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135 Cards in this Set
- Front
- Back
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Primary Hemostasis |
Platelet adhesion and activation Platelet activation Formation of platelet plug |
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Secondary Hemostasis |
Coagulation cascade Formation of the fibrin clot |
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Important points in the history to evaluate a bleeding disorder |
Sites of bleeds Age of onset Frequency of bleeds Severity of bleeds Spontaneous vs following trauma/surgery |
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Mucocutaneous bleeds usually occur when? What do they indicate a problem with? |
Usually occurs right after trauma Indicates problem in primary hemostasis (platelet phase) |
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Examples of deep tissue bleeds |
Hemarthrosis Muscle hematoma Intracranial hemorrhage |
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Deep tissue bleeds indicate what type of problem? |
Indicates a problem with secondary hemostasis (coagulation) |
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Prolonged PFA-100 closure time indicates? |
Problem in platelet/vWF interactions |
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Platelets will aggregate normally only with ristocetin but not other agonists |
Glanzmann's Thrombasthenia |
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Glanzmann's Thrombasthenia |
Deficient or nonfunctional GP2a/3b receptor |
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Platelets will aggregate normally with all agonists except ristocetin |
Bernard-Soulier Syndrome |
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Bernard-Soulier Syndrome |
Deficient or nonfunctional GP1b receptor |
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Von Willebrand Disease Type 1 |
Any degree reduced levels of vWF Most common and mildest form Will have a long PFA-100 or prolonged bleeding time and low ristocetin cofactor |
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Von Willebrand Disease Type 3 |
Severe VWD Undetectable vWF Since vWF stabilizes Factor 8, this can present and have similar labs to hemophilia A |
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Serves as a stabilization factor for Factor 8 |
Von Willebrand Factor |
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Immune Thromboctyopenia Purpura |
Antibody-mediated platelet destruction; bind to platelet receptors Will see increased platelet MCV in blood due to lots of new platelets being produced which start out slightly larger than mature platelets Will see increased megakaryocytes in bone marrow to help produce more platelets |
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Treatment for ITP |
Prednisone is first line Splenectomy if severe (2/3 respond) Vinca alkyloids or cyclophosphamide |
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Thrombotic Thrombocytopenia Purpura |
Caused by deficiency of ADAMTS13 (congenital or acquired) Larger, more active multimers of vWF remain attached to endothelium and promote platelet aggregation |
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ADAMTS13 |
Metalloproteinase that cleaves very high molecular weight multimers of vWF into smaller multimers |
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Lab findings of TTP |
Normal PT and PTT Increased LDH, bilirubin, and hemoglobinemia (indicate intravascular hemolysis) Deficiency of ADAMTS13 |
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Clinical Pentad of TTP |
Thrombocytopenia Microangiopathic Hemolytic Anemia (MAHA) Altered mental status (neuro) Fever Renal failure |
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Peripheral blood smear of TTP |
May or may not have schistocytes Polychromasia Thrombocytopenia |
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Prothrombin Time |
Measures extrinsic pathway - Factor 7 and common pathway of Factor 10, 5, 2, and fibrinogen |
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Tissue factor |
Activates Factor 7 |
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Partial Thromboplastin Time |
Measures intrinsic pathway - Factor 12, 11, 9, and 8 common pathway |
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Factor 12 |
Activated by subendothelial collagen or kallikrein No bleeding if it is deficient |
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Hemophilia A |
Deficiency in Factor 8 |
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Hemophilia B |
Deficiency in Factor 9 |
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Hemophilia PT and PTT |
Normal PT Increased PTT |
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Treatment for Hemophilia |
Recombinant protein for whichever factor is deficient |
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Vitamin K deficiency |
