Hematology James Kennedy, Danni Li and Erie Tseng, chapter editors, Ray Guo and Amold Jacob, associate editors Shauna-Dae Phillips, EBM editor Dr. Janey Hsiao, staff editor Basics of Hematology ...2..... 22022000002 ‘Complete Blood Count Blood Film Bone Marrow Aspiration and Biopsy Common Presenting Problems ...... 4 Anemia Polycytheria Thrombocytopenia Thrombocytosis Pancytopenia Neutrophitia| Neutropenia Lymphocytosis Lymphocytopenia, Eosinophilia Agranulocytosis Leukemoid Reactions Approach to Lymphadenopathy ...........10 Approach to Splenomegaly ..............11 Microcytic Anemia ....... suet Iron Metabolism Iron Deficiency Anemia ‘Anemia of Chronic Disease Lead Poisoning Sideroblastic Anemia Thalassemia Normocytic Anemia ..... cee TS Aplastic Anemia 18 Hemolytic Anemi Thalassemia Bota-Thalassemia Minor (Thalassemia Trait) Beta-Thalassemia Major Alpha-Thalassemia Sickie Cell Disease ‘Autoimmune Hemolytic Anemia (AIHA) Microangiopathic Hemolytic Anemia (MAHA) Hereditary Spherocytosis Hereditary Eliptocytosi GEPD Deficiency Macrocytic Anemia 2 Vitamin Bye Deficiency Folate Deficiency Homostasis ..... cece BB ‘Three Phases of Hemostasis Disorders of Primary Hemostasis ..........25 Immune Thrombocytopenic Purpure (ITP) Heparin-Induced Thrambacytopenia (HIT) Thrombotic Thromboeytopenic Purpura (TTP) and Hemolytic Uremic Syndrame (HUS) Von Willebrand's Disease (vWD) Disorders of Secondary Hemostasis .......28 Hemophilia A (Factor Vill Deficiency) Hemophilia B (Factor IX Deficiency) Factor XI Deficiency Liver Disease Vitamin K Deficiency Disseminated Intravascular Coagulation (DIC) Venous Thrombo: wees 80 Approach to Treatment of Venous Thrombosis Hypercoagulable Disorders 82 Hematologic Malignancies me) Myeloid Malignancies .... 33 ‘Acute Myeloid Leukemia (AMAL) Myelodysplastic Syndromes (MDS) Myeloproliferative Neoplasms ............35 Polycythemia Vera (PV) Chronic Myeloid Leukernia (CML) Idiopathic Myelofibrosis (IMF) Essential Thrombocythemia (ET) Lymphoid Malignancies... 239 Acute Lymphoblastic Leukernia (ALL) Lymphomas 40 Hodgkin's Lymphoma Non-Hedgkin’s Lymphoms ‘Malignant Clonal Proliferations of B Cells . ..43 Chronic Lymphocytic Leukemia (CLL) Multiple Myeloma (MM) Light Chain Disease Monoclonal Gammopathy of Unknown Significance (MGUS) Waldenstronys Macroglobulinemia Complications of Hematologic Malignancies . 47 Hyperviscosity Syndrome Tumour Lysis Syndrome Blood Products and Transfusions ..........47 Blood Products Red Blood Cells Platelets Coagulation Factors ‘Acute Blood Transfusion Reactions Delayed Blood Transfusion Reactions ‘Common Medications . 81 Antiplatelet Therapy Anticoagulant Therapy Chemotherapeutic Agents Landmark Hematology Trials ........2..-.54 References 55 “Toronto Notes 2010 Hematology HIHo Hematology ‘Basis of Hematology Toronto Notes 2010, oO FEASTS Reg Curie Hematopotc stem cl Proenthotest Lymphtlast — Manabiast sestyeiay ’ Dn @. BPP a {C4 bess Bey 4 Mopataneblt 3 Of -. O m6 & Basophl —_Ensinophil_—Nevtophil_——Lymphocyte— Mnocyte soe Graioene Agandoere Pte Leos ema Figure 1. Hematopoiesis avez wad ea ie oan at Sites of hematopoiesis in adults: pelvis, sternum, vertebral bodies + lifespan of mature blood cells * exythocytes (120 days); neutrophils (~1 day); platelets (10 days); lymphocytes (aries - memory cells persist for years) + role of lymphoid organs * spleen: part of reticuloendothelial system, removes aged RBCs, removes antibody- Coated bacteriaeells site of antibody production Erect care xg on lugsto peel sss Aatclecyte-nnsueevacie ewrop- ose ie + thymus: site of T-cell maturation, involutes with age ‘ney ‘bapi- rie nresprs fs epee ete aessinens Complete Blood Count atop cn ty ri tigre Aymocr reps climate + Iymph nodes: site of activation of B/T cells (adaptive immune response) Tabla 1. Common Terms Found on CBC — = var io Sees eee ere 2585 Tins erent ein) Avalon cag ain eos ‘HOM gt13 181 rt) tein rrogi wont eae set feoram dosent saet SER na er Some Rie u Manca are) Mme see OM Wea commer nice) Arnount of oxyger-canying Hb inside RBCS ‘2-32 pales Oaeree an cman ds Seay | Mamma eorcnmcnn a nom ee or Fei nemmatow | Rcd (ON) Mest So roams tesa ‘ eee yon | ital Vem rnb tsps ined tors eet rahe i es Sma ot Pret cant ‘erumbarcl pees pr lare ol Hod 18040010}! [cma camga ] tino) Nene ametuer : stash omhulion ine ie Romie .e)_. | ttn eceesiomintiiee, Keane! ERLE NEUTROPENIA “Ga sic d oma as ase“Toronto Notes 200 Basics of Hematology Hematology HS Approach for Interpreting CBCs ‘L.consider abnormal values in the context of individual's baseline @ Up to tof population without disease may have values outside “normal” range + anindividual may display a substantial change from their baseline without violating normal” reference range 2.is one Hneage allected or are several? all lines are down’ consider pancytopenia (ase Pancytopeni, HZ) {RBCs and plateots are down: concider MAHA & {single lineage affected soe coreespondng section in Common Presenting Problems, Ha Blood Film Interpretation naeoootaus Dv Size Schistesyia Sil et Iicrocytic (MCV.<80), normocytic (MCV=#0-100), macroeytic (MCV>100) * anisocytosis: RBCs of variable and abnormal size iton deficiency anemia thalassemia, myelofibrosis oO Oo Toardop col Nucleated RBC Nene bois Spurea! Syne Normal ABC Hypache Sponge nthe seth cent pallor normal thane hind | Mam eo WSs tS) : ‘come iron deficiency anemia, anemia of chronic disease, hemolytic anemias, sideroblastic e@e « polychromasia ~ increased reticulocytes (pinkish-blue cells) Sphoroeyto —Blictoyte increased RBC production by the marrow Shape (see Figure 2) * discocyte - normal (biconcave disc) + poillocytosis: increased proportion of RBCs of abnormal shape * iron deficiency anemia, myelofibrosis + spherocyte spherical RBC (due to loss of membrane) Tages col Burl 1b Gvalepige the RBC ong axe feeds de eng ofthe short axle see ees (oe peer che cdoaes aac {due to abnormal membrane lipids) Se is stn ermin maton etyun tice Distribution (see Figure 2) + rouleaus formation ~ aggregates of REC resembling sacks of coins > cause: increased plasna concentration of high molecular weight proteins + Senin pregnancy amot common cause; due toa physiological increase in fibrinogen} inflammatory conditions (due to polyclonal immunoglobulins), plasma cell dyserasias (de to monoclonal paraprotinemia; eg. multiple myloma, macroglobutinemia), storage artifact Inclusions (see Figure 2) + hucleus~ present in erythroblasts (immature RBCs) * hyperplastic erythropoiesis (scen in hypoxia, hemolytic anemia), extramedullary hematopoiesis (seen with BM infiltration) ‘+ Heinz bodiew denatured and precipitated Nemogiobin Gap defen + Howeltoly bes small nicer remnant eemblingapykotc nucleus tc) + petsponciomy hppa, meas mealies orhiic tipping "deeb panclaton indian seme aggregation

5 lobes suggets megatablastie proces (By 01 folate idengy) + let shift Incrase in granulocyte precursors (bands, metamyelocytes, myclocytes promycloeytes blast) in circulation, sen in acute infetions, pregnancy, hyponi, Brock blasts) immature, undiferentated cells associated with leukemia ‘Auer Tods: clumps of granular materia that form long needles n the cytoplasm of imyeloblass pathognomonic for Acute Myeloid Leukemia (AML) PLATELETS ‘= small purple anuclear cell fragments Bone Marrow Aspiration and Biopsy + sites: posterior iliac crest, sternum + posse analyses * aspiration ~ histology low cytometry, eytogenetics, molecular stadies, microbiology (Ces, AFB) + biopsy ~ for histology (keops tissue structure intact) + Ninoxplained CBC abnormalities + diagnosis and evaluation of plasma cell disorders and feukemias 1 diagnosis and staging of lymphoma or slid tumours + evaluate ion metabolism and stores + valate supectee deposition and storage disease (eg; amyloidosis, Gaucher's disease) 1 cralate fever of undetermined origin, inpcted myeobactoal, Ringel parasite into or anviomain disease + confirm normal hone martow in potential llogenic hematopoietic cell donor Contraindioations + absolute: hemophilia, severe DIC, INR >1.5 + thrombocytopenia nota contraindication ~ may need to transfuse platelets prior Common Presenting Problems Anemia Definition ‘+ a decrease in red blood cell (RBC) mass that ‘concentration, hematocrit (Het), and RBC cot * adull males: Hb <135 g/L, (135 g/dl) or Het 100), normocytic (MCV = 80-100) + if mormocytic, the reticulocyte count helps differentiate between decreased production {decreased relics) and increased destruction loss (increased retics) + causes assodated with decreased production can be * primary (le. bone marrow disorder aplastic anemia, myelophthisic/infiltrative process, hematologic malignancy) oF + Systemic [ee chronic diseave, hypothyroidism, chronic renal failure, liver seas, nutritional (ion, By folate decifiency)] + increased destruction Toss can be due to hypersplenism (sequestration and destruction), hemolytic disorders, blood loss“Toronto Notes 200 ‘Common Presenting Problems Tou Hanon oa FF Terao] [mie] | "tog ¥ A = | [Eee sheen iets ‘tenes amg ck Figure 3. Approach ta Anemia Clinical Features * Symptoms of anemia fatigue, malaise, weakness, dyspnea, decreased exes tolerance, palpitations headache, dizziness, Ennis + acute vs chronic, bleeding, systemic nes, diet, alco, family history serie panyopenia (arent incton, usc Beeding cay bby) BINS HIEENT: pallor in mucous membranes and conjunctiva a Hb <0 g/L (9 g/dL), cular bits at Hb 53 g/L (eB gral) + CVS: tachycardia orthostatic hypotension, systolic lowe murmur, wide pulse pressure, alga of CHF + dermatologic pallor in palmar skin creases at Hb <75 g/L (<75 g/dL, jaundice firduetohemblys) Investigations «rate ont dilutiona anemia (low Hb due to Increased effective circulating volume) CBC with diferent (pay special afention to MCV, RDW) relculeyte count biood fie 1 ditional laboratory investigations as indicated (se Micmeytc Anema FI, Normacyti Anerta, 18, Hemolytic Anemia, HIS and Macrestic anemis, 2) Polycythemia Definition ‘an increase in the number of RBCs: Hb >180 g/L or Het >52% (males); Hb >160 or Het 47% (emates and black males) Etiology + relative /spurlous erythrocytosis (decreased in plasma volume) diuretics, severe duhydration, burns, “stress” (Gaisbick’s syndrome) «absolute erythrocytosis primary, Peete vera PV) ee PY, HS) poor tssue oxygenation /hypon + Bigh ste " + pulmonary disease: COPD, sleep apnes, congenital + Gandiovaccular disease: R-> L shunt + hemoglobinopathies with increased O. affinity {gabon monoxide pooning * Inappropriate production of erythropoietin ‘+ renal cell carcinomas, cerebellar hemangioblastoma, pheoclwomocytoma, hepatocellular cancer, uterine leiomyomas “+ local renal hypoxia ‘= renal artery stenosis + benign ronal eysts (compress vessels) {Senay og ec at an hy * secondary #0 high re cell mass and hyperviscosity hesdacherdizines, itu, Visual disturbances + symptoms of angina, CHE + thrombosis (venous oF arterial) or bleeding (abnormal platelet function) + characteristic physical findings * plethora (rudy complexion) of face 70%), palms Hematology HS6 Hematology ‘Common Presenting Problems “Toronto Notes 2010, Investigations * principally directed at ruling out {RBC mass normal suggest relative erytheocytoss confirms increased ed el production; rules out decreased pasa volume Serum en thropoetn (Epo) ~Inceased suggests autonomous pretuction or hypoxia and rules out PY ® search for tumour as source of Epo