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307 Cards in this Set
- Front
- Back
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Erythropoietin Regulation (3 main steps)
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Local hypoxia in kidney (anemia) -> Epo production in juxtaglomerular cells -> Acts on committed myeloid progenitor to produce CFU-E -> RBC
|
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Thrombopoietin Regulation
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Produced in liver constitutively
Bind platelet precursors to stimulate platelet production Also binds platelets so if lots of platelets there is less signal for platelet production |
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Main signaling pathway for myeloid cytokines
|
JAK non-receptor tyrosine kinase
|
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Cyclic neutropenia manifestation and etiology
|
Have to rebuild entire blood cell system, take 21 days
Mutation in elastase gene dysregulates feedback for neutrophil production |
|
Bone marrow failure: 3 symptoms
|
Anemia - fatigue, dyspnea, angina
Leukemia - fever, infections Thrombocytopenia - petechiae, bleeding |
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Active sites of hematopoiesis in children and adults
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Children - entire skeleton
Adults - Pelvis, spine, ribs, sternum, skull |
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Normal myeloid: erythroid ratio in bone marrow aspiration
|
3:1
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Bone marrow aspiration vs biopsy uses
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Aspiration: morphology, counts, flow, cytogenetics
Biopsy: architecture, cellularity, IHC |
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4 congenital causes of aplastic anemia
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Fanconi - DNA repair defects
Schwachman-Diamond Dyskeratosis congenita - telomerase dysfunction Amegakaryocytic thrombocytopenia |
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Causes of acquired aplastic anemia (6)
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Radiation
Drugs (Mtx, chloramphenicol) Autoimmune - SLE Viral infections (parvovirus B19) Pregnancy Paroxysmal nocturnal hemoglobinuria |
|
Paroxysmal nocturnal hemoglobinuria
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Somatic mutation in PIG-A
PIG-A normally expresses CD55 and CD59 which inactivate complement PNH: abnormal sensitivity to complement mediated lysis -> hemolysis at night -> dark urine |
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Aplastic anemia treatment
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Immune suppression: ATG (anti thymocyte globulin), cyclosporine, steroids
Stem cell transplantation w radiation and chemo |
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Symptoms of anemia (5)
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Fatigue
Pallor Tachycardia Dyspnea Orthostatic HTN |
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MCV
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Size of RBC
Hct / RBC |
|
MCH
|
Hemoglobin concentration in a single RBC
Hb / RBC |
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MCHC
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Hemoglobin concentration in a given volume of RBC
Hb / Hct |
|
Reticulocyte morphology
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Large purplish cell w/ RNA remnants
Same size as RBC, no central pallor |
|
Reticulocyte index vs absolute reticulocyte count
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Index = Retic count X Pt's Hct / Normal Hct
*if appropriate response to anemia, > 2 Absolute count = Retic count x total red cell number |
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Hypoproliferative anemias (5)
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Anemia of chronic disease
Iron deficiency Lead poisoning Thalassemia B12 or folate deficiency |
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High MCHC
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Hereditary Spherocytosis
|
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Microcytic anemia with elevated retic
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Thalassemia
|
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Most common cause of iron deficiency
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Blood loss
|
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Iron deficiency symptoms/signs (4)
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Fatigue
Hair loss Pica Spoon shaped nails |
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Iron deficiency labs (5)
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Hypochromic Microcytic
Decr RBC Low retic Low serum ferritin High TIBC |
|
Where is iron absorbed?
|
Duodenum and upper jejunum
|
|
Pb toxicity (what type?, etiology, histo)
|
Microcytic
Lead inhibits heme and globin synthesis rRNA aggregates -> basophillistippling |
|
Anemia of chronic disease (3 key labs)
|
Normo or Microcytic
Low serum Fe Decreased TIBC Increased or normal ferritin A/w inflammatory disorders |
|
What does TIBC indirectly measure?
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Transferrin
Inflammation (anemia of chronic disease) suppresses transferrin Fe deficiency has high TIBC b/c iron is low but transferrin |
|
Anemia of chronic disease: Fe
|
Inflammation -> increased hepcidin -> decreased uploading of iron from intestinal epithelium and RES macrophages so bone marrow has low access to iron
|
|
Macrocytic anemias: megalo vs non megaloblastic
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Megalo: folate and B12 deficiency
Non-megalo: liver disease, med, bone marrow failure, alcoholism |
|
Where is folic acid absorbed?
|
Duodenum
|
|
Folate deficiency causes (4, 2 key drugs)
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Malabsorption
Pregnancy Drugs: bactrim and methotrexate Liver disease |
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Where is B12 absorbed?
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Terminal ileum
Bound to intrinsic factor (secreted by parietal cells) |
|
Function of B12
|
Coenzyme for production of methionine and conversion of methylTHF to THF
Thus required for synthesis of active folate |
|
Causes of B12 deficiency
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Decreased intake
Malabsorption (Crohn's) Pernicious anemia |
|
Folate vs B12 deficiency findings
|
Macrocytic
Both have hypersegmented neutrophils, decreased folate or B12, increased homocysteine B12 deficiency has INCREASED methylmalonic acid |
|
B12 neuropathy (findings, etiology)
|
Progressive affecting peripheral sensory nerves and posterior columns (vibration, proprioception)
Due to accumulation of s-adenosyl-homocysteine |
|
Fe overload causes (3 classes)
|
Increased absorption: hemochromatosis, chronic liver disease
Increased intake: sideroblastic anemia Transfusions |
|
Iron metabolism
|
Non-heme Fe -> enterocyte -> ferrotin transports from enterocyte to circulation -> transferrin in blood -> hepatocyte
|
|
Iron storage (2 forms)
|
Ferritin - water soluble protein
Hemosiderin - insoluble, visualized in macrophages |
|
Hemochromatosis (etiology, 3 signs)
|
HFE mutation -> dysregulated Fe uptake -> Fe overload
Signs: Fe deposition, skin pigmentation, arthropathy |
|
Intravascular hemolysis
|
Direct injury to RBC in circulation
Leads to transient hemoglobinemia followed by hemoglobinuria and decreased haptoglobin |
|
Extravascular hemolysis (clinical sign and 3 diseases)
|
In reticuloendothelial system of liver and spleen
Does not lead to hemoglobinuria Hereditary sphero, GP6D def, sickle) |
|
Hemolytic anemias: clinical (4)
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Pallor
Jaundice Splenomegaly Dark urine |
|
Hereditary spherocytosis: path and diagnosis (3)
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Defect in membrane proteins -> spherical RBC
Increased MCHC, spherocytes on smear, abnormal osmotic fragility test |
|
Hereditary spherocytosis: clinical (4)
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Hyper hemolytic crises w/ jaundice and anemia
Aplastic crises due to parvoB19 Gallstones Folic acid deficiency |
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GP6D deficiency pathophys and stressors (4)
|
GP6D enzyme mutation -> decr glutathione -> increased RBC susceptibility to oxidants
-> Heinz bodies -> which spleen makes bite cells Stressors: fava beans, sulfas, anti malarials, aspirin |
|
GP6D clinical and labs
|
Acute hemoglobinuria
Bite cells and Heinz bodies |
|
Heinz bodies (which 2 diseases?)
