~~~~Myeloid disorders: large grp 5 (13 w 3 PIC)~~~

------------CML:
*1. Leukemoid Reaction: (nonmalignant) >50K neutrophils & others. TOXIC GRANULAT
IONS & DOHLE BODIES all morphologically normal. Elevated leukocyte phosphatase s
core.
2. in differential: Chronic myelomonocytic leukemia (myelosDYSPLASTIC), overprod
uced monocytes, dysplastic change in myeloid lineage. Philidelphia NEGATIVE.
3. Myeloproliferative disorders' potention to evolve into AML: CML (100% if untr
eated), Myelofibrosis =5-25%; PV=10%, ET=3-4%
4. can become myelofibrosis: PV and ET
5. CML: (20% adult leuk), age >60. SPLENOMEGALY, elevated WBC. platelets, baso a
nd eosin elevated.
*6. CML Phases: Chronic 3-5 yr; accelerated phase= 6 months; BLAST crisis phase
(CML has Philidelphia chromosome, BCR-ABL fusion 9;22)
7. CML lifelong treatment (prevents AML-like blast crisis): Tyrosine Kinase Inhi
bitors (target BCR-ABL) = 2nd gen TKIs: NILOTINIB (QT prolong) & DASATNIB (Pleur
al Effusion) 90% effective, req for life. If fail, Allogeneic BMT.
----------Polycythemia Rubra Vera (JAK2):
8. PRV: high RBC, high WBC, high Hb, High platelets. JAK2 mutation, mean age >60
9. in differential: exogenous EPO, renal cell carcinoma; anything causing hypoxe
mia that is resulting in Epo thus more Hb and RBC; sleep apnea, high altitude, a
ndrogens, PV
10. secondary PV = polycythemia due to secondary to something else (ie . Not gen
etic)
11. PRIMARY PV = Polycythemia Rubra Vera; JAK2 mutation. abn in bone marrow (inc
reased WBC, Hb, RBC mass) can transform into myelofibrosis.
12. Diagnosis: check JAK2 mutation then do bone marrow biopsy.
13. PRV symptoms: INCREASED blood viscosity & volume. Persistant leukocytosis/th
rombocytosis. microcytosis due to iron deficiency, splenomegaly, pruritis (after
warm bath), unusual thrombosis, erythromelalgia
14. PRV phases: Proliferative phase --> Stable phase (decreased marrow prolif ac
tivity) --> SPENT phase = myelofibrosis (extramedullary hematoposies, marrow fib
rosis; thrombosis/hemorrhage)
15. PRV lifelong tx: (1) phlebotomy to keep Hg <15 g/dl (take out 500 cc blood 1
x/week); (2) Hydroxyurea (to decrease platelets/WBCs); (3) Aspirin (thromb preve
ntion)
-------------------------PRIMARY MYELOFIBROSIS
16. PRIMARY MYELOFIBROSIS: no good treatment (only palliative in elderly). marro
w fibrosis due to clonal prolif of megkaryocytes/monocytes/histiocytes. Only @ h
ematopoeitic lineages, JAK2 mutations in 50%. Common end stage of PV and ET.
17. Marrow Fibrosis leads to Extramedullary hematopoeisis (liver and spleen), ci
rculating BLAST cells.
