HIGH-YIELD SYSTEMS Hematology and Oncology “Of all that is written, love only what a person has written with his own blood. —Hriedrich Nietzsche “Tused to get stressed out, But my cancer has put everything into perspective.” —Delta Goodser “The best blood will at some time get into a fool or a mosquito.” —Austin O'Malley Study tip: When reviewing oncologic drugs, focus on mechanisms and side effects rather than details of clinical uses, which may be lower yieldEG CORUM PEELE UO e ag RSLS M ORCC eee ECO PEE Erythrocyte Carries O, to tissues and CO, to lungs ‘Anucleate and biconcave EX, with large surface stea-to-xolume ratio fr rapid gas exchange. Life span of 120 days. Source of energy is glucose (90% used in glycolysis, 10% used in HIMP shunt), Membrane contains CHHCO," antiporter, which allows RBCs to export HCO¥ and transport CO, from the periphery to the lungs for elimination. Eyth = red; eyte = cell. Exythroeylosis = polyeythemi Anisocytosis = va Poikilocytosis hematocrit saying shapes. Reticulacyte = immature RBC; reflects cexythroid proliferation, Thrombocyte (platelet) ees Involved in 1° hemostasis, Small eytoplasmie fragment [ derived from megakaryocytes Life span of 8-10 days. When activated by endothelial injury, aggregates with other platelets and interact with fibrinogen to form platelet plug. Contains dense granules (ADP, Ca?) and a granules (6 WE, fibrinogen) Approximately 4 of platelet poo is stored in the spleen avd ‘Thrombocytopenia ort platelet function results in petechiae WF receptor: Gplb. Fibrinogen receptor: Gpllbvllls, Leukocyte Divided into granulocytes (neutrophil, eosinophil, basophil) and mononuclear eels monocytes, lymphocytes). Responsible for defense against infections. Normally 4000 10,000 celisimm’ WBC differential from highest to lowest (normal ranges per USMLE)} Neutrophils (54-62%) Lymphocytes (25-33%) Monocytes (37%) Eosinophils (1-3%) Basophils (0-0.75%) Leuk = white; cyte = cell, Neutrophils Like Making Everything Better < contain ALP, collagenase lysozyme, and e > lactoferrin, Azurophil ~ mf ‘granules (Iysosomes) Hypersegmented polys (3 or more lobes) are seen in vitamin B,,/ folate deficiency. 1 band cells (immature neutrophils) reflect states off myeloid proliferation (bacterial infections, ML). Important neutrophil chemotactic agents: C5a, IL-8, LIB, kallikrein, plateletactivating factorGEE Oe OPO Differentiates into macrophage in tissues Large, kidneyéshaped nucleus £3. Extensive “frosted glass” cytoplasm, PALER TG ANOS eee ALOE Ast ‘Mono = one (nucleus); eyte= eel Monoeyte: in the blood Phagocytoses bacteria, cellular debris, and senescent RBCs EV. Long life in tissues. Macrophages differentiate from citculating blood monocytes. Activated by pinterferon, Can function as antigen-presenting cell via MIC IL Macro = large; phage = eater. Macrophage: in the tissue. Important component of granuloma formation (eg, TB, sarcoidosis) Lipid A from bacterial LPS binds CDI4 on macrophages to initiate septic shock, Eosinophil Ds ~ Defends against helminthic infections (major basic protein), Bilobate nucleus, Packed with large eosinophilic granules of uniform size DI. Highly phagocytic fr antigen- antibody complexes, Produces histaminase and major basi protein (MBP, a helminthotoxin), Kosin = pink dye; phil Causes of eosinophilia Neoplasia Asthma Allergic processes ‘Chronic adrenal insufficiency Parasites (invasive) Basophil Qo a n= Mediates allergic reaction. Densely basophilic granules [J contain heparin (anticoagulant) and histamine (vasodilator), Leukotrienes synthesized and released on demand. Basophilic—staining readily with basie stains Basophilia is uncommon, but ean be a sign of myeloproliferative disease, particularly CML Mast cell ? ® Mediates allergic reaction in local tissues. Mast cells contain basophilic granules and originate from the same precursor as basophils but are not the same cell type E3. Can bind the Fe portion of IgE to membrane. IgE crosslinks ‘upon antigen binding, causing degranulation, which releases histamine, heparin, and veh mma fenevic hana ete Sonuinaterean ee ee tecion ‘o Hemolyticdisease of IgM does not cross placenta; [gC does cross placenta, the newborn Rh~ mothers exposed to fetal Rh bload (often during delivery) may make anti-D IgG. In subsequent pregnancies, anti-D IgG crosses the placenta -» hemolytic disease of the newborn {erythroblastossfetais) in the next fetus that is Rh. Prevented by administration of RhoGAM to Rh= pregnant women daring third trimester, which prevents maternal anti-Rh IgG production, Rh— mothers have anti-D IgG only if previously exposed to Rh+ blood.EEUU Cae Coagulation and kinin pathways Inne eagulaton pathway ANTICOAGULANTS: factor Xa LWP gees eae) earn ret a nbs apiaban,rtorabar) ondaparnux Hemophii A deficiency of actor IN Hemophilia: cere) of acar KOR Hemophilia defen oft ete Kalienaiats brain: ACE activates Badin Segue C2 presahoid PRS LE NSM NOR CC eet ‘alive. ashen ANTICORGULANTS: 1a vombi) hepa eae eticay in ditepae, enor rec bomb bers gatoban, brain engae) Pasrinagen open 6 aepase retepnse, i Tereteise Eco Paina Fvinoytie system ein degaditon = hibedty ain Kalagonst warn “SE eau Hi -cotcor Fin mes tabs cialesbutretprtt coagulation eased ‘inlet ay a Coagulation cascade components Procoagulation ssa recusor LVI BLK GS Oxtived 9 seduced _ CH tame & veanink rate LM, KGS Anticoagulation Thorersmontenatun compe Freee iesemancs) $ Pron scivsed rien — cenit Pasminogen ——» pasrin — Farol: Leenage ofbea mesh 2sextuetona!ceaguiton aor Warfarin inhibits the enzyme vitamin K «epoxide reductase. Neonates lack enteric bacteria, which produce vitamin K. Vitamin K deficiency: § synthesis of factors Il VIL, IX, X, protein C, protein 8 WE earries/protects VIIL Antithrombin inhibits activated forms of factors UI, VIL, IX, X, XI, XIL Heparin enhances the activity of antithrombin. Principal targets of antithrombin: thrombin and factor Xa Factor V Leiden mutation produces a factor V resistant to inhibition by activated protein C {PA is used clinically as a thrombolyticTEU OX AOE LSet COSA NR eR eee OS WESC Platelet plug formation (primary hemostasis) ° e ° ® © ny ccaecaron Enel caage Finger rs Cla recporsardins atts Sree ‘asian