|
Oxidation of iron from ferrous to ferric form -> denatured hemoglobin precipitates and damages membrane
in alpha thalassemia and GP6D |
|
Warm acquired immune hemolytic anemia (3 causes)
|
IgG against RBC antigens
Fix but don't activate complement -> extravascular hemolysis SLE, CLL, methyldopa |
|
Cold acquired immune hemolytic anemia
|
IgM against I or i polysaccharide membrane proteins
Activate complement -> intravascular hemolysis |
|
Direct vs indirect Coombs
|
Direct - anti-Ig antibody added to patient's RBC agglutinate if pt has RBC Ig antigens (see if an AIHA is warm (IgG) or cold (IgM and C3)
Indirect - normal RBC added to pt's serium agglutinate if serum has anti-RBC surface Ig |
|
Non-immune hemolytic anemia (3 classes)
|
Idiopathic
Infections - clostridium, malaria Drugs - antigens form against RBC-drug complex or drug induces auto-Ab |
|
Polychromasia
|
Increased reticulocytosis (hyperproliferative anemia)
|
|
Neutrophils
|
6-12 hr lifespan in blood
Acute inflammatory cells Multilobed nucleus |
|
Eosinophils
|
Worms wheezes and diseases
Bilobed nucleus |
|
Basophils (which granule?)
|
Uncommon in peripheral blood
Bilobed nucleus Histamine release |
|
Lots of basophils
|
CML
|
|
Monocytes
|
Phagocytes, present antigens to T cells
Differentiates into macrophages in tissues |
|
Oxygen dependent vs independent killing
|
Dependent - respiratory burst via NADPH reducing O2 to H2O2
Independent - acidification, hydrolytic and proteolytic enzymes |
|
Toxic granulation
|
Infection or G-CSF
|
|
Dohle bodies
|
Cytoplasmic inclusions, ribosome-rich ER
Sepsis, G-CSF |
|
Pelger-Huet anomaly
|
Bilobed neutrophils instead of multilobed
Benign hereditary disorder usually Myelodysplastic syndrome |
|
Myeloperoxidase deficiency
|
Inherited phagocytic disorder
Respiratory burst affected but still able to make H2O2 Increased risk of infection |
|
Leukocyte adhesion deficiency
|
Lack ability to adhere to ICAM-1 on endothelium
Unable to phagocytose bacteria coated w/ C3 |
|
Chediak-Higashi syndrome
|
Failure of phagolysosome formation -> recurrent skin infections and systemic infections w/ skin rash
|
|
Elevated IgE
Eczema Recurrent skin rash |
Job's syndrome
Defect in chemotaxis |
|
Chronic Granulomatous Disease
|
Defect in respiratory burst w/ diminished H2O2 production
Can't kill catalase positive bacteria b/c catalase breaks down any H2O2 produced by the bacteria Skin and sinopulmonary infections Abscesses Sepsis |
|
Leukemoid reactions (causes?)
|
Incr WBC w/ left shift (80% bands) and incr leukocyte alkaline phosphatase
Due to infection or stress as opposed to blood malignancy |
|
Hemoglobin genetics
|
Alpha - chr16 with embryonic zeta and two alphas with a2 predominating
Beta - chr11 with epsilone, two gammas, and delta and beta |
|
Hemoglobin expression throughout life (3 types)
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HbF expressed by around 3rd fetal month = a2γ2 (ζ initially)
HbA = a2β2 δ is turned on at birth and is at steady state = HbA2 = a2δ2 |
|
Hemoglobinopathy vs thalassemia
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Hemoglobinopathy -Hemoglobin mutations that cause structural or qualitative changes -> variant hemoglobins
Sickle cell Thalassemia - quantitative mutation leading to decreased production |
|
Beta thalassemia classifications
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Major - homozygous complete loss of beta globin expression
Intermedia - mutations of both globin alleles but still some production Minor/Trait - mutation of a single beta allele |
|
Alpha thalassemia classifications
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Hydrops fetalis - 4 alpha globin mutations -> incompatible w/ life
HbH (tetrameric beta) disease - deletion of 3 alpha globin genes Minor - deletion of 2 alpha genes cis or trans Trait - deletion of 1 alpha gene, no anemia |
|
Thalassemia genetics (mutation or deletion?)
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Alphas - usually deletion
Beta - usually mutation |
|
Hb Constant Spring
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Alpha thalassemia that's a mutation and not a deletion
Common in Asia |
|
Alpha thalassemia path
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Excess of beta ->
Beta tetramers (HbH) precipitate -> Damage and RBC hemolysis |
|
Beta thalassemia path
|
Less betas ->
Alpha tetramers precipitate -> Damage RBC membrane and hemolysis |
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HbE
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Variant Hb caused by beta globin mutation with reduced beta-E chain synth and alpha thal phenotype
|
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Thalassemia diagnosis (Fe studies?)