Decreased synthesis of several coagulation factors Factors 2, 7, 9, and 10P Protein C and Protein S |
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PT and PTT of Vitamin K deficiency |
Increased PT Increased PTT |
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Inheritance of Hemophilia |
X-linked |
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Mixing Study |
Mix normal plasma with plasma of person with a prolonged PTT or PT PTT/PT corrects, then they have a clotting factor deficiency If it is still prolonged, then they have an inhibitor in their plasma |
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Anti-Thrombin 3 |
Irreversible serine protease inhibitor Made in the liver Activity is enhanced 1000x by heparin |
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Anti-Thrombin 3 deficiency |
Decreased inhibition, particularly thrombin and F10a Heparin resistance |
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Protein C |
Vitamin K dependent protease made in the liver Inactivates Factors 5a and 8a Activated by thrombin when it is bound to thrombomodulin |
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Protein S |
Vitamin K dependent protein made in the liver Cofactor for Protein C, not a protease Inactive when bound to C4b |
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Factor 5 Leiden |
Autosomal dominant; most common hereditary thrombophilia Increased risk of venous thrombosis - 7x in heterozygotes, 80x in homozygotes Not sensitive to warfarin or heparin |
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Diagnosing Factor 5 Leiden |
Measure PTT in presence of Factor 5 deficient plasma Confirm with PCR for the point mutation |
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Cause of Factor 5 Leiden |
Mutation at position 506 that makes Factor 5 insensitive to degradation by activated Protein C |
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Prothrombin 20210 Mutation |
Autosomal dominant Causes increased synthesis of prothrombin Increased risk of venous thrombosis - 3x in heterozygotes |
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Diagnosing prothrombin 20210 mutation |
PCR for point mutation |
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Acquired Risk Factors for thrombosis |
Old age Prior thrombosis Estrogens Antiphospholipid antibody syndrome Heparin-induced thrombocytopenia (HIT) Prolonged air travel |
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Antiphospholipid Antibody Syndrome |
Increased risk of arterial and venous thrombosis, thrombocytopenia, or recurrent fetal loss Antiphospholipid antibodies bind platelets causing them to activate which lowers platelet count |
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Common antiphospholipid antibodies assays |
Lupus anticoagulants (LA) Anticardiolipid antibodies (ACA) Anti-beta 2 glycoprotein 1 |
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Lupus Anticoagulant |
Prolongs the PT and PTT Prone to thrombosis, excess bleeding, and repeated miscarriages Historically associated with SLE Can be transient or associated with antiphospholipid syndrome |
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Detecting a lupus anticoagulant |
Prolong PTT or PT Evidence of inhibitory effect as seen by mixing study |
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Heparin Induced Thrombocytopenia (HIT) |
IgG binds heparin-PF4 complexes and Fc receptors on platelet surfaces Increased platelet clearance by phagocytes which leads to thrombocytopenia Causes platelet, endothelial cell, and monocyte activation which leads to thrombosis Antibodies are transient (<100 days) |
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Disseminated Intravascular Coagulation (DIC) |
"Consumptive coagulopathy" Never arises de novo but as a consequence of an underlying pathologic process Vascular damage leads to release of tissue factor ex. obstetrical complications, malignancy Bacterial sepsis is most common trigger Has elevated D-dimers |
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D-dimers |
Fragments of cross-linked fibrin produced when the clot is digested by plasmin Can be measured in the lab Increased in DIC |
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Other names for D-dimers |
Fibrin degradation products Fibrin split product |
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Lab findings for DIC |
Elevated D-dimers Thrombocytopenia Prolonged PTT, PT, and TT Fragmented red cells (schistocytes) |
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Tissue Plasminogen Activtor (TPa) |
Released from activated endothelium Cleaves plasminogen into active plasmin |
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Heparin and Low-molecular weight heparins |
Cofactor for activation of anti-thrombin 3 Immediate effect for pulmonary embolism, acute coronary syndrome, and DVT Not easily reversible Can cause heparin-induced thrombocytopenia |
