HemOnc Flashcards
[Anemia]
- Define anemia and normal levels
- Define hematocrit and normal values
- 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) - 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
[Anemia]
- Define reticulocytes and normal range
- Response to anemia intact vs inadequate
- Corrections for reticulocyte count
- Reticulocyte - immature RBC without a nucleus and with residual RNA, IDed via methylene blue stain (supravital staining)
Normal: 1-2% - 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
[Anemia]
- Classify RBCs based on size in terms of MCV
- Classify RBCs based on measure of hemoglobin
- 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 - 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
[Anemia] Define the following classifications of anemia including RBC size and possible causes: 1. Hypoproliferative 2. Ineffective 3. Blood loss / hemolysis
- 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 - 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 - Blood loss / hemolysis - RPI >2.5; bone marrow hyperplasia of erythroid lineage, normocytic
[Anemia] -
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
- Iron deficiency
- Anemia of chronic disease
Microcytic anemia - problem producing hemoglobin
Normal HbA - 2 alpha and 2 beta globins
- 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) - 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)
[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
3. Thalassemias
A. Alpha thalassemia incl types
- 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
[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
3. Thalassemias
A. Beta thalassemia
- 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
[Anemia]
Describe types of microcytic anemia (TAILS) incl causes, findings, treatment
4. Sideroblastic anemia
5. Lead poisoning
- 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 - 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
[Anemia]
Describe the types of normocytic, nonhemolytic anemia incl causes, findings, and treatment
- Iron deficiency
- ACD
- Aplastic anemia
Normocytic, nonhemolytic anemia
- Iron deficiency (Early) - due to hypoproliferation - low levels of substrate so cells are normocytic but fewer are produced
- 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) - 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
[Anemia]
Describe the types of normocytic, hemolytic anemia incl causes, findings
1. Intravascular
2. Extravascular
Hemolytic anemia - high RPI
Location of hemolysis: Intravascular vs extravascular
- 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)
- 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)
[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
- serum haptoglobin - absent in intra, mildly reduced in extra
- urine hemoglobin - present in intra, absent in extra
- urine hemosiderin - present in intra, absent in extra
- unconjugated bilirubin - mildly elevated in intra, very elevated in extra
- serum LDH (marker of RBC breakdown) - elevated in both
[Anemia]
Describe causes of intrinsic hemolytic anemia
1. Hereditary spherocytosis
2. G6PD deficiency
Cause of hemolysis related to the RBC: Intrinsic (e.g. RBC defect) vs extrinsic (e.g. autoimmune)
- 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) - 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
[Anemia]
Describe causes of intrinsic hemolytic anemia
4. Sickle cell disease
- Variants
A. HbSC
B. HbS/Beta thalassemia
- 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
[Anemia]
Describe causes of intrinsic hemolytic anemia
6. Paroxysmal nocturnal hemoglobinuria
- 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
[Anemia] Describe causes of extrinsic hemolytic normocytic anemia 1. Autoimmune hemolytic anemia 2. Microangiopathic hemolytic anemia 3. Macroangiopathic hemolytic anemia 4. Infections
- 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 - 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
- Macroangiopathic anemia - anemia secondary to prosthetic heart valves, aortic stenosis
- Infections - malaria, babesia (maltese cross)
[Anemia] Describe causes of macrocytic anemia 1. Megaloblastic A. Folate deficiency B. B12 deficiency
- 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)
[Anemia] Describe causes of macrocytic anemia 1. Megaloblastic C. Orotic aciduria 2. Non-megaloblastic
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
- 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
[Molecular Basis, Hematologic Malignancy]
Describe how sustained growth signals occur by the various ways to cause myeloproliferative disorders
- Receptor activation
- Non-receptor tyrosine kinases
A. Bcr-Abl - Downstream signal-transducing proteins
A. BRAF V600E
- Receptor activation - receptor can dimerize without ligand, can translocate to be ubiquitously expressed (balanced translocations most common chromosomal changes)
- 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 - 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)
[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
- 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
[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
- Cell cycle regulators
A. Cyclin D1
B. CDK4
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)