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Low MCV w/ RBC > 1/3Hb (RBC is normally 3x Hb) and incr reticulocyte
Can also have low Hb and Hct w/ anemia NORMAL Fe studies |
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Sickle cell genetics
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Autosomal dominant
Single base pair substituion |
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Sickle cell trait
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HbAS but still lots of HbA
Benign |
|
Sickle cell disease types
|
HbSS, HbSC + HbSE are one sickle cell globin and one abnormal beta globin
|
|
Sickle cell diagnosis (3)
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Hb < 10
Normal MCV in HbSS but low in HbSbeta RBC hemolysis - incr LDH, incr retic, low haptoglobin, elevated bilirubin |
|
Sickle cell path
|
Deoxygenation of RBC -> polymerization of HbS -> RBC membrane distortion
Shortened RBC survival |
|
Sickle cell crisis (4)
|
Vaso-occlusive - acute pain exacerabations due to rigid cells
Hemolytic: RBC hemolysis Aplastic: erythroid aplasia due to parvoB19 Sequestration: RBC pool in spleen w/ acute splenomegaly and shock |
|
Acute chest syndrome (4 sx)
|
Most common lung cx in sickle cell disease
New pulmonary infiltrate Pleuritic chest pain Fever Dyspnea |
|
Sickle cell FDA-approved drug
|
Hydroxyurea:
Increases total Hgb Decreases chronic pain and crises Improves survival |
|
Indications for transfusions in sickle cell (2)
|
Acute chest syndrome
Stroke prophylaxis |
|
What molecules mediates platelet plug adhesion? (2)
|
GpIb - vWF
GpIa/IIa - collagen |
|
What molecules mediate platelet adhesion?
|
GpIIb/IIIa - fibrinogen
|
|
Coagulation overall pathway
|
Endothelial injury -> activation -> platelet recruitment -> adherence -> aggregation -> platelet plug
Simultaneous w/: Activation of coagulation factors to drive prothrombin to thrombin -> fibrinogen to fibrin -> cross-linking by FXIIIa |
|
Endothelium: prostacyclin
|
Decreases platelet activation
|
|
Thrombomodulin
|
Decreases thrombin
|
|
Antithrombin III
|
decreases thrombin
|
|
Endothelium: NO
|
Decrease shear rate, platelet adherence, and leukocyte adherence
Increases vasodilation |
|
Tissue factor
|
Activates FVII to form TF:FVIIa complex ->
Initiates clotting cascade by activating FIX and FX |
|
What does thrombin do? (5)
|
Fibrinogen -> fibrin
Activates XI, V, VIII -> which all activate thrombin for pos feedback Activates platelets Inhibits fibrinolysis Activates FXIII transglutaminase |
|
Quiescent endothelium (4)
|
1. NO causes dilation, prevents thrombosis, and leukocyte adhesion
2. tPA breaks down fibrin 3. Prostacyclin inhibits platelet activation 4. Anti-thrombin III binds/inactivates thrombin |
|
Activated endothelium (3)
|
1. Denuded endothelial cells have exposed vWF and collagen
2. Thrombin activates factors, inhibits fibrinolysis, makes fibrin 3. PAI-1 binds/inactivates tPA |
|
Vitamin K dependent factors
|
II, VII, IX, X, C, S
|
|
Vitamin K function
|
Necessary cofactor for carboxylase in post-translation γ-carboxylation of glutamic acid residues
|
|
Warfarin
|
Inhibits vitamin K epoxide reductase which prevents salvage of vitamin K
|
|
Common pathway
|
Fibrinogen, prothrombin (FII), FV, and FX
|
|
Intrinsic pathway
|
common pathway + VIII, IX, XI, XII
|
|
Extrinsic pathway
|
Common pathway + VII
|
|
aPTT vs PT
|
aPTT - intrinsic (8, 9, 11, 12 + common)
PT - extrinsic (7) |
|
TT
|
Thrombin time: fibrinogen to fibrin
|
|
What 2 factors aren't reflected in aPTT and PT? (ie, what if PT, aTT, and TT are normal?)
|
vWF and XIII
|
|
Platelet structure
|
Anucleate
Alpha granules - large proteins Dense granules - small molecules for activation |
|
Platelet membrane proteins (3)
|
GpIb/IX - vWF receptor, always expressed
GpIIb/IIIa - fibrinogen receptor, only when activated GpIa/IIa - collagen receptor |
|
Platelet activating agents (5)
|
Epinephrine, ADP, thrombin, thromboxane A2, collagen
|
|
PFA-100 (affected by what 2 pathologic states?)
|
Platelet adhesion and aggregation test
Closure time: time to clot formation when whole blood is passed through two membranes with either collagen/epi or collagen/ADP Affected by thrombocytopenia and anemia |
|
Ristocetin (what happens if failure to aggregate? What happens if only aggregate to ristocetin?)
