HemOnc 02

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What syndrome is suggested by Low Fe and Normal/High Ferritin?: Anemia of Chronic Disease
?: Normal Lymphocyte. The nucleus of a normal lymphocyte is about the same size as a RBC (7 microns). Looking at this cell, I can't tell if it is a B cell or a T cell.
Notice the amount of central pallor that the normal RBC has. This is due to the biconcave disc shape of the RBC. The small purple things in the picture are platelets.
?: Variant lymphocytes. The cell on the left is a large granular lymphocyte (notice that it is larger than the RBCs and has granules in the cytoplasm- what a clever name). It corresponds to a natural killer (NK) cell.
The cell on the right is a plasmacytoid lymphocyte. It is of B cell derivation.
?: This is a monocyte. When it leaves the peripheral blood, it becomes a histiocyte/macrophage. It is large, and has a kidney bean shaped nucleus and gray cytoplasm which is sometimes vacuolated.
?: These are polymorphonuclear segmented neutrophils (also affectionately called polys, PMNs, or just neutrophils). They are usually the most abundant WBC in the peripheral blood (approximately 65%). They help to fight bacterial infections (see Dr. Dessypris's lecture). They are increased in infections.
?: This is a band form. It is also sometimes called a stab. This is a "not yet ready for prime time" neutrophil, and is the stage of granulocytic maturation right before the poly. Sometimes, when the body has overwhelming infection, it may push out cells which are not fully mature. That is why we often see these cells in patients who have infections.
?: This is an eosinophil. It has large refractile eosinophilic (red) granules. Unfortunately, these granules often don't photograph well. This cell, among other things, helps fight parasitic infections.
?: The cell on the left is a poly, the one on the right a basophil. As it's name implies, it contains basophilic (purple) granules. It is involved with histamine release and allergic reactions.
?: Peripheral smear from a normal newborn. Being born into this cold cruel world can be a very stressful event. In reaction to this, the marrow may release into the peripheral "young" cells which it ordinarily would not. The nucleated red blood cell (the uppermost of the two cells) is such a cell. It is a pathologic finding in an adult, but is seen in most normal newborn smears.
The lowermost WBC in the figure is a .......lymphocyte.
?: Peripheral smear from a newborn. In this case, we are seeing an immature granulocyte (myelocyte) in the peripheral blood. Once again, it represents release of an early cell due to stress. It is okay to see it in a newborn smear; look for something pathologic if you see it in an adult.
myeloid-erythroid ratio: Normally, there are three myeloid precursors for each erythroid precursor resulting in a 3:1 ratio, known as the M:E (myeloid to erythroid) ratio.

Accelerated red cell production would be expected to dec the M:E ratio.
the predominant leukocyte in the peripheral smear of a normal M-II student is what?: segmented neutrophil
left shift: In the course of an active infection, the bone marrow may begin to release immature leukocytes into the bloodstream, particularly neutrophil band forms. This is often colloquially referred to by physicians as left shift or blood shift.
what does HHT stand for?: Hereditary haemorrhagic telangectasia
HHT - genetics - desc - therapy: - autosomal dominant

- dilated microvascular sweelings in skin, mucous membranes and internal organs; may lead to formation of AVM, GI bleeding, iron deficiency

- embolization, laser Rx, antifibrinolytic agents, iron
Ehler-Danlos syndrome: - hereditary collagen abnormality

- hyperelastic, friable skin and hyperextensible joints

- purpura and defective platelet aggregation
Scurvy: due to vit C deficiency; defect in collagen synth; Scurvy leads to the formation of liver spots on the skin, spongy gums, and bleeding from all mucous membranes.
Henoch-Schonlein purpura (HSP): - IgA mediated vasculitis seen mainly in children

- follows acute infection

- purpuric rash with itching and local edema (buttocks and extensor surfaces of legs)

