Pharmacology Hematology and Oncology (UWORLD)

58 years man -Wound dehiscence -Had left subclavian catheter port placed 3 months ago to begin bevacizumab infusions for recurrent glioblastoma -Incision wound completely closed but now partially reopened -No signs of drainage from wound or erythema surrounding skin -Complication of bevacizumab is suspected -Primary mechanism of patient's wound dehiscence? a)Depletion of endothelial growth factors for angiogenesis b)Eccentric myointimal proliferation and luminal obstruction of the arterioles c)Impaired cytoskeleton microtubule development d)Impaired inflammatory cell migration to the wound site e)Inadequate hydroxylation of collagen polypeptides

answer: Depletion of endothelial growth factors for angiogenesis -Wound dehiscence is partial or complete separation of previously approximated wound edges. It occurs due to disruption of the wound-healing process and may be a complication of medications such as bevacizumab -Bevacizumab is a monoclonal antibody that binds vascular endothelial growth factor (VEGF), preventing it from binding to its cell surface receptor. This inhibits angiogenesis- the process by which new blood vessels sprout from surrounding, uninjured vessels and grow into the wound- because angiogenesis is largely stimulated by VEGF -Because bevacizumab suppresses growth of new blood vessels, it limits blood supply to tumor and is often referred to as cancer-starving therapy. However, because it also suppresses angiogenesis in healing wounds, it can cause wound dehiscence -The lack of angiogenesis leads to inadequate blood supply to support collagen production during the proliferation phase (3 days to 5 weeks) and collagen remodeling and cross-linking during the maturation phase (3 weeks to 2 years)= when these are inhibited, the tensile strength of the wound remains low and dehiscence can occur even weeks to months after initial wound closure option B= radiation therapy, commonly used in cancer treatment, causes DNA damage, resulting in apoptosis of susceptible (e.g., highly proliferative) cells; however, it damages surrounding noncancerous tissues, including local blood vessels, which can subsequently develop progressive eccentric myointimal proliferation and luminal obstruction option C= Vinca alkaloids such as vincristine and vinblastine inhibit cytoskeleton microtubule development; results in arrest of cell division and replication at the metaphase stage, leading to apoptosis option D= anti-inflammatory agents like glucocorticoids and thus, delay wound healing option E= vitamin C deficiency can result in inadequate hydroxylation of proline and lysine residues during collagen synthesis; hydroxyproline and hydroxylysine are essential for collagen cross-linking= vitamin C deficiency reduces maximal tensile strength of wound

12 years boy -Fever, fatigue, easy bruising -Exam: pallor, generalized lymphadenopathy and bone tenderness -Labs: anemia, thrombocytopenia, leukocytosis with atypical lymphoblasts -Biopsy: acute lymphoblastic leukemia -Combination chemotherapy, and 6-mercaptopurine (for maintenance of remission); enzyme that inactivates this drug? a)Adenosine deaminase b)Dihydrofolate reductase c)Hypoxanthine-guanine phosphoribosyltransferase d)Monoamine oxidase e)P-450 mixed-function oxidase f)Topoisomerase II g)Xanthine oxidase

answer: Xanthine oxidase -6-MP can be administered directly or in its prodrug form (i.e., azathioprine). Following ingestion, 6-MP is converted by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) into 6-thioguanine (6-TG) active metabolites (choice C) -The 6-TG metabolites are purine analogues that act as false nucleotides to disrupt DNA and RNA synthesis and inhibit proliferation of hematopoietic cells, a useful effect in treatment of autoimmune diseases, organ transplant rejection, and some types of cancer (e.g., leukemia) -6-MP is metabolized into inactive metabolites by 2 different enzymes, xanthine oxidase and thiopurine methyltransferase (TMPT), both of which are clinically important -Coadministration of 6-MP with a xanthine oxidase inhibitor (e.g., allopurinol, febuxostat) slows inactivation of 6-MP and shunts metabolism toward the production of 6-TG active metabolites, therefore, the dose of 6-MP should be reduced -In addition, roughly 12% of population has a genetic mutation resulting in low or absent activity of TMPT, creating a high risk of toxicity with administration of 6-MP; therefore, some clinicians recommend that patients undergo genetic testing for TMPT activity prior to initiating 6-MP or azathioprine therapy option A= converts adenosine to inosine as part of purine metabolism; this enzyme is deficient in severe combined immunodeficiency but may be overexpressed in some malignancies; Cladribine, which is used in treatment of hairy cell leukemia, is a cytotoxic purine analogue resistant to degradation by ADA option B= methotrexate is used in treatment of cancer and rheumatologic disease; inhibits dihydrofolate reductase= blocking conversion of dihydrofolate to tetrahydrofolate and disrupting synthesis of thymidine and, to lesser extent purine option D= MOA inhibitors are used in treatment of atypical depression; these agents inhibit degradation of norepinephrine, dopamine and serotonin option E= Cyclophosphamide, used to treat many types of cancer, requires bioactivation by cytochrome P450 mixed function oxidase system option F= inhibited by chemotherapeutic agents etoposide and teniposide

-In vitro study= tumor cell lines can become resistant after exposure to various anticancer agents; these cells express a specific cell surface glycoprotein that has which function? a)Tyrosine kinase-coupled receptor b)Adenylate cyclase-coupled receptor c)Cell adhesion molecule d)Transmembrane ion channel e)ATP-dependent transporter

answer: ATP-dependent transporter -Human tumor cells have developed ability to resist chemotherapy in much the same way that many bacteria have developed resistance to antibiotics -Mechanism of human tumor cell resistance: via human multidrug resistance (MDR1) gene -The prototype product of this gene= P-glycoprotein, a transmembrane protein that functions as an ATP-dependent efflux pump -P-glycoprotein is normally expressed in intestinal and renal tubular epithelial cells and functions to eliminate foreign compounds from the body -Also present in capillary endothelium of vessels= forms BBB= prevents penetration of foreign compounds into CNS -In tumor cells, this ATP-powered transmembrane pump protein actively removes chemotherapeutic agents, particularly hydrophobic agents like the anthracyclines -Drugs such as verapamil, diltiazem, and ketoconazole, among others, have been shown to reduce the action of the MDR1 protein option A= mediate effects of hormones that promote anabolism and cell growth such as insulin, IGF-1, EGF, PDGF, and others option B= utilized by beta-adrenergic receptors, V2 ADH receptors, calcitonin, glucagon, TSH, ACTH, and HCG receptors, and others option C= CAMs are proteins located on cell surface that mediate binding with other cells or with the ECM; e.g., selectins, integrins, and cadherins; cell adhesion molecules are generally downregulated in malignant tumors, which allows these cells to spread from their site of origin option D= selectively allow certain ions to pass into or out of cell

23 years man -Excessive bruising since childhood (some family members bleed easily) -Platelet aggregometry= abnormal -Genetic testing= defect in a platelet surface glycoprotein receptor that normally binds fibrinogen to support platelet aggregation -Targeted by which medication? a)Abciximab b)Argatroban c)Aspirin d)Clopidogrel e)Dabigatran f)Heparin g)Warfarin

answer: Abciximab Patient most likely has Glanzmann thrombasthenia (autosomal recessive)= deficient or defective glycoprotein IIb/IIIa on platelet surfaces= peripheral smear shows no platelet clumping (important clue for diagnosis) Platelets are responsible for formation of platelet plugs that stop bleeding from injured vessels (primary hemostasis). Vessel wall injuries exposes the subendothelial collagen and matrix. Platelet attachment to exposed collagen is strengthened by GP Ib binding to vWF on vessel wall. The resulting platelet activation leads: -Release of mediators (e.g., ADP, thromboxane A2) into circulation, which in turn activates other platelets -Conformational change of GP IIb/IIIa on platelet surfaces; this allows thousands of copies of GP IIb/IIIa to bind fibrinogen, thereby forming a platelet plug Abciximab, a GP IIb/IIIa inhibitor, inhibits binding of this receptor to fibrinogen. Abciximab and others from this class are useful for treatment of unstable angina and acute coronary syndrome, particularly in patients undergoing PCI option B= used in heparin induced thrombocytopenia= direct thrombin inhibitor option C= irreversible COX-1 and 2 inhibitor, inhibits TXA2 via platelet COX acetylation; preventing platelet aggregation option D= inhibits platelet aggregation by blocking P2Y12 on platelet ADP receptors option E= used in atrial fibrillation or DVT= direct thrombin inhibitor option F= potentiates antithrombin III activity, leading to inactivation of thrombin and factor Xa option G= prevents K-mediated carboxylation of several coagulation factors

52 years man -2 hours of burning substernal pain; took several tablets of antacids at home without relief -History: hypertension and hyperlipidemia -High BP; ECG= ST depression in leads II, III, aVF; troponin elevated -Treatment: enoxaparin initiated; drug binds? a)Antithrombin III b)Fibrin c)Plasminogen d)Protein C e)Prothrombin

answer: Antithrombin III -Signs of MI -Enoxaparin is a form of LMWH that, like heparin, functions by binding antithrombin III (AT III) via a pentasaccharide sequence -once activated, AT III binds to factor Xa and stops factor Xa from converting prothrombin to thrombin; less thrombin is produced= anticoagulant effect -Unfractioned heparin has more molecules than LMWH, allowing it to bind to factor Xa and thrombin; it is more effective than LMWH in inactivating thrombin option B and C= t-PA converts plasminogen to plasmin; plasmin functions to break down fibrin, resulting in thrombolysis; because t-PA can only bind plasminogen strongly in the presence of fibrin, its thrombolytic action is clot specific option D= protein C and S are endogenous antithrombotic molecules that are also vitamin-K dependent; due to their shorter half-lives in circulation, these molecules are depleted first during initiation of warfarin therapy, causing transient procoagulant state; patients are typically treated with heparin or LMWH during initiation of warfarin therapy option E= factor II is a vitamin-K dependent clotting factor; the factor, along with factors VII, IX, X is depleted by warfarin; LMWHs inhibit prothrombin production (through factor X inhibition), but they do not directly bind prothrombin