|
Platelet aggregation test
If failure to aggregate either vWD or Bernard Soulier's If platelets only aggregate w/ ristocetin -> Glanzmann's thrombasthenia |
|
Bernard Soulier's disease
|
Congenital thrombocytopathy
Deficient or defective GpIb/IX - vWF receptor |
|
Glanzmann's thrombasthenia
|
Congenital thrombocytopathy
GpIIb/IIIa receptor (fibrinogen binding platelets) Blood smear shows no platelet clumping Only aggregates to ristocetin |
|
Acquired thrombocytopathies (4)
|
ASA(irreversible)/NSAIDs(reversible) - reduced thromboxane A2 a vasoconstrictor and platelet aggregator
Cardiac bypass - platelet defect as platelets pass bypasspump Renal insufficiency - uremia leads to platelet dysfunction and bleeding DIC |
|
Disseminated intravascular coagulation (a/w, caused by, clinical)
|
A/w thrombocytopenia, excessive fibrinolysis, reduced coag factors
Initiated by endotoxin, infections, tissue injury, malignancy Bleeding and thrombosis |
|
Acquired thrombocytopenias
|
Decreased production (infiltrative disease, chemo)
Increased destruction (heparin) ITP TTP HUS Heparin induced thrombocytopenia |
|
DIC labs (5)
|
Microangiopathic hemolytic anemia
Thrombocytopenia Prolonged PT/aTT Decreased fibrinogen D-Dimer |
|
Idiopathic/Immune thrombocytopenia (1 lab)
|
Auto Ab-Ag complex on platelets
Targets platelet for removed by RES Incr megakaryocytes |
|
Thrombotic thrombocytopenic purpura and HUS (pentad of findings)
|
TTP - adults, HUS - children
Simultaneous clotting and bleeding Fever Thrombocytopenia Hemolytic anemia Acute renal failure Neurologic dysfunction |
|
TTP and HUS specific etiologies
|
HUS - shiga endotoxin from ecoli
TTP - ADAMS13 destruction -> ultra large vWF multimers -> platelet thrombosis |
|
von Willebrand's disease (path, labs, rx)
|
decr vWF -> normal or incr PTT (since vWF acts to carry/protect VIII)
Rx - DDAVP which releases vWF stored in endothelium |
|
Bleeding disorder mixing study
|
To determine if factor deficiency or inhibitor
Mix pt's blood w/ normal plasma, if correction after 2 hours, factor deficiency If no or only partial correction -> inhibitor |
|
von Willebrand Disease clinical
|
Mucocutaneous bleeding
|
|
vWD classifications
|
1 - partial quantitative deficiency of vWF
2 - qualitative vWF defects 3 - severe or complete vWF deficiency -> moderate FVIII deficiency |
|
vWF functions (2)
|
Mediates platelet adhesion to endothelium via Gp1b/IX
Stabilizes FVIII in circulation for coagulation |
|
vWD Type 2B (pathophys and Rx)
|
Loss of high mol weight vWF multimers -> causes high affinity for Gp1a binding -> clumping of platelets and thrombocytopenia
Rx - platelets |
|
vWD diagnosis
|
Normal PT and aPTT
Abnormal PFA-100 Incr bleeding time |
|
vWD treatment
|
Type 1 - DDAVP to release vWF from endothelium
Type 2 and 3 - vWF and FVIII replacement |
|
Hemophilia A vs B and clinical
|
A - FVIII
B - FIX Spontaneous hemarthroses and easy bruising appearing in 1st year of life |
|
Liver disease and coagulation
|
Coagulopathies - impaired factor synthesis
Vitamin K deficiency - impaired bile metabolism |
|
Physiologic inhibitory system (clotting)
|
TF pathway inhibitor blocks TF/FVIIa path
ATIII blocks thrombin, 9a, 10a, 11a Protein C and S block 5a and 8a |
|
Virchow's Triad
|
Stasis
Coagulation Endothelial damage |
|
Thrombophilia clinical (3)
|
First thrombosis occurs when young
DVT, PE Spontaneous |
|
Inherited prothrombotic disorders
|
Factor V leiden (mutated V can't be degraded by protein C)
Prothrombin gene mutation ATIII deficiency |
|
Clinical symptoms of thrombosis (6)
|
Acute chest pain
Extremity swelling Respiratory distress Abd pain Very ill w/ skin necrosis Neurologic symptoms |
|
Unfractionated heparin (MOA, one toxicity)
|
Enhances activity of ATIII
Large molecule Heparin induced thrombocytopenia |
|
Enoxaparin/Dalteparin (one toxicity)
|
LMWH
Binds and augments ATIII Also since it's shorter peptides binds and inhibits Xa Less HIT than UFH |
|
Fondaparinux
|
Pure anti Xa inhibitor
Too small to bind thrombin No HIT |
|
Treatment of heparin anticoagulation
|
Stop drug
Give protamine sulfate (100% effective for UFH, 80% for LMWH) No antidote for fondaparinux |
|
Lepirudin/Argatroban
|
Direct thrombin inhibitors
Indicated for HIT Inactivate thrombin in ATIII independent manner |
|
Warfarin monitoring and toxicity and toxicity reversal
|
Monitor via INR (reagent normalized PT)
Tox: bleeding Rx - discontinue drug and reverse anticoagulation w/ vit K and factor replacement |
|
Indications for tPA
|
(tPA directly activates plasminogen)
Life or limb threatening situations |
|
Contraindications for tPA
|
Major internal bleed in past 6 mo
Biopsy or op in preceding 10 days |
|
Dipyridamole
|
Phosphodiesterase inhibitor
Raises platelet cAMP -> blocks platelet response |
|
Clopidogrel
|
Blocks ADP activation of platelets
|
|
Abcixamab
|
GpIIb/IIIa antagonists -> reversible platelet inhibition
|
|
Heparin induced thrombocytopenia (MOA, signs, Rx)
|
Antibody against heparin:PF-4 complex (PF-4 is released from platelet granules to neutralize heparin)
-> platelet clumping and thrombocytopenia and THROMBOSIS Rx - stop heparin, switch to DTI |
|
ABO antibodies
|
Naturally occuring
IgM (mostly) and IgG - fix complement Intravascular hemolysis |
|
Rh antibodies
|
Mostly IgG - rarely activate complement
Extravascular hemolysis |
|
Hemolytic disease of the newborn
|
Rh- (D-) mother makes IgG anti D to newborn on reexposure
IgG crosses placenta RhoGAM (anti D) is given prophylactically to prevent maternal sensitization |
|
Indications for platelet transfusions (5)
|
Thrombocytopenia
Platelet dysfunction Invasive cardiology Cardiothoracic surgery SCT |
|
Cryoprecipitate content and indications
|
Rich in clotting factors like fibrinogen, vWF, VII, XIII.
