. renal failure (or insufficiency) more common in HUS
    v. fever
  5. Treatment
    A. HUS - supportive, NO antibiotics
    B. TTP - plasmapheresis (replace ADAMTS13) or corticosteroids (remove circulating antibody)
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27
Q

[Platelet Disorders]
Describe types of non-autoimmune platelet destruction incl causes, lab findings, and treatment
1. Disseminated intravascular coagulation DIC
—
2. Describe how sequestration leads to thrombocytopenia
3. DD for hypersplenism

A
  1. DIC - mixed platelet and coagulation disorder
    - small blood clot formation in bv everywhere –> use up available coagulation proteins, platelets –> clotting in some places (ischemia and infarction), bleeding in others (mucosal surfaces, IV sites)
    A. Causes - anything bad enough to kill you (tissue damage) can give you DIC eg drowning, adenocarcinoma, trauma, infection, sepsis, snake bite –> tissue factor/ VII extrinsic clotting cascade
    B. Lab findings
    - low platelet count
    - abnormal + prolonged clotting screens (PT, PTT)
    - low fibrinogen (used up in making platelet microthrombi)
    - schistocytes (microangiopathic hemolytic anemia)
    - fibrin split products eg D dimer (screening test)
    C. Treatment - treat underlying disease
  2. Sequestration - platelets become trapped in spleen –> thrombocytopenia and hypersplenism
  3. DD:
    - liver disease
    - portal hypertension or thrombosis
    - infection
    - Felty’s syndrome (lupus)
    - lyposomal or glycogen storage disorders
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28
Q

[Platelet Disorders]
Describe disorders of platelet function due to adhesion
1. Bernard-Soulier syndrome
2. von Willebrand disease

A
  1. Bernard-Soulier syndrome
    A. Cause - genetic (AR inheritance) deficiency of Gp1b (glycoprotein on platelets), which complexes with vWF for platelet adhesion
    B. Lab - mild thrombocytopenia (platelets don’t live as long) with very large platelets (“Big Suckers” created in bone marrow); long clotting times
    - abnormal ristocetin test (pt platelets + exogenous vWF)
    C. Clinical - mild to moderate bleeding esp mucosal bleeding (epistaxis, hemoptysis, hematuria)
  2. von Willebrand disease - most common inherited clotting disorder / coagulopathy (AD); vWF binds subendothelial collagen and GP1b on platelet; stabilizes VIII (which has short t1/2)
    A. Cause
    Type 1 - partial deficiency of vWF (most common)
    Type 2 - dysfunctional protein; A) improper assembly, B and M) changed binding, N) decreased VIII binding
    Type 3 - complete deficiency
    B. Lab - increased PTT (low VIII), VW antigen
    - abnormal ristocetin test (pt serum + fixed platelets)
    C. Clinical - easy bruising, menorrhagia, postop bleeding, gingival bleeding, prolonged bleeding after minor cuts
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29
Q

[Platelet Disorders]
Describe disorders of platelet function due to aggregation
1. Congenital afibrinogenemia
2) Glanzmann thrombasthenia

A
  1. Congenital afibrinogenemia - absence of plasma fibrinogen (activated into fibrin, cross-linked by XIII to form hard clot over platelet plug)
  2. Glanzmann thrombasthenia - deficiency or defect in GPIIb-IIIa (receptor for fibrinogen)
    A. Cause - AR; platelets can attach to endothelium but do not aggregate
    B. Lab - no aggregation with ADP, collagen, epi - only ristocetin (bc it involves Ib, not IIb-IIIa)
    C. Clinical - mucocutaneous bleeding, risk of platelet allo-immunization
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30
Q 
[Platelet Disorders] 
Describe disorders of platelet function due to storage granules
 1. Alpha granules
2. Dense granules 
A. Hermansky Pudlak syndrome
B. Storage pool disease
A
  1. Alpha granules - contain proteins e.g. TGFbeta, clotting proteins (vWF)
    - do not need to know disorders
  2. Dense granules - contain chemicals e.g. ADP, ATP, histamine, serotonin, Ca2+
    A. Hermansky Pudlak syndrome - AR, common in Puerto Rico, HPS gene mutation –> absence of dense granules

B. Storage pool disease - group of disorders with bleeding problems (nosebleeds), easy bruising due to defect in dense granules

31
Q 
[Bleeding Disorders] 
Hemophilias A and B
1. Difference between A and B
2. Clinical findings
3. Severity
4. Treatment
A 
Hemophilia - X-linked recessive 
1. Hemophilia A (80% cases) - Factor VIII deficiency, most common is inversion mutation of short arm of X; increased PTT
Hemophilia B (20% cases) - Factor IX deficiency (Christmas disease); increased PTT
  1. Clinical - A and B clinically similar, B is much less severe
    - bleeding into muscles and joints (ankles, knees) and can present in infancy –> joint deformity, disease, debility
    - other common bleeding spots: soft tissue, iliopsoas, thigh, calf, butt, deltoid, forearm
    - neck swelling (emergency)
    - most common cause of death is intracranial hemorrhage
  2. Severity
    A. Mild - up to 50% factor VIII –> bleeding uncommon
    B. Moderate - up to 5% –> bleed monthly
    C. Severe - <1% –> bleed weekly, joint disease
  3. Treatment - give hemophiliacs factor replacement concentrates prophylactically
    - some patients develop inhibitors (neutralizing antibodies against the infused factor) –> PTT does not correct when you mix normal plasma with patient’s plasma
32
Q 
[Bleeding Disorders] 
1. Hemophilia C 
2. Factor XIII deficiency
3. Acquired factor deficiencies
A. Vitamin K deficiency
B. Liver disease
C. Immune-mediated
A
  1. Hemophilia C
    A. Cause - AR, factor XI deficiency
    - common in Ashkenazi jewish population
    B. Clinical - mucocutaneous bleeding (not muscle or joint which is typical hemophilia presentation), clinically mild
  2. Factor XIII deficiency
    A. Cause - AR, v v rare
    B. Clinical - delayed bleeding (bc XIII has long t1/2), presents in infancy eg bleeding from umbilical stump; normal PT and PTT bc problem is later in clotting process
  3. Acquired factor deficiencies
    A. Vitamin K deficiency - gamma carboxylates factors II, VII, IX, X and is oxidized; reduced back by VKORC to active form; deficiency due to antibiotics, malabsorption, drugs (warfarin/coumadin, rat poison)
    B. liver disease - decrease in factors II, VII, IX, X; V, fibrinogen VIII preserved
    - decreased platelets
    - decreased anticoagulants
    - abnormal bv - esophageal, rectal varices
    - decreased clearance of activated clotting factors
    - decreased clearance of clot breakdown products
    - production of abnormal fibrinogen
    C. Immune mediated - antibodies against VIII, V, II when immune surveillance is off (cancer, pregnancy, auto-immune disease)
33
Q 
[Bleeding Disorders] 
Thrombotic disorders 
1. Describe anticoagulants:
A. Antithrombin 
B. Proteins C and S 
C. TFPI
2. Antiphospholipid syndrome
3. Purpura fulminans
A