- hematuria and GI bleeding

- joint swelling and renal failure are complications
differentiate between petechiae and ecchymoses: Purpura is the appearance of red or purple discolorations on the skin, caused by bleeding underneath the skin. Small spots are called petechiae, while large spots are called ecchymoses.
disorders of primary hemostasis: - vascular or platelet disorders; bleeding from mucous membranes and within the skin
disorders of secondary hemostasis: - coagulation disorders; bleeding into joints and soft tissues
thrombocytopenia: presence of relatively few platelets in blood
aplastic anemia: Aplastic anemia is a condition where the bone marrow does not produce enough, or any, new cells to replenish the blood cells.
Glanzmann's thrombasthenia: autosomal recessive; deficiency of platelet membrane glycoproteins IIb and IIIa leading to failure of aggregation
Bernard-Soulier: large platelets with deficiency in glycoprotein Ib leading to defective adherence and platelet binding to vWF
Von Willebrand factor: Von Willebrand factor is a blood glycoprotein involved in coagulation.
Hemophilia A: blood clotting disorder caused by a mutation of the factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. Inheritance is X-linked recessive
Factor VIII: an essential clotting factor
Hemophilia B: a blood clotting disorder caused by a mutation of the Factor IX gene. It is the second most common form of haemophilia, rarer than haemophilia A.
Factor IX: one of the serine proteases of the coagulation system
Hemophilia A&B - genetics?: X-linked
vWF two major roles: (1) promotes platelet adhesion to damaged endothelium

(2) carrier of factor VIII
Induction therapy: seeks rapid reduction in tumor cell burden
Consolidation therapy: seeks to complete or extend initial remission
Maintenance therapy: seeks to sustain the remission for as long as
possible
major categories of anticoagulants: (1) Heparin

(2) vit K antagonists

(3) direct thrombin inhibitors
Heparin: - cofactor for Antithrombin III

- in presence of Heparin, Antithrombin III is potentiated & turns off the clotting cascade
Is Heparin absorbed in GI tract?: No, must be given IV
PTT: Partial Thromboplastin Time

- performance indicator measuring the efficacy of both the intrinsic and common coagulation pathways
PT: Prothrombin Time

- measure of the extrinsic pathway of coagulation
give three examples of direct thrombin inhibitors: recombinant hirudin, argatroban, and bilavirudin
three major fibrinolytic agents: Streptokinase, Urokinase, and Tissue Plasminogen Activator
what is the major use of Streptokinase: treatment of acute MI; can only be used once or twice
name three anti-metabolites: methotrexate, 5-Fluorouracil, Ara-C
basic structure of methotrexate: folate analog
methotrexate MOA: tight binding inhibitor of dihydrofolate reductase

- prevents DHT --> tetrahydrofolate
- depletion of reduced folate cofactor pool
- inhibition of purine, pyrimidine, AA synth
is methotrexate specific for any stage of the cell cycle?: YES, S phase specific
toxicity associated with methotrexate: myelosuppression and GI mucositis; renal failure (high dose)
what is the basic structure of 5-fluorouracil?: analog of uracil
is 5-fluorouracil specific for any stage of the cell cycle?: S phase specific
5-fluorouracil MOA: conversion to 5-FdUMP, tight binding inhibitor of thymidylate synthetase

conversion to 5-FUTP, incorporation into RNA

conversion to 5-FdUTP and incorporation into DNA --> DNA fragmentation
clinical utility of 5-fluorouracil: breast and GI tumors
host toxicity of 5-fluorouracil: bone marrow suppression; mucositis; diarrhea
Ara-C basic structure: analog of deoxycytidine
is Ara-C specific for a certain stage of the cell cycle?: YES, S phase specific
Ara-C MOA: converted to ara-CTP (rate limiting enzyme is deoxycytidine kinase); competes with dCTP for incorporation into DNA; inhibits DNA synth

is incorporated into DNA --> premature chain termination
what is the most potent antileukemic in man?: Cytosine Arabinoside (Ara-C)
clinical utilization of methotrexate: acute leukemias, head and neck tumors, breast cancer, choriocarcinoma
6-mercaptopurine and 6-thioguanine basic structure: analogs of guanine (6TG) and hypoxanthine (6MP)
6-mercaptopurine and 6-thioguanine MOA: converted to deoxyribonucleotide derivatives by hypoxanthine guanine phophoribosyl transferase (HGPRT)

incorporated into DNA; also acts as inhibitor of de-novo purine synthesis
are 6-mercaptopurine and 6-thioguanine specific for any part of the cell cycle?: S phase specific
what is 6TG useful for?: remission induction in acute myelogenous leukemia
what is 6MP used for?: maintenance therapy
6TG / 6MP host toxicity: myelosuppression, damage to intestinal epithelium, hepatic dysfunction, pancreatitis
hydroxyurea MOA: inhibition of ribonucleotide reductase (enzyme responsible for conversion of ribonucleotides to deoxyribonucleotides); leads to inhibition of DNA synthesis
hydroxyurea used for what?: acute and chronic leukemia; myeloproliferative disorders; radiation sensitization by cell synchronization
name three anthracycline antibiotics: Adriamycin, Daunorubicin