tex Praggepslonacars Anlagpeaten ners: eaencabin ued “iy eued Prd NO peed Iromaimseseet| celal eis cy Beedfon Thee ew rms Cangtonensede Thrombogenesis, Formation of insoluble fibrin mesh. Aspirin inhibits eyclooxygenase (TXAy synthesis) Clopidogrel, prasugrel, and tilopidine inhibit ADP-indyced expression of Gpllbvllla Abciximab, eptifibatide, and tirofiban inhibit GpIb directly. Ristocetin activates vWF to bind Gplb, Failure of agglutination with rstoeetin assay occurs is von Willebrand disease and Bernard-Soulier syndrome seeatomcnt cesdeg psi “aire sorcepor + Defcon Grams tombachens te Date ema ‘er yneone ete tina Froweee Bgtine core, Vague engtal cle Ttbir—Tyembonoduln wet 8 LWictoEG CORUM BOLO Sed aR OCS OCS Per ERATE Ton Pathologic RBC forms Tee TE aaa 7a ‘Acanthocyte Liver disease, ‘Acantho = spiny (spur cell) aletalipoproteinemia (tates of cholesterol dysregulation). & a Basophilicstippling — [ Lead poisoning Degmacyte 4» Bo GOPD deficiency (bite cell”) ' Eliptocyte a = Hereditary eliptocytosis. ' Macro-ovalocyte Megaloblastic anemia (also hypersegmented PMNs), marrow failure a Q — Ringed sideroblast Sideroblastic anemia, Excess iron in mitochondeia = pathologic. Schistocyte g DIC, TTP/HUS, HELLP (helmet cell") syndrome, mechanical hemolysis (4, heart valve prosthesis)Tee OER nea Pathologic RBC forms (continued) ASLO M NOR NRC BESS Te ANE _SsuCATEDPATIONT co Sickle cell 0 ‘Sickle cell anemia, Sickling occurs with dehydration, deoxygenation, and at high altitude - Spherocyte Hereditary spherocytosis, drug- and Dacrocyte ("teardrop cell”) Target cell infection-induced hemolytic RBC “sheds a tear” because it's mechanically squeezed out ofits home in the bone matrow. Bone marrow infiltration (eg, myelofibrosis) HDG disease, Asplenia, Liver disease, Thalassemia {17 said the hunter to his Other RBC pathologies TE NRE Heinz bodies Howell Jolly bodies PRO OCT PATROL. Seen in G6PD deficiency; Heinz body-like inclusions seen in ‘Oxidation of Hb -SH groups to -S$—S- + Hb precipitation (Heinz bodies EI), with subsequent phagocytic damage to RBC membrane + bite eels thalassemia, Basophilic nuclear remnants EI found in RBCs Howell folly bodies are normally removed from RBCs by splenic macrophages. Seen in patients with functional hyposplenia or aspleniaEG CORUM BOLO Sed aR OCS OCS ‘Anemias our Terao oe icnenmcaces | (Resinmoe -) (_fareetne 3 bea heey precron ee Tae en Tee) a onamrarin oe =a ([Tralasenins 7) (Gronicherey disease) | Ger, oruwtekrase (— Grticscidara) (Cisipeseeg “Acoso acre aera a spe anomacylesreia unde oge'eamcoojearena Noppeeiceny cov casesmicegnecaebai em Microcytic, hypochromic (MCV < 80 fL) anemia Tron deficiency Vizon due to chronie bleeding (e.g, Gl loss, menorthagia), malnutition/absorption disorders, ort demand (eg, pregnancy} “+ H final step in heme synthesis. Vion, tTIBG, # ferritin, Fatigue, conjunctival pallor EX spoon nails (Koilony Microcytosis and bypochromia E. May manifest as Plummer-Vinson syndrome (triad of iron deficiency anemia, esophageal webs, and atrophic glossts). enjncivapallerin anemia ron deficiency. Nor ices: an pecvoma ental plo aro a-thalassemia Defect: a-globin gene deletions + # orglobin allele deletion: No aglobin. Excess ¥-globin synthesis forms y, (Hb Barts). Incompatible with life cis deletion prevalent in Asian populations; trans _(eauses hydrops fetal deletion prevalent in African populations. 3aallele deletion: HH disease. Very ttle caglobin, Excess globin forms B, (HBH). 12allele deletion: les clinically severe anemiaTee OER nea Microcytic, hypochromic (MCV < 80 fl) anemia (continued) RSL EUSA NOC CC ee gC Ast SRN ROS Brthalassemia Point mutations in spice sites and promoter sequences + 4 B-globin synthesis Prevalent in Mediterranean populations me ded oe me. y ) F “s i Map, [ethalasemia major. note snoop bes aglow apd 2; miceeyss 3h, 58 sehsoorestanow 4.2) Lead poisoning Lead inhibits ferrochelatase and ALA 5 dehydratase ~ + heme synthesis and t RBC protoporphyrin. Also inhibits 1RINA degradation, causing RBCs to retain aggregates of FRNA (basophilic stippling). High risk in old houses with chipped paint Sideroblasticanemia Defect in heme synthesis. Hereditary: Xdinked defect in 6-ALA synthase gene. Causes: genetic, acquired (myelodysplastic syndromes}, and reversible (aleohol is most ‘common; also lead, vitamin B, deficiency, copper deficiency, isoniazid) Brthalassemia minor (heterozygote) = Bechain is underproduced. = Usually asymptomatic = Diagnosis confirmed by t HBA, ( electrophoresis. Brthalassemia major (homozygote) = chain is absent ~ severe anemia [4 requiring blood transfusion (2° hemochromatosis) = Marrow expansion (‘crew cut” on skull + skeletal deformities, “Chipmunk” facies. 35%) on © Extramedullary hematopoiesis (leads to hepatosplenomegaly) rsk of parvovirus BI9-induced aplastic ess. Major + t HF (a7). HDF is protective in the infant and disease becomes symptomatic only after months HbS/B-thalassemia heterozygote: mild to moderate sickle cell disease depending on amount of f-globin production LEAD: ‘Lead Lines on gingivae (Burton lines) and on _metaphyses of lang bones El on xray. Encephalopathy and Erythrocyte basophilic stippling Abdominal colic and sideoblastic Anemia Drops—wrist and foot drop. Dimereaprol and EDTA ate Ist line of teeatment Suecimer used for chelation for kids (It “sucks” to be a kid who eats lead) Ringed sideroblasts (with ironcladen, Prussian blue-stained mitochondsia) seen in bone martow 1 iron, normalil TIBG, t ferstin, “Treatment: pyridoxine (B,, colactor for 6-ALA synthase)Agi) EEUU Cae Macrocytic (MCV > 100 fl) anemia ‘Megaloblastic anemia a e Folate deficiency B,, (cobalamin) deficiency Orotic aciduria Nonmegaloblastic macrocytic anemias scar Impaired DNA synthesis + maturation of nucleus of precursor cells in bone marrow delayed relative to maturation in cytoplasm, Causes: malnutrition (eg, aleoholies malabsorption, drugs (eg, methotrexate, trimethoprim, phenytoin}, requirement eg. pregnancy). ‘Causes: insufficient intake (¢., veganism), ‘malabsorption (eg, Crohn disease), pernicious anemia, Diphyllobothrium latum (fish tapeworm), gastrectomy. Inability to convert orotic acid to UMP {de novo pyrimidine synthesis