18. [PIC] Bone marrow reticulin stain for fibrosis (33 min)
19. [PIC] many teardrop RBCs in periph smear, early gran/eryth precursors
*20. RUXOLITINIB (myelofibrosis palliative tx) - works thru JAK2 pathway. Also T
halidomide, Androgen+prednisone, hydroxyurea (decreases spleen size)
-----------------------ET
21. ESSENTIAL THROMBOCYTOSIS: elevated platelets, to 1 MILLION! (age 60); typica
lly asymptomatic. JAK2 Mutation in marrow. if negative, do BM biopsy
*22. ET easily confused with secondary (reactive) thrombocytosis due to (1) iron
deficiency; (2) inflammation, (3) some malignancies
23. ET complications: Arterial thrombosis, DVT, Hemorrhage, <5% transforms into
primary myelofibrosis or AML
24. ET tx
-------------------------------MYELODYSPLASTIC SYNDROME (MDS) case 3
25. MDS diagnosis: macrocytosis, SOB, low platelets; polyclonal chromosomal abno
rmalities (5q- mutation). low reticulocytes. TSH, AST levels, albumin levels etc
. BONE marrow biopsy gold standard. (often diagnosed on routine CBC)
26. defective maturation in all 3 lineages; prior chemo risk (alkyl agents, topo

II inhibitors) --> 10-60% transform into AML.

*27. MDS classifications: (1) peculiar cell morphology = Ringed sideroblasts/ref
ractory anemia; CMMoL (increased monocytes) (2) # marrow BLASTS = Refractory ane
mia <5% blasts or w excess blasts 20%; Excess blasts in Transformation --> AML (
20-30% blasts)
28. [pic] ringed sideroblasts (1:16)
*29. Tx for RA, RARS: GROWTH FACTORS (G-CSF, Epogen for RA)
30. Tx for RAEB, RAEBIT: <50 yrs: eval for BMT. age >50 yrs: transfusion, antibi
otix, supportive care, chemo w demethylating agents
31.
32.
33.
---------------------------------Acute Myeloid Leukemia (case 4)
*34. AML=fatigue, conjunctive pallor, BLAST cells w Auer Rods. (40% blasts in MA
RROW! CBC w differential; BM biopsy to determine if lymphoid or myeloid blasts)
35. AML pathophys: Leukemia cells infiltrate/replace marrow--> diminishes normal
wbc/rbc/platelet production --> infections/anemia/hemorrhage. (most common deat
h due to infection; least common due to hemorrhage)
36. AML symptoms due to leukemia cells replacing normal marrow: Anemia, Neutroph
ia, Thrombocytopenia (but No organomegaly bc such FAST progression)
37. Classification of AML (M0 to M7 types).
*38. AML M3 Promyelocytic Anemia=HYPERGRANULAR w AUER RODS. t(15;17)
*39. AML M3 presents w DIC! severe mucosal bleeding/CNS bleeds/ecchymosis. Fibri
nolysis from plasminogen activator.
40. [PIC] AUER RODS (@ 1:35) 2 subtypes: (1) Classic: Auer rods; or (2) Microgra
nular: w small granules
*41. AML M3 treatment: ATRA (All Trans retinoic acid; Vitamin A). lethal if untr
eated. but best long-term prognosis if treatment works!
*42. AML M4: (monocytic forms) inv(16)
43. AML M5: (monoblasts) gum hypertrophy, luek cutis, CN nerve palsy [pics!]
44. AML erythroid M6: flow cyt GLYCOPHORIN A
45. AML megakaryocyte M7: flow cyt CD41 (gpIIb/IIIa), CD61 (gpIIa), vWF
46. Poor prognosis of AMLs: >60 yrs, antecedent hematologic disorder, WBC>20K at
dx, CNS inv at dx
*47. AML tx: "7+3 regimen" DAUNORUBICIN + CYTARABINE. goal; stabilize pt, reduce
leukemia burden to undetectable levels. careful monitoring for cytopenia/infect
ion/bleeding/tumor lysis syndrome.
*48. Repeat BM biopsy at day 28 (want no BLASTS); if good then Consolidation che
mo w CYTARABINE; BUT if still blasts, do "5+2 Regimen" re-induce w DAUNORUBICIN
+ CYTARABINE again.