Indicated for bleeding due to fibrinogen deficiency |
|
Frozen plasma indications (2)
|
When specific factor concentrates are unvailable
Reversal of warfarin when active bleeding |
|
Transfusion reactions
|
Hemolytic: acute due to ABO mismatch, delayed due to RBC alloantibody (IgE)
Non-hemolytic: minor allergic, fever TRALI |
|
Hypothetical oncogenetic causes of acute vs chronic hematapoietic malignancies
|
Chronic - mutations in tyr kinases cause growth in absence of growth signals
Acute - mutations in transcription factors that allow for growth of undifferentiated immature cells |
|
Symptoms of leukemia vs lymphoma
|
Leukemia - infections, anemia symptoms, bleeding
Lymphoma - weight loss, fever, specific to location of mass |
|
ALL and AML Epidemiology
|
ALL: Age 3-5, 1/60K
AML: Age 65 3/100K |
|
Acute leukemia risk factors
|
Down, Klinefelter, Turner
CML, MDS, P.Vera Ionizing radiation Chemicals: benzene Chemo: alkylators, topoI |
|
Acute leukemia clinical (5)
|
Bone marrow failure
Leukostasis Coagulopathy Extra-medullary Metabolic abnormalities |
|
Leukostasis (common in which malignancy?)
|
Feature of acute leukemia
Leukocytosis -> stasis of blood in cerebral and pulmonary circ -> Headache, stroke, dyspnea, tachypnea, hypoxia More common in AML |
|
Coagulopathy in acute leukemia
|
DIC
More common in AML than ALL (esp APL subtype) Incr PT and aPTT w/ low fibrinogen |
|
Metabolic abnormalities in acute leukemia (3)
|
Tumor lysis syndrome in ALL: rapid cell turnover/lysis -> hyperphosphatemia, hyperuricacidemia -> renal problems
Hypokalemia due to renal tubular damage caused by lysozyme from AML Artificial hypoglycemia from metabolism of tumor cells in vitro |
|
AML M3 (3 signs, 1 complication)
|
Promyelocytic leukemia
Bilobed nucleus Auer rods t(15;17) DIC |
|
IHC: TdT
|
ALL
Nuclear enzyme in lymphoblasts |
|
IHC: Myeloperoxidase and lysozyme
|
AML
|
|
B cell markers
|
CD10, CD19, CD20
|
|
T cell markers
|
CD2,3,4,5,7,8,
|
|
AML/Myeloid markers
|
CD13, 33, 117
|
|
AML WHO classification (4)
|
Genetic abnormalities
Multi-lineage dysplasia Therapy-related Not otherwise categorized |
|
Acute leukemia: general management
|
Transfusion w/ RBC and platelets
Rx leukostasis w/ IV fluids and leukapheresis |
|
AML favorable risk cytogenetics (3)
|
t(15;17) - APML
t(8;21) - CBF inv16 - CBF |
|
t(15;17)
|
in AML M3 (APML)
Fusion of PML and RARa binds w/ enhanced affinity to DNA and blocks differentiation |
|
AML unfavorable risk cytogenetics (and associated agents) (3)
|
11q23 deletion - associated w/ prior topoI treatments
5 or 7 deletions associated w/ alkylating agents Multiple cytogenetic abnormalities |
|
Acute leukemia therapy outline
|
Induction - quickly induce remission
Consolidation - prevent relapse by eradicating leukemia cells |
|
APML treatment (drug and SE)
|
ATRA - vitamin A analog
Binds PML-RARa fusion protein and prevents it from binding DNA Can cause retinoic acid/APL differentiation syndrome w/ rapid WBC and leukostasis -> Rx w/ steroids |
|
ALL favorable risk cytogenetics
|
t(12;21)
|
|
ALL unfavorable risk cytogenetics
|
t(9;22) Ph chromosome
t(4;11) |
|
Gompertzian growth curve
|
Early tumor growth has short doubling time which then plateaus
Chemo is more effective for smaller tumors |
|
Log-kill hypothesis
|
Fraction of cells killed w/ each cycle of chemo is constant
|
|
Maintenance and neoadjuvant therapy
|
Maintenance - prolonged therapy
Neoadjuvant - reduce tumor burden prior to surgical intervention |
|
Cell cycle non-specific agents (3)
|
Alkylators
Platinums Anthracyclines |
|
Cell cycle specific agents (4)
|
Mitosis:
Vinca alkaloids Taxanes Synthesis: Antimetabolites 5-FU |
|
Nausea/vomiting pathophys
|
Regulated by center in medulla w/ 4 inputs
GI Cerebral cortex Vestibular apparaus Chemoreceptor trigger zone (4th ventricle) |
|
Chemo induced N/V (3 types and treatments)
|
Acute - serotonin antag, NK-1 antag, corticos
Delayed (3-5d) - dopamine/NK-1 antag, corticos Anticipatory - benzos |
|
Ondanestron (use, SE)
|
5-HT antagonists anti-emetic
Acute SE: headache, QT prolongation, constipation |
|
Aprepitant (use, SE)
|
NK-1 antagonist (substance P blocker)
Acute and delayed SE: drug interactions, fatigue |
|
Prochlorperazine, metoclopramide (use, SE)
|
Dopaminergic antagonist anti-emetic
Delayed N/V SE: extrapyramidal, sedation |
|
Dexamethasone (use, SE)
|
Corticosteroid anti emetic
Acute and delayed N/V SE: glucose intolerance, insomnia |
|
Lorazepam (use, SE)
|
Benzodiazepine anti emetic
Anticipatory N/V |
|
Procrit
|
Epo stimulator for reduced RBC
|
|
Filgrastim, pegfilgrastim (uses, SE)
|
Granulocyte colony stimulating factor (G-CSF)
Enhances proliferation of myeloid cells especially neutrophils SE: fever, bone pain |
|
Protamine sulfate
|
Antidote for heparin
|
|
Alkylating agents MOA
|
Alkylate DNA via forming reactive intermediates covalently x-linking DNA
|
|
Cisplatin (what type? 3 SE)
|
Alkylating agent
SE: acute and delayed N/V Nephrotoxicity: prevent w/ hydration/saline Neurotoxicity |
|
Oxaliplatin and carboplatin (what type? 2 SE)
|
Alkylating agents
SE: neurotoxicity, N/V |
|
Cyclophosphamide (what type?, uses 4 SE)
|
Alkylating agent