1A. Antithrombin - inhibits serine protease clotting factors IX X, II
B. Proteins C and S - inhibit non-serine protease clotting factors V, VIII
C. TFPI - tissue factor pathway inhibitor, inactivates VII and X

  1. Antiphospholipid syndrome - can be primary or secondary; immune system creates antibody against phospholipid (component of viruses) –> cross-reacts with normal tissues –> activation of coagulation –> causes blood clots in arteries and veins and miscarriage
    - associated with lupus
    - prolonged PTT (bc of interference from Ab), even though pt has increased risk of thrombosis
  2. Purpura fulminans - severe Protein C deficiency
    - presents within hours of birth and progresses to DIC
    - purpuric lesions progress to black eschars (skin necrosis)
34
Q

[Acute Leukemia]

  1. Differentiate acute vs chronic leukemia
  2. Define acute leukemia
  3. Differentiate between the blasts
A

1A. Acute - excess myeloblasts or lymphoblasts (immature cells), presents suddenly with short clinical course
B. Chronic - mature granulocytes (CML) or lymphocytes (CLL); often present asymptomatic, can take months for diagnosis

  1. Acute leukemia - rapidly fatal disease characterized by proliferation and accumulation of abnormal immature hematopoietic cells (“blasts”) in bone marrow and other tissues
    - AML - 85% of acute leukemia in adults
    - ALL - 85% of acute leukemia in children
    - acute biphenotypic leukemia (2%) - both lineages

3A. AML: cytoplasmic granules and more cytoplasm, 2-5 nucleoli, Auer rods (red needle-like clumps of azurophilic granules)
B. ALL: no cytoplasmic granules and minimal cytoplasm, 1-2 nucleoli

35
Q

[Acute Leukemia]

  1. Describe pathogenesis of acute leukemia
  2. Other associated genetic abnormalities
A

1A. 2 Hit Model - Need 2 types of gene mutations

  • Class I - proliferative and survival advantage
    e. g. gain of function mutations of tyrosine kinases
  • Class II - blocks hematopoietic differentiation –> loss of maturation –> immature cells
    e. g. loss of function mutations of transcription factors for differentiation

2A. Point mutations - activated RAS oncogene, seen in both AML and ALL
B. Translocations - e.g. BCR-ABL in pre-B ALL and CML
C. Deletions - of both genes and chromosomes; commonly 5, 7, 11 (v poor prognosis)
D. Duplication or gene amplification - trisomy 8 has poor prognosis

*PCR is most sensitive diagnostic test for minimal residual disease (MRD)

36
Q

[Acute Leukemia]
1. How do you diagnostically differentiate AML vs ALL based on:
A. Flow cytometry markers
B. Cytohistochemistry

  1. Clinical manifestations of acute leukemia (AML and ALL)
    A. Constitutional
    B. Marrow replacement
    C. Organ infiltration
A

1A. Flow cytometry
AML - CD13, CD33
ALL - (B-ALL) CD 10, 19, 20 (T-ALL) CD2-8
B. Cytohistochemistry
AML - myeloperoxidase (+) - seen as Auer rods, Sudan black B (+)
ALL - TdT (+) DNA polymerase

2A. Constitutional - weight loss, anorexia, fever, night sweats, hyperkalemia and hyperuricemia
B. Marrow replacement (of marrow cells with blasts) –> pancytopenia:
i. anemia –> pallor, fatigue, dyspnea
ii. thrombocytopenia –> bruising and mucosal bleeding
iii. neutropenia (<1,000 neutrophils) –> fever, infections, mouth sores –> neutropenic diet with no fresh fruits, flowers, tap water, rectal exams, or IM injections
C. Organ infiltration –> hepatosplenomegaly, gingival hypertrophy
- bone pain and lymphadenopathy (more common in ALL)

37
Q 
[Acute Leukemia]
1. Acute lymphoblastic leukemia ALL
A. Clinical characteristics
B. Favorable vs poor prognosis factors in ALL 
C. Treatment of ALL
  1. Acute myeloid leukemia AML
    A. Favorable vs poor prognosis factors in ALL
    B. Treatment
A

1A. ALL - mostly in children
A. Clinical - abrupt onset
- 20% of ALL patients have CNS involvement (headache, vomiting, nerve palsies)
- bone marrow failure - bone pain
- organ infiltration - hepatosplenomegaly, particularly male testicular swelling
- T-ALL usually presents as mediastinal thymic mass in male teenager
B. Favorable: low WBC, B-ALL, t(12;21), hyperdiploidy (eg Trisomy 21), ages 2-10
Unfavorable: high WBC (50K+), T-ALL, adult or infant under 2 yrs, t9;22 BCR-ABL, CNS disease
C. Treatment: longer than AML (~3 years), but 80% cured
- chemo prophylaxis to CNS and scrotum
- then 2 years maintenance therapy

  1. AML - mostly in adults
    A. Favorable: younger age (under 50), low WBC, t(8;21) (seen in AML M2), inv16 (seen in AML M4), t15;17 (APML)
    Unfavorable - older age, poor performance, high WBC, t9;11 (seen in AML M5), prior chemo
    B. Treatment - conventional chemo with combo cytotoxics, transplant if relapse occurs
    - no maintenance chemo needed, no CNS prophylaxis
38
Q 
[Acute Leukemia]
Multiple Myeloma 
1. Diagnosis 
2. Pathogenesis 
A. MGUS
B. Smoldering
C. Intramedullary
D. Extramedullary 
3. Treatment
A

Multiple Myeloma - cancer of plasma cells; most common primary malignancy of bone (MCC overall is metastasis)
- increased IL-6 (stimulates plasma cell growth and Ig production)