pathway) because of defect in UMP synthase. Autosomal recessive, Presents in children as failure to thrive, developmental delay, and megalablastic anemia refractory to folate and B,,. No hyperammonemia (vs. ornithine transcarbamylase defeeieney—t orotic acid with hyperammoneria). Macrocstie anemia in which DNA synthesis is unimpaired Causes: alcoholism, liver disease, hypothyroidism, reticulocytosi, PASCUA CSCC ee ECO NaN RBC macrocytosis, hypersegmented neutrophils EL, glositis. normal methylmalonie acid mptoms (vs. B,» deficiency) t homocysteine, t methylmalonie acid Neurologic symptoms: subacute combined degeneration (due to involvement of By in fatty acid pathways and myelin synthesis spinocerebellar tract, lateral corticospinal tract, dorsal column dysfunction, Orotie avidin urine ‘Tieatment: uridine monophosphate to bypass ‘mutated enzyme. RBC macrocytosis without hypersegmented neutrophilsTee OER nea ASLO M NOR NRC BESS Normocytic, Normocytie, normochromic anemias are classified as nonhemelytic or hemolytic. The hemolytic normochromic aner ia anemias ate further classified according to the cause of the hemolysis (intrinsic vs. exteinsic tothe RBC) and by the location of the hemolysis ntuavascular vs. exteavasculay Intravascular hemolysis Findings: # haptoglobin, t LDU, schistocytes and t reticulocytes on blood smear. Characteristic hemoglobinuria, hemosiderinuria, and urobilinogen in urine. Notable causes are mechanical hemolysis (eg. prosthetic valve), paroxysmal noctumal hemoglobinuria, microangiopathic hemolytic anemiss Extravascular hemolysis Findings: macrophages in spleen clear RBCs. Spherocytes in peripheral smear, + LDH, no hhemoglobinuria/hemosiderinaria, t unconjugated bilirubin, which can cause jaundice Nonhemolytic, normocytic anemia ‘Anemia of chronic disease Inflammation - t hepeidin (released by liver, binds ferropostin on intestinal mucosal cells and macrophages, thus inhibiting iron transport) ~ 4 release of ion from macrophages. Associated with conditions such as theumatoid arthritis, SLE, neoplastic disorders, and chronic kidney disease. Aplastic anemia id 2 taused by filure or destruction of myeloid stem cells due to: Radiation and drugs (benzene, chloramphenicol, alkylating agents, antimetabolites) Viral agents (parvovirus BI9, EBY, HIV, HCV) * Fanconi anemia (DNA repair defect) + Idiopathic (immmune mediated, 1° ster cell defect}; may follow acute hepatitis Viton, VTIBC, t ferritin Normocytie, but ean become microcytic ‘Treatment: EPO (chronic kidney disease onl). Paneytopenia characterized by severe anemia, leukopenia, and thrombocytopenia. Normal cell morphology, but bypocellular bone marrow with fatty infiltration EN (dry bone marrow tap). ‘Symptoms: fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection ‘Treatment: withdrawal of offending agent, antithymoeyte globulin, eyelosporine), bone marrow allogralt, RBCiplatelet transfusion, bone marrow stimulation (eg, CM-CSF)Agi) EEUU Cae PASCUA CSCC ee ECO Intrinsichemolytic _E-= extravascular; l= intravascular. Hereditary Defect in proteins interacting with RBC Splenomegaly, aplastic ersis (parvovirus BID spherocytosis (E) G6PD deficiency (VE) Pyruvate kinase deficiency (€) HBC defect (E) Paroxysmal nocturnal hemoglobinuria () Sickle cell anemia (E) OF 44 ‘membrane skeleton and plasma membrane (eg, ankyrin, band 3, protein 42, spectrin) Results in small, round RBCs with less surface area and no central pallor (t MCHC, t red cell distribution width) — premature removal byspleen, Most common enzymatic disorder of RBCs, Xlinked recessive Defect in G6PD — 4 glutathione > t RBC susceptibility to oxidant stress. Hemolytic anemia following oxidant stress (eg, sulfa drugs, antimalarial, infections, fava beans). Autosomal recessive. Defect in pyruvate kinase = FATP = rigid RBCs. Glutamic acid-to-ysine matation in Beglobin. 1 complement mediated RBC lysis (impaired synthesis of GPI anchor for decay-accelerating factor that protects RBC membrane from complement), Acquired mutation in a hematopoietic stem cell. t incidence of acute Teuikemias. IbS point mutation causes a single amino acid replacement in § chain (substitution of elutamic acid with valine) Pathogenesis: low O,, high altitude, or acidosis precipitates siekling (deoxygenated HbS polymerizes) + anemia and vaso-occlusive disease. Newborns are intially asymptomatic because of 1 HDF and # HDS. Heterozygotes (sickle cell trait) also have resistance to malaria, 8% of African Americans carry an HS allele Sickle cells are crescent-shaped RBCs EI. “Crew cut” on skull xray due to marrow expansion from t erythropoiesis {also seen in thalassemia) infection). Labs: osmotic fragility test ®, Normal to 4 MCV with abundance of cells “Treatment: splenectomy. Back pain, hemoglobinuria a few days after oxidant stress Labs: blood smear shows RBCs with Heinz, bodies and bite cells “Stress makes me eat bites of fava beans with Heinz ketchup” Hemolytic anemia in a newborn Patients with HSC (1 of each mattant gene) Ihave milder disease than HBSS patients “Triad: Coombs © hemolytic anemia, pancytopenia, and venous thrombosis, Labs: CDS5/59 © RBCs on flow eytometry ‘Treatment: eculizumab {terminal complement inhibitor), Complications in sickle cll disease: * Aplastic crisis (due to parvovirus B19), * Autosplenectomy (HowelbJolly bodies) = f risk of infection by encapsulated organisms + Splenie infaretsequestration crisis * Salmonella osteomyelitis + Painful crises (vaso-ocelusve): dactylitis (painful swelling of hands/eet), acute chest syndrome, avascular necrosis, stoke Renal papillary necrosis (+ Po in papilla) and microhematuria (medullary infarcts) Diagnosis: hemoglobin electrophoresis. “Treatment: hydroxyurea (t HBF), hydration.Tee OER nea Extrinsic hemolytic normocytic anemia RSL EUSA NOC CC ee gC Ast Autoimmune hemolytic anemia Microangiopathic Macroangiopathic Infections TsCRPTON Warm agglutinin (Ig@)—chronic anemia seen in SLE and CLL and with certain drugs (eg, ‘d-methyldopa) ("warm weather is Great”) Cold agglutinin (IgM)—acute anemia triggered by cold; seen in CLL, Mycoplasma pneumonia infections, and infectious Mononucleosis (Ceold weather is MMMiserable”) Many warm and cold AIHAs are idiopathic