as indicated (eg abdominal U/S, CThead) + antral pO, ~ decreased suggests hyponcelology cep studisif story suggestive of seep apnea + catxyhemogfabin(hemoglobin-carbon manonide complex) level, hemoglobin O, any Treatments 1 ifsecondary ~ treat underlying couse * O, for hypoxemia, CPAP for sleep apnea, surgical for EPO-scereting tumours + phlebotomy Thrombocytopenia « platelet count <150.x10°/L jology and Approach + faatitious platelet clumping (Secondary to EDTA antibodies) + hemodilition (e massive fransfsion) + decreased production (disease process occurs in bone marrow) * nutritional e. severe B,9/ folate deficiency) + congenital (€4 Alport’s syndrome, Fancont's anemia) * injury: drugs, toxins, chemotherapy and radiation (acute or chronic damage) + inlilrative: malignancy, leukemia, myelofibrosis “ + failure: aplastic anemia + increased peripheral destction (increase in megakaryocytes in BM) ‘immune mediated: Immune Thrombocytopenic Purpar (ITP), Heparin Induced ‘Thrombocytopenia (HIT), drugs ey Hhvazidcm sulla, quinidine), vial infections (eg HIV, HCV, CMV, EBV), systemic discascs (eg SLE), Iymphoproliferative disoners (64, CLL, lymphoma) alloimmune destricton (eg. post-transtusion, neonatal) + hon-immune mediated: Disseminated Intravascular Coagulation (DIC), Thrombotic ‘Thrombocytopenic Purpurs (TTD), Hemolytic Uremic Syndrome (HUS), Antiphospholipid Ab Syndrome (APLAS), pre-cclampsia and HELLP syndrome (cce Dtsistss OB15) + platelet sequestration * any dscase process that lads to splenomegaly (upto 30% of circulating platelets are rormally in the spleen at any given time) = Seeman | G==] ousiten =" ot Figure 4. Approach to Thrombocytopenia gt oe sn tee Investigations = CBC and diferentist * blood film * decreased production: possible other call line abnormalities, blasts, hypersegmented PMNs, leukoorythroblastic changes * increased destruction: lange platelets, schistocytes (seon in MAHA, eg, DIC)‘Toronto Notes 210 ‘Common Presenting Problems Hematology H7 Thrombocytosis Definition THREE unso 0 \ + Etctive trombocytods acute phase reactant (go trauma, bleeding, ion deficiency, neoplasia) + Stlonins thsimbocpes mists de fo myeloprairaie o myelodysplastic disorder [e mary myofbrosi: pestis vera (PV) injeladysplaticsyndrome OS. AMT . « Senta hrombesytheats Cone ofthe myeloproiferaive disorders, diagnosis of San inflammation, infection, Ciinical Features * hse: aume,sngy planstomy nto, nlammation beng om deen, Prior diagnose of conic hematologic disorder constitutional symplons indicating Polguety instal stam: prtary thrombocytoss more likely to cas vasomotor symptoms * Bleidache,etutl disturbances lightheadedness, aypical chest pan, acral djecstheso sythromellgia vido seteulrn, aquagenie prsian) + Biting risk dd ray bleeding ra { how-apecihe markers of infection or inammation e- CRD, ESR, plasma bxinogen, ferritin) + ifa reactive process has been ruled out, bone marrow biopsy may be required to distinguish among the diferenct causes of autonomous theambs Pancytopenia or Definition 15 decrease in all hematopoietic cell lines Clinical Features anemia ~ fatigue 4 leukopenia ~ recurrent infections « thrombocytopenia ~ mucosal Bleeding and ecchymoses + investigate secondary cause: HIV test, serum Byy RBC folate, ANA 1 often requires bone marrovs biopsy to distinguish among different causes Hypocalla Bt Cela ae + Acquied elastic anemia 1 a see 2 to systenic dssose * iid paste anomia + Myuodyspisia + SLE + Some mysbodolsia syniomes + Hyperspleism + Acuto myologanous laksa “Vit flltedioncy + Ovanveimingiecions 9, bctesair + Alonotam “Tie depression of BM oe * Anoania varoea + Sacidsis + AOS Figur 5. Approach to Paneioena Penn ha retin at site Fete mircrasengamsccyee precasrs nh pelle Inve, metas, rye sts Hower my tinea te om tert fen nesopha. sre, mes reated anon procbon af parce fe. frat, bts. GoSF senna, OM, Neutrophilia Definition ‘ increase in absolute neutrophil count (ANC) above normal range (27.7 x 10°/L) Etiology * primary neatopilia 1 testa neutrophilia (autosomal dominant) 5 Shi ipati netopi nora thy patents + chronic myelogenous leukemia (CML)HS. Hematology Ta reser of denne Eas in ‘teperyer se wit eas eowao razr euoal rst Smet cra cel dsr 0S, ‘ealeuumash, Prt: enti er Sag Fassett ‘aon 0 071 Penida ‘rH ei Sete fete heewe mdteweth ane sy iter er “rojno yup Crores thay fed nr ike Se UE erg au ice ME a ‘not elton ZS tirseabOon arene Pac ecu en ‘foonlginie tera pet \roopey orgy te: aren @ ‘GSE = Neuogsn™ = Fatin ‘UCSF = Latin = Sangeeta Common Presenting Problems “Toronto Notes 210 + other myeloproifeative disorders (PY, ET, myelofbeesis) * foukoeyte adhesion deticiency + secondary neutrophilia * Smoking ~ most common cause of mild neutrophilia infection —lenleoeytoss with eft shi, + tox granulation, Dahl bodies hreopasmi ute compose of gta somes teres in {nllammation, cytoplasmic vacuoles in neutrophils on blood fl inflammation e.g RA, IBD, chronic hepatiie Ml, PE, burns + malignancy hematologic (ic. marrow invaded by tumote) and nonhematologic {Gspetially lange cll ing cancer range 12-3) can be as high 32 MN) de to maROW linvasion and Invlammation as wel as solid tumours secreting substances with Colony stimalating ctv) + Stes /evercse epinephrine ~ movement of neutrophils from manginated pool into Cieculating pool + medications eg, glucocorticoids, betaagonists (epinephrine), ithiam Clinical Features * look for signs and symptoms of fever inflammation, malignancy to determine appropriate further investigations + examine ora cavity, teeth, peri-rectal area genitals, skin for signs of infection Investigations mmplete Blood count and blood film review + WBC differential ~ mature neutrophils or left shif-bands ~20%% of to infection/ inflammation + blood film ~ Dahle bodies toxic granulation, cytoplasmic vacuoles if infection + review for abnormalities in other blood counts WBC suggesting Neutropenia Definition mild: ANC 10-15 10/L ‘+ moderate: ANC 05-1. x 10°/L (isk of infection starts to increase) # severe: ANC <5 10?/L. Evlogy FREE psten caer ee tN Ros annie pn a ead os LOR ete ent Ene 00 ein ET a se ceaee et natin) + mora inte Penton cee Macon Leann “IS noma ange poplin den oon il cn * fever, chills (only if infected) + infection by endogenous bacteria (., 5. aureus, gram negative organisms from Gl and GU tract) + painful ulceration on ski, anus, mouth and oat following colonization by opportunistic + Svoid digital rectal exam Investigations + depends on degree of neutropenia and symptoms {ranges from observation with Frequent CBCS to bone marrow aspirate and biopsy Treatment us + rogular dental care ~ chronic gingivitis and recurrent stomatitis major sources of morbidity cbile neutropenia (ce Infectious Disease, IDS) , ° + in severe immune-mediated neutropenia, C-CSF may inreased neutrophil counts + no response to G-CSF, then immenosuppresion (eg steroids, elope, methotrexate)‘Toronto Notes 210 ‘Common Presenting Problems Hematology H9 Lymphocytosis Definition « absolute lymphocyte count >4x 10%/L Etiology * infection * majority are viral infections + TB, pertussis, Brucellosis, toxoplasmosis physiologi response to stress (eg. trauma, status epilepticus) « hypersensitivity (eg. drugs, serum sickness) + autoimmune (eg. sheumatoid arthritis) ‘ neoplasm (eg. ALL, CLL, Iymphoma) Investigations /Treatment 1 choice of investigations dependent on history and physical (oe later sections) ‘oample + puipheral oar 1 range ells“ do flow eftanot + atypical iymphoeyies > suggestive of EBV infection + twostundaiyg cau Lymphocytopenia Definition + absolute lymphocyte count <1.5 x 10/1, Etiology + idiopathic CD4+ Iymphocytopenia + chemotherapeutic agents + radiation ‘+ HIV/AIDS, hepatitis B, hepatitis C, autoimmune disease + malignancy Clinical Features = opportunistic infections (see Infectious Diseases, 1030) Treatment treat /remove underlying cause + treat opportunistic infections aggressively and consider antimicrobial prophylaxis (see Infectious Diseases, 1D32)| Eosinophilia + absolute eosinophil count 905 x 10°/L, ‘most common causes are parasitic (ussally helminth) infections and allergic reactions + Jess common causes * polyarteritis nodosa Cholesterol embott Suse 1 ML (ten instr Cri tie + Hodgkin's disease Lest assed wa puts ie + adrenal insufficiency taoscesvehanine potion, + Hypercosinophilie Syndrome = 6 months of eosinophilia with no other detectable eases = can involve heart, BM, CNS Agranulocytosi «+ severe depletion of granulocytes (neutrophils, eosinophils, basophils) from the blood and [granulocyte precursors from the marrow «associated with drug use in 70% of cases: eg, clozapine, thionamides (antithyroid drugs), sulfasalazine and ticlopidine «+ pathogenesis immune-mediated destruction of ciculating granulocytes by drug-induced antibodies oF direct toxic effects upon marrow granulocytic precursors «+ abrupt onset of ‘fever, chills and weakness * oropharyngeal ulcers + high fatality sithout vigorous treatmentHin. Hematology ‘Common Presenting Prablems/Approach to Lymphadenopathy “Toronto Notes 2010, Investigations/Treatment + discontinue offending drug + pan-cultures i patient is febrile (blood cultures x2, urine culture as minimum) + consider bone marrow aspirate and biopsy 1 initiate broad-spectrum IV antibiotics ‘+ G-CSF — growth factor that stimulates neutrophil production Leukemoid Reactions + blood findings resembing those seen in certain types of ukemi which ref the response of healthy BM cytokines released du oinfeton or trauma + Keakoxytons 930. 1"/C, marked let shit myocytes, melomyecyts bands in peripheral blood) Important to rate out CML 5 melo eakemnia mimicked by 5 bier ate bacterial infections * invssations = buns 5 malignant disease 4 Siverehemorhoge o hemolysis + tymphold leukemia mimicked by pertussis iB + monocytic leukemia mimicked by ote OV ert mom atti + history ‘+ constitutional /B-symptoms - weightloss, anorexia, faver, night sweats * seen in TB, lymphoma, other malignancies ‘+ symptoms of infection or malignancy ‘exposures, eg. cas (cat scratch ~ Bartonella henselae), ticks (Lyme disease ~ Borrelia bburgdoyfer), high risk behaviors (HIV) + joint pain swelling, rashes * prutiis (seen in Hodgkins disease) ‘+ medications (can cause serum sickness -> lymphadenopathy) «+ physical exam * basic assessment: occipital, preauricular, submandibular, cervical, supra/ infra-lavicular, axillary, epitrochlear, inguinal, popliteal nodes * characteristics of Iymph nodes (Table 2) + Took for signs of infection in region which lymph nodes drain + detcrmine if lymphadenopathy is localized or generalized * localized: typically eactive (Le. 2° to infection) + generalized: sce Table 3 + a thorough examination is raquired to assess for systemic disease + labs "CBC and differential, blood film = PPD, HIV RNA, RPR/VDRL, monospot/ EBV, ANA, other imaging * biopsy if localized and no symptoms suggestive of malignancy, can observe 3-4 weeks (Gino resolution by then > biopsy) 1+ if generalized ~ [ab vrarkup, negative > biopsy + if signs suggestive of malignancy, biopsy immediately excisional biopsy is prefered as it preserves node architecture (essential for diagnosing lymphoma) ‘+ FNA (helpful for diagnosing recurrence of malignancy) ‘Table 2 Ditforetiating inflammatory vs. Neoplastic Lymph Nodes Featre Tafanntoy Modes Neoplastic ee wtbey Ferd ity Mobic Macrae Tends Tene Noten Sie elon >ton a tenon aL caf