  1. Diagnosis
    - 10%+ plasma cells in bone marrow
    - M (monoclonal) spike detected on electrophoresis, usually IgG (more common) or IgA + free light chains
    - Myeloma-related organ dysfunction (1+) CRAB
    i. Calcium disorders
    ii. Renal insufficiency from obstructive Bence Jones light chain proteinuria
    iii. Anemia - marrow replacement by plasma cells
    iv. Bone pain - plasma cell activate RANK receptor on osteoclasts –> lytic, punched out lesions –> severe bone pain, fractures
    - Rouleaux formation of RBCs (stacked on one another due to ↓ charge bw RBCs)
  2. Pathogenesis - most common among older patients
    A. MGUS (monoclonal gammopathy of unknown significance) state - buildup of clonal population of plasma cells in bone marrow
    - asymptomatic, just observation
    - need additional mutations to move to next step
    B. Smoldering state - 10%+ plasma cells in bone marrow
    - asymptomatic, just observation
    C. Intramedullary myeloma - 30%+ plasma cells in bone marrow
    - symptomatic -diagnostic criteria + bone pain
    - can remiss but eventually relapse
    D. Extramedullary myeloma - active outside bone marrow
  3. Treatment - can treat with:
    - imids (e.g. thalidomide - unknown etiology but teratogenic)
    - proteosome inhibitors (bortezomib, carfilzomib)
    - incurable, 10 year survival rate –> infection MCC of death (esp encapsulated organisms eg Strep pneumo)
39
Q 
[Cancer Chemotherapy]
Describe MOA and toxicity of the following drugs:
1. Cyclophosphamide 
2. Carmustine
3. Procarbazine
A
  1. Cyclophosphamide - nitrogen mustard
    A. MOA - DNA alkylation –> cross-linking, strand breaks, abnormal base pairing –> inhibits DNA synthesis; most effective in G1 and S phases (replicating cells most susceptible); activated by cyp450
    B. Toxicity - dose-related (acute) nausea and vomiting (delayed) - bone marrow depression –> leukopenia, thrombocytopenia
  2. Carmustine - nitrosurea
    A. MOA - DNA alkylation –> inhibits DNA synthesis
    A. Toxicity - (acute) nausea and vomiting (delayed) myelosuppression, neurotoxicity e.g. ataxia, dizziness
    - highly lipid soluble (can cross BBB, used for brain tumors)
  3. Procarbazine
    A. MOA - non-classic DNA alkylating agent
    B. Toxicity - (acute) nausea and vomiting (delayed) high risk of secondary malignancy eg AML
    - oral administration
    - acts as MAOI –> Drug interactions with sympathomimetic amines, TCAs, antihistamines, CNS depressants, alcohol
40
Q 
[Cancer Chemotherapy]
Describe MOA and toxicity of the following drugs:
1. Cisplatin 
2. Bleomycin 
3. Doxorubicin
A
  1. Cisplatin
    A. MOA - DNA alkylating agent; Platinum compound that sticks to DNA strands (also cytoplasmic, nuclear proteins) –> cytotoxic in all stages
    B. Toxicity - (acute) highly emetogenic (delayed) nephrotoxicity, ototoxicity, irreversible neurotoxicity (peripheral neuropathy in glove and stocking distribution)
  2. Bleomycin
    A. MOA - antitumor antibiotic; binds to DNA and produces free radicals –> causes single and double-stranded DNA breaks –> G2 phase arrest
    B. Toxicity - skin toxicity (rash), pulmonary toxicity (pneumonitis, infiltrates), alopecia, mucositis + stomatitis
  3. Doxorubicin (adriamycin)
    A. MOA - anthracycline - produces free radicals, intercalates in DNA –> blocks DNA and RNA synthesis
    B. Toxicity - generates semiquinone free radicals –> Cardiotoxicity
    - acute - arrhythmias and conduction abnormalities
    - delayed - dose-dependent dilated cardiomyopathy
    - give dexrazoxane (iron chelator) to protect the heart against the cardiotoxic side effects of anthracyclines
41
Q 
[Cancer Chemotherapy]
Describe MOA and toxicity of the following drugs:
1. Methotrexate 
2. 6-Mercaptopurine
3. Cladribine
A
  1. Methotrexate MTX
    A. MOA - folic acid analog that binds to and irreversibly inhibits DHFR enzyme –> disrupts folate metabolic pathway in thymidine (pyrimidine) synthesis, max effect in S phase
    - reverse effects with leucovorin (reduced folate)
    - excretion affected by ASA, penicillin, NSAIDs
    B. Toxicity - myelosuppression, pancytopenia
    - megaloblastic anemia
    - alopecia, mucositis, pulmonary fibrosis, hepatotoxicity
    - cellular resistance - via decreased drug transport, decreased formation of MTX polyglutamates, increased levels of DHFR
  2. 6-Mercaptopurine 6-MP- Purine analogs
    A. metabolized by HGPRT to become active; deactivated by xanthine oxidase
    - inhibits enzymes of purine nucleotide synthesis –> blocks synthesis of adenosine and guanine in S phase of cell cycle
    B. low TPMT enzyme–> toxicity (myelosuppression)
    - allopurinol (used to treat gout) inhibits xanthine oxidase –> need to reduce 6-MP dose
  3. Cladribine - purine analog, can cause myelosuppression
    - adenosine deaminase inhibitor; treats hairy cell leukemia
42
Q 
[Cancer Chemotherapy]
Describe MOA and toxicity of the following drugs:
1. 5-Fluorouracil 
2. Capecitabine 
3. Ironotecan
A
  1. 5-Fluorouracil 5-FU (inactive)
    A. MOA - cytotoxic pyrimidine analog, prevents conversion of THF –> DHF in thymidine synthesis
    - IV administration
    - catabolized by DPD enzyme (if pt has genetically low DPD levels in liver –> toxicity)
    B. Toxicity - myelosuppresion, neurotoxicity, cutaneous eg hand foot syndrome (blistering), photosensitivity
  2. Capecitabine
    A. MOA - pro-pro drug of 5-FU
    - orally available
    B. Toxicity - hand-foot syndrome, but does not cause alopecia
  3. Ironotecan
    A. MOA - Captothecans - inhibits topoisomerase I
    - results in S phase arrest; prodrug converted in liver
    B. Toxicity -serious diarrhea; first line for colorectal cancer (use when you want to preserve nerve function eg violinist)
43
Q 
[Cancer Chemotherapy]
Describe MOA and toxicity of the following drugs:
1. Vincristine 
2. Paclitaxel 
3. Abraxane 
4. Mitomycin C
A
  1. Vincristine
    A. MOA - Microtubule inhibitors, bind to beta tubulin to inhibit microtubule assembly –> mitotic arrest in Metaphase of cell cycle
    B. Toxicity - neurotoxicity (peripheral neuropathy), SIADH, autonomic dysfunction (paralytic ileus, orthostatic hypotension)
  2. Paclitaxel
    A. MOA - taxanes - spindle poison that binds directly to microtubules –> enhances polymerization and prevents degradation –> mitotic arrest in Metaphase
    - metabolized by p450
    B. Toxicity –> acute hypersensitivity, nausea, vomiting
    - delayed - neurotoxicity, alopecia
  3. Abraxane
    A. MOA - Paclitaxel with albumin carrier
    B. Toxicity - no hypersensitivity
4. Mitomycin C 
A. MOA - antitumor antibiotic; DNA X-linker 
- acts on tumors in hypoxic environment 
- active throughout cell cycle 
B. Toxicity - HUS
44
Q