~~~13 Q + 1 bonus: BLEEDING DISORDERS LG GRP #3~~~

1. BIG 4 Blood Tests: (1) PT (2) aPTT (3) Platelet Count (4) bleeding time
2. What can be missed with only the big 4: (1) Factor XIII deficiency (2) Mild F
actor deficiencies (ie Hemophilia A or B) (3) mild von Willebrand diseaes
3. ITP Tx: <30,000 Platelets--> PREDNISONE (then recount) --> try IVIG --> try W
in-Rho (in Rh+) --> Splenectomy (for longterm cure) or give RITUXIMAB (then rec
ount) ---> Thrombopoietin Receptor Agonists (TPO) (ROMIPLOSTIM or ELTROMBOPAG)
4. WIN-RHO: anti-D Ig for Rh+ Pts w a spleen with ITP. (hemolysis spares platel
ets, but may cause anemia)
5. RITUXIMAB = anti CD20 monoclonal Ab. reduces their ability to produce anti-p
latelet Abs. (also for non-hodgkins)
6. ROMIPLOSTIM (Nplate) and ELTROMBOPAG (TPO receptor agonists-increase platelet
production) expensive, req for life.
*7. EDTA in test tubes may cause platelet aggregation and FALSELY LOW PLATELET C
OUNTS. Use Sodium Citrate tube instead.
8. Drug-induced thrombocytopenia: heparin (HIT or HAT). quinine (supressed bone
marrow), sulfonamides, etc.

9. Hypersplenism (splenomegaly) due to chronic liver disease may cause thrombocy

topenia
10. [algorithm for thrombocytopenia evaluation]
11. ITP = autoantibodies vs platelets (in liver and spleen); shortens platelet
life span. cause unknown.
*12. Patients OVER 60 YEARS MUST GET BONE MARROW BIOPSY to R/O MYELODYSPLASTIC S
YNDROME vs ITP
13. PREGNANCY increases risk of ITP! Tx: IVIG temporarily, then splenectomy (2nd
trimester only)
14. vaccines given to splenectomy patients: (1) H Influenzae type B (2) Pneumoco
cci (3) Meningococci
15. Vit K dependent = 2,7,9,X,C,S
16. Hemophilia A (Factor VIII), Hemophilia B (Factor IX): X linked Recessive- in
creases PTT. bleeding into joints. hemoarthralgia. Tx: desmopressin to release e
ndogenous factor VIII.
17. von Willebrand Disease______________________________
18.
19.
20.
21. DIC: decreased fibrinogen, decreased platelets. increased fibrin degredation
products. elevated D-Dimer. prolonged PT & PTT.
22. Liver Cirrhosis: (h/o alcohol/viral hepatitis. Dx with biopsy) will decrease
production of clotting factors. Ascites, U/S abn. AST & ALT may be low to norma
l
23.
24.
25. UNILATERAL EDEMA differential: Ruptured popliteal (baker's) cyst, cellulitis
/erysipelas, superficial thrombophlebitis, chronic venous valve insufficiency (H
b --> hemosiderin dark pigment on feet; from yrs of DVTs)
26. Virchow's Triad for DVT: (1) alteration in blood flow (ie stasis) (2) Vascul
ar Endothelial Injury (3) alterations in blood components (i.e. inhereted or acq
uired hypercoaguable state)
27. Factor V Leiden (5% caucasians heterozyg). mutant Leiden factor V is slowly
inactivated by protein C (slowly un-clotted), increasing coagulation --> more cl
ots
*28. Inhereted Risk for DVT: (1) Factor V Leiden (2) Prothrombin gene mutation (
3) protein S defic (4) Protein C defic (5) Antithrombin III deficiency *[check f
or antiphospholipid antibodies: LUPUS and CARDIOLIPIN Abs]
29. DVT tx: IV Heparin or LMW or RIVARIXOBAN (Xarelto), direct thrombin inhibit
or.