in etiology Pathogenesis: RBCs are damaged when passing through obstructed or narrowed vessel lumina Seen in DIC, TTP/HUS, SLE, and malignant hypertension. Prosthetic heart valves and aortic stenosis may also cause hemolytic anemia 2° to mechanical destruction 1 destruction of RBCs (eg, malaria, Babesia) TRONS ‘Autoimmune hemolytic anemias are usually Coombs © Diseet Coombs test—anti-lg antibody (Coombs reagent) added to patient's blood. RBCs agglutinate if RBCs are coated with lg Indirect Coombs testnormal RBCs added to patient’ serum, serum has anti-RBC surface Ig, RBCs agglutinate when Coombs reagent added. Schistocytes (“helmet cell) ate seen on blood smear due to mechanical destruction of RBCs Schistocytes on peripheral blood smear. Lab values in anemia Serum iron. Transferrin or TBC Ferritin 1% transferrin saturation (serum iron/TIBC) Iron Chronie deficiency disease 10) ‘ 1 ¥ 1 10) u - ‘Transferrin—transports iron in blood. ‘TIBC—inditectly measures transferrin, eritin—I* iron storage protcin of body * Evolutionary reasoning—pathogens use citeulating iron to thrive. The body has adapted a system in which iton is stored within the cells of the body and prevents pathogens from acquiring circulating iron Hemo- Pregnancy/ chromatosis OCP use 10) - 4 1) 1 - 7 1 Leukopenias aur Neutropenia Lymphopenia Eosinopenia Teo ‘Absolute neutrophil count < 1500 eellsfmm* Absolute lymphocyte count < 1500 cells/mm { 3000 cellshnmn in children} ats ‘Sepsisipostinfection, drugs including chemotherapy), aplastic anemia, SLE, radiation IY, DiGeorge syndrome, SCID, SLE, corticosteroids radiation, sepsis, postoperative Cushing syndrome, corticosteroids *Corticosteroids cause neutrophilia, despite causing eosinopenia and lymphopenia. Corticosteroids activation of neutrophil adhesion molecules, impairing migration out of the vasculature ta sites of inflammation. In contrast, corticosteroids sequester phils in Iymph nodes and cause apoptosis of lymphocytes.PEUX AOE LST MeO MOCO ROCL Heme synthesis, ‘The porphyrias are hereditary or acquited conditions of defetive heme synthesis that lea tothe Porphyrias,andlead accumulation of heme precursors. Lead inhibits specific enzymes needed in heme synthesis, poisoning leading to a similar condition. como TELE ‘OUTLETS PERNT Lead poisoning Ferrochelatase and Protoporphyrin, ALA Microcytic anemia (basophilic sipping ED, GI = ALA dehydratase (blood) and kidney disease. Sf Children —exporure to lea paint + mental deterioration Adults—eswirnmental exposure batteries, ammunition) -» headache, memory los, » a demyelination Acuteintermittent Porphoblinogen __Porphoblinogen, Symptoms (5 P9) porph deaminase BALA, * Painful abdomen coporphobilinogen + Port wine-colored urine (arine + Polyneuropathy « Paychological disturbances * Precipitated by drugs eg, ytochtome 450 indacer, aleohol, starvation “Treatment licote and heme, which inhibit ALA synthase. Porphyria cutanea Uroporphyrinogen _Uroporphyrin (ea __Blistering cutaneous photosensitivity I. Most tarda decarbowsase colored urine) common porphyria, ‘end tae Dies Cn sig ok woo Orme, set sant | neh erase rephainegen rman ‘nwt Ine Uopentinom mre conoporrose ecnaie soot : a a rene Tasrseacity Theme > LAASmase scaryTEU LOX AOE SX MeCN OCMC ERC SSL aCNWENT High mortality rate with accidental ingestion by children (adult iron tablets may look like eandy) Gell death due to peroxidation of membrane lipids Nausea, vomiting, gastric bleeding, lethargy, scarring leading to Gl obstruction Chelation (eg, IV deferoxamine, oral deferasirox) and dialysis. Coagulation disorders P'P—tests function of common and extrinsic pathway (factors I, I, V, VIL, and X). Defect — 1 PT. PIVT—tests funetion of common and intrinsic pathway (all factors except VII and XII). Defect, “1 PTT, RoR 7 TTT ETS AN NETS Hemophilia A, B, or C Vitamin K deficiency = 1 Intrinsic pathway coagulation defect Ac deficiency of factor VIII = t PPT, Xdinked recessive + B deficiency affctor IX = 1 PTT; Xdinked recessive + deficiency of factorXI = t PTT, autosomal recessive Macrohemorrhage in hemophilia—hematthtoses (bleeding into joints, such askance), easy bruising, bleeding after trauma or surgery (e, dental procedures) ‘Treatment: desmopressin + factor VIII concentrate (A); factor IX concenteate {B); factor XI concentrate (C) ' + General coagulation defect. Bleeding time nor. 1 activation of factor Il, VIL, IX, X, protein C, protein S Platelet disorders Defects in platelet plug formation + t bleeding time (BT) Platelet abnormalities ~ microhemorrhage: mucous membrane bleeding, epistais, petechiae, ppurputa, t bleeding time, possibly decreased platelet count (PC) oan 7s CONT Bernard-Soulier at Defect in platelet plug formation. Large platelets syndrome 4 Gplb = defect in plateletto-vWF adhesion No agglutination on ristocetin cofactor assay Glanzmann - t Defect in platelet phig formation, thrombasthenia 4 Gpllbyllla + defect in plateletto-platelet aggregation, Labs: blood smear shows no platelet clumping. Agelutination with rstocetin cofaetor asay Immune ‘ t ‘Anti-Gpllb/lla antibodies ~ splenic macrophage consumption of thrombocytopenia plateletantibody complex. Commonly duc to viral illness. Labs: t megakaryocytes on bone marrow biopsy. ‘Treatment: steroids, intravenous immunoglobulin ‘Thrombotic ‘ t Inhibition or deficiency of ADAMI 13 (WE metalloprotease) thrombocytopenic = 4 degradation of WWF multimers. purpura Pathogenesis Targe vWF moltimers ~ t platelet adhesion — t platelet regation and thrombosis. bs: schistocytes, t LDH. Symptoms: pentad of neurologic and renal symptoms, fever, thrombocytopenia, and microangiopathic hemolytic anernia, ‘Treatment: plasmapheresis, steroids.Agi) PEUX AOE (ST MT SECO MOCO ROC ROC Mixed platelet and coagulation disorders sR i 7 a Te OREN ‘von Willebrand disease pic = t = ® Intrinsic pathway coagulation defect: § vWF = 1 PTT @WE acts to carnyfproteet factor vutn. Defect in platelet plug formation: 4 WWF + defect in platelettoaWF adhesion, Autosomal dominant. Mild but most common inherited bleeding disorder. Diagnosed in mast cases by rstocetin cofactor assay (G agglutination is diagnostic) Treatment: desmopressin, which releases WWF stored in endothelium, ' ' t t