Metabolized by liver to active forms: phosphoramide mustard and acrolein SE: delayed N/V acrolein -> hemorrhagic cystitis - prevent w/ Mesna cardiotoxicity immunosuppresion Uses: BMT, leukemia/lymphoma |
|
Ifosfamide (what type? 4 SE)
|
Alkylating agent
Metabolized to acrolein SE: acrolein -> hem. cystitis: prevent w/ Mesna Neurotox-penetrates BBB Neutropenia Nephrotox-ATN |
|
Mesna
|
Prevents acrolein induced hemorrhagic cystitis by binding acrolein when pt is given ifosphamide or cyclophosphamide
|
|
Non-Hodgkin's Lymphoma: epi
|
Most common hematological cancer
85% are B-cell origin (other are T and NK cells) Increases w/ age |
|
t(8;14)
|
c-MYC
Burkitt's Lymphoma (NHL) |
|
t(14;18)
|
Follicular lymphoma (NHL)
|
|
t(11;14)
|
Mantle cell lymphoma (NHL)
|
|
Non-Hodgkin's Lymphoma: symptoms (3 classes)
|
Asymptomatic
Local: lymphs, pain, organ failure Systemic: fevers, night sweats, wt loss |
|
Non-Hodgkin's Lymphoma: classification (and example of each)
|
Indolent - follicular lymphoma
Aggressive - diffuse large B cell, mantle cell |
|
Non-Hodgkin's Ann Arbor staging
|
Limited:
Stage I - single lymph node Stage II - two+ lymph nodes on same side of diaphragm III - two+ lymphs on diff sides IV - extramedullary disease B symptoms: fever, night sweats, >10% wt loss A-Asymptomatic |
|
Non-Hodgkin's Lymphoma: treatment by class
|
Indolent - slow growing and can't be cured -> watchful waiting
Aggressive - rapid growing and can be cured -> Rituximab-CHOP |
|
What heme malignancy is HIV a/w?
|
B-cell origin NHL aggressive
|
|
Hodgkin's Lymphoma Symptoms
|
Similar to NHL but w/ more pronounced B symptoms:
Progressive adenopathy in nech or mediastinum B symptoms: night sweats, fever, wt loss, pruritis Slow growing |
|
Hodgkin's Lymphoma Epi
|
Bimodal: early 20s and early 60s
3-4/100K EBV in 50% of cases EBV mimics B-cell proteins w/ inappropriate activation that can rescue non-productive Ig rearranged B cells |
|
Reed Sternberg cell (what disease, histo, what markers?)
|
Hodgkin's Lymphoma
Multinucleated giant cell Malignant B cell CD15 and CD30 |
|
Hodgkin's Lymphoma Classification (5)
|
Classical:
1. Nodular sclerosis (most common) 2. Lymphocyte rich 3. Mixed cellularity 4. Lymphocyte depleted Non-classical: Nodular lymphocyte predominance: CD20+ RS variants, like indolent NHL |
|
CD20+ RS cells
|
Nodular lymphocyte predominance Non Classical Hodgkin's Lymphoma
|
|
Hodgkin's Lymphoma treatment
|
HL is life-threatening and agressive, aim at cure
Limited stage (1/II non-bulky) - can do XRT alone or chemo, or chemo+XRT Extensive stage (III/IV) - chemo ABVD |
|
Hodgkin's treatment complications
|
XRT - breast/lung malignancies, cardiac disease, pulm fibrosis
Chemo - secondary leukemia |
|
What type of disease is Hodgkin's?
|
Variant B-cell lymphoma
|
|
NHL vs HL (age, chronicity, ln involv., CD marker, malignant cell, EBV associated)
|
Age: NHL-60s; HL-bimodal
Course: NHL-can be rapid; HL-usually slow LN involv.: NHL-random, HL-sequential Marker: NHL-CD20+; HL-CD20- Malig cell: NHL-large mononuc; HL-RS EBV: NHL-rare; HL-50% |
|
Methotrexate (type, MOA and uses)
|
S-phase specific antimetabolite
Reversibly binds dihydrofolate reductase to inhibit dTMP, DNA, and protein synth Uses: leukemia and lymphoma |
|
Methotrexate toxicity (4)
|
Myelosuppresion reversible w/ leucovorin
Hepatotoxicity Mucositis Teratogenic |
|
Leucovorin
|
Folinic acid
Rescues methotrexate toxicity by acting has FH4 (mtx blocks conversion of FH2 -> FH4) Synergistic with 5-FU |
|
Cytarabine (type, MOA, use (4), toxicity(3))
|
S-phase specific antimetabolite
Forms phosphorylated nucleotide inhibits DNA polymerase AML, ALL, high grade NHL, CML Tox: myelosuppresion |
|
What 2 chemo agents can be injected intrathecally?
|
Methotrexate, cytarabine, irinotecan
|
|
5-FU MOA and type
|
S-phase antimetabolite
Activated to 5F-dUMP -> complexes folic acid Complex inhibits thymidylate synthase -> decr dTMP, dcr DNA, drc protein synth |
|
5-FU use and tox (3)
|
Synergistic w/ leucovorin (leucovorin can't rescue 5-FU tox)
Tox: mucositis/diarrhea photosensitivity myelosuppression rescued w/ thymidine |
|
Gemcitabine (MOA and tox (2))
|
S-phase antimetabolite
Incorporated into DNA and RNA and inhibits polymerases Tox: myelosuppression, infusion reactions |
|
Fludarabine
|
Purine analog antimetabolite
|
|
Doxorubicin, daunorubicin (MOA, tox (4), use 1)
|
Anthracylines
MOA: generate free radicals and noncovalently intercalate DNA Tox: cardiotoxicity, myelosuppresion, alopecia, toxic to tissues by extravasation Use: dauno -> leukemia, doxo -> lymphoma |
|
Cardiotoxicity in anthracyclines
|
Acute - acute changes in EKG
Chronic - w/ cumulative doses, reduced LVEF, dilation, congestion Caused by Fe3+ anthracycline free radicals Rx - dexrazoxane chelation, liposomal anthacyclines (doxil, daunoXome) |
|
Dexrazoxane
|
Chelates Fe3+ anthacycline free radicals to prevent cardiotoxicity
Give w/ doxorubicin Tox: myelosuppression, alopecia, mucositis |
|
Doxil, Daunoxome
|
Liposomal doxorubicin and liposomal daunorubicin
Allow for slow release of anthracycline to prevent cardiotoxicity |
|
What drugs have resistance due to MDR?