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Argatroban and Bilvalirudin |
Direct inhibitors of thrombin Alternate therapy for HIT |
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Warfarin |
Interferes with to modify clotting factor with carboxyglutamate (Gla) residues Takes a few hours to shorten lab values of these factors Reversal with vitamin K |
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Aspirin |
Irreversibly blocks platelet activation by binding cyclooxygenase |
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Thienopyridines |
Clopidogrel (Plavix); Prasugrel (Effient); Ticoplidine (Ticlid) |
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Mechanism of Thienopyridines |
Block the ADP (P2Y12) receptor via the metabolite of the prodrug |
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P2Y12 receptor |
ADP receptor on platelet that causes platelet activation |
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Acute Therapy for Anticoagulation |
Inhibit thrombin or lyse the clot Use heparins or direct thrombin inhibitors Use fibrinolytics such as TPA |
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DOC for stroke |
TPA |
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Chronic therapy for Anticoagulation |
Prevent thrombin generation or platelet activation Use warfarin or anti-platelet drugs |
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Indications for Unfractionated Heparin |
DOC for rapid, short-term anticoagulant therapy Prophylaxis and treatment of venous thrombosis, pulmonary embolism, and peripheral arterial embolism Prevent post-op DVT and PE Atrial fibrillation with embolization Prevent clot in arterial and cardiac surgery Anticoagulant in blood transfusions, extracorporeal circulation, dialysis, and some blood samples |
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Mechanism of Unfractionated Heparin |
Heparin with MW=5,000-30,000 Enhances antithrombin inhibition of thrombin and Factor 10a (but not fibrin-bound thrombin) Inhibiting thrombin can have some anti-platelet effect May also cause enhanced release of tissue factor pathway inhibitor |
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Administration of Unfractionated Heparin |
Parenterally for direct and immediate effects; IV, deep SC (intrafat), but not IM Short duration - 30-90 min; variable and dose-dependent Requires monitoring of PTT time |
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Low Molecular Weight Heparin (LMWH) drugs |
Enoxaparin (lovenox) Dalteparin (fragmin) |
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Low Molecular Weight Heparin |
Fractionated heparin with average MW=5,000 Mechanism is similar to unfractionated heparin; has enhanced inhibition of Factor 10a and reduced inhibition of thrombin Similar indications to UFH; also used in DIC when no signs of bleeding |
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Protamine |
Antidote to heparin; only partially effective against low molecular weight heparin |
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Low Molecular Weight Heparin compared to UFH |
Easier administration, SC; can be used in outpatient More predictable so no monitoring required Longer half-life - about 4 hours Eliminated renally Lower incidence of thrombocytopenia; should not be used in patients with HIT |
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Abciximab |
Targets GP2b/3a Never used long-term; specialized for acute therapy |
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Organ Specific Tropism |
"Seed and Soil" hypothesis Metastatic cancer cells have a specific affinity for certain organs |
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Metastasis to liver |
Colon is main one; drained by portal vein which empties into the liver Colon > stomach > pancreas > breast > lung |
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Metastasis to bone |
Prostate and breast are the main two Metastasis can be bone-forming, bone destructive, or both |
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Metastasis to brain |
Has to get past blood-brain barrier Lung > breast > skin (melanoma) Pulmonary circulation immediately enters the brain once leaving the left heart |
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Metastasis |
Malignant tumors invade local tissues and spread to distant tissues |
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Invasion-Metastasis Cascade |
1. Epithelial to mesenchymal transition within the tumor; this facilitates invasion of local tissues 2. Intravasation into blood vessels 3. Transit through blood and lymph 4. Extravasation into distant tissues 5. Dormancy vs formation of micrometastases (undetectable) 6. Colonization - growth of micrometastases into metastases (detectable) |
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FNA in cancer surgery |
Fine needle aspirate Put a skinny needle into the tumor and aspirate some cells Seldom used in peds, but common in adults |