30. Management of FVL: oral anticoagation warfarin (coumadin) for 3-6 months
31. LIFELONG anticoagulation if: 2+ spont DVTs, 1 spont life-threatening thomb,
1 spont unusual site (mesenteric or cerebral V), 1 spont thromb WITH mult geneti
c defects predisposing
32. ENOXAPARIN (Lovenox, LMW heparin) SC bid.
33. FONDAPARINUX (Arixtra, synthetic heparin analog), 15 hr half life. SC qd.
34. Heparin complications: hemorrhage, HIT (1-4%, tx: direct thromb inhibitor/fo
ndaparinux), osteoporosis/fx
35. DIRECT THROMBIN INHIBITORS: LEPIRUDIN, BIVALIRUDIN, ARGATROBAN, DABIGATRAN (
oral)
36. WARFARIN: inhibits Vit K epoxide reductase, inhibits synthesis of factors 2,
7, 9, X, protein C and Protein S
37. FIBRINOLYTIC DRUGS: tPA (recomb form of endogen enzyme); Reteplase (recomb p
lasminogen activator); streptokinase (from b-hemolytic strep). HIGH risk of intr
acranial bleeds
LEUKEMIA & LYMPHOMA (10 Q)
1. ALL: 80% childhood leukemia. B or T cell ALL. lo/norm/hi WBC. CN palsy. (60-8
0% cure rate for children)

*2. Increased risk: Down Syndrome, Bloom Syndrom (AR), Fanconi's Anemia, Li-Frau
mini Syndrome, Identical Twins, Ionizing radiation, Benzene, Alkylating Agents;
HTLV-1 = risk Adult T cell leukemia/lymphoma.
3. Cyclophosphamide chemo exposure (5-7 yr latency) --> MDS --> secondary AML
4. Topoisomerase inhibitor chemo exposure (1-3 yr latency) --> RR 3x for AML, po
or prognosis (anthracyclines: doxorubicin, epirubicin, mitoxantrone)
5. Flow cytometry periph blood: determines ALL subtype; identifies myeloid vs ly
mphoid blasts (detects specific CD markers)
6. ALL diagnosis: (1) look at morphology of cells, (2) flow cytometry, (3) cytog
enetics--ie translocations t(8;14), t(8:22), t(2,8).
*7. PHILADELPHIA CHROMOSOME = t(9;22) cbr-abl oncogene. creates unregulated tyro
sine kinase activity --> uncont cell div
8. Poor ALL prognosis: male, black, WBC>30K, age <1 or >11, CNS involvement, mat
ure B-cell phenotype, hypodiploidy, Ph+ t(9;22)
*9. High WBC count at diagnosis = TUMOR LYSIS SYNDROME: cells grow and divide to
o fast, all cell contents spill into blood, DNA --> uric acid, (causes kidney fa
ilure, gout attacks). Prevention: before chemo give Pt normal saline, bicarb and
Allopurinol
---------------------------------------10. Chronic Myeloid Leukemia (CLL): no signs of disease at diagnosis. HIGH WBC,
HIGH LYMPHOCYTES. Smudge cells. (30% leukemias, 2x common in males, median age 7
0 years)
11. Lymphocyte doubling time < 6 months (significant prognostic of CLL) Pts will
need chemo sooner
12. Diffuse bone marrow involvement: thrombocytopenia, hypogammaglobulinemia (in
fections. Tx: IVIG)
*13. POOR PROGNOSIS GENETICS: deletion 11q23 and alteration 17p (also drug resis
tence)
14. CLL assoc symp: INFECTIONS-PNA/cellulitis, Autoimmune complications: Hemolyt
ic anemia, ITP, due to treatment
*15. CLL timing of treatment: (1) lymphocyte doubling time <6 mo (2) worsening a
nemia or thrombocytopenia (3) splenomegaly or hepatomegaly (4) recurrent infecti
ons bc of low IgG levels