- 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
[Molecular Basis, Hematologic Malignancy]
Describe how cells evade cell death to cause myeloproliferative disorders
1. General intrinsic apoptotic pathway
2. Bcl-2
- 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 - 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
[Platelet Disorders]
Describe examples of non-hematologic bleeding disorders
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
- Ehlers-Danlos syndrome - collagen defect with defective platelet binding –> pulling on vessels can cause bleeding
- Primary vascular defects - defects of vessel walls e.g. Berry aneurysm
[Platelet Disorders]
1. Describe common reasons behind thrombocytopenia
- Describe genetic causes behind decreased platelet production:
A. Thrombocytopenia absent radii (TAR) syndrome
B. Wiskott Aldrich syndrome
C. May-Hegglin anomaly - Describe acquired causes behind decreased platelet production
- 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 - 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) - Acquired causes: medications, infection, alcohol, bone marrow failure (aplastic anemia, myelodysplasia), bone marrow infiltration (leukemia, gaucher)
[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
Platelet destruction - low platelet count, high mean platelet volume MPV
ITP = immune platelet destruction; most common cause of thrombocytopenia in children and adults
- 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)
[Platelet Disorders]
Immune mediated destruction of platelets
2. Causes of Secondary ITP
3. Causes of neonatal ITP
- Secondary ITP (non-idiopathic)
- viral infections (HIV, CMV, EBV, parvoB19)
- vaccinations (MMR, varicella)
- immune (DiGeorge, CVID)
- autoimmune (Lupus, Crohn’s) - 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
[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
Microangiopathic hemolytic anemia - damaged platelets and RBCs bc of damage to blood vessels
- 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 - 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 - Lab findings:
- thrombocytopenia with increased bleeding time
- normal PT/PTT
- schistocytes
- increased megakaryocytes on bone marrow biopsy - 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 - Treatment
A. HUS - supportive, NO antibiotics
B. TTP - plasmapheresis (replace ADAMTS13) or corticosteroids (remove circulating antibody)
[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
- 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 - Sequestration - platelets become trapped in spleen –> thrombocytopenia and hypersplenism
- DD:
- liver disease
- portal hypertension or thrombosis
- infection
- Felty’s syndrome (lupus)
- lyposomal or glycogen storage disorders
[Platelet Disorders]
Describe disorders of platelet function due to adhesion
1. Bernard-Soulier syndrome
2. von Willebrand disease
- 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) - 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
[Platelet Disorders]
Describe disorders of platelet function due to aggregation
1. Congenital afibrinogenemia
2) Glanzmann thrombasthenia
- Congenital afibrinogenemia - absence of plasma fibrinogen (activated into fibrin, cross-linked by XIII to form hard clot over platelet plug)
- 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
[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
- Alpha granules - contain proteins e.g. TGFbeta, clotting proteins (vWF)
- do not need to know disorders - 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
[Bleeding Disorders] Hemophilias A and B 1. Difference between A and B 2. Clinical findings 3. Severity 4. Treatment
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
- 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 - Severity
A. Mild - up to 50% factor VIII –> bleeding uncommon
B. Moderate - up to 5% –> bleed monthly
C. Severe - <1% –> bleed weekly, joint disease - 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
[Bleeding Disorders] 1. Hemophilia C 2. Factor XIII deficiency 3. Acquired factor deficiencies A. Vitamin K deficiency B. Liver disease C. Immune-mediated
- 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 - 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 - 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)
[Bleeding Disorders] Thrombotic disorders 1. Describe anticoagulants: A. Antithrombin B. Proteins C and S C. TFPI 2. Antiphospholipid syndrome 3. Purpura fulminans
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
- 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 - Purpura fulminans - severe Protein C deficiency
- presents within hours of birth and progresses to DIC
- purpuric lesions progress to black eschars (skin necrosis)
[Acute Leukemia]
- Differentiate acute vs chronic leukemia
- Define acute leukemia
- Differentiate between the blasts
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
- 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
[Acute Leukemia]
- Describe pathogenesis of acute leukemia
- Other associated genetic abnormalities
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)
[Acute Leukemia]
1. How do you diagnostically differentiate AML vs ALL based on:
A. Flow cytometry markers
B. Cytohistochemistry
- Clinical manifestations of acute leukemia (AML and ALL)
A. Constitutional