78 years man -Unresponsive at home, brought to ED -Complicated medical history and takes multiple medications (no allergy) -Noncontrast CT= intracranial hemorrhage -Patient given recombinant biologic agent that has antigen homology with factor Xa but no catalytic effect -Agent most likely antagonizes effect of which drug? a)Apixaban b)Aspirin c)Dabigatran d)Ticagrelor e)Warfarin

answer: Apixaban -patient's intracranial hemorrhage was likely treated with andexanet alfa, biologic agent that shares homology with factor Xa but has no proteolytic effect -Administered to patients who have life-threatening bleeding while on a factor Xa inhibitor (e.g., rivaroxaban, apixaban) -Similarity of andexanet to factor Xa allows it to function as a decoy that binds factor Xa inhibitors= this restores intravascular coagulation by increasing the availability of endogenous factor Xa, which converts prothrombin to thrombin and generates fibrin clots (reserved for life-threatening bleeding because it increases risk of thrombosis) option B= inhibits cyclooxygenase, which prevents platelet aggregation by blocking the generation of TXA2; no reversal agent option C= direct oral anticoagulant, inhibits circulating and clot-bound thrombin; reversed by idarucizumab, a monoclonal antibody that binds to and inhibits dabigatran option D= blocks P2Y12 adenosine diphosphate receptor on surface of platelets, prevents platelet aggregation option E= vitamin K antagonist, prevents generation of vitamin K dependent clotting factors by blocking epoxide reductase in the liver; reversed by administration of vitamin K

52 years man -Recovering from acute MI, develops new chest pain (relieved by leaning forward, exacerbated by deep inspiration) -Admitted with acute inferior MI 2 days ago and didn't undergo revascularization due to his late presentation -Exam: friction rub present at left sternal border -Patient treated with medication that inhibits COX-1 and COX-2 via irreversible acetylation= relief of symptoms -Agent? a)Acetaminophen b)Aspirin c)Budesonide d)Celecoxib e)Colchicine f)Diclofenac g)Ibuprofen h)Indomethacin

answer: Aspirin -Patients presentation of recent (within 1-3 days) MI, pleuritic chest pain improved by leaning forward, and a friction rub on exam= peri-infarction pericarditis (most improve with supportive measures, those with persistent symptoms are treated with aspirin and colchicine) -Aspirin (acetylsalicylic acid) is an NSAID that irreversibly inhibits COX-1 and 2 enzymes via acetylation, preventing conversion of arachidonic acid to prostaglandins, prostacyclin and thromboxane -COX-1 acetylation inhibits generation of TXA2 in platelets (antithrombotic effect). COX-2 acetylation blocks prostaglandin production in inflammatory cells (e.g., activated lymphocytes, neutrophils) resulting in anti-inflammatory, antipyretic and analgesic effect option A= analgesic and antipyretic, reversibly inhibits COX enzymes, primarily in the CNS, lacks anti-inflammatory properties= weak inhibition of COX in peripheral tissues option C= glucocorticoid agent with potent anti-inflammatory activity; corticosteroids reduce COX-2 expression and decrease synthesis of arachidonic acid via phospholipase A2 inhibition option D= selective COX-2 inhibitor, provides anti-inflammatory benefits without interfering with the functions of COX-1; no significant effect on platelet function and are associated with lower incidence of GI bleeding; however, associated with increased risk of thrombosis option E= exerts anti-inflammatory effects by inhibiting polymerization of beta-tubulin into microtubules, preventing migration and activation of neutrophils option F, G and H= NSAIDs that reversibly inhibit COX-1 and COX-2

64 years woman -Hospitalized for elective hip replacement surgery -History: osteoarthritis, progressive right hip pain, hypertension, hypothyroidism -BMI is high, creatinine is normal; undergoes surgery without complications -Postoperatively stated on medication that is a low molecular weight fraction of a negatively charged chemical stored in mast cell granules -Mechanism of drug? a)Binds antithrombin III b)Binds to the thrombin active site c)Blocks ADP receptors d)Combines with proactivator plasminogen e)Inhibits arachidonate product formation

answer: Binds antithrombin III -Nonambulatory hospitalized patients= risk of developing DVT, which can lead to PE (especially if they don't undergo prophylaxis against DVT); DVT prophylaxis initiated within hours of wound closure -Unfractioned and LMWH are commonly used for DVT prevention in inpatient settings -Administration of heparin (negatively charged chemical naturally present in mast cells) increases effect of naturally occurring anticoagulant antithrombin III -Unfractioned heparin binds to AT III via a pentasaccharide in the heparin chain; this results in a conformational change of AT III, which subsequently inhibits factor Xa and neutralized thrombin, promoting anticoagulation -AT III is activated by LMWH (which has better bioavailability, doesn't need monitoring)= acts predominantly on factor Xa, not thrombin option B= direct thrombin inhibitors directly inhibit thrombin-mediated fibrin formation; lepirudin and argatroban (parenteral) are primarily used for management of HIT; dabigatran (oral) is used for DVT prevention and treatment for stroke prevention in atrial fibrillation option C= Clopidogrel and ticlopidine; after PCI, unstable angina, and NSTEMI option D= drugs that convert inactive plasminogen into plasmin leads to fibrinolysis and clot lysis; given for clot lysis in acute MI, PE, and arterial thrombosis option E= aspirin irreversibly acetylates platelet COX-1, leading to decreased TXA2; used for primary and secondary prevention of MI and stroke

44 years man -Unstable angina (hospitalized); 4th day= severe foot pain and right toe paleness -Labs: thrombocytopenia; treatment: argatroban -Mechanism of action? a)Binds to the thrombin active site b)Blocks glutamate residue carboxylation c)Block ADP receptors d)Block GP IIb/IIIa surface receptors e)Inhibits phosphodiesterase

answer: Binds to the thrombin active site -Heparin is the most important cause of thrombocytopenia in hospitalized patients (heparin-induced thrombocytopenia; more common with unfractioned heparin) -HIT= paradoxical thrombosis rather than bleeding commonly (serious disorder caused by antibodies to heparin and platelet factor IV) -Direct thrombin inhibitors (hirudin, lepirudin and argatroban) do not require antithrombin III for their action and are drugs of choice in treatment of HIT; patients with HIT need ongoing anticoagulation due to presence of, or possibility of thrombosis -Upon clinical suspicion of HIT, the most important initial step is to stop all forms of heparin option B= warfarin inhibits vitamin K dependent gamma-carboxylation of glutamic acid residues of clotting factors II, VII, IX and X option C= Ticlopidine and clopidogrel inhibit ADP mediated platelet aggregation; useful following PCI, treatment of unstable angina and non-Q wave myocardial infarction option D= inhibit binding of platelet Gp IIb/IIIa with fibrinogen and fibronectin; abciximab, eptifibatide, and tirofiban; used after PCI in acute coronary syndrome option E= dipyridamole and cilostazol inhibit platelet aggregation by inhibiting phosphodiesterase activity and increasing cAMP

62 years woman -Progressive chest and back pain; growing right breast lump (months ago) -Exam: 5-cm right breast mass, enlarged axillary lymph nodes, point tenderness along the right sided ribs and 10th thoracic vertebra -Biopsy: hormone-receptor positive, HER2-negative, invasive ductal carcinoma -Skeletal survey: lytic lesions of the ribs and thoracic vertebrae -Treatment: medication that inhibits cyclin-dependent kinase; most likely dose-limiting toxicity of this medication? a)Bone marrow suppression b)Cardiomyopathy c)Immune-mediated toxicity d)Peripheral neuropathy e)Sensorineural hearing loss

answer: Bone marrow supression The cell cycle consists of 4 distinct phases: G1, S, G2 and M; progression through the phases is controlled by surveillance systems (checkpoints) that interrupt the cell cycle and/or induce apoptosis if cells do not meet requirements to proceed forward: -Transition from G1 to S (initiation of DNA replication) is controlled by a combination of cell size and nutrient status, exposure to growth factors, and proper surveillance and repair of damaged DNA -G2 to M transition, cell again checks for DNA damage and repairs replication errors before they can be passed on to daughter cells during mitosis (additional spindle checkpoint ensures that duplicated chromosomes separate appropriately during cell division) Cyclin-dependent kinases (CDKs) 4 and 6 control cell cycle progression from G1 to S; these CDKs are activated by cyclin D and subsequently inhibit the retinoblastoma tumor suppressor protein, leading to upregulation of transcriptional factors that progress the cell cycle to S phase (cancers exploit this; upregulation of cyclin D or inactivating mutations to retinoblastoma gene) CDK4/6 inhibitors (e.g., Palbociclib) can be used to block cyclin D binding site on CDK, which results in decreased CDK 4/6 activation, increased activity of Rb tumor suppressor protein, and cell cycle arrest Generally well tolerated, they often inhibit cellular replication in other rapidly dividing cells, particularly hematologic cells in the bone marrow (neutropenia, anemia, leukopenia) option B= anthracyclines (e.g., doxorubicin) and HER2 antibodies (e.g., trastuzumab) option C= immunotherapy that targets PD-1, PD-L1 and CTLA-4 enhances immune response against cancer and often used in treatment of malignant melanoma; side effects= autoimmune-related= skin, liver, GI, and endocrine inflammation option D= vincristine and bortezomib option E= platinum-based chemotherapy (e.g., cisplatin)

52 years woman -2 weeks of constant back pain; several months of nonproductive cough, anorexia, and weight loss; 40 pack years (smoker) -Exam: diffuse muscle wasting, left lung crackles, and vertebral tenderness -Imaging: left lung mass with lytic lesions in vertebrae -Diagnosis: metastatic non-small cell lung cancer -Treatment: cisplatin-based chemotherapy and neurokinin-1 receptor antagonist; why NK-1 antagonist? a)Chemotherapy-induced nausea b)Malignancy-related anorexia c)Metastases-related hypercalcemia d)Opioid-induced constipation e)Tumor lysis-induced renal failure

answer: Chemotherapy-induced nausea Chemotherapy-induced nausea and vomiting (CINV) is a common side effect of cancer treatment. It is caused by both peripheral and central mechanisms, as follows: -acute-phase CINV (<24 hours after chemotherapy) is mediated primarily by the release of serotonin from intestinal enterochromaffin cells that have been damaged by chemotherapy. Serotonin stimulates vagal afferent fibers (5-HT3) in the bowel wall, which project to the brainstem and stimulate the vomiting reflex. Therefore, serotonin receptor antagonists (e.g., ondansetron) can be used for treatment -Delayed-phase CINV (1-5 days after chemotherapy) is mediated primarily by increased levels of substance P in the brainstem due to chemotherapy-associated emetic stimuli in the CSF and bloodstream. Substance P binds to and activates the NK-1 receptor in CTZ, area postrema, nucleus tractus solitarius. Therefore, NK-1 antagonists (e.g., aprepitant, fosaprepitant) are often used Usually both combined to inhibit both types of CINV option B= is loss of muscle and fat caused by elevated levels of circulating inflammatory cytokines. Progesterone analogs (e.g., megestrol acetate) are first-line treatment, corticosteroids and cannabinoids are also used option C= treated with bisphosphonates (e.g., zoledronic acid), which reduce osteoclast-mediated bone resorption option D= occurs due to opioid-mediated effects on the bowel wall, which reduce peristalsis; methylnaltrexone, an opioid antagonist that has limited ability to cross the BBB (doesn't trigger withdrawal), can be used as treatment option E= patients who have highly aggressive lymphomas and leukemias are at risk of tumor lysis syndrome with chemotherapy. Its primary manifestation is renal damage from elevated uric acid levels (catabolism of nucleic acids released from tumor cells increases uric acid). Rasburicase, a drug that breaks down uric acid, is used to prevent TLS in high-risk patients