16. CLL: ONLY LEUKEMIA WE CAN just OBSERVE (CBC every 3 months), no immediate tx
necessary
*17. Two ways to get thrombocytopenia in CLL: (1) bone marrow packed with CLL ce
lls (inhibits megakaryocytes); (2) Auto-antibodies vs platelets (NOT ITP, since
its assoc w CLL)
*18. Rai CLL staging system: 0 =low risk (lymphocytosis); stage 1 intermediate (
lymphocytosis+LAD, 7 yr survival); stages 2-4 =high risk (lymphocytosis+organome
galy, anemia, thrombocytopenia; 2 yr survival)
*19. SLL = lymph node counterpart of CLL (same cancer cell, but in LN medulla) s
low-growing lymphoma
-----------------Case 3 MULTIPLE MYELOMA
*20. Requirement to diagnose MGUS: (1) serum monoclonal prot < 3 g/dl; (2) BM Pl
asma Cells <10%; (3) NO end-organ damage related to plasma cell dysplasia (every
thing else is normal! asymptomatic)--> 1% chance PER YEAR that change into MM
21a. Smoldering Myeloma (SMM): (1) serum monoclonal prot >= 3 g/dl or 10-60% BM
clonal plasma cells; (2) NO end-organ damage related
*21b. Solitary plasmacytoma: NO clinical criteria of meyloma; cured by radiation
; 25% lifetime risk of developing MM
22. Multiple Myeloma: Plasma cell clonal disorder. 60 yrs. bone pain, hypercalce
mia, proteinuria, hyperviscosity, anemia, Nephropathy.
23. depending on which plasma cell: myeloma can be: IgG>IgA>light chain>IgM>IgD>
IgE
24. MM dx: roloux formation, lytic lesions in bones. (1) serum protein electroph
oresis (2) IMMUNOFIXATION (3) free light chain ratio (4) 24 hr urine prot elect
& immunofix (5) BM biopsy (6) XR all bones
*26. POOR MM PROGNOSIS: Chromosome 13 Deletion! (also increased B2 microglobulin

; increased C-reactive Protein)

27. MM tx: Chemo, STEROIDS, Velcade etc., Autologous stem cell transp (not curat
ive--only 2 yrs), allogeneic stem cell transplant (potentially curative, toxic)
----------------Case 4 Hodgkin Disease
*24. FOUR subtypes of Hodgkins. lymphocytic predominant subtype tx = rituximab;
all else is _______
25. Lymphoma Overview ______________(1:36)
26. Risk factors: BMT, HIV, EBV, autoimmune disorders, immunosuppression
27. PET-CT scan: radiolabeled glucose. best test for staging any lymphoma. also
bone marrow biopsy
28. 8;14 8;22 2;8 burkitt's translocations
PARSA hr 1: coagulopathies = 2 Q
1. Bernard-Soulier syndrome: deficiencey in gpIb
2.
3.
4.
PARSA wbc disorders = 7 Q (w 1 PIC)
1. "Left Shift" in neutrophil maturation (example of leukocytosis): see more BAN
D NEUTROPHILS & METAMYELOCYTES
*2. Leukocytosis - BACTERIAL infection: see DOHLE BODIES, CYTOPLASMIC VACUOLES,
TOXIC GRANULATION
3. Transient leukocytosis: in myocardial infarction (leukocytosis due to increas
ed stress, cytokine release)
6. CML: BCR-ABL fusion ALWAYS. t(9;22) Ph+, splenomegaly
7. ET: platelets > 1 MILLION. abn morphology. assoc w bleed/thromb/splenomeg
8. Differentiate acute from chronic disorders by presence of BLASTS in smear (no
maturation occuring)
*9. [see/memorize table of PV, CML, ET, PMF]
*10. MDS: pancytopenia w/ OVAL MACROCYTES, EOSINOPHILS, BASOPHILS, PSEUDO-PELGER