Widespread activation of clotting - deficieney in clotting factors + bleeding state Causes: Sepsis (gram-negative), Trauma, Obstetric complications, acute Pancreatitis, Malignaney, Nephrotic syndrome, ‘Transfusion (STOP Making New Thrombi) Labs: schistocytes, fibrin spit products (o-dimers, # fibrinogen, + factors V and VII "PTT may also be normal in von Willebrand disease. Hereditary thrombosis syndromes leading to hypercoagulability SESE TERT ‘Antithrombin Inherited deficiency of antithrombin: has no direct effect on the PT, PTT, or thrombin time but deficiency diminishes the inerease in PT'T following heparin administration Factor V Leiden Protein Cor S deficiency Prothrombin gene mutation Can also be acquired: renal ful + 1 inhibition of factors Ila and Xa, -inephrotic syndrome + antithrombin loss in urine Production of mutant factor V that i resistant to degradation by activated protein C. Most common cause of inherited bypercoagulability in whites 4 ability to inactivate factors Va and Villa t risk of thrombotic skin necrosis with hemorthage following administration of warfarin Skin and subcutaneous tissue necrosis after warfarin administration — think protein C deficiency. “Protein C Cancels Coagulation.” Mutation in 3” untranslated region ~ t production of prothrombin ~ t plasma levels and venous clotsTee OER nea Blood transfusion therapy RSL EUSA NOC CC ee gC Ast OPO aE ET MCLE Packed RBCs T Hb and O, carrying capacity ‘Acute blood oss, severe anemia Platelets 1 platelet count (1 -5000/mm*funit) ‘Stop significant bleeding (thrombocytopenia, Fresh frozen plasma Cryoprecipitate * coagulation factor levels Contains fbrnogen, fetor VII, fator XII, WE, and fibronectin qualitative platelet defects) DIC, ‘Coagulation factor deficiencies involving fibrinogen and factor VIIL cirrhosis, immediate warfarin reversal Blood transfusion risks include infection transmission (low), transfusion reactions, iron overload, hypocalcemia (irate isa Ca? chelator), and hyperkalemia (RBCs may lyse in old blood units). Leukemia vs. lymphoma Leukemia Lymphoma Lymphoid or myeloid neoplasm with widespread involvement of bone marrow: ‘Tumor cells are usually found in peripheral blood. Discrete tumor mass arising ftom lymph nodes, Presentations often blur definitions Leukemoid reaction Acute inflammatory response to infection. t WBC count with t neutrophils and neutrophil precursors such as band cells (left shift) leukocyte alkaline phosphatase (LAP). Contrast with CML falso t WBC count with left shift, but | LAP) Hodgkin vs. non-Hodgkin lymphoma Hodgkin Localized, single group of nodes; extranodal rate; contiguous spread (stage is strongest predictor of prognosis). Prognosis is much better than with non-Hodgkin lymphoma Characterized by Reed-Stemnberg cells Bimodal distibution-young adulthood and > 55 yeats; more common in men except for nodular sclerosing type. Strongly associated with EBV. Constitutional (°B”) signslsymptoms: low-grade fever, night sweats, weight oss Non-Hodgkin ‘Multiple, peripheral nodes; extranodal involvement common; noncontiguous spread. ‘Majority involve B cells (except those of lymphoblastic T-cell origin) Peak incidence for certain subtypes at 20-40 years old “May be associated with HIV and autoimmune diseases Fewer constitutional signsisymmptoms400 SECTION INI | HEMATOLOGY AND ONCOLOGY __> HEMATOLOGY AND ONCOLOGY—PATHOLOGY Reed-Sternbergecells Distinctive tumor giant cell seen in Hodgkin 2 owl eyes x 15, disease; binucleate or bilobed with the 2 halves mgr as mirror images (“owl eyes” EI). RS cells are CDIS+ and CD30+ B-cell origin. Necessary but not sufficient fora diagnosis of Hodgkin disease, Better prognosis with strong stromal or lymphocytic reaction against RS cell Nodular sclerosing form most common (affects women and men equally) Lymphocyte-rich form has best prognosis. Lymphocyte mixed oF depleted forms have worse prognosis Non-Hodgkin lymphoma a acu aoe oan Neoplasms of mature 8 cells Burkitt lymphoma Adolescents or young —_8;14)—translocation adults ‘of e-mye (8) and heavy-chain Ig (M4) (arrows) Associated with EBV. Jaw lesion [J in endemie form in Africa; pelvis ‘or abdomen in sporadie form, "appearance E1,sheets of tes with interspersed macrophages Diffuselarge B-cell Usually older adults, ‘Most common type of non-Hodgkin lymphoma lymphoma but 20% in children in adults Follicularlymphoma Adults {(14:18)—tuanslocation Indolent course; Bel2 inhibits apoptosis. of heavy-chain Ig (14) Presents with painless “waxing and waning” and BCL-2 (18) Iymphadenopathy. Nodular, small cell; cleaved nuclei Mantle celllymphoma Older males {(IH)—translocation CD54. of eyelin DI (11) and heavy-chain Ig (4) Neoplasms of mature T cells, ‘Adult T-celllymphoma Adults Caused by HTLV Adults present with cutaneous lesions; especially fassociated with IV affeets populations in Japan, West Africa, and) drug abuse) the Caribbean Lytic bone lesions, hypercalcemia Mycosis fungoides/ Adults ‘Mycosis fungoides presents with skin patches [3 Sézary syndrome f plaques (cutaneous Teeell lymphoma}, characterized by atypical CD4+ cells with “cetebriform” nuclei. May progress to Sézary syndrome (T-cell leukemia)Cee U 16d a POROUS eee UOC WLS Multiple myeloma Monoclonal plasma cell (“fied egg” ‘Think CRAB: appearance) cancer that asses in the marrow HyperCaleemia and produces large amounts of IgG (55%) or Renal involvement f\ Mite IgA (25%), Most common I°tumorarising Anemia ‘within bone in people > 40-50 years old Bone lytic lesions/Back pain Associated with ‘Multiple Myeloma: Monoclonal M protein spike Distinguish from Waldenstrm rmacroglobulinemia + M spike = IgM = hyperviscosity syndrome (eg, blurred vision, Raynaud phenomenon); no "CRAB" * Primary amyloidosis (AL) * Punched-out Iie bone lesions on xay EI + Mapike on serum protein electrophoresis ® Ig light chains in urine (Bence Jones findings protein) + Roulen formation [1 (RBCs tacked like poker chips in blood smear) Numerous plasma cells [with “elock-face” chromatin and intracytoplasmic inclusions containing immunoglobalin Monoclonal gammopathy of undetermined significance (MGUS)—monoclonal expansion ‘of plasma cells, asymptomatic, may lead to multiple myeloma, No “CRAB” findings