36 years woman -Mitral valve prolapse= dyspnea, severe mitral regurgitation -2 weeks later= undergoes mechanical mitral valve replacement -Continuous heparin infusion and oral warfarin are initiated following the procedure -Patient achieves the goal of INR > 2.5 on postoperative day 5 and heparin infusion is discontinued -Cause of delay in achieving therapeutic INR in this patient? a)Clotting factors generated before warfarin initiation b)Formation of anti-platelet factor 4/heparin antibodies c)High total body stores of vitamin K d)Induction of an enzyme that metabolizes warfarin e)Slow onset of steady state drug concentration

answer: Clotting factors generated before warfarin initiation -Warfarin is a vitamin K antagonist that blocks epoxide reductase in the liver, leading to impaired vitamin K recycling= depletes reduced form of vitamin K, which is required for gamma carboxylation of vitamin K dependent clotting factors (II, VII, IX, and X) -In absence of gamma carboxylation, vitamin K dependent clotting factors cannot bind calcium or phospholipid membranes to induce coagulation -Because warfarin inhibits gamma carboxylation of new vitamin K-dependent clotting factors, therapeutic efficacy is delayed until preexisting clotting factors in the plasma are consumed. Although INR tends to slowly increase in the first few days of administration due to short half-life of factor VII (4-6 hours), full therapeutic effect does not typically occur for 3 days due to long half-life of factor II -Warfarin also inhibits gamma carboxylation of proteins C and S (short half-life). Because these proteins exert an anticoagulant effect, initiation of warfarin can be associated with initial procoagulant state option B= cause heparin induced thrombocytopenia, which typically arise 5-10 days after heparin initiation; condition marked by thrombocytopenia and high risk of arterial and venous thrombosis, but would not result in a delay in therapeutic INR following warfarin administration option C= doesn't contribute to warfarin efficacy; increased intake of vitamin K rich food can lead to subtherapeutic INR due to increased vitamin K availability in the liver option D= warfarin is metabolized by P450 2C9; can cause drug interactions option E= warfarin reaches maximal plasma concentration approximately 90 mins after administration

62 years woman -Painless neck mass that is enlarging; fatigue, night sweats, weight loss -Exam: rubbery, nontender, bilateral cervical lymphadenopathy -Imaging: mediastinal and abdominal lymphadenopathy; subsequent excisional lymph node biopsy= diffuse large B cell lymphoma -Patient receives combination chemotherapy= rapid lysis of neoplastic cells -Also receives Rasburicase prior to and during treatment -Protects normal organs with which mechanism? a)Converting uric acid into more soluble metabolites b)Forming insoluble complexes with phosphate c)Inhibiting uric acid formation after cell lysis d)Supplying a thiol group to inactivate toxic metabolites e)Supplying necessary cofactors blocked by a chemotherapeutic agent

answer: Converting uric acid into more soluble metabolites Tumor lysis syndrome (TLS) is an oncologic emergency that primarily develops during initial chemotherapy for high-grade lymphomas, leukemias, and other cancers with rapid cell turnover, substantial tumor burden, or high sensitivity to chemotherapy. When large numbers of tumor cells are destroyed in a short period, massive quantities of intracellular tumor products are released into circulation, which frequently result in: -hyperkalemia= arrhythmias -Hyperphosphatemia= precipitates calcium in renal tubules and collecting system= systemic hypocalcemia and acute renal injury from calcium-phosphate stones -Hyperuricemia= precipitates urate crystals in renal tubules= acute renal injury Aggressive IV fluids during and after chemotherapy can help prevent kidney injury by flushing metabolites out of kidneys. Treatment with agent that reduces formation of uric acid also used to limit formation of uric acid stones; including one of the following: -Rasburicase (recombinant version of urate oxidase; an enzyme present in mammals, but not humans)= urate oxidase converts uric acid into allantoin, a purine metabolite that is 5-10 times more soluble than uric acid and therefore less likely to precipitate in kidneys -Allopurinol is a purine decoy=competitively inhibits xanthine oxidase= reduces conversion of purine metabolites to uric acid (choice C); febuxostat is non-purine selective inhibitor of xanthine oxidase option B= phosphate binders; e.g., sevelamer; are used to manage hypophosphatemia in patients with chronic kidney disease option D= mesna can prevent hemorrhagic cystitis in patients receiving cyclophosphamide or ifosfamide, it supplies a thiol group that inactivates the toxic metabolite (acrolein) of these chemotherapeutics option E= Folinic acid (leucovorin) provides a reduced form of folic acid to counter the methotrexate-induced block in folic acid metabolism; it rescues GI mucosa and bone marrow cells from effects of MTX

23 years woman -Comes to ED with vaginal bleeding and lower abdominal cramps -Last menstrual period (6 weeks ago) and home pregnancy test= positive -Pelvic ultrasonography= gestational sac in left fallopian tube without evidence of rupture -Single dose of methotrexate is administered; which substances will most likely accumulate in embryonic tissues as a result of treatment? a)Dihydrofolate polyglutamate b)Folinic acid c)Para-aminobenzoic acid d)Tetrahydrofolate e)Thymidylic acid

answer: Dihydrofolate polyglutamate -Methotrexate, a folate antagonist, is the drug of choice for non-surgical treatment of an early, unruptured ectopic pregnancy -Folic acid is a required precursor to nucleic acid synthesis; barriers to its metabolism are especially effective in hindering the growth of rapidly proliferating cells such as in a developing embryo or certain types of cancer -Normally, folic acid is reduced to dihydrofolate (DHF) by dihydrofolate reductases and then reduced further to tetrahydrofolate (THF), an integral precursor of DNA synthesis -MTX is structurally similar to folic acid and competitively and irreversibly inhibits DHF reductase (prevents formation of THF; option D) -After entering target cells, MTX undergoes polyglutamation, which prevents movement of MTX out of cell, resulting in intracellular accumulation of MTX for later use; similarly, folate and recycled DHF are stored within the cell via polyglutamation; because MTX inhibits DHF reductase, folic acid and DHF polyglutamate will accumulate in cells option B= leucovorin is a reduced form of folic acid that can be used to counter toxic effects of MTX chemotherapy; Folinic acid selectively rescues normal cells by competing with MTX for DHF reductases binding sites; it can reactivate DHF reductase option C= PABA is a folic acid precursor for prokaryotes; sulfonamide antibiotics are chemical analogs of PABA that inhibit the enzyme dihydropteroate synthetase, preventing bacterial conversion of PABA to folic acid; humans lack ability to convert PABA to folic acid and require dietary folate option E= is a nucleotide that contributes to pyrimidine formation; its synthesis is inhibited by MTX

45 years woman -Follow up after acute pyelonephritis (2 week hospitalization) -Treated with morphine and broad-spectrum antibiotics -History: mechanical mitral valve replacement and takes warfarin -INR increased to 6.2 from 2.5 despite no change to warfarin therapy; explanation? a)Decreased production of thromboxane A2 b)Disruption of intestinal bacterial flora c)Formation of anticlotting factor antibodies d)Increased cytochrome P-450 activity e)Increased dietary vitamin K absorption

answer: Disruption of intestinal bacterial flora Warfarin is a vitamin K antagonist= inhibits epoxide reductase in liver, thereby preventing gamma carboxylation of vitamin K-dependent clotting factors (II, VII, IX and X). This creates an anticoagulant state that is reflected on lab assessment as a prolonged INR. Patients are at risk for subtherapeutic or supratherapeutic INR due to: -Change in dietary vitamin K intake: increased vitamin K intake= more vitamin K in liver= counters inhibitory effect of warfarin on epoxide reductase (eat consistent amount of vitamin K containing foods like leafy greens, brussels sprouts) (Choice E) -Disruption to intestinal flora: flora produces vitamin K as byproduct; antibiotics that target gram-negative bacteria such as metronidazole, macrolides, fluoroquinolones, can cause supratherapeutic INR due to destruction of vitamin K producing bacteria in gut; administration of antibiotic (e.g., ciprofloxacin) for pyelonephritis likely destroyed bacteria in gut= reducing vitamin K production -Alteration to cytochrome P450 2C9 activity (P450 2C9 degrades warfarin); 1) phenytoin, carbamazepine and rifampin increase P450 2C9 activity= subtherapeutic INR (choice D) 2) metronidazole, fluconazole, and amiodarone inhibit P450 2C9 activity= supratherapeutic INR option A= aspirin; interferes with platelet aggregation= prolongs bleeding time, not INR option C= can occur due to recent pregnancy, malignancy, or rheumatologic disease; most cases involve inhibition of factor VIII, which leads to bleeding diathesis and prolonged aPTT (not INR, which reflects PT)

24 years pregnant woman -Comes to ED due to left leg swelling and pain (past 2 days) -No other conditions; exam: 1+ edema of left lower extremity to the knee, associated with mild erythema -Left calf diameter measures 3cm greater than the right -Doppler ultrasonography= left popliteal and femoral vein thrombosis; creatinine is normal -Most appropriate treatment? a)Apixaban b)Clopidogrel c)Dabigatran d)Enoxaparin e)Low-dose aspirin f)Tissue plasminogen activator g)Warfarin

answer: Enoxaparin Pregnancy increases risk of venous thromboembolism due to anatomic changes (e.g., uterine compression of IVC and iliac veins) and physiologic hypercoagulability (e.g., increased production of clotting factors, decreased protein S levels, protein C resistance) Heparins are ideal anticoagulants for most pregnant women as they do not cross placenta and the risk of fetal bleeding and teratogenicity is low -Low molecular weight heparin (e.g., enoxaparin, dalteparin) is preferred as it has a relatively long half-life (4.5 hours) and does not require routine lab monitoring. However, it is renally cleared and can't be used in patients with severe renal insufficiency (creatinine clearance <30ml/min) -Unfractioned heparin (short half-life: 1-2 hours) and requires frequent lab draws (i.e., PTT) due to its more varied anticoagulant effect. However, it may be used in patients with renal insufficiency; also used in place of LMWH at term (37 weeks gestation) as it can be discontinued at onset of labor to minimize hemorrhagic risk option A and C= direct thrombin inhibitors are not recommended in pregnancy; fetal toxicity option B= no role in VTE treatment; blocks ADP receptor; used in coronary artery disease, acute coronary syndrome, and prevention of recurrent ischemic stroke option E= prescribed to certain pregnant patients at risk of preeclampsia option F= used in clot lysis; high risk of major bleeding and is reserved for those with massive deep vein thrombosis at risk of limb ischemia or life-threatening pulmonary embolism with hypotension option G= crosses placenta, increasing risks of teratogenicity and fetal hemorrhage, avoided in pregnancy