Actinomycin D
adriamycin, daunorubicin structure: complex; 4 rings; planar; derived from bacteria
daunorubin used for what?: acute leukemia
adriamycin used for what?: solid tumors (e.g. breast)
actinomycin D MOA: intercalation (b/t G-C sequences in DNA) prevents polymerase movement along DNA template

inhibits RNA synthesis at low concentrations; inhibits DNA synthesis at higher concentrations
what is actinomycin used for?: choriocarcinoma; neuroblastoma
give an example of a anthracenedione: mitoxantrone
mitoxantrone structure: analog of anthracycline; synth'd with the purpose of reducing cardiotoxicity
mitoxantrone used for what?: acute nonlymphocytic leukemia; breast cancer; lymphoma
what are the epipodophyllotoxins?: VP-16 (Etoposide), VM-26 (Teniposide)
MOA of the Epipodophyllotoxins: inhibition of topoisomerase II; induction of protein-associated DNA strand breaks and DNA-protein cross links
epipodophyllotoxins used for what?: acute leukemias; lymphomas; small cell carcinoma of lung; combined with cis-Pt for testicular carcinoma
Campothecin MOA: inhibition of topoisomerase I
Campothecin clinical use: note very toxic; but campotothecin derivative CPT-11 clinical trials for lung cancer
name two microtubule inhibitors: vincristine and vinblastine
vincristine / vinblastine -- specific to which phase of cell cycle?: M phase specific
Taxol source: bark of yew tree; chemical synth
Taxol MOA: interacts with microtubules; unlike vinca alkaloids, stabilizes tubulin polymers; prevents depolymerization
nitrogen mustards, sulfur mustards, nitrosoureas, and cyclophophamide are all part of which group of anti-cancer agents?: Alkylating agents
Alkylating Agents MOA: alkylation of DNA; binding of DNA molecule

induction of interstrand and intrastrand cross links

prevent dissociation DNA and blocks DNA replication
for alkylating agents which phase of cell cycle is most sensitive?: G1 phase
Platinum Compounds MOA: activated in contact with water; activation slowed in saline solutions; binds to DNA forming interstrand and intrastrand cross links; interferes with DNA transcription and translation
Platinum Compounds clinical utility: testicular, ovarian, bladder, head and neck
Platinum Compounds host toxicity: nephrotoxicity most serious; ototoxicity, myelotoxicity, peripheral neuropathy, nausea and vomiting
Bleomycin MOA: breaks DNA by free radical mechanism
Bleomycin clinical utility: active against squamous cell carcinoma; Hodgkins and non-Hodgkins lymphoma
Bleomycin host toxicity: minimal marrow toxicity; NOTE pulmonary toxicity; skin peeling
Asparaginase MOA: - breaks down asparagine in blood, preventing asparagine uptake by cancerous t-lymphocytes

- low concentration of L-asparagine synthetase in lymphocytes

- inhibition of protein synth

- prevents entry into S phase; tends to work in G1
Asparaginase clinical utility: childhood acute leukemia
Asparaginase host toxicity: hypersensitivity rxns (bronchospasm); dec hepatic protein synthesis
Steroid Hormone therapy: antiestrogens MOA: e.g. tamoxifen

compete with normal estrogens; prevent growth in estrogen-dependent tumors such as estrogen-receptor positive breast tumor cells
Steroid Hormone therapy: antiandrogens MOA: e.g. flutamide

compete with normal androgens for binding sites, e.g. prostate cancer cells
Steroid Hormone therapy: adrenocorticosteroid MOA: appear to lyse malignant T-lymphocytes

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