bv Fe ai a“Toronto Notes 200 Approach to Lyrmphadenopathy/ Approach a Splenomegaly/Miroeytc Anemia Hematology HL Table 3. Differemial Diagnosis of Generalized lymphadenopathy Aascive Taamtry Newgate Other acer Tyre Cat des) Aarne PASI. Yrpions ‘Seon Saree Vil BY OMY.) Ougtyprenstviy ——Yerpoislakaris Amos Past (ooplaoosis Sars amiss Metastatic caes Sais Furl isles) Hiss ON Torte Curr] or * differential diagnosis * hyperplastic (increased demand for splenic function), congestive and infiltrative causes le 4. Differential Diagnosis of Splenomegaly Tneeacd demand fe splrc ncn Coote erate ‘aoinmoe Cross Sphomcyss RAFatys) ——Spen insboucion Haogetopahis SE Prd vancsnuten Naren seme Sscoise = OH ips Hstpaoss leat + history * constitutional symptoms * signe or symptoms of infection or malignancy * history of liver disease, hemolytic anemia or high risk exposures « physical exam * percussion (Castells sign; Traube's space) and palpation * Signs of chronic iver disease + associated lymphadenopathy or hepatomegaly + jaundice, petechiae * Signs of CHF + labs * CBC and differential, blood film * as indicated haptoglobin, LDH, infectious and autoimmune workups irae Nonna ‘Arvedsas Iysosnra soroge dss (Gach Noman Pit Mgnt eke (OAL) byrpara Hokies dept ests Nexataic rox nol Exam or Spenomensty hin 170 201821 ‘re exanton or serene rotten does ona tts ma ae tlhe spe tat 1 Persson rer sot ies Speen atin 5 agai tes fr elromony cay ose tes eal dae ete iver enzymes/liver function tests, reticulocyte count, Monospot, a tat tests Fortin Sorum Iron TIBC ROW. lronofclorey Aronia ISB) Anemia of Crone Disease WY = YN Sidowdbesic emia = WN Thalessonia we oN MONA Figure 6. ron Indices and Blood Film in Microcytic Anemia (MCV- rtclocyte count will begin to increase after one week Hb normalizes by 10 g/L per week + Fe supplementation rouited for 4-6 months to replenish stores Hematology HIS Table 5. The Uslty of Feritin inthe Diagnosis of ron Deficiency Anemia Festa gt) Witined a Tor tron deficency anemia > 10 08 om 4s eas an <8 a Fate ES erdefecrcy ens ecarenan ‘sara croic wa ode Ing ed coset canst ida a) Inte end pst. nepal ema Gwap cs ‘wena Pationt with microeyticanomia Fern 48 npn Ferrin 46-89 npn Fein =100 n/n Assess other Fe indent | _— -_—— oe 7 Ti8C, V seam Fe 1 Tec, * serum Fe stration Any ota esa 1 saat Order sh = o_o es \<— +i SiR NO Fesdeficoncy anemia Figure 7. Approach to interpreting Fe indices Apel pet a yan 20785718HI Hematology ron detlency AnanisComesiy Chests wth Ams of Choe Dense sunpestd br 1 Sane =T0DUp ating Svewnertannsay daca. + Benten ef sahbevanorn ones ari tmarow sprains + Rosana rape il en bone CGasidr sd xcs nny ce (iho enews but lore 176 ‘scare ort 107 m he USA ‘Microytic Anemia “Toronto Notes 2010, Anemia of Chronic Disease Etiology ‘ infection; malignancy; inflammatory and rheumatologic disease; chronic renal and liver disease; endocrine disorders (eg. diabetes mellitus, hypothyroidism, hypogonadism, hypopituitarism} Pathophysiology ‘Tinea anereodcton duet ips Fe ition * trapping o ron in macrophages > reduced plain iron levels making ion relatively unavallase for new hemoglobin synthesis * + erythrypottn levels are normal or lightly elevated bu the marrow is unable to sespond with increased in ey hopoiie + a mtd emetic component i often present {fed bod cll surcval modestly dacessed Investigations ‘Fa diagnosis of exclusion ‘ associated with clevation in acute phase reactants (ESR, CRP, fibrinogen) ‘ “classic” serum ion indices (sce Figure 6) * serum iron and TTBC low, & saturation normal + serum feritin is normal or increased ‘however, ancmia of chronic disease often co-exists with Fe-deficioncy, presenting 3 diagnostic dilemma (see sidebar) + peripheral blood * mild: usually normocytic and normochromic ‘moderate: may be microcytic and normochromic if the anemia is severe: may be microcytic and hypochromic * absolute rliculocyte count is frequently low, reflecting overall decrease in RBC production + bone marrow * normal or increased iron stores in bone marrow * decreased or absent staining for iron in erythroid precursors Treatment 1 nein males if underlying diame is rete «only treat patients who ean Benefit fom a higher hemoglobin level + erpthropoletin may normalize the hemoglobin value he required dose of erythropotetin is hight than the dove routed for pttnts ith renal disse) Lead Poisoning ‘1: Lead Lines on gingivae and epiphyses of long bones on x-ray ‘+ E: Encephalopathy and Erythrocyte basophilic stippling ‘+ A: Abdominal colic and microcytic Anemia (sideroblastic) D: Drops = wrist and foot drop ‘Tieatment: dimercaprol and EDTA are first line agents Sideroblastic Anemia ‘+ uncommon compared to iron deficiency anemia oF anemia of chronic disease Sideroblasts ‘erythrocytes with Fe-containing (basophilic) granules inthe cytoplasm. ‘+ “normal”: granules are small, randomly spread in the cytoplasm found in healthy individuals ‘+ “ring": Fe deposits in mitochondria, forming a ring around the nucleus * abnormal, large granules * the hallmark of sideroblastic anemia Etiology * due to defects in heme biosynthesis in erythroid precursors ‘hereditary (care) linked, median survival 10 years ‘idiopathic (acquired) ‘aka refractory anemia with ringed sideroblasts~ a subtype of MDS (Gee Myeledysplastc Syndrome, H34) z may be precukemic phenomenon (10 transform o AML) * drugs (isoniazid, chloramphenicol, alcohol, lead, copper deficiency, zinc tonicity, hypothyroidism“Toronto Notes 20 MicosyticAnemiNormocytc Anemia Hematology HIS Clinical Manifestations * standard anemia symptoms + hepatosplonomegaly, Fe overload syndrome Investigations + serum iron indices * increased serum Fe, normal TIBC, increased ferritin, increased soluble tansfersin receptor STIR) + blood film /bone marrow biopsy inged sideroblasts (diagnostic hallmark) ‘+ RBCs are hypochromic. can be miero-, normo-, or macrocytic + anisocytosis, poilylocytasis, Bsophilie sipping Treatment “depends on etiology’ + Xlinked: high dose pyridoxine (vitamin B,) in some cases * acquired: Epo and G-CSF + reversible: remove precipitating cause + supportive transfusions for severe anemia Thalassemia + see Hemolytic Anemia, H6 a ‘Vatetten oma Reyes 2) i f —4 oan ¥ aus of Norm (ieee —] (Titan) Fea] Rema) Sunt oe - cesta seneae| | SSE D deficiency, TTP, DIC and PNH * extravascular: AIHA and hereditary spherocytosis Clinica! Features Specific to HA * junds 2 dark urine + Sioleltass (pigment stones) 1 pote fora splat ers (ce. BM suppression in overwhelming infection) + Fin ovelond with extovascular mole $ fondeianey ith intravascular Remeyes Investigations ‘screening tests * increased reticulocyte count decreased haptoglobin * increased unconjugated bilirubin * increased urobilinogen * increased LDH“Toronto Notes 20 Hemolptic Anemia Hematology HIT «+ tests speciic for intravascular hemolysis * sehistocytes on blood film * free hemoglobin in serum + methemalbumincmia (heme + albumin) we + hemoglobinuria immediate) + homosiderinuria (delayed) «+ teste specific for extravascular hemolysis * direct Coombe’ test (direct antiglobulin test) * detects IgG or complement on the surface of RBC ‘add anti-IgG or ant-complement antibodies tothe patient's RBCS; testis ponitive ifthe RBCs agglutinate + Indications “hemolytic disease of newbom = autoimmune hemolytic anemia (AIHA) = hemolytic transfusion reaction * indirect Coombs tes (indirect antiglobulin test) ss antibodies in serum that can recognize antigens on RBCs paticnt’s serum with donor RBCs and then Coombs’ serum (anti-human Ig, antibodies); testis postive if RBCs agglutinate + indications “"crose-matching of recipient serum with donor's REC = atypical blood group = blood group antibodies in pregnant women. = AIHA, Ty Bhetentcae Thalassemia Definition «defects in production ofthe alpha or beta-chains of hemoglobin; the resulting imbalance in globin chains leads to hemolysis in the spleen or BM + clinical manifestations and treatment depends on specific gene and numberof alleles affected * common features @ * increasing severity with increasing number of alleles invelved, * hypochromic microeytic anemia * basophilic stippling; abnormal shaped RBCs on blood fil (th > prevalent in Medtaranean SEA; ‘oThit— prevalent in South East Asia (SEA). Pathophysiology ‘defect may be in any of the Hb genes * normally 4 c genes in total, 2.0m each copy of chromosome 16 * normally 2 genes in total, Ion each copy of chromosome IT * fetal hemoglobin, HBF (c:1.) switches to adult forms HBA (af) and HbA, (ap) at 3-6 months of life + HbA constitutes 97% of adult hemoglobin + HbA, constitutes 3% of adult hemoglobin Beta-Thalassemia Minor (Thalassemia Trait) Definition ‘+ dofect in single allele of beta gene (heterozygous) + common among people of Mediterranean and Asian descent Clinical Features * palpable spleen (rare) Aeros in Bets Th nr Investigations Terns rte rr nt + Hb e140 g/L or 9-14 g/dL, MCV<70, normal Fe fe ani rch arth ao Fe + peripheral blood film ~™microcytesis basophilic sippling etc + Hb electrophoresis * specific: HbA; increased to 255% (normal 15-35) ‘nonspecific: 30% have slight increased in HF ®) Treatment ‘not necessary ‘+ genetic counselling for patient and familyHis. Hematology Hemolytic Anemi Toronto Notes 2010, Beta-Thalassemia Major Definition ‘ dofoct in both alleles of beta gene (homozygous; autosomal recessive) Pathophysiology ‘ineffective chain synthesis leading to ineffective erythropoiesis, hemolysis of RBCs, and increase in HEP Clinical Features © inal presentation at age 6-12 months when HbA normally replaces HBF severe anemia jaundice tuned growth and development (hypogonadal dear) rose hepatosplenonnega (duc to extramedullary hematopoiesis) 1 fhdiologle changes (ue to expanded marrow cavity) "sry hos hainomend” appa + pathological fractures common + evidence of increased HY catabolism (eg. pigmented gallstones) '* death can result from. ere a untreated anemia (ehould tranafuse) 1 Infection Ghould identity and teat ely) 1 iron overloads late complication, secondary to repeated transfusions and ineltecive erythropoiesis Investigations Hb A080 g/L 4-6 g/l.) 1+ Hb electrophoresis HA: 0-10% (normal >95%) * Hb: 99-100 Treatment lifelong regular transfusions folic acid supplementation Fe chelation to prevent iron overload (eg. deferoxamine) allogenic bone marrow transplantation Alpha-Thalassemia + defve(s) in alpha genes + Sinulargcographit dstabtion as beta-thalassemia but a higher requeney among Asians and Atricane Clinical Features # I defective « gone: clinically silent; normal Hi, normal MCV + 2 defective « genes: decreased! MCY, normal Hb #3 defective a genes: HbH (P4) disease; presents in adults, decreased MCV, ‘decreased Hb, splenomegaly + Adefective «genes: Hb Barts (yt) disease (hydrops falls) not compatible with tie Investigations reripheral blood film ~ sercen for HbH inclusion bodies with special stain ib electrophoresis not diagnostic for acthalassemia + DNA analysis using « gene probes Treatment + depends on degre of anemia who treatment required for carirs of 1 or 2 defective «genes 1 TibtF disease: stl to thalssemia major Sickle Cell Disease + see Pediatrics, a7 Definition « sickling disorders arise due to a mutant globin chain, most commonly caused by 3 ‘Glu = Val substitution at position 6 resulting in HDS rather than TTbA, ' increased incidence OF HS allele in people of African or Mediterranean heritage