Patients with MGUS develop multiple myeloma at a rate of 1-2% per year Myelodysplastic Stem-cell disorders involving ineffective Pseudo-Pelger-Huet anomaly—neutrophils syndromes hematopoiesis defects in cell maturation of with bilobed nuclei. Typically seen after all nonlymphoid lineages. Caused by de novo chemotherapy. ns or environmental exposure (¢g, benzene, chemotherapy). Risk of transformation to AML.EG CORUM BOLO Sed aR OCS OCS Leukemi Unregulated growth and differentiation of WBCs in bone marrow ~ marrow failure -+ anemia (1 RBCs, infections (4 mature WBCs), and hemorrhage (t platelets). or } number of circulating WBC: Leukemie cell infiltration of liver, spleen, Iymph nodes, and skin (leukemia cutis) possible, Tt FERPA HOCO SNE cous Lymphoid neoplasms ‘Acute lymphoblastic Age: < IS years. cell ALL can present as mediastinal mass (presenting as SVC- leukemia/lymphoma Associated with Down syndrome. (au) Peripheral blood and bone marrow have 111 lymphoblasts EX “TAT (marker of pre-T and pre-B cells), CD10+ (pre-B cells only) Most responsive to therapy May spread to CNS and tests. (12,21) + better prognosis. Smalllymphocytic Age: > 60 years. Most common adull leukemia. CD20+, CD5+ B-cell neoplasm. Often c syndrome). lymphoma (SLLI/ asymptomatic, progresses slowly; smudge cells [Jin peripheral blood smear; autoimmune chronic lymphocytic hemolytic anemia leukemia (CLL) SLL same as CLL except CLL has t peripheral blood lymphocytosis or bone marrow involvement Hairy cellleukemia Age: Adults. Mature B-cell tumor in the elderly. Cells have filamentous, hait-ike projections [3 ‘Causes martow fibrosis ~ dry tap on aspiration, Stains TRAP (tartrate-resistant acid phosphatase ©). TRAP stain largely replaced with flow cytometry Treatment: cladribine, pentostatin. ‘Myeloid neoplasms Acute myelogenous Age: median onset 6 years. Auer rods Ds peroxidase @ cytoplasmic inclusions seen most leukemia (AML) AML, 111 circulating myeloblasts on peripheral smear, adults Risk factors: prior exposute to alkylating chemotherapy, radiation, myeloproiferaive disorders, Down syndrome. (15317) + M3 AML subtype responds to allrans retinoic acid (vitamin A), inducing differentiation of myetoblasts; DIC is a common presentation in MB Chronic myelogenous Age: peak incidence 45-85 years, median age at diagnosis 64 years. Defined by the Philadelphia leukemia (CML) chromosome it[;22], BCR-ABL}; myeloid stem cell proliferation; presents with t neutrophils, ‘metamyelocytes, basophils [3 splenomegaly; may accelerate and transform to AML or ALL. (last crisis’) Very low LAP as a result of low activity in mature granulocytes (vs, leukemoid reaction, in which LAP is t) Responds to imatinib (a small-molecule inhibitor of the ber-ab tyrosine kinase. BESS BasieTee OER nea Chromosomal translocations ASLO M NOR NRC BESS TRANSLOCATION SCTE DRERGER 18:14) Burkitt lymphoma femye activation) {(9:22) (Philadelphia CML (BCRABL hybrid) Philadelphia CreaML cheese chromosome) tc) Mantle cell lymphoma (cyclin Di activation) 14:18) Follicular lymphoma (BCL-2 activation) 40517) MB type of AML Responds to all-trans retinoie avid Langerhans cell Collective group of proliferative disorders of histiocytosis dendritic (Langerhans) cells, Presents ina child as lytic bone lesions EV and skin rash ot as recurrent otitis media with a mass involving. the mastoid bone. Cells ate functionally immature and do not effectively stimulate primary’T cells via antigen presentation Cells express $-100 (mesodermal origin) and CDla, Birbeck granules (“tennis rackets” or tod shaped on EM) are characteristicAgi) Chronic myeloprol lisorders rative Polycythemia vera Essential thrombocytosis, Myelofibrosis PEUX AOE (ST MT SECO MOCO ROC ROC ‘The myeloptoliferative disorders represent an often-overlapping spectrum, but the lassie findings are described below. JAK2 is involved in hematopoietic growth factor signaling. JAK2 gene ‘mutation is often found in chronic myeloproliferative disorders except CML (which has BCRABL translocation) Disorder of t hematocrit, often associated with JAK2 mutation. May present as intense itching after hot shower (due tot basophils). Rate but classic symplom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodie blood clots in vessels ofthe extremities 2 polyeythemi: tural or alifical tin EPO levels. Similar to polycythemia vera but specific for overproduction of abnormal platelets ~ bleeding, thrombosis. Bone marrow contains enlarged megakaryocytes Obliteration of bone marrow due tot fibroblast activity in response to proliferation of monoclonal cell lines [3 “Teardrop” RBCs and immature forms of the myeloid line. “Bone marrow is erying because i’ fibrosed and is a dry tap.” Often associated with massive splenomegaly. as Wier mas PALADIN GRONOSOHE AC UAT Polycythemiavera ft t t 6 @ Essential - - t ° © 30-50%) thrombocytosis Myelofibrosis + Variable Variable © © (30-50%) ML + t o Polycythemia PUBNRTOTORE RICH TamRATON OTE eT Relative + - - = ¥ plasma volume (dehydration, burns) Appropriate absolute — t 4 t Lang disease, congenital heart disease, high altitude, Inappropriate absolute — t - t Renal cell eareinoma, hepatocellular carcinoma, hydronephrosis, Due to ectopic KPO. Polycythemiavera tt - 1 EPO 4 in PCY due to negative feedback suppressing renal EPO production,GEESE Ce Ma CAE CSCC eee UCR MESSE Cena Heparin ec ‘Activator of antithrombin; | thrombin and # factor Xa. Short half comcast Immediate anticoagulation for pulmonary embolism (PE), acute coronary syndrome, MI, deep venous thrombosis (DVT), Used during pregnancy (does not cross placenta) Follow PTT. roe Bleeding, thrombocytopenia (HIT), osteoporosis, drug-drug interactions. For rapid reversal {antidote}, use protamine sulfate (positively charged molecule that binds negatively charged heparin) nates Low-moleculareweight heparins (¢ , enoxaparin, dateparin) and fondaparinux act more on factor Xa, have better bioavailability, and 2-4 times longer halflife; can be administered subeutaneously and without laboratory monitoring, Not easly ceversible. Heparin-induced thrombocytopenia (HIT)—development of IgG antibodies against heparin- bound platelet factor 4 (PIF4), Antibody-heparin-PF4 complex activates