B. Marrow replacement
C. Organ infiltration
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)
[Acute Leukemia] 1. Acute lymphoblastic leukemia ALL A. Clinical characteristics B. Favorable vs poor prognosis factors in ALL C. Treatment of ALL
- Acute myeloid leukemia AML
A. Favorable vs poor prognosis factors in ALL
B. Treatment
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
- 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
[Acute Leukemia] Multiple Myeloma 1. Diagnosis 2. Pathogenesis A. MGUS B. Smoldering C. Intramedullary D. Extramedullary 3. Treatment
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)
- 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) - 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 - 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)
[Cancer Chemotherapy] Describe MOA and toxicity of the following drugs: 1. Cyclophosphamide 2. Carmustine 3. Procarbazine
- 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 - 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) - 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
[Cancer Chemotherapy] Describe MOA and toxicity of the following drugs: 1. Cisplatin 2. Bleomycin 3. Doxorubicin
- 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) - 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 - 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
[Cancer Chemotherapy] Describe MOA and toxicity of the following drugs: 1. Methotrexate 2. 6-Mercaptopurine 3. Cladribine
- 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 - 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 - Cladribine - purine analog, can cause myelosuppression
- adenosine deaminase inhibitor; treats hairy cell leukemia
[Cancer Chemotherapy] Describe MOA and toxicity of the following drugs: 1. 5-Fluorouracil 2. Capecitabine 3. Ironotecan
- 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 - Capecitabine
A. MOA - pro-pro drug of 5-FU
- orally available
B. Toxicity - hand-foot syndrome, but does not cause alopecia - 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)
[Cancer Chemotherapy] Describe MOA and toxicity of the following drugs: 1. Vincristine 2. Paclitaxel 3. Abraxane 4. Mitomycin C
- 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) - 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 - 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
[Cancer Biologics]
Describe the target, toxicity, and resistance of the following biologic drugs:
1. ATRA/arsenic
2. imatinib (Gleevec)
- 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 - 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)
[Cancer Biologics] Describe the target, toxicity, and resistance of the following biologic drugs: 3. trastuzumab (Herceptin) 4. erlotinib (Tarceva) 5. cetuximab (Erbitux)
- 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) - 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 - 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)
[Cancer Biologics] Describe the target, toxicity, and resistance of the following biologic drugs: 6. crizotinib 7. vemurafenib 8. bevacizumab
- 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 - 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 - 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
[Cancer Biologics] Describe the target, toxicity, and resistance of the following drugs: 1. nivolumab (Opdivo) 2. bortezomib (Velcade) 3. rituximab (Rituxan)
- 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 - bortezomib (Velcade) - proteosome inhibitor –> prevents breakdown of proteins that kill cancer cells
- treats MM and MCL
- toxicity - neuropathy and myelosuppresion - 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)
[Lymphoid Malignancies] Lymphoma 1. General features 2. Diagnosis 3. Indolent vs Rapid growing
Lymphoma - begins from one cell that gains survival advantage (tumor cells are clonal / all the same)
- 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) - diagnosis via histopathology
- 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
[Lymphoid Malignancies] NHL --> B-cell --> indolent 1. Follicular lymphoma A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- 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)
[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
- 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)
[Lymphoid Malignancies] NHL --> B-cell --> indolent 3. Mantle cell lymphoma A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- 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
[Lymphoid Malignancies] NHL --> B-cell --> indolent 4. Chronic lymphocytic leukemia CLL A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- 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)
[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
- 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
[Lymphoid Malignancies] NHL --> B-cell --> rapid-growing 2. Burkitt lymphoma A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
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)
[Lymphoid Malignancies] NHL --> T-cell 1. Anaplastic large-cell lymphoma (ALK+) A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- Adult T-cell Leukemia/lymphoma
- Mycosis fungoides
- 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 - 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 - 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