|
Anthracyclines doxo and daunorubicin
Irinotecan (campothecin alkaloid) Taxanes |
|
Bleomycin (MOA, 1 use, 1 tox)
|
Antitumor antibiotic
Induces free radical formation -> DNA strand breaks Use: HD Tox: pulmonary fibrosis |
|
Irinotecan (type of drug, MOA, tox (3))
|
Plant alkaloid camptothecin PRO-DRUG
Topo I inhibitors Tox: myelosuppression, diarrhea, |
|
Vincristine, vinblastine, vinorelbine (MOA, tox (2), 1 use)
|
Bind and block microtubule polymerization
Tox: vinCristine/neurotox, vinBLASTine and vinorelbine myelosuppresion Uses: Hodgkin's |
|
Paclitaxel and docetaxel (type, MOA, 3 tox)
|
M phase specific taxanes
Hyperstabilize microtubules in M-phase so spindles can't break down Tox: myelosuppresion, neuropathies, hypersensitivity |
|
Chronic lymphocytic leukemia Epi (SLL?)
|
Most common leukemia in world
Age - 60s SLL is the same thing just found in lymph nodes rather than blood |
|
CLL - clinical
|
Most asymptomatic
Local: swollen lymphs, pain, organ failure Systemic: fatigue, B symptoms are uncommon |
|
Lots of mature B cells with smudge cells
|
CLL
Cells are smudged due to fragile membranes |
|
CLL Immunophenotype
|
B cell markers CD10, 19, 20
CD20 is dim compared to normal B cells T cell CD5 Either kappa or lambda light chains |
|
CLL clinical and complications (4)
|
Hypogammaglobinemia
AUTOIMMUNE hemolytic anemia (warm AIHA coombs positive) Richter's transformation Secondary malignancies-AML |
|
Richter's transformation
|
in CLL
Development of diffuse large immunoblastic tumor |
|
CLL Staging
|
Rai:
I - Lymphocytosis on blood/marrow II - Lymphadenopathy or hepatosplenomegaly III - Anemia or thrombocytopenia |
|
CLL - Ig V mutations
|
Unmutated Ig V - oncogenic hit is to naive B cell prior to SHM and Ag sensitization
Mutated Ig V - oncogenic hit is after B cell Ag sensitization Unmutated as much worse prognosis-- think like more acute, progenitor type |
|
CLL - CD38
|
> 30% CD38 expression -> much worse progression
Surrogate marker for Ig V mutated for unmutated CD38 = unmutated |
|
CLL - ZAP-70
|
Associated w/ worse prognosis
|
|
Adverse cytogenetics in CLL
|
17p del
11p del |
|
CLL treatment
|
Most are indolent so watch and wait
Chemo - fludarabine and chlorambucil w/ rituximab |
|
CLL vs CML (cytogen, course, smear)
|
Cyto: CLL-multiple; CML-BCR-ABL
Course: CLL-long, rare leukemic transformation; CML-25%/year risk of AML Smear: CLL-uniform small cells w/ dense cytoplasm; CML-varied cells w/ large granular cytoplasms |
|
Mantle Cell Lymphoma
|
NHL
Can look like CLL but presents much more aggressively t(11;14) |
|
Plasma cell dyskrasia (general feature and histo)
|
Clonal proliferation of abnormal mature plasma cells that produce immunoglobulins
Pinkish golgi apparatus extends from nucleus Clockface nucleus |
|
IgG vs IgM
|
IgM - primary response, pentamers, fixes complement, can't cross placenta
IgG - secondary delayed response, monomers, can't fix complement, crosses placenta |
|
Monoclonal gammopathy of unknown significance (MGUS) (epi, path, dx(2), prognosis)
|
Epi: increases w/ age
Leaky faucet: immune system is not turned off after infection Dx: serum Ig < 3 gm/dl and < 1% plasma cells in marrow Px: good |
|
Multiple myeloma (epi, diagnosis and key acronym)
|
Uncommon, age-65
Dx: Ig > 3 gm/dl, plasma cells > 10% in BM CRAB end organ involvement hyperCalcemia Renal dysfunction Anemia lytic Bone lesions |
|
Multiple myeloma path
|
Clonal population of plasma cells, typically late B cell
Usually remains in BM w/ reinforcing signals b/w myeloma cells and osteoclasts -> lytic bone lesions |
|
Multiple myeloma ISS (2)
|
Serum B2 microglobulin
Serum albumin |
|
Multiple myeloma course and Rx (3)
|
Fatal w/in a year w/ standard Rx
Rx - melphalan and prednisone w/ BMT Thalidomide disrupts microenvironment (lenalidomide less SE) Bortezomib - proteasome inhibition prevents cell cycle progression -> apoptosis |
|
Waldenstrom's macroglobulinemia
|
IgM M-spike w/ hypersensitivity symptoms and no lytic bone lesions
|
|
Cryptoglobulinemia
|
Ig in serum that precipitate at < 37C
|
|
Zumab vs umab
|
Zumab - humanized Ab
umab - human Ab |
|
Rituximab (type, tox, use(2))
|
Chimeric anti-CD20
Tox: reactivates hepatitis Use: CD20+ NHL, rheumatoid arthritis |
|
Trastumab (type, tox)
|
Humanized anti-Her2/Neu
Tox: cardiotoxicity |
|
Gemtuzumab (type)
|
Humanized anti CD33
|
|
Bevacizumab (type, 3 tox)
|
Humanized anti VEGF
Tox: impaired wound healing, hemorrahge, GI perf |
|
Cetuximab (type, tox)
|
Chimeric anti EGFR
Tox: acneiform rash (means its working) |