platelets > thrombosis and thrombocytopenia, Argatroban, Bivalirudin is related to hiradin, the anticoagulant used by leeches; inhibit thrombin directly bivalirudin, Alternatives to heparin for anticoagulating patients with HIT dabigatran Warfarin econ Interferes with earboxylation of vitamin K- ‘The EX-PresidenT went to war(arin}. dependent clotting factors Il, VIL, IX, and X, and proteins C and S. Metabolism affected by polymorphisms in the gene for vitamin K epoxide reductase complex (VKORC) In laboratory assay, has effect on EXtrinsic pathway and t PT. Long halflife. cuncausse Chronic anticoagulation (eg, venous thromboembolism prophylaxis, and prevention of stoke in atrial fibrillation). Not used in pregnant women (because warfarin, unlike heparin, crosses placenta. Follow PTYINR, onary Bleeding, teratogenic, skiniissue necrosis For reversal of warfarin, give vitamin K. LL drugedrug interactions, Proteins C and $ have shorter halFlives than clotting factors II, VI, IX, and X, resulting in early transient hypercoagulability with warfarin use Skinftissue necrosis believed to be de to small vessel microthromboses. For rapid reversal, give fresh frozen plasma, Heparin “bridging”: heparin frequently used ‘when starting warfarin, Heparin’s activation of, initial, transient hypercoagulable state caused by warfarin. Initial heparin therapy reduces isk of recurrent venous thromboembolism and skinvtissue nectoss,06 ___ section Heparin vs. warfarin smuctt AOUTEOFAoMMsTRATON smreoracio onseroF acon censor con uRatouoF acon waaisconuuaiowe veo ouroan asstsmuacen EEUU Cae Heparin Large, anionic, acidic polymer Parenteral (IV, SC) Blood Rapid (seconds) Activates antithrombin, which 4 the action of. Ila (thrombin) and factor Xa Acute (hous) Yes Protamine sulfate PLT fintrinsie pathway) No RSLS Me NORRIS EA Warfarin Small, amphipathie molecule Oral Liver Slow, limited by half-lives of normal clotting factors Innpais activation of vitamin K-dependent clotting factors I, VIL, IX, and X, and anti- clotting proteins C and $ Chronie (days) No Vitamin K, feesh frozen plasma PITINR (extrinsic pathway) Yes (teratogenic) Direct factor xa Apixaban, rivaroxaban, inhibitors ecu Bind to and directly inhibit factor Xa carers ‘Treatment and prophylaxis for DVT and PE (rivaroxaban); stroke prophylaxis in patients with atrial fibrillation. ‘Oral agents do not usually requite coagulation monitorin tony Bleeding (no reversal agent available) Thrombolytics Alteplase (PA), reteplase (#PA), streptokinase, tenecteplase (TNK-PA. ec Directly or indirectly aid conversion of plasminogen to plasmin, which cleaves thrombin and fibrin clots? PT, t PTT, no change in platelet count. cacase Early ML early ischemic stroke, direct thrombolysis of severe PE, row Bleeding, Contraindicated in patients with active bleeding, history of intracranial bleeding, recent surgery, known bleeding diatheses, or severe hypertension Treat toxicity with aminocaproic acid, an inhibitor of fibrinolysis. Fresh frozen plasma and eryoprecipitate can also be used to correct factor deficienciesGEESE Ce Ma CAE CSCC eee UCR MESSE Aspirin cin Inreversibly inhibits cyclooxygenase (both GOX-1 and COX.2) enzyme by covalent acetylation. Platelets cannot synthesize new enzyme, so effect lasts until new platelets are produced: 1 bleeding time, § TA, and prostaglandins. No effect on PT of PTT, cane se Antipyzetic, analgesic, ant-inflammatory, antiplatelet (b aggregation) roxy Gastric ulceration, tinnitus (CN VII), Chronic use can lead to acute renal failure, interstitial nephritis, and upper GI bleeding, Reye syndrome in children with viral infection. Overdose initially causes hyperventilation and respiratory alkalosis, bt transitions to mixed metabolic acidosisrespiratory alkalosis, ADP receptorinhibitors Clopidogrel, prasugiel, ticagrelor (teversible),ticlopidine. cin Inhibit platelet aggregation by irreversibly blocking ADP receptors. Prevent expression of glycoproteins Ib/Ills on platelet surface cuntausst Acute coronary syndrome; coronary stenting # incidence or recurrence of thrombotic stroke. ovary Neutropenia (ticlopidine). TTP may be seen, Cilostazol, dipyridamole ec Phosphodiesterase III inhibitor; t eAMP in platelets, resulting in inhibition of platelet aggregation, vasodilators cuca ust Intermittent claudication, coronary vasodilation, prevention of stoke or TAs (combined with aspirin) angina prophylaxis ovary Nausea, headache, facial flushing, hypotension, abdominal pain. GP llb/llainhibitors Abciximab, eptifibatide, tofiban. cin Bind to the glycoprotein receptor Hb/IIla on activated platelets, preventing aggregation. Abeiximab is made from monoclonal antibody Fab fragments cane se Unstable angina, percutaneous transluminal coronary angioplasty: ron Bleeding, thrombocytopenia,Ae Co Cancer drugs—cell cycle Beomcin poate ‘epone] Antimetaote. Tuthoprne hare ative Shomer ronjres etree ‘eperatonuine ‘Sthoguane EEUU Cae Nba pstroduate G fection oie 6 CO aia W) —~ RSLS Me NORRIS EA Microtubule inhibitors Pale: Vins Alois "nbasine Verse say omer — Cat Camus Antineoplasties Nes AIK > ih A Pte SN Cia donGEESE Ce Ma CAE CSCC eee UCR MESSE Antimetabolites De NT CME Toa ‘Azathioprine, urine (thiol) analogs Preventing organ rejection, Myelosuppression, Gl, liver G-mercaptopurine + b de novo purine synthesis. rheumatoid arthritis, IBD, _ Azathioprine and 6-MP are (6-MP),6-thioguanine Activated by HGPRT. SLE; used to wean patients metabolized by xanthine (676) ‘Azathioprine is metabolized off steroids in chronic disease oxidase; thus both have into 6-MP. Cladribine (2-CDA) Purine analog + multiple mechanisms (eg. inhibition of DNA polymerase, DNA strand breaks) Cytarabine Pyrimidine analog -+ inhibition {arabinofuranosyl ‘of DNA polymerase. S-fluorouracil(5-FU) Pyrimidine analog bioactivated to 5I-dUMP, which, covalently complexes folie acid ‘This complex inhibits thymidylate synthase = 4 dTMP = 1 DNA. synthesis Methotrexate (MTX) Folic acid analog that competitively inhibits dihydrofolate reductase + bdTMP + ENA. synthesis All are S-phase specific and to treat steroid-refractory chronic disease Hairy cell leukemia, Leukemias (AML), lymphomas Colon cancer, pancreatic cancer, basal cell carcinoma