HUET cells (bilobed wbcs)
*11. MARGINAL ZONE LYMPHOMA [PIC]: (1) arise in chronic inflamed tissues (Sjogre
ns, H. pylori, salivary/parotid gland etc) (2) remain in LN for long time; only
spread systemically late in course; (3) often regress when inflammation is treat
ed
*12. HODGKINS LYMPHOMA classifications: (1) Classical Hodgkin- w reed-sternberg
cells; (2) Lymphocyte Predominant Hodgkin - w Lacunar Cells "popcorn"
*13. IMMUNOFIXATION for MULTIPLE MYELOMA dx: detects monoclonal gammopathies (wi
ll see IgG and kappa light chain); also punched out bone in X-Ray
WALTERS (6 Q):
1. DOXORUBICIN cardiotoxicity antidote = DEXRAZOXANE (chelates Fe, reduces free
radicals)
2. CYCLOPHOSPHAMIDE / ACROLEIN hemorrhagic cystitis antidote = MESNA (Na Mercapt
oethanesulfate)
3. MECHLORETHAMINE vesication antidote = SODIUM THIOSULFATE
4. HIGH DOSE METHOTREXATE + LEUCOVORIN rescue = selectively protects healthy cel
ls bc tumor cells cant take up leucovorin or folate
5. ARA-C "arab's stole the pyrimids": inhibits DNA polym/improper stacking/fragm
entation of DNA
6. 6-MP purine analog of hypoxanthine (w ALLOPURINOL). 6-MP --> 6-Thio-IMP into
DNA/RNA, inhibits IMP/AMP, forms 6-T-GMP...INHIBITS DNA TRANSCRIP & REPLICATION
7. Y-IBRITUMOMAB TIUXETAN: binds CD20 on B Cell Neoplasms. TIUXETAN chelator rel
eased beta emissions inside cell; IBRITUMOMAB induces apoptosis.

KAPLAN: Leukemia (3 Q)
1. ALL: childhood, lymphoblasts in marrow; TdT marker=on Immature B or T cells
2. GOOD PROGNOSIS for ALL = CALLA+/CD10 and t(12;21)
3. CLL: >60 years, SMUDGE CELLS, hypogammaglobinemia; WARM autoimmune hemolytic
anemia (IgG vs RBCs)
4. Hairy Cell Leukemia: elderly. mature B cell tumor. TRAP+ in stain (Tartrate-r
esistant acid phosphatase)
5. AML: Auer rods, M3 subtype (acute PROmyelocytic Leukemia = ATRA tx all trans
retinoic acid), Lymphadenopathy/Splenomeg
6. CML: myeloproliferative. Philadelphia t(9;22) bcr:abl fusion. low LAP.
7. CML: can transform to BLAST crisis --> lead to ALL or AML. Rx = IMATINIB (mon
oclonal Ab vs Ph+ chromosome)
8. Auer Rods: more common in M3. when burst, contents can cause DIC.
9. t(8;14) c-myc -->Burkitt's
10. t(14;18) bcl-2 overexpression (cell proliferation) --> Follicular Lymphoma
11. t(15;17) responds to Vit A. --> M3 AML
12. t(11;22) MSK disease regulator --> Ewing's Sarcoma
13. t(11;14) cyclin D1 overexpression --> Mantle Cell Lymphoma
KAPLAN: MDS's = PV/CML/ES/PMF (1 Q)
1. PV (low Epo; hi RBC; hi Hg/Hct) JAK2. From RCC/HCC/Wilm's tumor/hydronephrosi
s
2. ET (hi platelets) JAK2
3. PMF (fibrotic marrow; pancytopenia -all cell decreased) JAK2
4. CML (decreased RBCs) Ph+
5. MYELOID METAPLASIA: (increased RBC) erythropoeisis occurs in spleen/liver to
compensate for the fibrotic marrow's decreased RBC production. [all MDSs can get
this]
KAPLAN Clotting
1. Prokallikren
Kallikren also
2. ACE degrades
3.
4.
5.

Cascade = 1 Q
(via XIIa) to Killikren. Kallikren converts HMWK --> bradykinin;
converts plasminogen to plasmin.
Bradykinin