61 years man -2 days of right leg swelling; flew back to US from Japan -History: hypertension and hyperlipidemia -Tenderness and swelling of lower extremity up to mid thigh; coagulation times= normal; doppler= occluding thrombus in the right femoral and popliteal veins -Patient started on rivaroxaban; inhibits? a)Factor VIII b)Factor Xa c)Glycoprotein IIb/IIIa d)Platelet P2Y12 e)Thrombin

answer: Factor Xa -Has right lower extremity DVT (due to long flight) -Many patients with DVT receive long-term anticoagulation with warfarin. Alternates include direct factor Xa inhibitors (e.g., rivaroXaban, apiXaban), which bind to the active site of factor Xa and prevent thrombin formation -These drugs can be administered orally as monotherapy and do not require lab monitoring. They are used for venous thromboembolism treatment as well as for stroke prophylaxis in patients with atrial fibrillation (who are at risk for embolic stroke) option A= factor VIII replacement is mainstay for hemophilia A treatment option C= Eptifibatide inhibits platelet aggregation and thrombosis by blocking Gp IIb/IIIa receptor, which is binding site for fibrinogen; typically used for acute coronary syndrome and in patients undergoing PCI option D= Ticagrelor binds ADP P2Y12 receptor on platelets, which prevent platelet aggregation by blocking ADP-mediated activation of Gp IIb/IIIa receptor complex. This drug is also used in acute coronary syndrome and in patients undergoing PCI option E= dabigatran is an oral direct thrombin inhibitor that inactivates both circulating and clot-associated thrombin; also used for treatment of thromboembolic disease and stroke prophylaxis in atrial fibrillation

56 years man -Non-Hodgkin lymphoma, undergoing systemic chemotherapy -Vincristine is part of regiment, suspect accidental overdose -Presentation? a)Finger numbness and tingling b)Burning on urination and urgency c)Leg swelling and orthopnea d)Dry cough and exertional dyspnea e)Tarry stool and fatigue f)Abdominal pain and jaundice

answer: Finger numbness and tingling -Vincristine causes neurotoxicity by interfering with microtubule formation in nerve axons -Patients with vincristine toxicity most commonly complain of peripheral neuropathy, and neurotoxicity (dose-limiting side effect) -All vinca alkaloids (vincristine, vinblastine) inhibit microtubule polymerization after binding to beta-tubulin= prevents synthesis of the mitotic spindle in dividing cells= without spindles, replicated chromosomes are unable to align and segregate into their respective daughter cells during mitosis= failure of division and cell death= M-phase specific agents option B= cyclophosphamide or ifosfamide induced hemorrhagic cystitis option C= anthracycline antibiotic and chemotherapeutic intercalating agent) is associated with CHF option D= bleomycin, associated with pulmonary toxicity; causes progressive pulmonary fibrosis that can lead to death in a minority option E= any chemotherapeutic agent that affects rapidly dividing cells, but are most classically associated with alkylating agents; cause death in both rapidly-dividing tumor cells and other groups of cells that have a high turnover, hair, skin and mucosa of GI system option F= seen with mercaptopurine use; mercaptopurine is an S-phase specific purine analogue that is associated with cholestasis and hepatitis; chronic methotrexate ingestion used in RA is also associated with cirrhosis

57 years woman -Vomiting (coffee ground), lightheaded -History: warfarin for DVT and aspirin for occasional joint pain -Low BP and high pulse; substance that would provide fast reversal of warfarin's effects? a)Vitamin K b)Protamine c)Aminocaproic acid d)Fresh frozen plasma e)Cryoprecipitate f)Desmopressin

answer: Fresh frozen plasma -warfarin= used for long-term anticoagulation in setting of DVT and PE -Warfarin inhibits vitamin K dependent gamma-carboxylation of glutamic acid residues of clotting factors II, VII, IX and X= production of dysfunctional coagulation proteins -Therapeutic effect monitored by PT or INR -Therapeutic INR (2-3); bleeding is a common complication of warfarin therapy and the risk is increased with INRs above 3 -Treatment: rapid reversal using fresh frozen plasma. Vitamin K can help reverse action, but effect takes time (Choice A) option B= heparin reversal option C= antifibrinolytic agent that inhibits plasminogen activators, and to a lesser degree, antiplasmin activity; helps achieve hemostasis when fibrinolysis is cause of bleeding option E= FFP contains all coagulation factors; cryoprecipitate contains only cold-soluble proteins (factor VIII, fibrinogen, vWF and vitronectin) option F= synthetic analog of ADH, used in diabetes insipidus and mild vWD and mild hemophilia A

-Study to determine effectiveness of a novel humanized monoclonal antibody in patients with metastatic colorectal cancer -Medication binds programmed cell death-1 receptor on T cells to block its ligands from binding -Most effective in patients with a high degree of microsatellite instability or defects in DNA mismatch repairs -Explanation of favorable drug effect in this subset of patients? a)Higher expression of P-glycoprotein b)Higher number of cancer neoantigens c)Higher rate of KRAS mutations d)Higher rate of p53 mutations e)More intense desmoplastic reaction

answer: Higher number of cancer neoantigens The genetic mutations that drive oncogenesis also create unique proteins not found in healthy cells. Antigens from these proteins (neoantigens) are displayed on the surface of tumor cells and may be subsequently recognized by patrolling cytotoxic T cells as "not self" and destroyed Cancers with defects in mismatch repair proteins and high microsatellite instability (reflecting DNA polymerase errors during replication) are particularly susceptible to immune recognition because they rapidly accumulate mutations and generate 20-fold more neoantigens than tumor cells that have normal mismatch repair. Cancer cells use a wide range of mechanisms to thwart cytotoxic T cell detection, including: -Downregulating cell surface receptors involved in immune recognition; for instance, decreased expression of MHC leads to decreased neoantigen presentation on surface of cells -Overexpressing cell surface proteins that inhibit the immune response; For instance, cancer cells can overexpress programmed death-ligand 1 (PD-L1), which binds to programmed cell death-1 (PD-1) receptor on the T-cell surface and inhibits the cytotoxic T cell response (T-cell exhaustion) Cancer cells that overexpress PD-L1 are less susceptible to cytotoxic T cell-mediated destruction (enhanced T-cell exhaustion). These tumors can be treated with monoclonal antibodies that block PD-1 receptor on T cells (e.g., pembrolizumab, nivolumab) or the PD-1 ligand on cancer ells (e.g., atezolizumab). Treatment stimulates cytotoxic T cell response, it is particularly effective against tumors with large quantities of neoantigens (e.g., those with deficits in mismatch repair) because these tumors are particularly susceptible to recognition as "not self" option A= multidrug transport that can be used by cancer cells to pump cytotoxic chemotherapy out of the cell option C= proto-oncogene that is part of the signaling pathway for the epidermal growth factor receptor. Tumors with activating KRAS mutations are resistant to monoclonal antibodies against epidermal growth factor receptor because they have an activating mutation in a downstream signal option D= tumor suppression protein that inhibits cellular replication when DNA is damaged and induces apoptosis; mutations to p53 can lead to unregulated cellular growth and may inhibit cytotoxic chemotherapy-mediated cancer cell apoptosis option E= desmoplasia (dense fibrosis) around a tumor can reduce the ability of cytotoxic chemotherapy to enter cancer cells

12 years boy -Prolonged oral bleeding (after tooth extraction); several hours; stops after desmopressin administration -Family history of prolonged bleeding after dental procedures (father and paternal grandmother) -Review of systems: positive for mild bruising on his legs -Mechanism of desmopressin in this patient? a)Binding to renal tubular cell receptors b)Increase in endothelial protein release c)Increase in liver protein synthesis d)Inhibition of fibrinolysis e)Vascular smooth muscle contraction

answer: Increase in endothelial protein release -Most likely vWD (autosomal dominant deficiency of vWF)= increased bruisability and mucosal bleeding (commonly prolonged bleeding during dental procedures or menstruation) -vWF is secreted by endothelial cells and circulates in multimers that are non-covalently attached to clotting factor VIII, increasing its stability. vWF helps with platelet binding at endothelial injury sites (helps in formation of platelet plug) -Treatment: most don't need; some can receive desmopressin (or 1-desamino-8-d-arginine vasopressin), a synthetic analog of vasopressin (ADH), which is normally released by posterior pituitary; DDAVP increases vWF release from endothelial cells -DDVAP also raises factor VIII levels and is used for treatment in mild hemophilia A (X-linked recessive); unlikely here (family history pattern of inheritance) option A= DDVAP also acts as an ADH analog by binding to V2 receptors in renal tubular cells= increased aquaporin channels= increased water reabsorption= decreased urine output; can be used in central diabetes insipidus and nocturnal enuresis option D= aminocaproic acid is anti-fibrinolytic used to treat excessive postoperative bleeding option E= endogenous vasopressin acts via V1 vasopressin receptor to raise BP through vascular SMC contraction