[Lymphoid Malignancies] Hodgkin's Lymphoma 1. General features 2. Unique features 3. Pathogenesis 4. Clinical presentation 5. Treatment
Hodgkin’s lymphoma
- General features - 10% of all lymphomas
- bimodal age distribution - 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) - Pathogenesis - constitutive activation of NF-kappaB (inflammatory response marker)
- etiology unknown, risk factors are EBV, immunosuppression; childhood illness protective - Clinical presentation -
- painless lymphadenopathy in neck (70%), axilla (20%)
- 2/3 have mediastinal lymphadenopathy
- 1/3 have B symptoms (fever, chills, weight loss) - Treatment - good prognosis
- more patients due of treatment complications than disease
[Lymphoid Malignancies]
Hodgkin’s Lymphoma
1. Classical HL - subtypes
2. Non-classic HL
- 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 - 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
[Myeloproliferative disorders] 1. Chronic myelogenous leukemia CML A. General features B. Pathogenesis C. Histopathology in blood and bone marrow D. Clinical features E. Treatment
- 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)
[Myeloproliferative disorders] 2. Essential thrombocytosis A. General features B. Pathogenesis C. Histopathology in blood and bone marrow D. Clinical features E. Treatment
- 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)
[Myeloproliferative disorders] 3. Polycythemia vera A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- 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)
[Myeloproliferative disorders] 4. Myelofibrosis A. General features B. Pathogenesis C. Histopathology D. Clinical features
- 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)
[Myeloproliferative disorders] 5. Mastocytosis A. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
- 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
[Myeloproliferative disorders] Myelodysplasia 1. General features B. Pathogenesis C. Histopathology D. Clinical features E. Treatment
Myelodysplasia - bone marrow failure disorder
- 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
[Molecular Basis 2]
1. Link mutations in epidermal growth factor receptors (EGFR) to cancers:
A. ERBB1
B. ERBB2 (HER2/NEU)
- Link mutations in Ras to cancers
1A. ERBB1 - lung cancer, adenocarcinoma, squamous cell carcinoma, epithelial head and neck
B. ERBB2 (HER2/NEU) - breast cancer, poorer prognosis but treatment with herceptin
- 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%)
[Molecular Basis 2] Describe connection between mutations in following tumor suppressor and cancer: 1. Rb 2. p53 3. Adenomatous polyposis coli (APC)
- 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 - 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
- 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
[Molecular Basis 2] Describe connection between genomic instability and cancer 1. Mismatch repair A. MSH2, MLH1 B. BRCA
- Difference between leukemia and lymphoma
- 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
[Blood products]
- List ABO blood groups with corresponding RBC antigens and plasma antibodies
- Describe Rh antigen system
- Compare and contrast IgG vs IgM antibodies with regard to their association with RBC antigens and properties with regard to RBC agglutination
- 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 - 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
[Blood products]
- Explain pathogenesis of Rh mediated hemolytic disease of the newborn
- Treatment
- Contrast to ABO hemolytic disease of newborn
- 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 - 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
- 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
[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
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
[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
TR - any adverse signs within 24 hrs, most commonly within 15 minutes
- febrile, non-hemolytic TR - most common, benign; fever, chills, mild dyspnea –> due to cytokines generated by WBCs that accumulate during storage
- 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 - 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) - response to massive transfusion - warm the blood to prevent hypothermia, can lead to hypocalcemia (citrate chelates Ca2+), hyperkalemia
- can lead to febrile NHTR
[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
- 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 - urticarial TR - allergenic substance in plasma of donated product reacts with existing IgE –> degranulation –> hives
- give benadryl and continue transfusion - 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 - 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
[Neoplasia] 1. Describe differences between benign and malignant tumors 2. Define and describe A. Anaplasia B. Dysplasia
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
[Neoplasia]
1. Define and compare
A. Sarcoma
B. Carcinoma
- Lab diagnosis of cancer
- Describe cancer staging
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
- 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 - Staging: TMN
T - invasion, T0-T4
M - metastases, M0-M2
N - lymph node spread, N0-N3