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IR in cancer surgery |
Can use larger needles and can into tumors that are deeper Cut cords of tissues out to look at Used in peds and adults |
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Radiation Therapy |
Provides local treatment to tumors
Causes direct DNA damage and mutation; final effect is apoptosis of radiated cells Cells resistant to apoptosis are resistant to radiation |
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Opposing Fields of radiation |
Targets a single point but has large off-target effects Not used much anymore |
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3-D Conformal Radiotherapy |
Most of the dose is delivered to tumor with decreased off-target dose |
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Intensity-Modulated Radiotherapy (IMRT) |
3-D targeting with modulation of intensity of various beams to increase dose delivered to tumor while further decreasing off-target effects |
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Stereotactic Radiosurgery (gamma knife) |
Delivers a single dose that exceeds tissue tolerance to cause necrosis |
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Brachytherapy |
Implant small masses of radioactive material that deliver gamma rays High dose, limited time, small volume Minimizes off target effects |
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Radiopharmaceuticals |
Used for thyroid cancer Provides systemic therapy |
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Characteristics of Benign Tumors |
Cells resemble morphology and function of parent tissue Minimal or no nuclear atypia Compresses but does not invade adjacent tissue Localized and does not metastasize Usually can be removed by surgery |
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Characteristics of Malignant Tumors |
Cells differ in morphology and function from parent tissue Abnormal nuclear features - increased nuclear/cytoplasm ratio, increased number of mitoses, bizarre mitotic figures Invade and destroy adjacent tissues Most will eventually metastasize |
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Teratoma |
Tumor that involves all 3 germ layers Able to proliferate in a tissue foreign to site which they occur Mature is benign Immature is malignant |
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EBV Carcinogenesis |
Endemic Burkitt Lymphoma Nasopharyngeal carcinoma Classical Hodgkin lymphoma Non-Hodgkin lymphomas Post-transplant lymphoproliferative disease |
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EBNA2 gene |
EBV gene that transactivates c-myc |
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LMP1 |
EBV gene that mimics CD40 |
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HPV Carcinogenesis |
HPV 6 and 11 cause condyloma acuminate and recurrent respiratory papillomatosis HPV 16, 18, 31, 33, 45, 52, and 58 cause cervical cancer |
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Gardasil-9 |
HPV vaccine Covers HPV 6 and 11 for the condyloma; and 16, 18, 31, 33, 45, 52, and 58 for cancer |
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HPV gene E6 |
Alters p53 so that cells cannot undergo apoptosis in response to genotoxic damage |
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HPV gene E7 |
Alters pRB so that cells cannot exit the cell cycle |
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HHV8 Carcinogenesis |
Kaposi sarcoma in those with HIV/AIDS and endemic types Castelman disease Body cavity based lymphoma |
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LANA1 gene |
HHV8 gene that alters p53 and VHL |
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VGCPR gene |
HHV8 gene that alters Akt and mTOR |
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Monoclonal Antibodies mechanisms |
Trigger antigen and complement dependent cellular cytotoxicity Trigger direct receptor-mediated growth arrest and apoptosis Block signals needed for tumor cell growth or angiogenesis Checkpoint inhibitors - block T cell down-regulation by inhibitory molecules from tumor cells |
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Monoclonal antibodies names |
trastuzumab - Herceptin rituximab - Rituxan bevacizumab - Avastin cetuximab - Erbitux ipilimumab - Yervoy nivolumab - Opdivo |
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trastuzumab - Herceptin |
Targets HER2/neu Used in breast cancer |
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rituximab - Rituxan |
Targets CD20 Used in B-cell non-Hodgkin Lymphoma |
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bevacizumab - Avastin |
Targets VEGF Used in all kinds of cancer |
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cetuximab - Erbitux |
Targets EGFR Used for colon cancer |
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ipilimumab - Yervoy |
Targets CTLA-4 Is a checkpoint inhibitor that stops down-regulation of T cells Used in melanoma and lymphomas |