[Cancer Biologics]
Describe the target, toxicity, and resistance of the following biologic drugs:
1. ATRA/arsenic
2. imatinib (Gleevec)

A
  1. ATRA (all trans retinoic acid) - used to treat acute promyelocytic leukemia (APML); nuclear receptor
    A. MOA - allows for differentiation of immature promyelocytic APML cells that had been arrested due to PML-RARa fusion protein –> they spontaneously apoptose (ATRA does not directly kill malignant cells)
    B. Toxicity - ATRA syndrome with leukocytosis (high neutrophils), capillary leak syndrome (pulmonary edema, respiratory failure), renal failure –> emergency!
    - treat with steroids, chemo
    *arsenic is also an approved treatment
  2. imatinib (Gleevec) - used to treat chronic myelogenous leukemia (CML) caused by Philadelphia chromosome (BCR-ABL due to 9;22 translocation)
    A. MOA - binds to ATP binding site of ABL –> inhibits BCR-ABL (constitutively active tyrosine kinase)
    B. Toxicity - imatinib resistance due to mutations in binding cleft; fluid retention
    *dasatinib designed to overcome imatinib resistance (also inhibits PDGF-R and c-KIT –> treats GIST GI tumor)
45
Q 
[Cancer Biologics]
Describe the target, toxicity, and resistance of the following biologic drugs:
3. trastuzumab (Herceptin)
4. erlotinib (Tarceva)
5. cetuximab (Erbitux)
A
  1. trastuzumab (Herceptin) - monoclonal antibody used for HER2+ breast cancer
    A. MOA - binds to HER2 receptor (type of EGFR tyrosine kinase) –> interferes with HER2 dependent signaling –> antibody-dependent cellular toxicity of tumor cells
    B. Toxicity - cardiac toxicity (decreased LVEF, heart failure)
  2. erlotinib (Tarceva) - tyrosine kinase inhibitor that blocks EGFR; works well on female, non-smoking patients with non small cell lung cancer (NSCLC)
    - can cause diarrhea, papulopustular acneiform rash
  3. cetuximab (Erbitux) - chimeric monoclonal antibody that binds to EGFR tyrosine kinase; niche in head and neck cancer
    - toxicity - papulopustular acneiform rash; infusion rxn (within 1 hour), serum sickness (within 7-10 days)
46
Q 
[Cancer Biologics]
Describe the target, toxicity, and resistance of the following biologic drugs:
6. crizotinib
7. vemurafenib
8. bevacizumab
A
  1. Crizotinib - targets ALK tyrosine kinase - 4% of NSCLC have translocations with EML4-ALK1 (constitutive kinase activity)
    - works well on younger, non-smoking patients wild type for EGFR and RAS
  2. vemurafenib - inhibits BRAF - V600E tyrosine kinase –> pathognomonic for malignant melanoma
    - treats melanoma but can cause other skin cancers –> use with MEK inhibitor (to prevent secondary malignancy)
    * colon cancers with V600E are resistant to vemurafenib (BRAF inhibition leads to EGFR activation)
    - sorafinib also targets RAF
  3. bevacizumab - binds VEGF and prevents interaction with receptor –> inhibits endothelial cell angiogenesis
    - monoclonal antibody; treats metastatic cancers (lung, colorectal)
    - added to standard chemo for lung cancer, but causes pulmonary hemorrhage in patients with squamous NSCLC
    - risk of bleeding, thrombotic events, GI perforation
47
Q 
[Cancer Biologics]
Describe the target, toxicity, and resistance of the following drugs:
1. nivolumab (Opdivo) 
2. bortezomib (Velcade)
3. rituximab (Rituxan)
A
  1. nivolumab (Opdivi) - PD-1 inhibitors bind to programmed death receptor on T cells, prevents T cells from binding and inactivating T cells –> T cells activated and can induce antitumor response
    - toxicity - ??
    - HL, metastatic melanoma (in combo with anti-CTLA-4 inhibitor ipilimumab), NSCLC, RCC, head and neck
  2. bortezomib (Velcade) - proteosome inhibitor –> prevents breakdown of proteins that kill cancer cells
    - treats MM and MCL
    - toxicity - neuropathy and myelosuppresion
  3. rituximab (Rituxan) - chimeric monoclonal antibody against CD20 (transmembrane cell surface protein on B cells)
    - used to treat B-cell NHL (FL, MCL, MALToma)
    - other anti-CD20 antibodies are Gazyva and Arzerra (treat CLL but HBV reactivation)
    - toxicity - infusion rxn (within 1 hour), serum sickness (within 7-10 days)
48
Q 
[Lymphoid Malignancies]
Lymphoma
1. General features
2. Diagnosis
3. Indolent vs Rapid growing
A

Lymphoma - begins from one cell that gains survival advantage (tumor cells are clonal / all the same)

  1. General features - painless lymph node enlargement (non-tender; tender implies reactive lymphadenitis with real antigen)
    - immune dysfunction - increased risk infection, devlpt of auto-antibodies (eg against RBCs - hemolytic anemia)
  2. diagnosis via histopathology
  3. Types
    A. Indolent - slower growing, harder to catch, no B symptoms –> follicular lymphoma FL, MALToma, mantle cell lymphoma MCL, chronic lymphocytic leukemia CLL
    B. Rapid growing - present acutely with rapidly growing mass, B symptoms, and high serum LDH and uric acid –> diffuse large B cell DLBCL, Burkitt, anaplastic large T cell lymphoma
49
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> indolent 
1. Follicular lymphoma 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Follicular lymphoma
    A. General features - most common indolent lymphoma, mean age at dx is 65
    - cells express CD19,20,10, surface Ig, BCL6, and BCL2