70 years man -Progressive fatigue and easy bruising; unintentional weight loss and episodic fevers -Exam: splenomegaly, enlarged cervical, axillary and inguinal lymph nodes; CBC: thrombocytopenia, and leukocytosis -Blood smear: small, mature-appearing, abnormal lymphocytes, which express CD20 and kappa light chains -During treatment: patient receives agent that directly binds and inhibits BCL-2 protein -Most likely effect of this therapy? a)Accumulation of ubiquinated intracellular proteins b)Greater susceptibility to cytotoxic T cells c)Increased activation of caspases d)Increased single-strand DNA breaks e)Interruption of cell growth in S phase f)Targeting of antibody-dependent cellular cytotoxicity

answer: Increased activation of caspases -lymphadenopathy, splenomegaly, and increased number of mature lymphocytes in blood that express B-cell marker (CD20+, kappa light chains) indicate chronic lymphocytic leukemia (CLL) -Disease is characterized by progressive accumulation of mature B cells in hematopoietic tissues (leading to anemia, thrombocytopenia, lymphadenopathy, and splenomegaly) and peripheral blood (leading to leukocytosis) due to genetic mutations that lengthen B-cell survival -In most cases of CLL, B-cell survival is promoted by the overexpression of BCL-2 on the mitochondrial membrane; BCL-2 is an antiapoptotic protein that prevents stress signals from triggering the intrinsic apoptotic cascade, which is mediated by release of cytochrome C from the mitochondria and subsequent activation of caspases -Treatment of CLL with BCL-2 inhibitors (e.g., venetoclax) makes tumor cells more sensitive to stress signals (e.g., chemotherapy) by increasing activation of caspases, which leads to cell death option A= Bortezomib, proteasome inhibitor that prevents destruction of ubiquinated intracellular proteins, can be used against neoplasms that generate excessive amounts of proteins; e.g., multiple myeloma option B= tumor cells produce neoantigens not seen in normal cells, they generally have mutations that allow them to evade cytotoxic T cell detection; immune checkpoint inhibitors, such as antibodies against PD-1 (pembrolizumab) or CTLA-4, prevent cancer cells from evading cytotoxic T cell detection option D= Olaparib inhibits poly-ADP ribose polymerase, the enzyme that mediates the repair of single-stranded DNA breaks; often used to treat breast, ovarian, or prostate cancer in individuals with BRCA mutations option E= many drugs target this, antimetabolites (e.g., purine analogs) option F= Rituximab is a monoclonal antibody against B cell surface marker CD20; often used for CLL, it mediates cell death by binding to the B-cell surface= antibody-mediated cytotoxicity

67 years man -Persistent lower back pain and fatigue; labs: anemia and renal dysfunction -Serum total protein levels are elevated, electrophoresis= narrow spike in gamma globulin region -Bone marrow biopsy= abnormal marrow cells -Medication used to block cellular proteasome action; effect on abnormal cells? a)Augmented cytotoxic T-cell response b)Decreased DNA methylation c)Impaired RNA splicing d)Improved differentiation e)Increased apoptosis

answer: Increased apoptosis -anemia, back pain, renal insufficiency, gamma globulin spike and biopsy= multiple myeloma, a plasma cell malignancy associated with overproduction of monoclonal Ig's or IgG fragments (e.g., IgG light chains) -Treatment= drugs that block proteasome function (e.g., bortezomib) -Proteasome= degrades ubiquitin tagged proteins; proteasome inhibition= accumulation of damaged and misfolded proteins that have a cytotoxic effect -MM cells are particularly susceptible to proteasome inhibition because they generate extremely high quantities of secretory proteins (e.g., monoclonal Ig's), some of which misfold and aggregate in ER= increased stress on ER triggers an unfolded protein response that eventually leads to activation of caspases and cellular apoptosis option A= augmented by checkpoint inhibitor immunotherapies such as those that target the programmed cell death 1 receptor and CTLA-4 option B= Azacitidine is a cytidine analog that inhibits DNA methyltransferase; it reduces DNA methylation and alters gene expression, leading to reduced protein synthesis and increased cellular differentiation. Toxic to abnormal hematopoietic cells but is used to treat myelodysplastic syndrome option C= done by the nuclear spliceosome, which removes introns from transcribed pre-mRNA option D= all-trans-retinoic acid is used in treatment of acute promyelocytic leukemia; it works by promoting differentiation of neoplastic cells into mature neutrophils

23 years woman -History of sickle cell disease (homozygous for hemoglobin S and has had frequent episodes of painful vasoocclusive crises), takes folic acid supplementation -Additional therapy with hydroxyurea planned; mechanism? a)Decreased red blood cell dehydration b)Direct inhibition of red blood cell polymerization c)Increased hemoglobin A2 synthesis d)Increased fetal hemoglobin synthesis e)Increased red blood cell antioxidant levels f)Stimulation of red blood cell production

answer: Increased fetal hemoglobin synthesis -Patients with sickle cell disease have a missense mutation in the beta globin gene that leads to substitution of valine for glutamic acid in the 6th position of the beta globin chain= altered form is called hemoglobin S; unlike normal adult hemoglobin (HbA), HbS polymerizes when deoxygenated or dehydrated, leading to erythrocyte membrane damage (i.e., intravascular hemolysis) and clogging of small vessels (e.g., painful vasoocclusive crises, ischemia) -Heterozygotes for Hb S are usually asymptomatic because there is enough HbA to prevent extensive polymerization of Hb S, but homozygotes typically have severe disease. These individuals often require repeated blood transfusions for symptomatic anemia and treatment with hydroxyurea, an antimetabolite that inhibits the ribonucleotide reductase enzyme -Although inhibition of ribonucleotide reductase leads to the myelosuppressive effects of hydroxyurea (it causes cell cycle arrest in rapidly dividing hematopoietic cells), hydroxyurea also shifts globin gene transcription from beta globin locus to the gamma globin locus (via unclear mechanisms), thereby increasing circulating levels of fetal hemoglobin (HbF) -HbF is unaffected by sickle cell mutation (not composed of beta chains) and has physiologic properties similar to HbA2, therefore, hydroxyurea is often used in treatment of SCD to improve oxygen delivery, reduce vasoocclusive crises, and lessen need for transfusions option A= the calcium-dependent (Gardos) potassium channel regulates the transport of potassium and water through the erythrocyte membrane, blocking this channel could help prevent erythrocyte dehydration, doesn't improve symptoms though option B= Voxelotor directly inhibits polymerization of HbS by binding to the alpha chain of the molecule and causing an allosteric change that results in increased oxygen binding option C= can help with disease; but not hydroxyurea mechanism option E= L-glutamine, a precursor to antioxidant glutathione, reduces oxidative stress in erythrocytes with Hb S; used in patients with SCD who have persistent vasoocclusive pain or those who can't tolerate hydroxyurea option F= via erythropoietin would likely worsen vasoocclusive crises by increasing circulating levels of HbS; hydroxyurea inhibits synthesis of RBCs, WBCs and platelets by blocking ribonucleoside reductase, but patients still benefit from administration due to stimulated HbF production

64 years man -Several weeks of worsening back pain, fatigue and polyuria -Exam: mucosal pallor and diffuse bony tenderness -Labs: normocytic anemia, hypercalcemia and renal failure -Serum protein electrophoresis: monoclonal spike in the gamma globulin region; biopsy: abnormal plasma cells -Treatment: lenalidomide (increases affinity of E3 ubiquitin ligase enzyme to substrate transcription factors); effect on transcription factors? a)Decreased cell surface expression b)Decreased lysosomal proteolysis c)Increased binding to promoter region d)Increased intracellular degradation e)Increased nuclear translocation

answer: Increased intracellular degradation -Multiple myeloma is a plasma cell neoplasm associated with the overproduction of monoclonal immunoglobulins. Proliferation of neoplastic plasma cells in the bone marrow= bone pain (e.g., back pain), hypercalcemia (e.g., polyuria) and osteolytic lesions; patients also frequently develop normocytic anemia and renal insufficiency -Treatment: proteasome inhibitors (e.g., bortezomib) or increase ubiquination of regulatory proteins produced in excess in neoplastic cells (e.g., lenalidomide) -Lenalidomide is a derivative of thalidomide, an antiemetic agent used in pregnancy until significant teratogenic effects were identified. Lenalidomide increases the binding affinity of the E3 ubiquitin ligase complex to specific transcription factors (TFs) (e.g., Ikaros and Aiolos 2 zinc finger transcription factors) that are overexpressed in myeloma cells -Tags them for destruction by the proteasome. (they are required for myeloma cell survival) -Other mature B-cell malignancies such as mantle cell lymphoma and myelodysplastic syndrome (some cases are caused by B cell proliferation) also overexpress these transcription factors; therefore, lenalidomide can be used against them option B= lysosomes destroy extracellular proteins, and ubiquination is not required

5 years boy -Hour of epistaxis (after being elbowed); history: prolonged bleeding from gums after brushing teeth -Has scattered bruises along arms and legs; receives desmopressin= stops bleeding -Therapeutic mechanism? a)Binds to antidiuretic hormone receptors b)Increases circulating factor IX c)Increases circulating von Willebrand factor d)Increases platelet count e)Increases vitamin K-dependent coagulation factors f)Relaxes vascular smooth muscle cells

answer: Increases circulating von Willebrand factor -History of prolonged mucosal bleeding, easy bruising and responsiveness to desmopressin= vWD -vWD caused by qualitative or quantitative defect in vWF, a multimeric glycoprotein synthesized by endothelial cells and platelets; vWF contributes to hemostasis by forming a bridge between platelets and exposed subendothelial components at sites of injury and by serving as a carrier protein for factor VIII -Treatment of minor bleeding episodes in patients with vWD often involves desmopressin, a synthetic analog of ADH that doesn't induce vasoconstriction -DDAVP= induces rapid and transient increase in vWF and factor VIII by indirectly releasing these compounds from endothelial storage sites= most useful in acute setting, as repeated doses have limited effectiveness due to tachyphylaxis (endothelial stores deplete) option A and F= ADH binds to V2 on renal tubular cells, which leads to increased aquaporin channels= water reabsorption= decreased urine output; also binds V1 receptor on vascular smooth muscle= vasoconstriction; desmopressin only acts on V2 option B= factor IX deficient in hemophilia B; vitamin K dependent factor; must be treated with factor IX replacement