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nivolumab - Opdivo |
Targets PD-1 Is a checkpoint inhibitor that stops down-regulation of T cells Used in melanoma and lymphoma |
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Chemotherapy |
Provides systemic therapy for cancer Only affects cells in the cell cycle; ineffective on those in G0 Many drugs work in specific phase Cells that are resistant to apoptosis are resistant to chemo |
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Advantages of Chemo |
Can be given in repeated cycles so as tumor cells re-enter the cell cycle they'll become susceptible to chemo Treats overt metastatic and occult micrometastatic disease |
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Disadvantages of Chemo |
Has off-target systemic effects Resistance to the drug can occur |
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M Phase-specific Chemo Drugs |
Vincristine, Vinblastine, Vinorelbine Taxols (paclitaxel, docetaxel) |
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G2 Phase-specific Chemo Drugs |
Bleomycin |
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S Phase-specific Chemo Drugs |
Methotrexate Mercaptopurine and thioguanosine Nelarabine Deoxyadenosine analogs (fludarabine, cladribine, clofarabine) Cytosine arabinoside Gemcitabine Fluorouracil Hydroxyurea |
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Key Side Effect of Anthracyclines |
Cardiotoxicity - CHF is dose limiting effect; also cause arrhythmias Prevented by dexrazoxane |
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Key Side Effects of Asparaginase |
Pancreatitis Coagulopathy (bleeding or thrombosis); bc asparagine is critical in the liver production of many proteins, this drug can push the liver to one direction or the other |
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Key Side Effects of Bleomycin |
Pulmonary fibrosis is dose limiting; have to monitor lung function Raynaud's phenomenom |
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Key Side Effects of Cisplatin |
Most emetogenic drug known to man so lots of nausea and vomiting Irreversible ototoxicity Nephrotoxicity is dose limiting |
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Key Side Effects of Carboplatin |
Same as cisplatin but not as strong of side effects Is more myelosuppressive than cisplatin |
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Key Side Effects of Cyclophosphamide/Ifosfamide |
Hemorrhagic cystitis - bloody, painful urination; prevented with MESNA and hydration Secondary AML - long latency; caused by abnormalities on chromsome 5 and 7 |
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Key Side Effects of Cytosine Arabinoside (ara-C) |
Can make people dizzy and have difficulty writing Cerebellar toxicity Hemorrhagic conjunctivitis |
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Key Side Effects of Dactinomycin |
Hepatic veno-occlusion disease |
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Key Side Effects of Etoposide |
Anaphylaxis Secondary AML - short latency; caused by abnormalities to chromosome 11 |
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Key Side effect of Irinotecan |
Severe diarrhea Treated with atropine and Imodium Can be prevented by giving cefpodoxime pre-treatment |
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Key Side Effects of Rituximab |
Hep B reactivation; screen patient for Hep B PML |
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Key Side Effects of Taxols |
Peripheral Neuropathy Hypersensitivity reactions |
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Key Side Effects of Vincristine |
Peripheral Neuropathy SIADH - syndrome of inappropriate antidiuretic hormone secretion |
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Antidotes to methotrexate |
Leucovorin (folinic acid) Glucarpidase |
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Antidote to 5-fluouracil |
Thymidine |
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MESNA |
Helps with hemorrhagic cystitis from cyclophosphamide/ifosfamide Helps clear the acrolein better/easier??? |
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Dexrazoxane |
Decreases cardiotoxicity of anthracyclines |
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Dexamethasone eye drops |
Used with cytosine arabinoside to help with hemorrhagic conjunctivitis |
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H1 and H2 blockers |
Used with taxols to help prevent infusion reactions |
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Atropine and Imodium |
Treat diarrhea caused by irinotecan |
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Cefpodoxime |
Prevent diarrhea caused by irinotecan if given prior to treatment |
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Doxorubicin |
Main anthracycline Called the red devil because it is red and will hurt the heart |