B. Pathogenesis - cells of origin are germinal center B cells with 14;18 translocation –> BCL-2 gene under control of Ig heavy chain promoter –> overexpression of BCL2 –> protects cells that should die from apoptosis

C. Histopathology - nodular growth pattern closely packed follicles overtake lymph node architecture

  • no light spaces in dark zone of germinal center –> no macrophages bc there are no apoptotic cells
  • BCL2 expression in the follicular cells in germinal center, whereas in reactive lymphadenitis, BCL2 expression is in the mantle zone cells

D. Classic presentation - waxing and waning painless lymphadenopathy

  • uncommon to have “B symptoms” (fever, weight loss, fatigue)
  • uncommon to involve other organs/extranodal sites but 80% have bone marrow involvement

E. Treatment - no cure, so treatment (rituximab - anti-CD20 Ab) initiated until patients symptomatic, Gazyva if Rituxan resistant
- can progress to diffuse large B cell lymphoma (DLBCL)

50
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> indolent 
2. Extranodal marginal zone B cell lymphoma of MALT type
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Extranodal marginal zone B cell lymphoma of MALT (mucosal associated lymphoid tissue) type ~ MALToma

A. General features - associated with chronic inflammation (H. pylori - gastric MALT | Sjogren’s - salivary gland MALT | Borrelia - cutaneous MALT | C psittaci - ocular MALT)

B. Pathogenesis - cells of origin are post-germinal center memory B cells in the marginal zone

i. chronic inflammation in stomach bc of heliobacter
ii. B cell proliferation + gene translocation –> clonal expansion of B cells

C. Histopathology - bullseye appearance with a halo (marginal zone) surrounding the darker mantle zone

D. Clinical features - peptic ulcer disease/abdominal symptoms, associated auto-immune disease

E. Treatment - H. pylori treatment can make lymphoma resolve
- can progress to diffuse large B cell lymphoma (DLBCL)

51
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> indolent 
3. Mantle cell lymphoma 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Mantle cell lymphoma
    A. General features - males 50+

B. Pathogenesis - cells of origin are mature, naive pre-germinal center B cells in the mantle zone - region immediately adjacent to the follicle (B cells from original primary follicle that weren’t a good fit and got pushed aside)
- over-expression of cyclin D1 due to translocation t(11;14) –> phosphorylates and inactivates Rb –> it can no longer inhibit transcription factor E2F –> allows cell cycle to progress from G1 to S –> allows DNA damage to accumulate

C. Histopathology - stains positive for cyclin D1
- cells are T cell antigen CD5+ (only other disease is CLL)

D. Clinical features - poor prognosis, significant extranodal involvement (spleen, GI, bone marrow)

  • 1/3 have B symptoms
  • lymphatomatous polyposis (GI submucosal nodules)

E. Treatment - moderately aggressive yet incurable

52
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> indolent 
4. Chronic lymphocytic leukemia CLL 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Chronic lymphocytic leukemia CLL

A. General features - most common leukemia in adults; if it presents as lymphoma is called small lymphocytic lymphoma SLL; mean age is 72

B. Pathogenesis - cell of origin is mature, naive B cells (mantle cells) - express Ig but have not been exposed to antigen

  • monoclonal B cell lymphocytosis –> accumulation of functionally incompetent lymphocytes
  • cells express B cell markers (CD19, 20, 23) and T-cell antigen CD5 (only other B cell condition that expresses CD5 is mantle cell lymphoma) but have low surface Ig
  • etiology unknown - NOT translocations, but deletions

C. Histopathology - increased # of mature lymphocytes in the blood (peripheral smear)
- lymph node histology - sheets of small lymphocytes with proliferation center and smudge cells (both are pathognomonic)

D. Clinical features - usually asymptomatic

  • most common sign is lymphadenopathy
  • cytopenias (immune-mediated via autoantibodies)
  • hypogammaglobulinemia –> frequent infections (most common cause of death)

E. Treatment - treat only when symptomatic

  • can progress to diffuse large B cell lymphoma (DLBCL)
  • treat with alemtuzumab (binds CD52)
53
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> rapid-growing 
1. Diffuse large B cell lymphoma DLBCL
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Diffuse large B cell lymphoma DLBCL
    A. General features - most common lymphoma overall, M>F, mean age 65

B. Pathogenesis - cells of origin are mature germinal center B cells

  • can be de novo, transformation from low grade (MALT, follicular, CLL), or associated with HIV (75% of HIV patients get DLBCL)
  • gene translocation or point mutation (more common) –> overexpression of BCL6 (transcriptional repressor)–> inhibits cell differentiation, response to stress/DNA damage

C. Histopathology - sheet of large lymphoid cells that replaces lymph node architecture (no nodules)

  • large cell size with prominent nucleoli
  • diffuse growth pattern and high growth rate

D. Clinical features - most aggressive (rapidly fatal), fast growing symptomatic mass, 1/3 is extranodal (esp to stomach) and 1/3 have B symptoms

E. Treatment - 50% survival rate, responsive to aggressive chemo

54
Q 
[Lymphoid Malignancies]
NHL --> B-cell --> rapid-growing 
2. Burkitt lymphoma
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A 
2. Burkitt lymphoma - 
A. General features - three forms 
i. endemic (West Africa)- in young children (4-7), associated with EBV
ii. sporadic - mean age 11, seen in USA 
iii. HIV-associated

B. Pathogenesis - cells of origin are mature germinal center B cells
- t(8;14) gene translocation –> c-MYC overexpression

C. Histopathology - starry sky pattern due to rapid turnover of cells (stars are macrophages eating apoptotic tumor cells)
- normal architecture gone - no nodularity, just sheet of cells

D. Clinical features

i. endemic - jaw tumor
ii. sporadic - abdomen with ascites
iii. HIV-associated - variable

E. Treatment - fastest growing (most mitotically active neoplasm) but curable with aggressive chemo
- Ki-67 cell growth fraction ~100% (expressed only in growing cells)