thought tobe protective against mari + sickle cell disease occurs when an individual has two HbS genes (homozygous, HSS) or ‘one HES gene + another mutant figlobin gene (compound heterozygote) = most commonly HbS.f-thal and HSC disease“Toronto Notes 200 Hemdltic Anemia Pathophysiology (Fur 9) ‘tle POs dats Hs poismertzes ang od costae ros tds + The pO level at which sickling occurs relatod tothe percontageof HIS prosent Feteroeygotes (HbAS) icing occurs ats pOr of AU mint in homozygotes (FSS), sckling cur ta pO, of 80 cult + sickling ie aggravated by incensed f,incessed CO, incremed 2+DPG, increased temperature and osmolality «+ sichlc celle fap and emolyz; they also block small vessels Clinical Features STAs (reterosygous): patent wll appear norma except at times of extreme hypoxia and Inceton ihe ald «SS (homorygu) * chronic hemolytic anemia 1 parece neyo a fe 1 Rip hve veanded fer and degelopnen 1 Spcneatngd in itd and sophie ht 1 on proert wisest Peat tte infctions lapel parvovi iS) are suppras bone tra el igplends epsteaton cles Pali in ie, with igficant pooling of lod in splen, sulting in weit Jems san sc «Teton ad fect a functions apni from repeated infertin a veer cate teeny Ty ee cnr oes sig ya epic sect ln Shun and eke) leer and ecko esate dl sydome) « predplted by incor dekydraon capil change tempers, Frcahancy mies an sl 4. celts fc dco) «scl! common compound heterozygote) *epldendlogy: 1838 fe bit In Adtea-Amricans, common in West fa 1 Shir amet than 085 + dni omen a 5 thug Splonal leave ue mange + Spsca vol beayeatpetn oda skelotal changes ically milder and less frequent, with the oy Figure 8. Pathophysiology of Sick + Stnnat [stearate wa ———— ‘eat Chest Spaone ‘et ft rar i cect Asem rd may bee tren. Freeones eos hs fi oe ues acon {nd puiraary wt o 8 Cnety ns cn tener ulna trou om etre Investigations 7 ——— TWh 6. Investigations for Sickle Col Dcease i lac SEE as es gm Poke m "ara ered ws ded Hy dd i _em an Feipelboot ‘alway fowtmtcs Sie & ea Rtrmten Veber Hac 05 (5) ab, cn a gis cpg | SE ante etm iS emt) cave sie Bee Fite toremnn + sickle cell pep: determines the presence of a HBS alll (ie positive in HBAS, HSS, Se Ele ne HSC; etc) ere «+ Hb electrophoresis distinguishes HAS, HbSS, HESC and other variants ae as tein fam Treatment fen Stem 1 gna comalng fe” Rom + BAS no treatment quired oe ber 4 HISC treatment isthe same as HBSS, but is dicated by symptom severity ‘eradied fale nee 4 HbS5-— see Poa Pa Er eee ible aad rps deieney Zyionpagd o eaaee poucion of HE vacchanle of ah spe represen of Hb>ganma chains and/or ies ierenoton of stents when he ge actve presenca bE inthe $5 calls deerasedfuymetcaton and precptaton of HES + Bier llerpores i cyotse ant ay edo am mato eden Steinem of vse Seca vonypen 1 pyelsin educes scsi) 1 Shtmlebuts Lteadets 1 Shapes mets 1 Ranges (nb potastum and water fis from RBCa therchy preventing Sabon) ndaon fr cxchange traslusln: ale chest syndrome, stoke, bone marov! rere proms CRS cesHan Hematology ‘abcd oka N Co {espe oes pee: be ‘mutA Serta Aton ‘hevulacates ct dee ‘ha Sein tnd ‘Site nse ogee ‘Sey eee ante ce Soma toe sl ym ‘a wean ‘me ar sy eo Seman Itunes reer fiend pata 6 ‘Stale ec 8 ‘eeu ler eee ‘Steptnom hans ertae Seba praiunebe reuse Seegandnnanconane eee (iceman Sic itiean ranean Societe Sate orieen tate nse inate ieee ‘Prcetensoe at | woe He =e x € Cy ¥ aa? | jon O Spheiecye Figure 10. Spherocyte Schistonte fC Figure 11, Sehistocyte Hemolytic Anemi Toronto Notes 2010, 4. prevention of crises is key *cotablih diagnosis + avoid conditions that favour sickling (hypoxia, acidosis, dehydration, fever) + Vaccination in childhood (eq, proumococus (hoptavalont and 2>-valen), Imeningococeus, Hib) + prophylactic penicilin from 3 months until 5S yeses of age + good iygiene nutrition and soil support 5 seen for potential complications + regular bloodevork (CBC, reticulate, iron indices, BUN, LET, creatinine) + trinaysis anally transcranial doppler annally until 16 yeas old retinal examinations analy fom 8 years ofd + echocardiography every two years from 10 years old (to Seren for pulmonary. inypestension) Autoimmune Hemolytic Anemia (AIHA) or ‘Table 7. Classification of AINA Warm ta Aol Resoe 8 a Ahan engrave 0 sare Diet Comms ast Faso Poste cone (drt an-gbin est) Bios ih oa Seeeyyrphperve dancer Spey erten 4-H 9. mycopaaa sro, BY ‘Srey aire disse Seana hyrpepae 24.5 ep ecogotrena, Blot Fin Acpitcin Management Tatung case ‘Warps Inmnosirrssen teresupessin Spenectomy Prams Microangiopathic Hemolytic Anemia (MAHA) (3 Definition * hemolytic anemia due to intravascular fragmentation of RBCs Etiology + Uuombotic thrombocytopenic purpura (TTP) hemolytic uremic syndrome (HUS) {sce Table 11) + bic 4 eclampsia, HELLP syndrome + malignant hypertension vasculitis malfunctioning heart valves + metastatic carcinoma Investigations * blood film: evidence of hemolysis, schistocytes + hemolytic workup * urine: hemosiderinuria, hemoglobinuria Hereditary Spherocytosis we abnormality in RBC membrane proteins (Le. spectrin) Spleen makes defective RBCs more spherocytotic (and more fragile) by membrane removal and also acts as site of destruction futosomal dominant with variable penetrance ‘ost common type of hereditary hemolytic anemia Investigations: Blood film shows spherocytes, Increased osmote fragility (rarely done today), molecular analysis for spectrin gene + treatment: splenectomy (immunize against pneumocaccus, meningococcus and Hib first) but avoid in arly childhood“Toronto Notes 200 Hemolytic Anemia/Macractic Anemia Hereditary Elliptocytosis «+ abnormality in spectrin interaction with other membrane proteins * autosomal dominant £25.75) elliptocytes * homolysis i astally mild + treatment splenectomy for severe hemolysis (immunize against pneuimococsus, ‘meningocaceus, and fib frst) GGPD Deficiency Defi * deficiency in glucose-6 phosphate dehydrogenase (SPD) leads to a sensitivity of RBC to ‘oxidative stress due toa lack of reduced glutathione (Figure 12) Pathophysiology Tinked! tesessive, more prevalent in black males Clinical Features + Xelinked form frequently oxidative tress ‘drugs (eg, sulfonamide, antimalarials, nitrofurantoin) infection * food (fava beans) + in neonates: can present a prolonged, pathologic neonatal jaundice resents as episodic hemolysis precipitated by: Investigations neonatal screening + CAPD assay * should not be done in acute crisis when reticulocyte count is high since reticulocytes have high GerD levels * blood fil Heinz bodies (granules in RHCs duc to oxidized Hl Inthe generation ot bite cells, * features of intravascular hemolysis (eg. RBC fragments) passage through spleen results Treatment «transfusion in severe cases ‘= stop offending drugs or food and avoid Wiggers Hematology H21 — Pemose Prosphate Figure 12. G5PD Pathway Cs os Causes = megaloblastic * vit, deficiency * folate deficiency *# drugs (methotrexate, azathioprine) + non-mogaloblastic * reticuloeytosis * myelodysplastic syndromes * liver disease alcoholism hypothyroidism Table 8. Comparison Between Megaloblastc and Nom Megalablstic Macrocytic Anemia Mops Nor apltiatc Worbaoey Lae once RBC poss Tage od RO Hipesemaied aes Natal noaephis Fathphysilogy Faluect OMA yates aut inayactenos Reacts rena ahomy wth trea rrewrten eFC nas vos rd Vitamin B,2 Deficiency B,, (cobalami + binds to intrinsic factor (IF) secreted by gastric parietal cells * absorbed in teeminal ileum + Lota body stores sulficent for 3-4 yearsHE Hematology eee Characters of Hegel Macro Aronia |. Faneyepenia 2 hypersepnated neo 3: Megas bore mara By, NT hires so ies of ths ag + Neral» exec oom ‘een len be see te owe Bwascuete day acne) Pat? * Samoa gu 1. urea ven we oars feo + Soo dre ry tt stage ows ind eter + hae tee (5 oxen) + fara sas xn) ‘mesic (eben) ‘avn wes mst in tevin, oat Cas ss er SCS Say Soenac en 2A rte tesa ptr tga Sito trte nme eee aot este py oe sme Sema Mere rns 8,0 ge, era ‘Sake arbalautenaedae ve eal Fete nonusers sept eg irre eae Crim nolo yup pte Stoo wens gastro ar (eas tov hats ann es ‘Sars sys Ts ‘Sart srg ue ‘nappa ater tee, ‘aerate wet ae (ent fs ean: Pi Lesbo pay caw Macrostc Anemia “Toronto Notes 210 Etiology diet * strict vegan (rare, more likely to present in infants and toddlers) + gastric + mucosal atrophy secondary to chronic gastritis * pernicious anemia (see below) + post-gastrectomy. + testinal absorption + malabsorption (eg. Crohn's, cella sprue, pancreatic disease) + stagnant bowel (e.g, Blind loop, stricture} * fish tapeworm + resection of leum «rare genetic causes (e.g, transcobalamin Il deficiency) Pathophysiology of Pernicious Anemi ‘ oulo-antibodies produced against gastric parital cells leading to achlorhyciria and lack of intrinsic Factor secretion + intrinsie factor is required to stabilize By» asi passes through the bowel * decreased intrinsic factor leads to decreased ileal absorption of Bis # may be associated with other autoimmune disorders (polyglandular endocrine insufficiency) 4 femaleimale = L6:1, often 260 years old Clinical Features * neurological * cerebral (common; reversible with By. therapy) * confusion * delirium + dementia * cranial nerves (rar) ic atrophy * cond ireversible damage) * subacute combined degeneration posterior columns ~ decreased vibration sense, proprioception and 2point discrimination ~ pyramidal tracts ~ spastic weakness, hyperactive reflexes * poripheral neuropathy (variable reversibility) * usually symmetrical, affecting lower limbs more than upper limbs Investigations * anemia often severe neutropeni + McV>tl0 iL * low reticulocyte count relative to the degree of anemia (<2%) «+ serum B,» and RBC folate * caution: low serum B,, leads to low RBC folate because of failure of folate polyglutamate synthesis m the absence of By. + blood fle * oval macrocytes + hyperegmented neutrophils + bone marrow * hypercelulanty + nuclear-cytoplasmic asynchrony in RBC precursors (Jess mature nuclei than what ‘could be expected from the development ofthe cytoplasm) « bilinsbin and LDH * clevated unconjugated bilisubin and LDH due breakdown of cells in BM «Schilling test can distinguish pemicious anemia from other cates Gee Gastroenterology G19) ‘Treatment «vitamin By» 100 4g IM monthly for life or 1000-1200 ug PO daily if intestinal absorption intact + less frequent, higher doses ate probably as effective (eg. 1000 yg IM q3 months) + watch for hypokalemia and rebound thrombocylosis when treating severe megaloblastic thrombocytopenia Folate Deficiency "uncommon duc to extensive dietary supplementation in developed countries folate complexes with gastric R binder complex then binds to intrinsic factor in the duodenum, this complex is absorbed in the jejunum folate stares are depleted in 3-6 months“Toronto Notes 200 Macrorytic Anemi/Hemastsis Hematology HS Etiology * dict (folate is present in leafy green vegetables, fortified cereals) ‘+ most common cause traditionally; however with universal supplementation in foods itis nov less frequent * seen mainly in infants, elderly, alcoholics «+ intestinal * malabsorption + drugs/chemicals © alcohol * anticonvulsants * antifolates (methotrexate) * birth contro! pills + increased demand * pregnancy * prematurity Remolysis = hemodialysis * psoriasis, exfoliative dermatitis, Clinical Features = mild joundice due to hemolysis of RBCs secondary to ineffective hemoglbin synthesis + plosstis and angular stomatitis * melanin pigmentation * purpura secondary to thrombocytopenia. «+ folate deficiency at time of conception and early pregnaney has becn linked to neural tube defects ai + unlike B, deficiency, folate deficiency has no neurologic manifestations ver gue clove ah sia wept rea bees ‘amt, ere ane ous epoeraton wl coninve Investigations + similar to By, deficiency (CBC, reticulocytes, film, RBC folate, serum By.) + iis crucial to rule out B, deficiency as the cause of the decreased RBC folate Management + folic acid 15 mg PO OD x3 months; then 5 mg PO OD maintenance if cause not a Three Phases of Hemostasis 1. Primary Hemostasis aly 1 goal iety rapidly stop bleeding 24____ 1 Sel injury results in collage subendothelial matrix exposure and release of eae Sapoconstictore ontanes paved « blood low simpeded and patlets come in contact with damaged vessel wall {nlc es adhesion Platelets adore to suvendothelium via iN * activation: platelets are activated resulting in change of shape and release of ADP : land thromboxane A a Te es arc ai ih mis ane cana eergiien fe pect pg item deme Vase espage ad plat 2. Secondary Hemostasis pliers ve * platelet plug (formed through primary hemostasis) is vinforced by production of fibrin | 2. secanary hares lot in sécondary hemostasis Fin ctfaraton «+ extrinsic pathway {Reston * the only way coagulation is initiated in vivo + Fomatis «+ intrinsic pathway * allows for amplification once coagulation has started @ 3. Fibrin Stabilization and Fibrinolysis (resolution) « * canversion fom soluble to insoluble lt “et Seon Heo 4 nce healing intated, cot dissolution anticoagulant patineay) Fieaceaea conchae PTE Tate Ter spned noe Ares PeteyHat Hematology Hemostsis, Toronto Notes 2010, eceiefctgntttbeeran ee seni acs vn cs . \ semedsan Bf wenhie ne ee sone ——S . |-m—tm tans 07 csatroncet Figure 13a, Platelet Activation Cascade Figure 136. Coagulation Cascade Table 8. Commonly Used Tests of Homostasis Tipe Hemostasis Tet Tafeence ange Purpose Exams of Asn Dagneses Primary Fasicccot ISD450x 10% To quis pataet rare Low ne HUSmTIEO Boxsigine | N8rin eck or aca is No be act n OC lew nasty dey ogen Ober Fino Foye doyoaton oda (FS Ceness Seater assays Tests pyslogal ita atenbn, pc pats eed este APC) “ais ofoacoge ibis en tps econ Table 10. Signs and Symptoms of Disorders of Hemostasis Pinay Pat) ‘Secondary (oaplatin) ‘Stace Gute cess, roll Basing Namal rare Beng Onset Aer iary ered Odayad ‘Stect Beading Suef. ucosd ed, Grgiat Dp ots muds, ae Uva, Glee, were sin Exes prac sions Potcha, chproses Hearts hertomas Table 11, Lab Values of Disorders of Hemostasis r PIT ‘Patt Cunt RBC Cot enepiio AB 7 N w wo " * N 8 oe s * ’ Ne ver Faire s we Ny " m " 4 ’ " 7 " u ’ ¥“Toronto Notes 200 Disorders of Primary Hemostasis Disorders of Primary Hemosta: Definition ‘inability to form an adequate platelet plug duc to disorders of blood vessel * disorders of platelets “abnormal function + abnormal numbers (thrombocytopenia) * disorders of WE + characterized by superficial bleeding, potechiae, ecchymoses «life-threatening bleeding sites in thrombocytopenia: intracranial and retroperitoneal "Homestar wi racks tle M rae NeMkaan, tse sebc bg monte omcytekn Remaastcin Santon ety deci EE “Sino "Smatimie Gamba 204 aa ies * ees =e = az, &* Figure 14. Approach to Disorders of Primary Hemostasis Immune Thrombocytopenic Purpura (ITP) Table 12, Immune Thrombocytopenie Purpura Fenwes ete TP Crome TP ak ge 26 yas prey SoxPaecion Nae F>Me) staryatecet ection Caren fae Ore toes Ange hasdas Dain sey ts Maso ers Sporn tension ohormoe Ucommon ACUTE (CHILD-TYPE) ITP See Pediatrics, P48 CHRONIC (ADULT-TYPE) ITP * most common cause of isolated thrombocytopenia 4+ agnosis of exclusion (.. isolated thrombocytopenia with no clinically apparent eases) Pathophysiology «antiplatelet antbodies bind to platelet surface ~ incroased splenic destruction and clearance Investigations + Thrombocytopenia, increased bleeding time Pind oP Proeral + peripheral blood fim: decreased platelets ant platelets + Bone matrow increased number Of megakaryocytes rial test to mle out other estses of thrombocytopenia in people > years old, ke snyelodysplasia Mergen T ble sd of. » AvEmergency Treatment (active bleeding or in need of emergency surge *metiyipredmsolone 1 g/d for 3 days then prednisone Sma! kg aay 2 IviGT rkgy dn? days ranexainic acid 1g IV oh sccination (pneumococcal. meningococcal, hemophilus influenza B) for lfe-teatoning bleeding platelet tanstusions ane appropaate (max. 1 pool i-6h) mengeney splenectomy may be considered + imanagement of intracranial bleeding should include: IV steroids, IVIG, platelets tmengeney splenectomy, snd then craniolomy; manisin pit S10 fr at feast ? days ont ICH where possible B. Non-Urgent Treatment {platelet count <20-30 x 10*/L and no bleeding OR the patients ‘experiencing significant bleeding symptoms and the platelet count is fess than Bd 10?) Hematology #25 or Drage Asrocatd wah Thambecrtopeia Ws oan ADS orca yor atren ar Nese Ehen ental Oude aegis peace Die oy Mechniam or abecied| ‘Toomineroperia bie fic t en arm 1 Inrne itd ptt desruan 2 See artrtonnds roc tet proueen Sta a ei are Nae Pine Crt NE Papa rvslrBtg Inetasy eta gincon ate & cm eas splint ‘cy Mths Sareea ambien ‘tps gran el ae reves pier gions ‘rmgoecnidtts Uno arate ocd ahd ‘max Aeneas Devoe ‘coer tn boo es Lexy fons a (et Dd etee rg ‘etre cns tae Serhan tro Cano ot tomsmee sna "asa ape ow Sao ca A re ‘tesraets ber saan acute man teeta rnermn el ‘el fetesnaeine end egy tein stray ante eee yr bg gts at iegowaoyryHs, Hematology we r———_—_——_ Nachos fr Hasaeitad ‘hrominetpena Ore oe HY rene 2 ire madd aaoe 4. Some revo rue pave edu ‘Senn ee oer Sleaze Pie ce “nba rtp! 7808 Paper pi ‘anew snoeionany a ‘esgintoy essay dc ged ‘glare ee re ‘hte ene ‘epua ngamedyOa h ‘Srgsondtrs tonnes setts login Erocmrapmas ined nS ‘i fone ‘Sebyriceriza valance ‘egy Ne Tey Dee ata 2 ‘inmost wracs a maa toast rang Uren ese eane aera rad atseyaeey Aamo ‘eset tes aes ‘aipatbonescd gee a ‘tei reed etd ae ‘reteset prvi hatte ‘ray be son ans yep Dreamer acting su Unwed wh at ‘herss thar ucts ee [az Tipe! Mepaiszocied ‘tenbecyepa "rete mcd vs sapeastor hove) -Patcon > x10 1 Sate ino drone) 1 ocr wh hep erp Sve aerehoe Disorders of Primary Hemostasis “Toronto Notes 210 Jatlt transfusion docs not work + BiG snot appropriate fr palents not actively bleeding * psn {Pgs taper one esp ie se alt 0x10) by SO Every Midays + al ptents should be vaccinated (preumocsccl, meningococcal acme intenea B) + Patri ao patient elapse on tapes oF rte > prednisone 10/mg daily to tmainaina platelet count of >20 10 AND havea persttent severe thrombocytopenia (20 107/L or 20 1° t0 30s TO with Bleding), splenectomy uy be conatlened + itpatent relapses post splenectomy (See Figure 15) Prognosis + fluctuating course + overall relatively benign, mortality 12% + major concern is cerebral hemorthage at platelet counts <5 x 10?/L nom eta OR Bg Wea s Pa tic, Ti ‘at olga dvsness ‘Serie AA Deana Ongena ees w ecu wicarcbawoati nis oe \cetfogh pane Seopa Sts mend alocinet ral POb0r 4th EG gant ‘ants gi kas TO agnog wen ale Figure 15. Suggestive Care Path for Pationts with Post-Splenactomy Refractory ITP Na om wanlmayuon sna ape rte Heparin-Induced Thrombocytopenia (HIT) Table 13. HIT (Heparin induced thrombocytopenia, type It) Pathopslony Teme mated Abaco of hapa apa ae (8 dro pata ve plat Fear an acon of camydtan Digs ‘xfredutonin asia wil onkeparn win 15 oy of ttn Onset of dcreasedpaelts 5:18 da pein expose then I can dase inks sk ftronbosis ~205 ek menswear) iia nos ‘ong complestonsncararen Vous eboss OV, trl ambos MY, ce fnb nd eset ates, eal ord voter epi! kin acess feet cin ens ase ema eats tet aig.) Fans gob anes Speci tts sen eae say aes eps wih "Cnn departs pias) EUS or HT fnersed snste dened spc tn satan 527) Fw eyemeny Mnogoment Cie ssi oF HT shud poet dorset hen spec ats sv ey) Bocuse 0 css acuity LMWH shoul ate abst tana apes rede apn (cna ha avad we dss), stab (chez orb iii, rented wih 2, use wean nb das), ped“Toronto Notes 200 Disorders of Primary Hemostasis Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) Table 14, TTP and HUS is idensony Parra cto Petar ast ilogy Shop texin Ecol seeype 01577 Dado of metepatsse ht eas down sarge ‘i miners Conga genet secs of ADANTS 13) * Raut gs malay, arent Hae, ‘Goyatie) Giricsl —|.Smaetiontnoynpena: (paper, Thembuepna features "eis hart henopnys, ites) 2 Mizergopeic hrc emia (MAHAL 2 hlcrangopshichorays ama (HANA) 3. Newdegal syrpons| HA, cra cal os, ots) 5. Rallaue [aroma utes cgi, Rael faue eae aie) 5 eer Investiaons C8 nd fi: schisooyis an dered tees sie sis hah TH HUS) PP feope nad Notas of farays:nceasd ub nceased OK deceased api eqs Combs es Crating ea len cn Sel 5 045) Management _Pasraphressis te wien ce = seis {hath THUS) Pacer ssh contend reese icroeszu orbs), Para inson fpasmephoess ret inmediay ae TP meray 90 fue Von Willebrand Disease (vWD) Pathophysiology feterogeneous group of defects Usually autosoral dominant (ype 3s autosomal recessive) 4 fnitdive or quanstative sbneaaliy of OE ‘WE needled for platelet adhesion and acts as carir for Factor Vill abnormality of YWE Can affect bath primary and secondary hemostasis 1 VIVE exis asa sere of multimers ranging in size * he arget ones are most ative ir mednion of platelet adhesion + ot lage and small complex with Factor Vill + usually mild in severity Classification Siype I= mild quantitative defect (decreased amount of vWE) in 75% of cases 1 pe 2—qualitive detect (dysfunctional VWF) in X25 of cae J iype 3 severe total quantitative detec (no vWF produced) rare Clinical Features ia al and cutaneous bleeding, easy bruising, epistaxis, menorthagia ‘as abowe duit more severe, occasionally soft-tissue hematomas, petechiac (rare) GI bleeding, hemarthwoces * re ed bleeding time and PTT 4+ dscreased Factor OIE (50') TRE cpuntnomst gr aety derased iin Vie sion 1 Tcreased ristocetin cofactor activity (normally causes WF to bind platelets tight 1 decreased von Willebrand antigen in types Land 3) Pisces Uhl) 4 blood group fas antigen quantiication ference range differs dependent on blood group) 1 analysis of WE mulimets to detect variants = = Treatment + Cesmopressin (DDAVP™) is treatment of choice for type L vWD hises release of vWF and Factor Vil from endothelial cells Vatiableelicacy depending on disease type need good response before using with farther bleedin ihe deen type IIB (will use worsened thrombocytopenia) if Cantifbrinalytt) to stabilize cot formation Factor VII concentrate containing WWF (Ftemate F™) in select eases and type, PEP noe sett = a + conjugated estrogens (increase vWWF levels) Prognosis Tay ftetuate, often improves during pregnancy and with age Hematology 27 Prthopysitogy af TP ‘oF ere ens eso ver lao ple pycared ‘yh ADMATS 1 prtate + Cogan TPs dot ‘suas 13 + Abode opst ADAMTS.13, pear aad TP or eur ripest Ab sete an yore (atone eric anema TP) erie Ga oe tt eur A Syma ie ‘eam aa Fay: irene epesiecsion {Sen acne th owe ‘San Steet daybed toa a (tome eed ‘ee eee i ag ont mance Osan er ‘Sevommane te itd Secu seamen tae ‘aren 24 Neves at as {EAHA 1509 Me peaks intabemtasutee ov aeeo 62 Counts es Aros se ‘uence Tia = 00) ay booms dames se fcc) Persea tas len stro ai ae Fis mc A ep gers Vat (rc oo es We ‘henarowed evened craps ‘ss teuntgrasomesrabopertHas. Hematology Disorders of Secondary Hemostasis Toronto Notes 