topical) neers: Ieukemiz (ALL, lymphomas, chorioearcinoma, sarcomas. Non-neoplastic: ectopic pregnancy, medical abortion (with misoprostl), rheumatoid arthritis, psoriasis, IBD, vasculitis su t Tyme sytase aun 7 ~ sm cys N nF sme HF X fesvease He a * toxicity with allopurinol or febuxosiat Myelosuppression, nephrotoxicity, and neurotoxicity Leukopenia, thrombocytopenia, rmegaloblastic anemia, CYTarabine causes panCYTopenia Myelosuppression, which is not reversible with leucovorin {folinie acid, Myelosuppression, which is reversible with leucovorin Hepatotoxicity Mucositis e.g, mouth ulcers) Pulmonary frosis,Agi) Antitumor antibiotics EEUU Cae RSLS Me NORRIS EA nue Bleomycin actinomycin (actinomycin D) Doxorubicin, daunorubicin TaN Induces free radical formation + breaks in DNA strands. Intercalates in DNA, Generate ftee radicals Interealate in DNA + breaks in DNA = 4 replication MCLE "Testicular cancer, Hodgkin ymphoma Wilms tumor, Ewing sarcoma, rhabdomyosarcoma, Used for childhood tumors ("children act out”), Solid tumors, leukemias, Iymphomas. Tonar Pulmonary fibrosis, skin hyperpigmentation, mucositis, Minimal myelosuppression ‘Myelosuppression Cardiotoxicity (dilated cardiomyopathy), myelosuppression, alopecia, “Toxic to tissues following, extravasation, Dexrazoxane (iron chelating agent), used to prevent cardiotoxicity Alkylating agents hue Busulfan Cyclophosphamide, ifosfamide Nitrosoureas (carmustine, lomustine, semustine, streptozocin) Pen ‘Cross-links DNA. Cross-link DNA at guar N27. Requite biouctivation by liver. Require bioactivation. Cross blood-brain bartier + CNS. Crosslink DNA, aC CML. Also used to ablate patients bone marrow before bone mareow transplantation Solid tumors, leukemia, Iymphomas Brain tumors (including glioblastoma maltiforme), onary Severe myelosuppression (in almost all eases), pulmonary fibrosis, byperpigmentation. Myelosuppression; hhemorthagie cystitis, partially prevented with mesna (thiol ‘group of mesna binds toxic metabolites) CNS toxicity (convulsions, dizziness, ataxia)GELS OER Microtubule inhibitors > HEMATOLOGY AND ONCOLOGY—PHARMACOLOGY | SECTION ve CN MCE Toa Paclitaxel, other taxols Hyperstabilize polymerized Ovarian and breast carcinomas. Myelosuppression, alopecia, :mierotubules in M phase so hypersensitivity. Vincristine, vinblastine that mitotic spindle cannot break down (anaphase cannot occur) “Ibis taxing to stay polymerized.” Vinca alkaloids that bind Solid tumors, leukemias, {Betubulin and inhibit Hodgkin (vinblastine) and its polymerization into non-Hodgkin (vincristine) microtubules ~ prevent Iymphomas. mitotic spindle formation (Mephase arrest Vincristine: neurotoxicity {areflexia, peripheral neuritis), paralytic ileus, Vinblastine blasts bone marrow (suppression). Cisplatin, carboplatin cin Grosslink DNA comcast ‘Testicular, bladder, ovary, and lung carcinomas ovary Nephrotoxicity, ototoxicity: Prevent nephrotoxicity with amifostine (free radical scavenger) and chloride (saline) diuresis, Etoposide, teni icin Etoposide inhibits topoisomerase Il = t DNA degradation cumcaLust Solid tumors (particularly testicular and small cell hing cancer), leukemias, lymphomas. roar Myelosuppression, GI upset, alopecia lrinotecan, topotecan cin Inhibit topoisomerase I and prevent DNA unwinding and replication, cumcaLust Golon cancer (irinotecan); ovarian and small cell lung cancers (topotecan) roxy Severe myelosuppression, diarrhea Hydroxyurea icin Inhibits ribonucleotide reductase ~ + DNA Synthesis (S-phase specific). camcaLuse ina Melanoma, CML, sickle cell disease (t HDF), Severe myelosuppression, Cl upsetAgi) EUCLA OE CCST Ma SUCROSE NSEC Prednisone, prednisolone ces Various; bind intracytoplasmic receptor; alter gene transcription, carmcase ‘Most commonly used glicocorticoids in cancer chemotherapy. Used in CLL, non-Hodgkin lymphoma (part of combination chemotherapy regimen), Also used as immunosuppressants (¢., in autoimmune diseases) tony Cushingllike symptoms, weight gain, central obesity, muscle breakdown, cataracts, acne, ‘osteoporosis, hypertension, peptic ulcers, hyperglycemia, psychosis. Bevacizumab ccs Monoclonal antibody’ against VEGF Inhibits angiogenesis. cancause Solid tumors (colorectal eancer, renal cell carcinoma) ron Hemorthage, blood elots, and impaired wound healing, Erlotinib cs EGER tyrosine kinase inhibitor. camteaLuse Non-small cell lung eateinoma tony Rash Imatinib ec “Tyrosine kinase inhibitor of BCR-ABL (Philadelphia chromosome fusion gene in CML) and c-kit (common in GI stromal tumors) cancaLuse CML, GI stromal tumors. row Fluid setention, Rituximab ec Monoclonal antibody against CD20, which is found on most B-cell neoplasms. cca Non-Hodgkin lymphoma, CLL, IBD, rheumatoid arthritis. row 1 risk of progressive multifocal leukoencephalopathy Tamoxifen, raloxifene econ camaLuse roxtaty Selective estrogen receptor modulators (SERMs)—receptor antagonists in breast and agonists in bone. Block the binding of estrogen to FR © cells Breast cancer treatment (tamoxifen only) and prevention. Raloxifene also useful to prevent osteoporosis. ‘Tamoxifen—partial agonist in endometrium, which tthe risk of endometrial cancer; “hot ashes Raloxifene—no t in endometrial carcinoma because its an estrogen receptor antagonist in endometrial tissue,GEESE Ce Ma CAE CSCC eee UCR MESSE Trastuzumab (Herceptin) coms Monoclonal antibody against HER-2 (-erbB2), a tyrosine kinase receptor. Helps kill cancer cells that overexpress HER-2, through inhibition of HER2 ated cellular signaling and antibody- dependent eytotoxieity cumcaase HER-2& breast cancer and gastric cancer (tas2zumab), row Cardiotoxicity. “Heartceptin” damages the heart Venurafenib econ Small molecule inhibitor of BRAF oncogene ® melanoma cama us Metastatic melanoma Common chemotoxicities isplatin/Carboplatin ~ acoustic nerve damage {and nephrotoxicity) Vincristine -+ peripheral neuropathy Bleomycin, Busulfan - pulmonary fibrosis Doxorubicin -+ cardiotoxicity ‘Trastuzumab — cardiotoxicity Cisplatin/Carboplatin + nephrotoxic (and acoustic nerve damage) ‘CYelophosphamide -+ hemorthagic cystitis 5-FU ~ myelosuppression 6-MB = myelosuppression Methotrexate + myelosuppressionSECTION Il | HEMATOLOGY AND ONCOLOGY Cs