55
Q 
[Lymphoid Malignancies]
NHL --> T-cell
1. Anaplastic large-cell lymphoma (ALK+)
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
  1. Adult T-cell Leukemia/lymphoma
  2. Mycosis fungoides
A
  1. Anaplastic large-cell lymphoma (ALK+)
    A. General features - uncommon tumor of young adults, mean age 30, in males
    B. Pathogenesis - 2;5 translocation –> ALK positive (normal cells do not express ALK), have better prognosis if so
    - cells express CD30
    C. Histopathology - hallmark cells (large, anaplastic = really atypical, horseshoe shaped nuclei, lots of cytoplasm)
    D. Clinical features -
    E. Treatment - 80% cure rate with chemo – brentuximab vedotin
  2. Adult T cell Leukemia/lymphoma (ATLL) - linked to HTLV-1 retrovirus which is endemic in West Africa, Japan, Caribbean
    - clover leaf mature CD4+ T cells in the bloodstream
    - lytic bone lesions with hypercalcemia and rash
    - rapidly progressive, fatal
  3. Mycosis fungoides - cutaneous lymphoma of mature CD4+ T cells
    - malignant CD4+ T cells invade epidermis and form Pautrier microabscesses
    - rash –> plaque phase –> tumor phase
    - cells can spread into blood –> Sezary syndrome
56
Q 
[Lymphoid Malignancies]
Hodgkin's Lymphoma 
1. General features 
2. Unique features
3. Pathogenesis
4. Clinical presentation 
5. Treatment
A

Hodgkin’s lymphoma

  1. General features - 10% of all lymphomas
    - bimodal age distribution
  2. Unique features - All HL originate from germinal center B cells, BUT do not express B cell markers (CD19, CD20)
    - Reed-Sternberg cell (large, multiple nuclei, prominent “owl eyes” nucleoli) –> reprogram and acquire other cell markers e.g. CD15, CD30–> make inflammatory cytokines to attract other cells (mixed cell infiltrate)
    - usually involves single group of nodes; distinct pattern of spread (contiguous)
    - most tumor cells not neoplastic but inflammatory
    - eosinophilia due to increased IL-5 (produced by RS cells)
  3. Pathogenesis - constitutive activation of NF-kappaB (inflammatory response marker)
    - etiology unknown, risk factors are EBV, immunosuppression; childhood illness protective
  4. Clinical presentation -
    - painless lymphadenopathy in neck (70%), axilla (20%)
    - 2/3 have mediastinal lymphadenopathy
    - 1/3 have B symptoms (fever, chills, weight loss)
  5. Treatment - good prognosis
    - more patients due of treatment complications than disease
57
Q

[Lymphoid Malignancies]
Hodgkin’s Lymphoma
1. Classical HL - subtypes
2. Non-classic HL

A
  1. Classical HL - subtypes
    A. Nodular sclerosis subtype - 70%, most common subtype
    - young adult females - classically present with mediastinal/neck lymph node
    - collagenous bands
    - cellular background of T-cells, eosinophils
    - 70% present with limited stage, rarely associated with EBV
    B. mixed cellularity - associated with EBV, older individuals, more advanced, more eosinophils
    C. lymphocyte rich - T cell infiltrate, best prognosis
    D. lymphocyte depleted - associated with EBV, rare except in HIV+, worst prognosis
  2. Non-classic HL - nodular lymphocyte predominance
    - young males
    - variant of Reed-Sternberg cells resembling popcorn
    - excellent prognosis, not associated with EBV
    - express B cell markers (CD20, BCL6) and NOT CD15 or CD30
58
Q 
[Myeloproliferative disorders]
1. Chronic myelogenous leukemia CML 
A. General features
B. Pathogenesis
C. Histopathology in blood and bone marrow
D. Clinical features
E. Treatment
A
  1. CML
    A. General features - M=F, age is 50; most commonly sporadic origin

B. Pathogenesis - cell of origin is hematopoietic stem cell –> all hematopoietic lineages (lymphoid, granulocyte, erythroid, megakaryocytic) will have single molecular abnormality = Philadelphia chromosome t(9;22) –> BCR-ABL fusion protein
- blast crisis - rapidly progressing phase where mature neutrophils (chronic form) transform into different immature cells (acute form of disease) –> can lead to AML (2/3) or ALL (1/3)

C. Histopathology

i. peripheral blood - (chronic) see all stages of WBC forms, from mature neutrophils to blasts, increased basophils –> basophilia
- (blast phase) - looks like AML with just blasts (immature WBCs)
ii. bone marrow - (chronic) different phases of WBC devlpt; (blast) just blasts

D. Clinical features - presents with fatigue, malaise, weight loss, early satiety (splenomegaly), bleeding (platelet dysfunction), chloroma (solid collection of CML cells), but often asymptomatic

E. Treatment - imatinib (Gleevec) - specific BCR-ABL tyrosine kinase inhibitor –> binds to ATP site and prevents phosphorylation of substrate
- point mutations leads to resistance –> use newer TKIs (nilotinib, dasatinib)

59
Q 
[Myeloproliferative disorders]
2. Essential thrombocytosis
A. General features
B. Pathogenesis
C. Histopathology in blood and bone marrow
D. Clinical features
E. Treatment
A
  1. Essential thrombocytosis
    A. General features - platelet count > 450,000 per microliter with no other identifiable cause (normal: 150-450K)
    - diagnosis of exclusion; DD includes reactive thromboctosis, CML, polycythemia vera, MDS

B. Pathogenesis - JAK2 V167F mutation in 50% cases

C. Histopathology

i. peripheral blood - big platelets, increased #
ii. marrow - increased # megakaryocytes

D. Clinical features - asymptomatic but can present with thrombosis or bleeding; fatigue, light-headedness
- rarely progresses to acute leukemia, marrow fibrosis; no risk of hyperuricemia or gout

E. Treatment - prevent ischemic complications of high platelet count (aspirin + hydroxyurea)

60
Q 
[Myeloproliferative disorders]
3. Polycythemia vera 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Polycythemia vera PV

A. General features - overproduction of RBCs, granulocytes (50% pts), platelets (50% pts)

  • rule out causes of secondary erythrocytosis –> familial or renal cell carcinoma (high EPO), responses to hypoxia (low Sa02, high EPO)
  • EPO in PV is decreased (response to high RBC count)

B. Pathogenesis - mutation in JAK2 V617F signaling molecule (constitutively active) –> excess transcription, inhibition of apoptosis, excess hematopoietic cell growth

C. Histopathology
i. bone marrow - hypercellular marrow (lot of RBC precursors), little fat content

D. Clinical features - splenomegaly (75% pts)

  • dyspnea (viscosity from increased hematocrit), neurologic impairment (blurry vision and headache), thrombosis, burning pain in digits, itching made worse with hot water (histamine release from increased mast cells)
  • increased risk of hyperuricemia and gout

E. Treatment - prevent complications of hyper-viscous blood (phlebotomy, low dose aspirin)

61
Q 
[Myeloproliferative disorders]
4. Myelofibrosis 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
A
  1. Myelofibrosis
    A. General features - rare; proliferation of mature myeloid cells esp megakaryocytes