2010, Disorders of Secondary Hemostasis ‘Table 15, Classification of Secondary Hemastasis Disorders Hoey ‘Reguiad + aa iManage —~SC Un ‘Far Oc Hono Birmas Osea] + DIE Fear + Vianney hacer ioc a Pcie iis Hemophilia A (Factor VIII Deficiency) @ Pathophysiology linked recessive, 1/5,000 males ‘+ mild (5% of normal factor level), moderate (1-5%), severe (1% Clinical Features Sue Table 10 Sighs and Symptoms of Disorders of Hemostasis lnvestigations «prolonged PTT, normal INR (PT) Sccreased Factor VIII (0% of normal) WE usually normal or increased Treatment + desmopressin (DDAVP™) in mill Hemophilin + recombinant Factor VII concentrate for amen ee + Ini bit ot wil beeing (eg, hemartroses) + major potentially itehreateting bleeding (eg multiple trauma) + ant Abnnolvtic agents ey tronesamie acid) Hemophilia B (Factor IX Deficiency) aka. Christmas disease Kelinked recessive, 1/30,000 males lintcal and laboratory features identical to Hemophilia A (except decreased Factor IX) 1 treatment: recombinant Factor IX concentrate and use of ant-fibrinolytie agents Factor XI De aka, Rosenthal syndrome Autosomal recessive; more common in Ashkenazi Jews Usually mild, often diagnoced in adulthood level of Factor XI docs not predict bloeding risk tratment: fresh frozen plasma, Factor XI concentrate ‘iency Liver Disease é + pathophysiology’ ro 1 delice’ yest ofl actors except Vit * abecrant synthesis: fibrinogen ee * deficient clearance of hemostatic ‘debris’ and fibrinolytic activators ae deficient clearance of hemostatic ‘debris’ and fibrinolytic activa 1 sccisoted destruction due djnmogenemar increased Abrnolys, DIC sitmatemiiawdcceres | 5.1m inblton of sconce heme by FDI ‘ependaeteoeaede © Pesta! blood Ai: anger els Primary hemostasis afeced * theonbeeytopauss we hyperpleisn, fate deiiency, alcohol intoxication DIC 5 plot vstenction ep Rode sous, + seconary hemgetas ated located I i) PTE and thrombin i treatment supportive es frozen plasms platelets iver disease Vitamin K Deficiency © Etiology iar) + Seen nt do whieh pode Sef smn sappy por dept cS“Toronto Notes 20 Disorders of Secondary Hemastasis Hematology #25 * biliary obstruction + chronic liver disease (decreased stores) + malabsorption (eg, celiac disease) + hemorshagic disease of nowbom, sce Pediatrics, P71 Ineaigatone a eet TH NEE at in See Trestment i aeogutont x 1 min 90 for INR between 45 and 10 and no bledng (exces hemonagie Suwon bene a the Sewborn) attest attor « Hblocing ve vito K 10 mg V/PO andi ie treotning bleeding ae Plone (E «Rote excessive amounts of vitamin K wil delay therapeutic warfarin anticoagulation once reanea sh frozen, Disseminated Intravascular Coagulation (DIC) Den * uncontrolled release of plasmin and thrombin leading to uncontrolled intravasclae Coagulation and depletion of platelets, coagulation factors and ibrinogen subsequently iv ise to risk of lfe-threstening hemorthage sen saissgueny Etiology #122" dborder that occurs as a complication of a number of other conditions aly + He unlping canoe relate to widepbvend ondothlial damage secnaivehelaximatony 3 aera ‘ = caer * activation of procoagulant activit oe T RatphSpholigad Antibody Syndeome erases Vika + intravascular hemolysis (incompatible blood, malaria) wow a * tissue injury (obstetric complications, trauma, burns, crush injuries) een da 5 malignancy Gold tumours hematologic malignances espectalyscue promyelocytic | 2 mal teaknia AMUN) + snake venom 2 atenbelism aly 2 fear toke === + endothelial injury ees infers epee tenet i wascultis metastatic diseae(adenocareinoms) fon acu 2 gant hemangioma + reticuloendothelil injury * liver disease 2 splenectomy + vaca ati 2 hypovolemia + pulmonary embolus + other ate hypoxia acidosis * extracorporeal circulation Clinical Features + signs of microvascular thrombosis Ler ro nro * neurological: multifocal infarcts, delisium, coma, seizures {POC aan tae acta + Shin ost ier, supertal gangrene Sete dn * renal: oliguria,azotemia, cortical necrosis ees eee * pulmonary: ARDS: gee 2 Gti ae alceration = REC: microangiopathic hemolysis + signs of hemorshagicdiahesis + Seeting fom any site inthe body is possible because decrease platelet and clotting factor vel neurologie: intracranial bleeding Shin: potechiae,echymosis, oozing from puncture sites renal hematuria mucosal: gingival oozing, epistaxis, massive bleeding Investigations «primary hemostasis: decreased platelets + Secondary hemostasis: prolonged INR (PT), aPTT, TT, decreased fibrinogen and other factors rinolysis: increased FDPs of D-dimers, short euglabin Iysis time (ue. accelerated inolysis) brn deposition: urine output, urea, RBC fragmentation50. Hematology fot_______ Wich’ Wd Soda ooge Sore ycospaty sgaretnzeaseéaecetene ‘a i Aone Sunt nt Paso er as Ine rant venga ces ee als ne Onypap ecs eet eto eS ‘uganda eer ges). Cac ta a ty inearenshes torso tg har ay Disorders of Secondary Hemostasis/Venous Thrombosis, “Toronto Notes 210 Treatment 2 recognize early 5 fret underiving disorder 5 individualized entcal care support + in hemorthage: replacement of hemostatic elements with platelet transfusion, FFP yopredplite « in rombotie phase: LMWH (controversial) Harepil Aan orn de Vian Kat wo bron de ‘stan Hepa Facer Vand X et Ueda eget RD Sov ie sce Facer Winitrs Feces Facer Van, pratt Sriagan iia UE deiney Excessive oncmaaion ACM Definition + the presence of thrombus and subsequent inflammatory response in a supestcil or ocp vain + throm propagate in the discon of blood flow (commonly originating incall veins) {more commen in ower extremity than upper exten 4 incdonee “1% ifage >60 1 the most important seqace ave palmonary embolism ¢ nd chron wens insiiconey Etiology (Virchow's Triad) * endothelial damage * Ieads to dectased inhibition of coagulation and local fibrinolysis * immobilization (post Ml, CHE, stroke, post-op), inhibits clearance and dilution of coagulation factors + hypersnagulability inherited (sce Mypereoagulable Disorders, H32) + aequited * age (risk increases with age) + surgory (especially orthopaedic, thoracic, Gl and GU) + trauma (especially fractures of spine, pelvis, femur, oF tibia and SCI) + neoplasms (especially lung, pancreas, colon, rectum, kidney and prostate cancer) + blood dyscrasias (myeloproliferative disorders, esp. PRV, Et), PNH, hyperviscosity (multiple myeloma, polycythemia, leukemia, sickle cll) + prolonged immobilization (CHE. stroke, MI, leg injury) + hormone related (pregnancy, OCP, HRT. SERMs) + antiphospholipid antibody syndsome (APLAS) + hyperhomoeysteinemi + heart ailuee (risk of DVT greatest in patients with RHF and peripheral edema) + idiopathic (10-20% are later found to have cancer) a" chance with proximal DVT) Clinical Features + absence of physica findings does not rule out disease + unilateral leg edema, erythema, warmth and tenderness + palpable cord (thrombosed vein) + phlegmasia cerulea dolens and phlegmasia alba dolens with massive thrombosis + Homan’s sign (pain with foot dorsiflexion) is unreliable Differential Diagnosis ‘= muscle strain or tea, [ymphangits or lymph obstruction, venous valvu ruptured popliteal cysts, cellulitis, arterial occlusive disease Insufficiency, Investigations + D-dimer test only useful to rule out DVT if negative and low clinical suspicion of disease + doppler ultrasouind is most useful diagnostic test for DVT sensitivity and specificity for proximal DVT -95% + sensitivity for calf DVT ~70 + other non-invasive tests include MRI and impedence plethysmography + venography is the gold standard, but is expensive, invasive, and higher risk“Toronto Notes 20 ‘Venous Thrombosis Approach to Treatment of Venous Thrombosis Purpose = prevent furier clot extension 5 Prevention facts pulmonary embolism (occurs in So untested patents) 1 fees the risk of recurent thrombosis # “Tremont of mse eoferal hyo with ace lower ib schema and/or nous gangrene (pegmass ces doles) « Timit development of late complications, Le. postphlebitic syndrome, chronic venous iutiench and chronic sroetcmbelc palmar) HTN Intl Treatment nfostonted heparin (UFH or lo-molcular weight heparin LMWH) * UFH m ners * sogltes bolus (501-1000) flowed by contnsous 1 infson {iris 10) «eight tase heparin nomograms help to achive proper desing {dente ray revertble by protamine in eave o bleeding J Asaape! mt montor at Peith agjstnent of dose teach therapeutic evel (2s conte vale); mont plate! sonnts or development ohiebestcrtspein tT) sunwi 2 niminstered SC; a east a efoiv as UFH 1 Ai ntoges predicate dove response anced dosing schedule ab Amour g ot eure: nce kof Hs sa nd ete supe therapy «+ disadvantages: only partially reversible by protamine; nally cleated, may need tadhst doo fh patients wih eva ytueton + stemativesto LMG and UF heparin pats es HIT), diet tonbin inhibvors Ged, kepiadin, agatoban Factor Xa nhbitar ondepsrnun) Rrombolytc eg, steptoninas WA) Grgs eneved for inb/eteatenng thrombony sect eyepoms low Needy Sak Long-term Treatment «Standard weatmentf warfarin which should be initiated concomitantly with heparin ‘overlap for atleast 3 days and Gbcontinue heparin after INR 220 for two consecuive days + Warfatin should be dose to maintain INR a.23 except in select cases monitor INR tice weekly for I-2 weeks then weekly until NR stable then every 2 weeks Tocent evidence suggests that a therapeutic INK canbe reached quicker by using ‘Warfarin inition protocol that stare with 10 mg dove rather then a 5 mg dose + LMWH shown to be more effective than Warfarin at preventing recsrente of Venous thrombosis in cancer patient + duration of anticoagulant treatment (with warfarin unless otherwise noted) fist eplode BVT with trandent nk factor 3 months + frst episode DVT with ongoing risk actor such ax cance, oF antiphospholipid tribsdy ot nor that ont it actor consider niche heey + ftstephode DVT vith no identifiable rc factors (dopa single inherited rs factor (be Factor V Leiden etc) 6-12 months or indefinte therapy (conversa) + recurent DVT @ or more episodes) indefinite therapy + 1VC filters use in those with contraindication to antiooagulant therapy, recurrent thromboembolism despite adequate anticoagulation, chron recurrent embolism with pulmonary EITN, or require emergent surgery without tne t inate anticoagulation + rognancy treat eth LMWH during pregnancy then warfarin fr 46 weeks Postpartum, chicving a tinimnum toll anticoagulation ime of 2-6 months «+ perioperative: surgery sae when INR <5; warfarin should be discontinued fora east + {ays preoperatively to allow INR to al > bvoid elective surgery in he frst month of either a venous or arterial thromboembolic event + IW heparin may be used upto 6 hours pe-operatively intravenous heparin or LMWH (ondging) shouldbe given before and after the roedure while the INR ks below 2.0 for patients at Nigh risk for hromboembolism (VTE <12 wooks; current VIE, lupus anticoagulant, aa balan with pl stroke, mechanical heat valve) + postoperaely, IV heparin or LMWH can be used for anticoagulation safely (12 hours her major stingery) unt therapeutic INR levels are reached after restarting warfarin Prophylaxis ‘canelder for those with a moderate to high risk of thrombosis without contraindications ‘+ non-pharmacological measures include: carly ambulation elastic compression stockings (TEDs); intermittent pneumatic compression (PC) ‘+ UFH 5000 TU 5C bid for moderate risk * UFET 5000 IU SC td or enoxaparin 40 mg SC OD for high risk Contraindications