24 years man -Diagnosed with Hodgkin lymphoma (4 months ago) and received combination chemotherapy -Has nonproductive cough and dyspnea with exertion (2 weeks) -Exam: no jugular venous distention or pedal edema; heart sounds are normal; lung= bilateral fine inspiratory crackles -Chest X-ray= bilateral reticular interstitial opacities -Pulmonary function testing= restrictive pattern with decreased diffusion capacity for carbon monoxide -Tests were normal prior to chemotherapy; mechanism of drug that caused symptoms? a)Disrupts microtubule polymerization causing M-phase arrest b)Impairs DNA synthesis by inhibiting thymidylate synthase c)Induces free radical formation and DNA strand breaks d)Inhibits topoisomerase II leading to DNA strand breaks e)Inhibits tyrosine kinases and cellular replication f)Produces cell-cycle arrests and apoptosis by inhibiting proteasomes

answer: Induces free radical formation and DNA strand breaks -Bleomycin is commonly used in treatment of Hodgkin lymphoma and germ cell tumors; exerts antineoplastic effect by binding iron and oxygen molecules to create free radicals that cause DNA strand breaks; lung toxicity, usually in form of pulmonary fibrosis, is the most clinically important adverse effect of drug -Mechanism: oxidative free-radical damage to healthy tissue, leading to a cycle of tissue damage and repair; lungs are susceptible because they lack bleomycin hydrolase (inactivates it) -Symptoms: dyspnea, nonproductive cough, and crackles on lung auscultation (within 6 months of therapy); bibasilar interstitial opacities are typically seen on chest x-ray and spirometry shows reduced FVC with preserved FEV1, consistent with a restrictive pattern (in addition there is reduced diffusion capacity for carbon monoxide due to impaired gas exchange across fibrosed interstitium option A= Vinca alkaloids (e.g., vincristine, vinblastine) bind to beta-tubulin to disrupt microtubule polymerization and prevent mitotic cell division; peripheral neuropathy is most common side effect option B= 5-FU inhibits thymidylate synthase to impair DNA synthesis; bone marrow suppression can occur option D= Etoposide inhibits topoisomerase II to cause DNA strand breaks, and is commonly associated with bone marrow suppression; anthracyclines (e.g., doxorubicin) also exert at least part of their antineoplastic effect by binding to topoisomerase II and cause cardiotoxicity= dilated cardiomyopathy option E= imatinib and erlotinib are used to treat CML and lung cancer respectively; disrupt cellular replication and commonly cause diarrhea and skin rash option F= e.g., Bortezomib is used in treatment of multiple myeloma; these drugs can cause bone marrow suppression and sometimes peripheral neuropathy

56 years man -Right lower extremity pain and swelling -Symptoms after he flew back to US from 7-day cruise to Indonesia -Doppler= femoropopliteal venous thrombosis, and patient is given anticoagulation with rivaroxaban -Compared to vitamin K antagonists, benefit? a)Better patient compliance b)Greater efficacy c)Less risk of thrombocytopenia d)No need for loading dose e)Less variability in therapeutic effect

answer: Less variability in therapeutic effect -Rivaroxaban is a direct oral anticoagulant (DOAC) that binds to and inhibits factor Xa, thereby preventing conversion of prothrombin to thrombin -DOACs are generally preferred over vitamin K antagonists such as warfarin for most conditions requiring prolonged anticoagulation due to less variability in therapeutic effect -The therapeutic effect of VKAs is affected by changes to dietary intake of vitamin K, disruption to vitamin K-producing intestinal flora (e.g., antibiotics) and a wide range of medications that inhibit or induce cytochrome P450 2C9; patients given VKAs require coagulation monitoring (e.g., INR) to ensure adequate anticoagulation -In contrast, the therapeutic effect of DOACs is not typically altered by environmental or medication changes, therefore, lab monitoring is not required. DOACs may also have a lower risk of intracranial bleeding, the most serious risk of anticoagulation, compared to VKAs option A= similar compliance in DOACs and VKAs option B= VKAs and DOACs roughly have same efficacy option C= heparin can cause thrombocytopenia; type 1 (nonimmune) or type 2 (immune mediated); VKAs target vitamin K dependent clotting factors not platelets= do not typically cause thrombocytopenia option D= loading dose is required with heparin; some DOACs (e.g., rivaroxaban) also require higher dose for first few weeks prior to initiating a lower maintenance dose; VKAs do not require loading dose

18 years man -History: recurrent hemarthroses and severe mucosal bleeding (Hemophilia A) -Occasional breakthrough bleeding despite prophylactic VIII infusions -Testing= has inhibitor alloantibodies against factor VIII, and factor replacement products can no longer be used -Treatment= medication that prevents bleeding by mimicking function of factor VIII -Mechanism? a)Anchoring platelets to subendothelial collagen b)Binding of factor VIIa to mediate factor X activation c)Cleaving non Willebrand factor multimers d)Cross-linking fibrin molecules e)Linking factors IXa and X to create activated X (Xa)

answer: Linking factors IXa and X to create activated X (Xa) -Hemophilia A (X-linked recessive)= mutations to genes encoding clotting factor VIII -Factor VIII is part of intrinsic coagulation cascade, it acts as a bridging protein that brings together the catalytic component of factor IXa (the protease) with factor X (the substrate), thereby amplifying formation of factor Xa, which promotes fibrin clots -Treatment: factor VIII replacement products (e.g., factor VIII concentrate from plasma); long-term efficacy is limited by formation of neutralizing antibodies (factor VIII inhibitors) -Emicizumab, a bispecific monoclonal antibody, mimics normal physiologic function of factor VIII and can be used to prevent or treat bleeding in patients who have factor VIII inhibitors= this antibody has 2 binding sites= one site to bind factor IXa and the other binds to factor X, which brings them into close proximity and allows factor IXa to cleave factor X into its active form option A= vWF, large glycoprotein produced by endothelium, aids platelet clot formation by binding platelets to subendothelial collagen at sites of injury; also carrier protein for factor VIII; patients with vWD will have mild deficiencies in factor VIII option B= extrinsic pathway= tissue trauma= factor VII + tissue factor= factor X activation option C= vWF multimers are cleaved to smaller subunits by metalloprotease ADAMTS13; loss of ADAMTS13 leads to thrombotic thrombocytopenia purpura option D= factor XIIIa cross-links loose fibrin molecules into a dense network, thereby forming stable fibrin clots

61 years man -Tingling of hands and feet; history: diffuse large B cell lymphoma and has received several cycles of systemic chemotherapy including cyclophosphamide, doxorubicin and vincristine -Exam: symmetric distal neuropathy in a "stocking and glove) distribution -Drug responsible for symptoms inhibit which phase of cell cycle? a)G0 b)M c)G1 d)S e)G2

answer: M -Diffuse large B cell lymphoma (most common type of non-Hodgkin lymphoma) has peripheral neuropathy likely due to vincristine -The vinca alkaloids (e.g., vincristine, vinblastine)= inhibit microtubule formation (they bind beta-tubulin, preventing polymerization of microtubule proteins)= cell-cycle specific cytotoxicity (during the M phase) as the replicated chromosomes are unable to align and subsequently unable to segregate into daughter cells -Vincristine is most classically associated with neurotoxicity, which is often dose-related and most commonly present as peripheral neuropathy -Neurotoxicity likely results from disruption of neuronal microtubules, which are responsible for transporting organelles and other cellular products between the neuronal cell body and axon terminals -Taxanes also inhibit M phase -Some agents are cell-cycle nonspecific; cyclophosphamide (alkylating agent that causes bone marrow suppression, alopecia, and hemorrhagic cystitis) option A= resting stage option C= cells in this phase prepare the building blocks for DNA synthesis option D= DNA replication during this phase; topoisomerase I and II inhibitors (e.g., etoposide, irinotecan) as well as antimetabolites (e.g., methotrexate, 5-fluorouracil) function during this phase option E= DNA is checked for errors and corrections are made if possible; If corrections can't be made then apoptosis will result unless loss-of-function mutations to the genes controlling this process are present, a condition frequently encountered in tumor cells; drugs that intercalate DNA and induce free radical formation function here (bleomycin= causes pulmonary fibrosis; doxorubicin= cardiomyopathy

5 years girl -Evaluation of rash; mother noticed few red spots on child's cheeks this morning, subsequently spread to neck and trunk as day progressed -History: partial complex seizures (controlled with carbamazepine) -Lips slightly pale, and oropharynx is clear, no lymphadenopathy -Skin= flat, red, pinpoint lesions that don't blanch on face, neck, trunk and extremities -Labs: anemia, thrombocytopenia, leukopenia -Peripheral smear: paucity of cells with normal morphology of all cell lines; mechanism of symptoms? a)Autoantibodies against hematopoietic stem cells b)Impaired DNA synthesis due to vitamin deficiency a)Medication-associated adverse effect b)Peripheral cell sequestration in splenic sinusoids c)Thrombotic microangiopathic hemolysis

answer: Medication-associated adverse effect Takes carbamazepine, developed pancytopenia with normal morphology= drug-induced aplastic anemia; aplastic anemia (form of bone marrow failure caused by damage to multipotent hematopoietic stem cells); most are due to direct toxicity to hematopoietic stem cells or alteration of stem cell surface antigens (leads to destruction by cytotoxic lymphocytes) Aplastic anemia can be idiopathic; often triggered by ionizing radiation, toxic chemicals, viral infections, or medications; drug-induced AA is categorized as follows: -dose-dependent reactions are caused by medications (e.g., chemotherapy, immunosuppressives) that are toxic to bone marrow when drug levels exceed certain concentration of a certain period (predictable in onset) -Idiosyncratic reactions are often caused by antiseizure medications (e.g., carbamazepine, valproic acid), sulfonamides, or nifedipine; they are unpredictable, unrelated to dose of drug, and may occur at any point of therapy (mechanism is unclear, likely genetic mutations in metabolizing enzymes or efflux pumps) Because multipotent hematopoietic cells generate all mature blood cells, patients with AA usually have signs of pancytopenia (petechiae, bleeding; pale mucous membranes; infections); biopsy= hypocellular marrow with lipidoses option A= autoantibodies not part of aplastic anemia mechanism option B= leads to hypersegmented neutrophils, macrocytic RBCs on peripheral smear because of delayed nuclear maturation option D= hypersplenism can cause sequestration with increased destruction of blood cells in splenic sinusoids; most cases arise in those with portal hypertension, which leads to increase in splenic volume and activity; cytopenia can occur, but usually mild and doesn't cause symptoms option E= associated with clot formation in microvasculature and shearing of red blood cells, leading to thrombocytopenia (e.g., petechiae) and anemia; peripheral blood smear would reveal schistocytes