B. Pathogenesis - JAK2 V167F mutation (50% cases)
- megakaryocytes produce PDGF –> marrow cavity becomes fibrosed –> affects hematopoiesis –> anemia (Hb < 10), thrombocytopenia, leukopenia (WBC <4)

C. Histopathology

i. peripheral blood - tear drop cell (dacrocyte)
ii. bone marrow - positive collagen stain

D. Clinical features

  • hepatosplenomegaly (due to extramedullary hematopoiesis)
  • fatigue and pallor and SOB, bleeding, bruising, fever, bone pain (spleen not able to produce adequate number of platelets, WBCs, RBCs)
62
Q 
[Myeloproliferative disorders]
5. Mastocytosis 
A. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A
  1. Mastocytosis = mast cell disease (produce histamine, heparins, tryptase)

A. General features - different types
- bone marrow biopsy to diagnose; dense infiltrates of MCs in bone marrow or other extracutaneous organs

B. Pathogenesis - c-kit oncogene mutations

C. Histopathology - spindle-shaped mast cells, heavily granulated

D. Clinical features - anaphylaxis, hive-like skin lesions, osteoporosis / lytic lesions (excess heparin weakens bones), diarrhea (excess histamines), anemia, splenomegaly

E. Treatment -anti-histamines, anti-leukotrienes

63
Q 
[Myeloproliferative disorders]
Myelodysplasia
1. General features
B. Pathogenesis
C. Histopathology
D. Clinical features
E. Treatment
A

Myelodysplasia - bone marrow failure disorder

  1. General features - clonal stem cell disorder occurring in older patients (mean age 65), can transform into AML, classifications based on % myeloblasts

B. Pathogenesis - chromosomal abnormalities esp deletions in 5 and 7 –> e.g. 5q- syndrome (anemia but normal WBC, platelets; F»M) –> problem with maturation of cells

  • radiation exposures
  • previous alkylating agent therapy

C. Histopathology

i. peripheral blood - large, hypernucleated RBC precursor blasts
- single nucleated megakaryocytes
ii. bone marrow - hypercellular bone marrow due to ineffective hematopoiesis, altered apoptosis –> cytopenia

D. Clinical features - pancytopenia

  • macrocytic anemia - fatigue, SOB
  • thrombocytopenia –> bruising, bleeding
  • neutropenia (mild)
  • leukopenia or leukocytosis (if transforming into AML)

E. Treatment - hypomethylating agents (chemo drugs) - not curative
- only curative tx is stem cell transplant

64
Q

[Molecular Basis 2]
1. Link mutations in epidermal growth factor receptors (EGFR) to cancers:
A. ERBB1
B. ERBB2 (HER2/NEU)

  1. Link mutations in Ras to cancers
A

1A. ERBB1 - lung cancer, adenocarcinoma, squamous cell carcinoma, epithelial head and neck
B. ERBB2 (HER2/NEU) - breast cancer, poorer prognosis but treatment with herceptin

  1. Ras - point mutation –> permanent activation –> growth, differentiation, survival signaling
    - most commonly mutated proto-oncogene in human tumors
    - pancreatic cancer (90%), colon endometrial thyroid cancers (50%), lung adenocarcinoma and myeloid leukemia (30%)
65
Q 
[Molecular Basis 2]
Describe connection between mutations in following tumor suppressor and cancer: 
1. Rb
2. p53
3. Adenomatous polyposis coli (APC)
A
  1. Rb - checkpoint between G1 and S phase: CDK/cyclin levels increase –> phosphorylate Rb –> release it from E2F – allowing transcription to occur
    - directly or indirectly inactivated in most cancers, gain of function of CDK4/cyclin D, loss of function of CDK inhibitors
    - mutations - deletions, point mutations, promoter hypermethylation
    - germline loss of Rb –> retinoblastoma
  2. p53 - genome surveillance, regulates cell response to DNA damage (repair, cell cycle arrest at G1-S, senescence, or apoptosis)
    - biallelic acquired loss in breast, colon, lung
    - AD germline mutation in one allele –> Li Fraumeni syndrome (cancer predisposition syndrome)

*DNA viruses (HPV, HBV, EBV) bind to both p53 and RB and nullify protective functions

  1. Adenomatous polyposis coli (APC) - part of WNT signaling (controls cell polarity, adhesion)
    - normally APC keeps beta catenin levels low
    - when APC is gone –> beta catenin goes to nucleus –> transcription factor that promotes growth
    - somatic loss of both alleles –> sporadic colon cancers
    - AD inherited single gene mutation –> familial adenomatous polyposis –> colon cancer
66
Q 
[Molecular Basis 2]
Describe connection between genomic instability and cancer 
1. Mismatch repair 
A. MSH2, MLH1
B. BRCA
  1. Difference between leukemia and lymphoma
A
  1. Mismatch repair
    A. Mutations in 2 mismatch repair genes discovered (MSH2, MLH1) –> allows mutations to accumulate –> results in Lynch syndrome (AD genetic) –> high risk of colon and other cancers
    B. Mutations in BRCA1 and 2 (tumor suppressor that repairs breaks in dsDNA)–> increased risk of breast and ovarian cancer
    i. BRCA1 - early onset, high grade, triple negative (lacks estrogen receptor, progresterone receptor, HER2) –> poor prognosis bc few treatment options

2A. Leukemia - mainly bone marrow and blood involved
B. Lymphoma - mainly lymph nodes and solid organs involved; are always clonal

67
Q

[Blood products]

  1. List ABO blood groups with corresponding RBC antigens and plasma antibodies
  2. Describe Rh antigen system
  3. Compare and contrast IgG vs IgM antibodies with regard to their association with RBC antigens and properties with regard to RBC agglutination
A
  1. Carbohydrate antigen and isohemeagglutinin antibodies
    A - A antigen, anti-B antibody
    B - B antigen, ant-A antibody
    AB - A and B antigens, no antibody
    O - only H antigen, anti-A and anti-B antibodies
    N/A - no H antigen Rare Bombay phenotype
  2. Rh - protein antigen
    Rh positive - D antigen, no anti-D antibody more common
    Rh negative - no D antigen, no anti-D antibody (only when exposed)

3A. Isohemeagglutinins are IgM antibodies –> pentamers that can cross-link several RBCs + can fix complement –> intravascular hemolysis (breakdown of RBC in blood vessel - hemoglubinemia, hemoglobinuria, cold autoimmune hemolytic anemia)
B. Rh have IgG antibodies –> too small to cross-link antigen and fix complement –> extravascular hemolysis
- can cross the placenta
- warm autoimmune hemolytic anemia