|
Alemtuzumab (type, use)
|
Humanized
CLL |
|
Erlotinib (MOA, tox)
|
Inhibit EGFR tyrosine kinases
Tox: acneiform rash |
|
Imatinib/Dasatinib tox
|
Edema, fluid retention
|
|
Thalidomide/Lenalidamide
|
Antiangiogenesis and immune modulatory (suppress NFkB)
Thal - multiple myeloma |
|
Azacytadine/Decitabine (MOA, 3 tox)
|
Hypomethylators
Tox: myelosuppresion, N/V, diarrhea |
|
Prednisone
|
Immunosuppresive
Lympholytic - ALL, NHL |
|
Flutamide/bicalutamide
|
Anti-androgens
|
|
Tamoxifen, raloxifen
|
Anti-estrogen by competing w/ estrogen for receptor binding
Tox: menopausal, fluid retention |
|
Anastrazole, letrozole
|
Aromatase inhibitors
|
|
5 most common cancers in men
|
Prostate
Lung Colon Bladder NHL |
|
5 most common cancers in women
|
Breast
Lung Colon Uterine NHL |
|
3 most common cancers if < 19 y/o
|
Lymphoma
Leukemia CNS tumors |
|
Colorectal cancer familial genes
|
APC
LKB1 MisMatch Repair (MMR) |
|
Colorectal cancer familial genes
|
APC
LKB1 MisMatch Repair (MMR) |
|
3 drugs that cause delayed N/V
|
Doxorubicin, cyclophosphamide, cisplatin
|
|
Key feature of myeloproliferative neoplasms (4)
|
Overproduction of a particular myeloid or erythroid lineage w/ normal differentiation
Can progress to acute leukemia Associated w/ hemorrhage+thrombosis Usually caused by dysregulated tyrosine kinase |
|
CML epi
|
1-2/100K but high incidence b/c pts live a long time
Age - 50 |
|
CML course
|
Triphasic
Chronic: increase in pool of committed progenitors, excess neutrophils, left shift, leukocytosis Accelerate: more active, incr leukocytes, spleen, tissue infiltration Blast crisis: block in terminal differentiation -> >20% blast crisis, unpredictable which pts progress to blast |
|
Blast % difference in CML vs AML
|
> 20% blasts in BM is acute leukemia
CML blast crisis has >20% blasts in BM |
|
CML diagnosis and management
|
BCR-ABL t(9;22)
Imatinib, nilotinib (more potent), dasatinib (inhibits more enzymes) alloSCT IS THE ONLY CURE |
|
Chronic eosinophilic leukemia
|
MPN - overproduction of eosinophils
Exclude other causes of eosinophilia: allergies, parasitic infection |
|
Polycythemia vera (what is it, epi,rx)
|
MPN - overproduction of RBC in absence of epo stimulation
Age - 60 Poor prognosis w/o Rx Rx - lower Hct via phlebotomy and ASA |
|
Polycythemia vera (clinical, dx)
|
Elev Hct and hgb
Post-shower pruritis JAK2 mutation allows for signaling in absence of epo |
|
Essential thrombocytosis (what is it, epi)
|
MPN with too many platelets, 30-50% have mutJAK2
|
|
Essential thrombocytosis (dx, rx)
|
Dx of exclusion w/ platelets >600K
Rx - ASA, hydroxyurea to decrease platelets |
|
Primary myelofibrosis (what is it, 1 clinical, 2 lab, prognosis)
|
MPN - overproduction of polyclonal fibroblasts -> marrow fibrosis
Clinical - splenomegaly Tear drop cells, mutJAK2+ Poor prognosis |
|
Leukocytosis and splenomegaly with normal Hgb and platelets?
|
MPN
|
|
Myelodysplastic syndromes key features
|
Clonal HSC disease
Cytopenia w/ a cellular bone marrow Dysplasia in erythroid, myeloid, or megakaryocyte lineages A/w variable progression to AML |
|
Myelodysplastic syndromes (epi, major clinical problem)
|
70 y/o
Often due to chemo Poor prognosis Infection due to neutropenia |
|
What is the classifications of MDS based off?
|
Peripheral blood cytopathies: macrocytotic anemia, pelger-huet
BM morphology: 1+ lineage dysplasia, 80% are hypercellular BM cytogenetics: most pts have abnormal- del5q and del7q |
|
MDS findings
|
Ringed sideroblasts
Pelger-Huet anomaly |
|
5q- syndrome
|
MDS
Good progress Dysplastic megakaryocytes |
|
IPSS for MDS (4)
|
Marrow blast percentage
Marrow karyotype # and degree of cytopenias Age |
|
MDS Rx
|
alloSCT is only cure
NOT conventional chemo Lenalidamide (for 5q- syndrome) and hypomethylators (azacytidine and decitabine) |
|
Types of stem cell transplantation
|
Syngeneic - twin
Autologous - self Allogeneic - anyone else |
|
Rationale for autologous transplant
|
Can administer high doses of chemo b/c stem cells are rescued
But lack graft vs tumor effect of allogeneic |
|
Rationale for allogeneic transplant
|
Initiate a donor driven immune response: graft vs tumor effect
|
|
Indications for stem cell transplant
|
Plasma cell disorders and lymphomas
Allogeneic for AML |
|
Signs of acute GvH disease (3)
|
Skin rash
GI - N/V Liver - transaminase, bilirubin |
|
Signs of chronic GvH
|
Resembles autoimmune disease
Vitiligo Scleroderma Esophageal strictures |
|
What are the chances of finding a full HLA donor match in family?
|
25%
|