62 years woman -Refractory nausea and vomiting -Diagnosed with ovarian cancer and underwent surgery and on highly emetogenic adjuvant chemotherapy -Takes ondansetron around the clock, but still vomiting -Exam is normal; additional therapy blocking which receptors would be useful? a)Endogenous opioid b)Motilin c)Neurokinin-1 d)Neuropeptide Y e)Nicotinic acetylcholine

answer: Neurokinin-1 -Vomiting is a reflex that can be activated by either humoral or neuronal stimuli -Area postrema in the 4th ventricle has a chemoreceptor trigger zone that can respond to many neurotransmitters, drugs or toxins -The nucleus tractus solitarius (NTS) in the medulla receives information from the area postrema, GI tract via vagus nerve, vestibular system and CNS (e.g., meninges, hypothalamus). Neurons from NTS project to other medullary nuclei and coordinate the vomiting process -The 5 major receptors involved in stimulating the vomiting reflex in the area postrema and adjacent vomiting center nuclei are M1 muscarinic, D2 dopaminergic, H1 histaminic, 5-HT3 serotonergic, and neurokinin 1 receptors -5-HT3 receptor antagonists (e.g., ondansetron) and dopamine receptor antagonists (e.g., metoclopramide) are particularly helpful for chemotherapy-induced vomiting. When these do not control symptoms, NK1 receptor antagonists (prevent substance P releases) can be considered, they prevent both acute vomiting and delayed emesis associated with chemotherapy option A= opioid receptor antagonists (e.g., naltrexone) competitively bind opioid receptors to prevent action of endogenous or exogenous opioids. They are used mainly for opioid dependence option B= regulates interdigestive migrating contractions. Erythromycin is a motilin receptor agonist used for gastroparesis option D= is a polypeptide neurotransmitter found in the CNS and ANS. It is thought to play a role in appetite and pain perception. NPY antagonists have been investigated as potential antiobesity drugs option E= nicotinic antagonists are primarily used for muscle paralysis during surgery. Some antihistamines (e.g., promethazine, meclizine) and antimuscarinics (e.g., scopolamine) have anticholinergic activity and inhibitory effects on both the vomiting center and vestibular apparatus= useful for motion sickness

72 years woman -Brought to ED due to shortness of breath, tachypnea and pleuritic chest pain (similar episode 3 weeks ago; takes warfarin since) -Labs: PT (18 secs) and INR (1.6) -Patient's INR is subtherapeutic compared to target of 2.0-3.0 with warfarin -Patient taking which medication? a)Acetaminophen b)Amiodarone c)Aspirin d)Cimetidine e)Diazepam f)Indomethacin g)Metronidazole h)Oxycodone i)Phenytoin

answer: Phenytoin -Pleuritic chest pain, dyspnea, tachypnea, tachycardia and hypoxia= recurrent pulmonary embolism in setting of a subtherapeutic INR level, reflecting decreased warfarin efficacy -Warfarin is an oral anticoagulant that inhibits activation of vitamin K-dependent clotting factors, particularly factor VII= warfarin prolongs PT and INR (compared to normal) -in patients with atrial fibrillation, DVT, or PE who are taking warfarin for anticoagulation, the dose is usually adjusted to achieve a target therapeutic INR range (generally 2.0-3.0) -Warfarin elimination occurs mainly via hepatic metabolism by cytochrome P450 enzymes= 1) drugs that increase P450 activity, increase warfarin elimination (phenytoin, phenobarbital, rifampin)= subtherapeutic INR -Increased vitamin K intake during therapy, or cholestyramine (binds warfarin) in the intestines= can also decrease warfarin therapeutic effect option A, C, F= aspirin and other NSAIDs increase risk of bleeding due to antiplatelet effects and GI ulcerations; can also displace warfarin from plasma protein binding sites (increasing concentration of free warfarin); acetaminophen can interfere with vitamin K metabolism and enhance effect of warfarin option B, D, G= inhibit P450; increase warfarin effects

63 years man -Sudden chest pain and dyspnea -History: glioblastoma multiforme (radiation therapy) -CT pulmonary angiogram= left-sided pulmonary embolism -Started on continuous unfractioned heparin infusion -Hours later= severe headache and quickly becomes unconscious -CT= bleeding into tumor; after stopping heparin infusion; administration of causes reversal of anticoagulation? a)Fresh frozen plasma b)Platelets c)Protamine d)Prothrombin complex concentrate e)Tranexamic acid f)Vitamin K

answer: Protamine -Heparin increases the effect of naturally occurring anticoagulant antithrombin III (AT III) (aPTT is measured to monitor therapeutic effect of heparin) -Bleeding and heparin induced thrombocytopenia are serious complication of heparin therapy -Bleeding due to heparin toxicity is treated with protamine sulfate, a specific antagonist; protamine sulfate is a peptide that binds to heparin, forming a complex that has no anticoagulant activity (doesn't completely reverse anti-Xa activity of LMWH) -Vitamin K is used for reversal of warfarin overdose but requires new synthesis of coagulation factors (full effect takes time to manifest); in setting of acute life-threatening bleeding due to warfarin, fresh frozen plasma (contains all blood proteins and clotting factors) should be given -However, FFP is not useful for heparin overdose as it contains ATIII, which can further potentiate effects of heparin -Prothrombin complex concentration, which contain the vitamin K dependent factors II, VII, IX, and X, can be used to treat bleeding due to warfarin (not heparin) overdose option E= aminocaproic acid and tranexamic acid inhibit fibrinolysis by inhibiting plasminogen activation

68 years man -Lightheadedness, generalized weakness and palpitations -History: hypertension (takes amlodipine); pulse is high and irregular -ECG= irregularly irregular rhythm and absent P waves -Started on beta blockers for rate control; long term anticoagulation is initiated to prevent atrial thrombus formation (discharge on warfarin); best test to monitor anticoagulation? a)Activated partial thromboplastin time b)Bleeding time c)Fibrin split products d)Fibrinogen levels e)Prothrombin time

answer: Prothrombin time -ECG= suggests atrial fibrillation, which alters cardiac flow dynamics, making thrombus formation more common -If thrombus detaches from atrial wall= risk of stroke -Oral anticoagulant warfarin (coumadin) reduces thrombus formation risk by inhibiting activation of vitamin K dependent clotting factors II, VII, IX, X (vitamin K antagonist)= decreased levels of these factors, particularly factor VII, and therefore prolongs prothrombin time -Another useful lab value is the INR, a ratio of the patient's PT to a control (usual INR target for AF: 2.0-3.0) -Examples of indications include AF, DVT, and PE; outpatients who take warfarin typically have their INR checked every few weeks (more frequently initially) -Most common side effect= excessive anticoagulation leading to bleeding (which can require vitamin K and fresh frozen plasma if rapid reversal is needed); -skin necrosis can occur during the first few days of treatment due to transient hypercoagulable state (reduction in protein C anticoagulant activity before affecting other coagulating factors)= for this reason, heparin is typically administered temporarily at the start of warfarin therapy ("heparin bridge"). -Warfarin should not be used during pregnancy because it is teratogenic and can cause fetal bleeding option A= used to monitor unfractioned heparin which primarily affects intrinsic coagulation pathway option B= used for assessment of platelet function; increased bleeding time can be seen with thrombocytopenia, vWD, defects of platelet aggregation, DIC and aspirin therapy option C and D= decreased in DIC

-age: elderly -Diagnosis: aggressive non-Hodgkin's lymphoma -Tumor cells stain strongly for the CD20 marker -Biologic agent? a)Infliximab b)Rituximab c)Interleukin-2 d)Imatinib e)Abciximab

answer: Rituximab -Lymphoma that expresses surface CD20, a B cell marker -Rituximab is a monoclonal antibody used in lymphoma immunotherapy that specifically targets CD20 -Another monoclonal antibody used in cancer treatment is trastuzumab (Herceptin), used in breast cancer treatment option A= chimeric (human/murine) IgG1 monoclonal antibody to TNF-alpha; significant impact on management of RA; can be used for ankylosing spondylitis and fistulizing Crohn's disease too option C= cytokine; regulates activation and differentiation of T cells to aid in tumor cell destruction; FDA approved for treatment of renal cell carcinoma and melanoma option D= Diagnosis of CML requires presence of Philadelphia chromosome= BCR/ABL fusion gene; imatinib mesylate is a potent inhibitor of BCR/ABL protein tyrosine kinase; inhibits cellular proliferation of BCR/ABL expressing cells without inducing apoptosis option E= chimeric mouse-human monoclonal antibody against platelet GP IIb/IIIa receptor; blocks final step in platelet aggregation; often administered during angioplasty in patients with acute coronary syndrome

-Cancer cells from 23-year-old man with testicular cancer demonstrate high sensitivity to etoposide -Etoposide= caused double stranded DNA fractures; cause dysfunction in? a)Thymidylate synthase b)Topoisomerase I c)Topoisomerase II d)Microtubules e)Dihydrofolate reductase

answer: Topoisomerase II -Etoposide is a semisynthetic derivative of the plant alkaloid podophyllotoxin, which targets topoisomerase II -Topoisomerases are enzymes that relieve the DNA supercoiling that occurs during DNA replication as a result of separation and unwinding of the double helix -Topoisomerase I makes single stranded nicks to relieve negative supercoiling, while topoisomerase II induces transient breaks in both DNA strands simultaneously to relieve both positive and negative supercoiling -Etoposide and podophyllin specifically inhibit topoisomerase II's ability to seal the strand breaks it induces, causing chromosomal breaks to accumulate and eventual cell death -2 major uses of etoposide= testicular cancer and small cell lung cancer; Podophyllin is used topically for genital warts option A= 5-fluorouracil and 5-deoxyuridine option B= irinotecan and topotecan option D= vincristine and vinblastine; taxanes like paclitaxel too option E= methotrexate

51 years woman -3 weeks ago mammogram= malignancy -Biopsy= invasive ductal carcinoma -Underwent lumpectomy with axillary dissection= no metastatic disease -Immunohistochemical analysis: Estrogen receptor positive, progesterone receptor positive, human epidermal growth factor receptor 2 positive -Adjuvant therapy with monoclonal antibody is initiated; target? a)Estrogen receptor b)Peripheral aromatase enzyme c)Receptor activator of nuclear factor kappa-B ligand d)Tyrosine kinase receptor e)Vascular endothelial growth factor

answer: Tyrosine kinase receptor -Breast carcinoma that is ER positive, PR positive and HER2 positive -Trastuzumab is a monoclonal antibody used in management of HER2 positive breast cancer -it binds a portion of the extracellular domain of HER2 and prevents activation of a transmembrane tyrosine kinase= this downregulates cellular proliferation and promotes apoptosis= approximately 20% of invasive breast cancers overexpress HER2; this can also be found in other solid tumors (e.g., stomach, lung, ovary) option A and B= ER and/or PR overexpression is treated with antiestrogen medications to reduce tumor cell proliferation; premenopausal patients are treated with selective estrogen receptor modulators (e.g., tamoxifen) while postmenopausal women with aromatase inhibitors (e.g., anastrozole, letrozole); but they are not monoclonal antibodies option C= receptor activator of nuclear factor kappa-B (RANKL) activates osteoclasts; RANKL expression on bone may contribute to bone metastases by binding to RANK on tumor cells; Denosumab, a human monoclonal antibody against RANKL is used to reduce skeletal-related events if metastases of bone occurs option E= VEGF which also binds to a tyrosine kinase receptor, induces angiogenesis; VEGF inhibitors, such as the monoclonal antibody bevacizumab has a role in treatment of some metastatic cancers (e.g., colon, lung)