68
Q

[Blood products]

  1. Explain pathogenesis of Rh mediated hemolytic disease of the newborn
  2. Treatment
  3. Contrast to ABO hemolytic disease of newborn
A
  1. Mother is RhD (-) but fetus is RhD (+) –> mother is exposed to RhD antigen at delivery –> memory B cells anti-D antibodies made
    - second pregnancy with RhD+ fetus –> rapid IgG anti-D produced by mother –> anti-D crosses placenta and attaches to fetal RBCs –> fetal hemolytic anemia –> jaundice, anemia –> hydrops fetalis (fluid in 2+ compartments) –> death
  2. Treatment - Rhogam is IgG anti-RhD antibody –> binds to and blocks RhD antigen from activating maternal B cells –> mother does not make any IgG anti-D antibodies
  3. ABO hemolytic disease
    - mother is group O, baby A or B; mother happens to have anti-A, B, or AB IgG antibodies in plasma –> Cross placenta in first pregnancy –> mild hemolytic anemia
69
Q 
[Blood products]
1. List blood components available for transfusion and ABO compatibility requirements
A. Packed red cells
B. Platelet concentrate
C. Fresh frozen plasma
D. Cryoprecipitate
A

1A. Packed red cells - must be ABO compatible, refrigerated

  • leukodepletion - filter out WBCs
  • irradiate to kill WBCs (esp T cells) and prevent graft vs host disease

B. Platelet concentrate - all ABO acceptable, but donor match recommended; contains WBCs, plasma, RBCs (doesn’t create any reactions)

  • room temp (cold will activate the platelets to stick to vWF - consumed by macrophages)
  • risk of bacterial contamination and infection

C. Fresh frozen plasma - contains all coagulation factors + other proteins (and antibodies) present in blood; must be ABO compatible
- frozen, use within 24 hrs when thawed

D. Cryoprecipitate - ABO acceptable; contains fibrinogen, factors VIII and XIII, vWF

70
Q 
[Blood products]
Describe mechanisms and clinical presentations for the following transfusion rxns TRs: 
1. febrile, non-hemolytic TR
2. acute immune-mediated hemolytic TR
3. delayed immune-mediated hemolytic TR
4. response to massive transfusion
A

TR - any adverse signs within 24 hrs, most commonly within 15 minutes

  1. febrile, non-hemolytic TR - most common, benign; fever, chills, mild dyspnea –> due to cytokines generated by WBCs that accumulate during storage
  2. acute immune-mediated hemolytic TR (IgM-mediated)- within 5-10 min medical emergency!
    - restlessness with fever, flank pain, SOB, pain at infusion site, diffuse bleeding
    - intravascular hemolysis - hemoglobinuria, pink plasma, DIC, renal failure
    - due to ABO incompatibility (error) –> transfused RBCs are being destroyed by patient’s IgM (positive direct coombs test)
    - Tx supportive: give saline –> maintain urine output –> prevent Hb from damaging kidneys
  3. delayed immune-mediated hemolytic TR (IgG-mediated)- occurs 3 to 30 days post transfusion
    - anamnestic antibody response to previously encountered RBC antigen (undetectable on screening)
    - extravascular hemolysis –> slight fever, mild jaundice, positive direct coombs test)
  4. response to massive transfusion - warm the blood to prevent hypothermia, can lead to hypocalcemia (citrate chelates Ca2+), hyperkalemia
    - can lead to febrile NHTR
71
Q

[Blood products]
Describe mechanisms and clinical presentations for the following transfusion rxns TRs:
5. anaphylactic TR
6. urticarial TR
7. transfusion-related acute lung injury TRALI
8. transfusion-related circulatory overload TACO

A
  1. anaphylactic TR - immediate medical emergency! rapid onset of anaphylaxis (shock, hypotension, respiratory distress)
    - IgG anti-IgA antibodies in patients who are IgA deficient
    - can have passive transfer of anaphylaxis to peanuts
    - give epinephrine
  2. urticarial TR - allergenic substance in plasma of donated product reacts with existing IgE –> degranulation –> hives
    - give benadryl and continue transfusion
  3. transfusion-related acute lung injury TRALI - sudden onset respiratory distress during transfusion, due to pulmonary endothelial cell injury (just like ARDS)
    - pink frothy sputum, ground glass lung infiltrates, SOB (due to hypoxemia), hypotension
  4. transfusion-related circulatory overload TACO - most commonly in elderly, give them too much volume or too quickly –> CHF with compromised cardiac function and positive fluid balance (give diuretics)
    - elevated JVD, elevated PCWP, hypertension (elevated systolic), low EF
72
Q 
[Neoplasia]
1.  Describe differences between benign and malignant tumors
2. Define and describe 
A. Anaplasia 
B. Dysplasia
A

1A. Benign - ends in “oma”
- well differentiated - neoplastic (irreversible, unregulated monoclonal) cells represent normal equivalents, morphologically and functionally
- capsule
- slow growing, no vessel invasion or metastases
B. Malignant
- poorly differentiated - irregular, invasive borders with hemorrhage, necrosis
- no encapsulation, increased chromatin and mitoses
- rapid growth, vessel invasion and metastases

2A. Anaplasia - loss of differentiation of normal cells (cancer in stem cells)
- many mitoses, tumor giant cells
- pleomorphism (loss of uniformity) - variable nuclei size and shape
B. Dysplasia - disorderly but non-neoplastic proliferation in epithelium (predates cancer)
- pleomorphism + hyperchromatic nuclei, increased mitoses

73
Q

[Neoplasia]
1. Define and compare
A. Sarcoma
B. Carcinoma

  1. Lab diagnosis of cancer
  2. Describe cancer staging
A

1A. Sarcoma - cancer of mesenchymal cells (e.g. bone –> osteosarcoma); metastasizes via blood vessels (most common sites are liver and lung)
B. Carcinoma - cancer of epithelial cells or organ lining; metastasizes via lymphatic system

  1. Morphology - from biopsy, fine needle aspiration, or cytologic smears
    - immunophenotyping - Ab conjugated to cell molecules to assay presence on tumor cells
    - tumor markers assayed in blood to screen/monitor eg PSA
    - karyotyping, cytogenic sequencing
    - molecular profiling of genes
  2. Staging: TMN
    T - invasion, T0-T4
    M - metastases, M0-M2
    N - lymph node spread, N0-N3

M2 (11 decks)

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