63 years man -1 hour of sudden onset chest pain (after eating, no relief with antacids) -History: hypertension, hyperlipidemia, T2D -ECG= ST depression in inferior leads, and troponin T is positive -Anticoagulants being considered: 1) unfractioned heparin (molecular weight: 5000-30,000 u) 2) enoxaparin (molecular weight: 3000-8000 u) 3) Fondaparinux (molecular weight: pentasaccharide) -Anticoagulant most effective in inactivating thrombin? a)Enoxaparin b)Fondaparinux c)Unfractioned heparin

answer: Unfractioned heparin -Presents with acute coronary syndrome, with ongoing injury as evidenced by positive troponin -Therapy: noy only treating existing clot but also preventing propagation; coagulation cascade amplifies generation of thrombin, which activates platelets to form a plug and also helps convert fibrinogen to fibrin to reinforce platelet plug. Antithrombin can inhibit both factor Xa in the coagulation cascade and also thrombin -Both unfractioned heparin and LMWH contain a pentasaccharide sequence that binds to antithrombin and causes a conformation change that increases its ability to inactivate factor Xa -However, heparin must bind to both antithrombin and thrombin together to form a ternary complex to inactivate thrombin. Only unfractioned heparin (not LMWH) has a pentasaccharide chain long enough (>18 saccharide units) to bind to both antithrombin and thrombin -As a result, unfractioned heparin has equal activity against factor Xa and thrombin option A= LWMH= acts mainly on factor Xa, not thrombin option B= synthetic pentasaccharide factor Xa inhibitor

62 years woman -Worsening anemia; admitted 2 days ago (acute pyelonephritis) -Treatment: IV ceftriaxone, fever and urinary symptoms improved -No history of anemia, or symptoms of urinary or GI bleeding -Labs: low hemoglobin, increased bilirubin -Antibiotics changed to different class= anemia improved; cause of anemia? a)antibody-mediated erythrocyte injury b)Cytokine-mediated iron dysregulation c)Drug-induced myelosuppression d)Erythrocyte enzyme deficiency e)Microthrombi-induced erythrocyte injury

answer: antibody-mediated erythrocyte injury -Anemia + hyperbilirubinemia after ceftriaxone= drug-induced hemolytic anemia -Most common drugs: anti-inflammatory drugs, penicillins, and cephalosporins (e.g., ceftriaxone) -Mechanism either oxidative damage or complement mediated; penicillins and cephalosporins cause hemolysis by binding to erythrocyte surface, which creates a hapten for IgG attachment (antibody coated RBCs are then partially or wholly phagocytized by splenic macrophages, leading to extravascular hemolysis) -Labs: elevated indirect bilirubin, elevated LDH, reticulocytosis, and lowered haptoglobin (binds free hemoglobin); diagnosis confirmed with direct Coombs test, which detects IgG or C3 (complement fragment) on RBC surface option B= anemia of chronic disease; gradual in onset and not associated with hyperbilirubinemia option C= certain antibiotics (e.g., sulfa medications, chloramphenicol) are associated with myelosuppression; cause pancytopenia option D= G6PD deficiency is marked hemolysis in setting of oxidative stress due to infection, oxidizing medication, or oxidative foods option E= severe infections can trigger DIC, a consumptive coagulopathy associated with anemia due to erythrocyte injury from microvascular thrombi, they would have prolonged coagulation times and thrombocytopenia

9 years boy -sickle cell disease brought due to fatigue -Medications: penicillin, hydroxyurea, folic acid -Exam: conjunctival pallor, rest is normal -Low Hb, high MCV, 0.5% reticulocytes low platelets and leukocytes -Cause? a)antibiotic-associated autoimmune hemolysis b)Decreased methyl group donors involved in DNA synthesis c)Loss of complement inhibition in hematopoietic stem cells d)medication-induced inhibition of a nucleic acid synthesis enzyme e)Sequestration of cells in the reticuloendothelial system

answer: medication-induced inhibition of a nucleic acid synthesis enzyme Patient with sickle cell disease has pancytopenia. Pancytopenia is caused by hematopoietic stem cell dysfunction, bone marrow infiltration, or peripheral destruction of mature blood cells -Low reticulocyte count: patients with severe anemia usually have increased reticulocytes due to increased bone marrow erythropoiesis. The presence of pancytopenia with an inappropriately low reticulocyte count usually indicates the bone marrow is impaired and is unable to adequately generate new cells despite strong growth signals (e.g., increased EPO) -Macrocytosis: pancytopenia + macrocytosis= vitamin deficiency (e.g., vitamin B12, folate) or medication (e.g., hydroxyurea) is impairing DNA synthesis in hematopoietic cells Hydroxyurea inhibits ribonucleoside reductase, an enzyme that generates deoxyribonucleoside triphosphates for DNA synthesis/repair= lack of deoxyribonucleoside triphosphates slow erythrocyte nuclear development= decreased cellular division with overall increase in erythrocyte size= high doses of hydroxyurea also impair nuclear development of precursors of leukocytes and thrombocytes= pancytopenia Hydroxyurea is the major disease modifying medication in SCD; it reduces production of mutated beta-globulin gene and increases production of fetal hemoglobin gene, which increases HbF (functions normally; RBCs with HbF are less likely to sickle) option A= autoimmune hemolytic anemia is associated with high reticulocytes due to increased erythropoiesis; reticulocytes have higher MCV than RBCs; but no leukopenia or thrombocytopenia option B= folate is a methyl group donor for synthesis of purines and pyrimidines; folate deficiency impairs DNA synthesis, can lead to pancytopenia and macrocytosis; but patient is taking folic acid option C= paroxysmal nocturnal hemoglobinuria is an acquired disorder of hematopoietic progenitor cells marked by lack of complement inhibitors (CD55, and C59) on erythrocyte surface; hemolytic anemia is primary manifestation, reticulocytosis is common, and pancytopenia only rarely occurs option E= SCD can cause hypersplenism due to splenic congestion with damaged RBCs; can cause pancytopenia, but patients will have splenomegaly and normocytic anemia

-2 antineoplastic drugs inhibit intracellular thymidylate formation -Drug X: can be overcome by N5-formyl-tetrahydrofolate supplementation (drug Y is unaffected by it) -Drugs are? a)Drug X: cytarabine; Drug Y: gemcitabine b)Drug X: fluorouracil; Drug Y: leucovorin c)Drug X: fludarabine; Drug Y: methotrexate d)Drug X: methotrexate; Drug Y: fluorouracil e)Drug X: gemcitabine; Drug Y: fludarabine

answer: option D (Drug X: methotrexate; Drug Y: fluorouracil) -Methotrexate is a folic acid analog that functions by binding and inactivating dihydrofolate reductase, an enzyme responsible for reducing folic acid to tetrahydrofolate -Tetrahydrofolate participates in the transfer of carbon groups in certain intracellular reactions including purine and thymidine synthesis -5-fluorouracil is a pyrimidine analog that primarily functions to inhibit DNA synthesis by inhibition of thymidylate synthetase after enzymatic conversion to its nucleotide floxuridine monophosphate -Methotrexate prevents reduction of folic acid to tetrahydrofolate, while 5-FU binds THF and thymidylate synthetase in a stable-reaction intermediate form, thereby effectively decreasing the amount of thymidylate synthetase available for thymidine synthesis -Leucovorin (N5-formyl-tetrahydrofolate) is a tetrahydrofolate derivative that does not require reduction by dihydrofolate reductase before it can function as a cofactor for thymidylate synthase and other enzymes involved with purine and amino acid synthesis (it bypasses dihydrofolate reductase; thus, can be used for methotrexate toxicity) -5-FU requires presence of THF in order to form complexes with thymidylate synthetase (5-FU= reduced cytotoxicity in cells that are deficient in THF); leucovorin can be used to potentiate toxicity of 5-FU by helping bind thymidylate synthetase option A= cytarabine like 5-FU is a pyrimidine analog antimetabolite that is incorporated into DNA leading to strand termination= doesn't affect folate metabolism; Gemcitabine is another pyrimidine analog that functions like cytarabine, but it is not S-phase specific due to inhibition of ribonucleotide reductase option C= Fludarabine is a deamination-resistant purine analog, inhibits DNA polymerase, DNA primase, DNA ligase, and ribonucleotide reductase; used to treat CLL

68 years man -Sudden onset, severe right lower extremity pain -Exam: right leg is pale and cold to touch with absent distal pulses -Auscultation: irregular tachycardia; ECG: atrial fibrillation -Ultrasonography= arterial embolus; IV heparin infusion is initiated; medication causes? a)Thrombin time: no change; Partial thromboplastin time (PTT): prolonged; Activity of factor Xa: decreased b)Thrombin time: no change; Partial thromboplastin time (PTT): prolonged; Activity of factor Xa: increased c)Thrombin time: prolonged; Partial thromboplastin time (PTT): no change; Activity of factor Xa: increased d)Thrombin time: prolonged; Partial thromboplastin time (PTT): prolonged; Activity of factor Xa: no changed e)Thrombin time: prolonged; Partial thromboplastin time (PTT): prolonged; Activity of factor Xa: decreased

answer: option E (Thrombin time: prolonged; Partial thromboplastin time (PTT): prolonged; Activity of factor Xa: decreased) Heparin is an endogenous anticoagulant that exerts its effect indirectly by binding to antithrombin III, a serine protease inhibitor that irreversibly neutralizes clotting factors. Heparin binding alters the shape of AT III, which converts it from a slow to rapid inactivator of clotting factors and increases its activity >1000 fold AT III inhibits some clotting factors in intrinsic pathway, but mainly inactivates factor Xa and thrombin. Effects: -Prolonged thrombin time: thrombin inactivation is strongest with unfractioned heparin infusion because length of heparin chains in this formulations are longer, which inactivates thrombin more rapidly; LMWH also inactivates thrombin (lesser extent) -Decreased activity of factor Xa: all forms of heparin have strong activity against it (monitored to determine adequate anticoagulation is achieved) -Prolonged partial thromboplastin time: heparin primarily inhibits the intrinsic and final common clotting pathway (thus, PTT is prolonged)