and Adverse Reactions of Anticoagulant Therapy see Anticuagulation Therapy, HB2 Treatment of Pulmonary Embolism (PE) + see Respinology: R19 Hematology 31 ‘ne nanan ot Nearer ‘uy Abas ne Gua fi, aa pi dy Sete nook ‘Sermimeio era ce Sep nd me ern dae See meres atl pap a prs ot ‘Sse M00 es ane arb waco ‘eine ores (het Eanes ‘emetic arene pester ‘eater an ‘rates a ‘Natron Ch ate Sa eis 2, fer Suey uae AC cover desea mat \Garntags ncaa oer: eecteceneet, ‘ests ‘Rootes al oe auras rae eo Cleopatra [QUA nae teva oes ‘esti ME armestinigessaid audi eae ch 2 Hoe po toe ‘amilname eases Eerste EF. ois (ir og tment ‘See a eyed act ‘Svein eo wlan ‘ato og Se coro, ‘eather ase ree gue oon (Bete ntdarn Vc ee fe ete ero ‘gard aracrcosrat “yy Seacancn eames, nos seen Een samen seen aia a popes eee Eectianeme a Soon Se ou a urgent <0, rove eta r IE grea Store Al 30 mip mar ‘eit aber se sry Moderate sik supa paints: > 20 Yr stist lero VEGA >a rs igh i sien ptents: 40s, sare ke agarey oon exseiyochoped uray tea $00in ers Getenoy 2 ‘herr coe ig risk mdi patent not fare sera eapty diese, {sca eve ado as coreda tot shave <1 tera at Teg civ cet, frevaus VIE sep cane ‘sone 1D.HS Hematology @ ge ___ amma Cases of ypercougality coumesuare Prete cetceney rps Abs factor teen Proto detenoy ested Narcyeohe ‘eva datcarey Primm Gz0210A essed Fate ‘ious cog prs Prt asin cht ‘ombors Pron pS, A ae estado — Utrera tetar eer, mst teste ate is te er Gants of Both Vanes and Ariat ‘hepsi aibesoe Iypetomerterens { Mieputeie dso “hep es ewe tsena | Som 1 Mareen andPap tenses *Psxinmass 1 tate) Dose lo Hypercagulable Disorders Toronto Notes 2010, Pa etcrte cle MPC ley Hypercoagulable Workup — Venous Thrombosis 1 Woorasp for malignancy’ er hypereonglale state may be in presence of the following features: age <30, recurrent VIE. Ete of DVT. heparin-resistantdiscese (AT deficeney), warta reonatal purpura fulminan (Protein or deficiency) Workup mayinclade init + cae 5 malignancy work up 2 NPLAACS (ontieaiolipin antibodies) and LA (haps anticoagulant) + fasting homocysteine + APCI (activated protein C resistance) + BNA~EVL {factor V Letden), PT (prothrombin G20210A), MTHER, G,1d-methylenetetrahydrofolateructace) + postacite event Pos’ Jantihrombin (aot on heparin) + FVII increased levels proditor of recurrence) + post ueatment * Protein, § (not on warfarin) ed for idiopathic VTE in history of VIE, unusual ininduced skin necrosis and HERITABLE CAUSES OF HYPERCOAGULABILITY LEADING TO VENOUS. ‘THROMBOEMBOLISM, Activated Protein C Resistance (Factor V Leiden) ‘most common cause of hereditary shvombophilia, 1+ 5lsof general population are hetezygoten {point futation i the Facior V gene (AtgS06GIn) resus in resistance to inactivation of Factor Va by activated Protein Prothvembin G202108 ain iy 2'G'SA transposition at nucleotide positon 20210 of the promoter rion ofthe prothrombin gene results in increased levels of prothrombin subsequently leading to Frere thetmbin generation Hyperhomocysteinemia Botha genete and sequired abnormality 5 jes ens areotnd in iain BB and folate deficiencies chronic eel airs, wypathyroidism malignaney, methotrexate: phenytoin, dheoph line + folne 3m day can decrease plasma homocysteine by 50% although effect on thrombosis Fale echucton sinclene + also Increases isk of arterial Uurombesis Protein C and Protein S Deficiency «Protein C inactivates Factor Va and Vlla using Protein Sas a cofactor 4 Protein Cdeiieney ‘ul + eterozy os, pep Type decreased Protein C levels 1 type ls decreased Protein C functional activity + aoguied iver disc, sopts DIC waririn 13 ot patients with warlsrin necrosis have underlying Protein C deficiency + Protein S deficiency * type I: decreased free and total Protein 5 levels + type Hs decreased Protein 5 functional activity peli decreased free Protein S levels + scquiliver disease, DIC, pregnancy Antithrombin Deficiency ‘antithrombin slowly inactivates thrombin in the absence of heparin, rapidly inactivates, thrombin m the presence of heparin «autosomal domuhant transmission of urinary Josses in nephrotic syndrome iype decreased AT levels type It decreased AT functional activity iggnosis must be made outside Window of acute thrombosis and fnticoagulation {reatment [acute thrombosis, heparin, systemic diseave all decreased antitfrombin levels) «+ deficiency may result in tesistaie to unfractionated heparin (LMWH rust be used) Elevated Factor Vill Levels ‘ amindependent marker of increased thrombotic risk 1 enctic bass for increased levels poorly understood nephrotic sydrome, inflammatory Disorders of Fibrinolysis * include congenital plasminogen deficlen ‘Antiphospholipid Antibody Syndrome (APLAS) feinipen: sl einical and =f laboratory cateria 4 clinical thrombosis, spontaneous abortions, fetal loss, premature bith before 34 whs 1 laboratory" anticardiolipin o lupus anticoagulant antibodies ‘+ mechanism: not well understood, interact with platelet membrane phospholipid and Increased adhesion and aggregation also can interfere with action Of protein C&S tissue plasminogen activator deficiency‘Toronto Notes 200, Hematologic Malignancies/Myeloid Malignancies Hematologic Malignancies Tye ts Tiss er y Toes TAL] [tga ewan Ta] [Rapa = Pale aecas | | “Naages Nain | [Sytem ih ee ca + Fasc Oyose and ‘a eae Sow ies “hope iin ates Figure 16, Overview of Hematologic Malignancies Myeloid Malignancies Acute Myeloid Leukemia (AML) Definition * rapidly progressive malignancy characterized by failure of myeloid coll to differentiate beyond blast stage Epidemiology ‘incidence increased with age, median age of onset is 6 * accounts for 10-15% of childhood leukemias Risk Factors + myelodysplastic syndromes (MDS), benzene, radiation and alkylating agents for previous malignancy Pathophysiology ‘etiology subdivided into * primary de novo + Secondary ~ to hematologic malignancies (e.g, myeloproliferative disorders and MDS) or to previous chemotherapeutic agents (i. alkylating agents) «+ uncontrolled growth of blasts in marrow leads to * suppression of normal hematopoietic cells * appearance of blasts in peripheral blood * accumulation of blasts in other sites + metabolic consequences ofa lange tumour mass Clinical Features + thrombocytopenia (associated with DIC in promyelocytic leukemia) * neutropenia (even with normal WBC) > infections, fever {+ accumulation of blast cells in marrow * skeletal pain, bony tendemess, especially sternum ‘+ ongan infiltration with leukemic cells * gingival hypertrophy ~ may present to dentist frst splenomegaly ~ early satiety, LUQ fullness hepatomegaly Iymphadenopathy (not marked) skin — leukemia cutis gonads eves ~ Roth spots, cotton wool spots vision changes (uncommon) ostasis (medical emergency) * patients with increased WBCs can present with symptoms of leukostasis (ie. respiratory distress, altered mental status, bleeding) Hematology 153, Tiel Age of Pesetatin ot shaman Ch 4080 ys Mees ye Newroph Maturaie yas. Pease \ Mycore Meaney fant Y‘est ese Defition-(¥H0} Paseo 204 bea one rr preecaton. lain die io mlid (AM andympti AL epg nether bss re mado Iympbetasts respecte 8 8 al3] F : i z| | BREESE & aig Ree {Ho MDs Cassin 1. facto anois MA) 2 Rtn nana wit Foe std RAS] 2c yep wih rate dys ROMO) ‘arc ope wth atte gi rsd Seats (ROMS) 5 Baroy ono oes thse ane £5 some (M0 wt Ea) 1. Medel nas a a Tasesmes et mga ‘yeas wih ei an chs) Myeloid Malignancies “Toranto Notes 2010 + metabolic effects, aggravated by treatment (rare) increased uric acid ~ nephropathy, gout + release of phosphate > decreased Ca, decreased Mg, * release of procoagulants > DIC + decreased K before treatment, increased K after treatment Investigations bloodwork © CBC anemia, thrombocytopenia variable WBC 1 INK aPF FDR ibvinogen nose of DIC eased LDH, ners ric ac increased PO, (leased by leukemic last), incrensed & decresed ca + onder baseline RFs LET + psn i“ bss ith Ave aarp gras) + Bone marrow aspirate blast count AML 20% (normal is <5%) 1 Hlstologic lication (enc Americans (FAB) + MOAMP) based on Sage a which cll differentiation slope += Gpgenatic, inmunophenotyping + Cx ide pneumonia ECC, MUG sean prior to chemotherapy (ardlotoxie) Treatment hemoth ‘mainstay of treatments chemotherapy * cure defined ae survival tht parlels age-matched population 1 SIIAML subtypes treated simariy * except promyelocytic varia with (15:17) translocation ~ all-trans seid (ATTRA) aclded, to induce differentiation + treatment strategy ‘L'induction ~ chemotherapy to induce complete “remission” of AML (noemal peripheral blood film, normal bone marrow with <5 blasts, normal clinical state) * several possible regiments; example reginen is cytarabine with anthracycline (eg, daunorubicin? + patients with poor response to inital induction therapy - poorer prognosis 2. Adjuvant Therapy leukemia will recur if no further treatment given) ‘intensive cwoidation chemotherapy + stem cell traneplantation ~stfolognns or llogenei (younger patients wi better performance states) “sameness + consider acceleration with hematopoietic govt Factors (e.g. G-CSF) if increased incidence of severe infection + supportive care PP jteening for infection via regular C&S of uring, stool, sputum, oropharynx, Catheter sites, perianal srea fever ~ C&S ofall orifices, CXR, start antibioties + platelet and RBC transfusions (radiated to prevent transfusion related GVHD) = Exythropoietin + prevention and treatment of metabolic abnormalities (allopurinol shouldbe started {or prophylaxis of hyperuricemia) Prognosis «+ achievement of first remission (no visible evidence of disease and normal blood counts) * 70-80% if 60 years old, 50% if >60 years old + median survival 1224 months + Syear survival 40% + survival may be improved by BMT — 50-60% cure rate « adverse prognostic factors: age >60, poor performance score before treatment, AML secondary to chemotherapy br MDS chronic myeloproliferative disorder, WBC >20 000/me, increased LDH, unfavourable cytogenetics e.g. monosomy or deletion of chromosomes 5 0¢ 7) Myelodysplastic Syndromes (MDS) Definition + heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective blood cell production, resulting in peripheral cytopenias + syndromes defined according to French-American-British (FAB) or World Health (Organization (WHO) classifications Pathophysiology + disordered maturation ~ ineffective hematopoiesis despite presence of adequate numbers ‘of progenitor cells in bone marrow (which is usually hyperceular) + intramedullary apoptosis (programmed cell death within bone marrow) both processes leading to reduced mature cells in periphery + considered preleukemic: 30-70% develop AML“Toronto Notes 200 “Myeloid MalgnancesMyeloproliferative Neoplasms Risk Factors. + clderly, post chemotherapy, benzene or radiation exposure + occurs in Tin 500 patients aged 60-75 years old Clinical Features + insidious onset + fatigue, weakness hepatosplenomegaly infections and bleeding can occur out of proportion with peripheral counts or. infections, bruising, epistaxis, and rarely weight los, fever, and Investigations + diagnosed by anemia «thrombocytopenia 4 neutropenia * bone marrow hypercelutarty with trilineage dysplastic changes (dysmyelopoiesis, dyserythropoiesis, dysthrombopoiesis) + CBC and peripheral blood film = REC: usually macrocytic with oval shaped red cells (macrorovalocytes), decreased reticulocyte count + WBC: decreased in granulocytes and abnormal morphology (eg, bilobed or tunsegmented nuclet = Pelger abnormality) + platelets: thrombocytopenia, size and cytoplasm abnormalities (e.g. giant Fypogeanular platelets) + bone marrow aspirate and biopsy with cytogenetic analysis required for definitive diagnosis * bone marrow ~normocellala/hypercelular (bt 10% hypocelila), often with ‘mieromegakaryocytes; HIF: have marross fibrosis * also may see ring siderablasts in varying proportion * cytogenetics ~ including partial or total loss of chromosomes 5,7, Y, or trisomy 8 Treatment «depends on whether MDS classified as "low tisk” or "high leukemia «Tow risk (<5% blasts in marrow) * supportive care: RBC and platelet transfusion, antibiotics, antifungals * erythropoietin SC weekly may be effective in reducing transfusion requirements in some patients + hemaiopoietic growth factors (G-CSF, GM-CSF) may decrease risk of infection, «high risk (25 blasts in marrow) * supportive care * single agent chemotherapy - often hydroxyurea, mercaptopurine, or other agents intensive chemotherapy = chemotherapy as in AML. * stem cell transplantation - may be curative Myeloproliferative Neoplasms (MPNs) Definition + clonal myeloid stem cell abnormalities leading to qualitative and quantitative changes in erythroid, myeloid, and platelet cells of transformation to acute Epidemiology ‘mainly middle-aged and older patients (peak 60480 years) Prognosis ‘+ may develop marrow fibrosis with time #alldisorders may progress to AML Table 17. Chronic Myeloprliferative Disorders Pr a ca te oy ¥ W wor * N Pe * nib ey Mano rss 2 2 +H Splenamaiy + +H + + Hepat + + + - Goneic Assoc JAD mit SR) Berm +8) JAK |-$08) ACD mut (50) Weenies CM Hecmnninaane —ME=aipmlewpltiass — eT~ ase xiao Hematology 105 wv _ MOS case mrp nari hel Det iP Cat ee pte Ain Say ae gy ‘a a ‘esas srr oA) erent soe aban pe = bein deretrnt oe Come tem aoe ‘area #t enone lie ‘te ets ete tier ase sere Aspen ‘ensayo tess. Sans ose spares ‘pests ytevan sony ists an eter ae nd ati some ‘artes eka soon tpt wens ‘Meare eaenytees Basha sweanmonin tar rredclcecon+6 Hematology Veneer te en ig oo = ‘rovontdttn Sy Fens Otime i eat Meta 9c aus ncaa Aspirosyeraenadmreue eee Feats Pnnyonons a se ‘nonsman cmon PRO Pedbhac 04 POE pec Tee ‘meme aaundrsonmte sv rey et es ‘ean or tn po ‘Mortara note seen “Myeloprliferative Neoplasms “Toronto Notes 200 Polycythemia Vera (PV) Definition ‘ stem cell disorder characterized by elevated RBC mass (erythrocytosis) accompanied by increased white cell and platelet production Clinical Features + those secondary to high red cell mass and hypervisosity (see Plyeythemia, H5) + bleeding complications epistaxis, gum bleeding, ecehymoses, and Cl biceding * diet platelet abnormalities + shombotic complications: DVT, PE, thrombophlebitis, increased incidence of stroke, Ml * due to increased blood viscosity, inereaved platelet number and/or activity + ersthromelagia (burning poin in hands and feet} + associated with platelets 400 § HP /L + pathognomonic microvasculaetheombotic complications + pruritus, especialy after warm bath of shower (O') * due to extancous mast cl degranation with release of histamine + epigastric distress, PUD ‘cto increased histamine from issue basophils, alterations in gastric mucosal blood flow dae to increased blood viscosity + gout hyperuricemia) * due to increased cell mover + characteristic physical findings * plethora (rudy compton) of face 70%), pols + Splenomegoly (0%) hepatomegaly (0's) Investigations + see Polyeythenia, HS + must rule out secondary polycythemia * diagnosis (WHO) involves two requi + A Criteria (Major) ‘+ clevated red cell mass” (+25 above mean predicted value) no cause of 2° erythrocytosis "(e, arterial PO, 292%) * palpable splenomegaly + Clonal genetic abnormality other than ber-abl fusion gene * endogenous erytheoid colony formation in vitro * B Criteria (Minor) * thrombocytosis (400 x 10°/L) + Teukocytosis (12 x 10°/L) * bone marrow biopsy revealing panmyelosis with erythroid and rogakaryocytic proliferation + Iow serum EPO level + JAK2 mutation identified in most cases sl (*)Acriteria + 1 other A or 2 B criteria Treatment «+ phlebotomy to keep hematocrit 5% «+ hydroxyurea (age >65, prior thrombosis or symptoms). %P (age >80 or lifespan <10 years) ‘+ low-dose aspirin (for erythromelalgia and /or antithrombotic primary prophylanys) «allopurinol as needed «+ antihistamines ~ as needed Prognosis #10220 year survival with treatment + complicated by thrombosis, hemosthage, leukemic transformation (AML) Chronic Myeloid Leukemia (CML) Definition + mycloprolilerative disorder characterized by increased proliferation ofthe granulocytic Celt line without the loss oftheir capacty to differentiate = Epidemiology ‘tgenerally presents in fourth or fifth decade of life Pathophysiology + Philadelphia chromosome (Ph) translocation between chromosomes 9 and 22 * the eabl proto-oncogene is translocated trom chromosome 9 rugion’” (ber) of chromosome 2? to produce ber-abl fusion ger Kinase “breakpoint cluster an active tyrosine“Toronto Notes 20 -Myeloprlifeaive Neoplasms Clinical Features * 3 nial phases hone phase ~ dicase proces en controle (856 dingnosed here) fe bass (in ppl lin 2 Nighy elevated coSnop sand hasophis * hoaiplifcant eyepiece + accelerated phase inpatedneutopaldiferenatin, dificult to conta * elating Blasts 10-19% with increasing peripheral basophil prerits) + Rorningcontttoalsymptome and plenomepaly xan hematopsless) + CBC thrombocytopenia 100, WBC count unresponsive to therapy 2 Gjtogena vides of cana! evletion + bias Gls ~moreaggeseve cours basta to diferente * Sas 2 in perpheral bod or bone mar tvolstion tacit ekemia (7/3 ALL-2/3 AMI) {ing fot of bans n hoe matron examedlay blast profferation + cinial prseraion 2059 € patents ar asymptomatic when diagnose (inde Iabfnding) 1 Tonmpeatt symptoms ingue, weight os, malaise, excessive sweating, fever + wacendat lene nveironent cary satiety LUG panfalinesy, shoulder tip pain rrr) 1 Splenomegaly nt common ysl find + blbeding sccondary to platlet dysfunction + pruntas: PUD "secondary to increased Blond histamine + Fetkostass,priapiom,encephalopahy (care) ~secondary to highly increased WBC (eae) Investigations ‘high increase in WBC, decreased /normal RBC, increased decreased platelets, increased. basophils «+ peripheral blood film * Ieukoerythroblastic picture (immature red cells and granulocytes present, €g iyelocytes and normoblasts) + presence of different mid-stage progenitor cells differentiates from AML * bone marrow * myeloid hyperplasia with a left shift, increased megakaryocytes, mild ibrosis + molecule and togente tudes of bone marrow or peripheral Hood for Plladsiphia «+ abdominal imaging for spleen size (used in Sokal prognostic scoring system) Treatment "symptomatic ™ allopurinol and antihistamines + chronic phase imatinib mesylate (Gleeace™) — inhibits proliferation and induces apoptosis by {inhibiting tyosine kinase activity in cells positive for ber abl * clinical success with imatinib (eytogenic remission) has resulted in fewer patients requiring bone marrow transplantation * dasatinib({yrosine kinase and ste "dual inkibitor”) or nifotinib (selective berabll Inhibitor) for those who fail imatinib interferon-alpha ~ virtually obsolete with advent of tyrosine kinase inhibitors hhydeoxyurea (Cor initial stabilization Wf WBC counts >20) * one marrow transplantation (curative) + accelerated phase * Gleevec 600 mg PO dally «+ blast crisis * Gleevec up to 800 mg PO daily + stem cell transplantation may be curative ~to be considered in young patients who do not meet therapeutic milestones «+ treatment success is monitored based on therapeutic milestones: * hematologic ~ improved WBC and platelet counts, reduced basophils * cytogenetic — reversion of bone marrots to Philadelphia-chromosome negativity + molecular ~ reduction/ absence of ber-abl transcripts in periphery and marrow Prognosis, « [survival dependent on response + those achieving complete cytogenetic response (CCR) on imatinib by 18 months of therapy ~6 year 05 290% + those who did NOT ackieve CCR on imatinib - 6 year 05 of 66% + acute phase (baat crisis usually within 3-3 years) = FS devetop a picture similar to ANIL > tinresponetve fo remission induction + 1/3 develop a picture similar to ALL +rmision induction (return o chronic phase) achievable Hematology H37 wy Dato of bral on ge 8 dares wef oaet moet ‘opens in Ae tr rata 8 Sruasmiroyesa rem ‘sisalakinnaon pets Farmers} Gage wigs mmo gape HNWSCIEID anders events cate pc He ‘sade fe ‘EVE Ae ea as ci AT AT Fr este one pepssen east (ante gag oestrus <0 ae ‘leet care, Canine roms do ‘pagent ey Mores gears om Neos nana Insts ates re Sa saeHi6. Hematology eds bod im RBC and yaulosye ocr) nas Sone ara een th alae og is, uma treme eres eg MF) ioc ya spite nt dp Peele’ -Myeloprlifeaive Neoplasms “Toronto Notes 210 Idiopathic Myelofibrosis (IMF) Definition ‘excessive bone marrow fibrosis leading to bone marrow failure + characterized by anemia, extramedullary hematopoiesis, leukoerythroblastoss, the presence of teandrop-shaped red cells in peripheral blood, and hepatosplenomegaly Epidemiology ‘rare, median age at presentation is 65 Pathophysiology ‘+ abnormal myeloid precursor postulated to produce dysplastic megakaryocytes that secrete fibroblast growth fSctors stimUates fibroblasts and stroma to deposit collagen in marrow + increasing fibrosis causes early release of hematopoictic precursors to peripheral blood, leading t© *= Teukoceythroblatic blood film (primitive RBC and WBC present in blood) * migration of precursors to other sites ~ extramedullary hematopoiesis hence hepatosplenomegaly) Clinical Features + ancmia (severe fatigue is most common presenting complaint, pallor on exam in >60%%) + weight loss fever, night sweats > secondary to hypermetabotie stale + splenomegaly (90%) = secondary to extramedullary hematopoiesis; may cause early saticty + hepatomegaly (70°) > may get portal hypertension + bone and joint pain > secondary to osteosclerosis, Rou! + signs of extramedullary hematopoiesis (depends on organ involved) Investigations ‘CBC anemia, variable platelets, variable WBC * biochemistry: increased ALP (liver iavalvement, bone disease), increased LDH (2°t0 fective hematopoiesis) increased uric acid (increased cell turnover, increased By (2° ta increased neutrophil mass), increased leukocyte alkaline phosphatase (LAP) + blood film: leukoorythroblastesis with tcardrop-shaped RBCS, nucleated RBCS, variable polychromasia large platelets and megakaryocyte fragments ‘bone mantow aspirate: “dry tap” in as many as 50% of patients * bone marrow biopsy (essential for diagnosis: fibrosis, atypical megakaryocytic hyperplasia, thickening and distortion ofthe bany trabeculae (osteoselerasis) Treatment ‘ allogeneic stem cell transplant is potentially curative ransfusion for anemi * erythropoietin ~ 50% of patients respond + danazol has shown transient response with response rates of <30% += hydroxyurea for splenomegaly, thrombocytosis, leukocytosis, systemic symptoms ‘alpha interferon (as second line therapy) + splenectomy’ (as tied line therapy-associated with high mortality and morbidity) * XRT for symptomatic extramedullary hematopoiesis, symptomatic splenomegaly. * allopurinol Prognosis ‘median survival for patients with AMM is 355.5 years 4 Hsk of transformation to AMI. (S-10%) Thrombocythemia (ET) * overproduction of platel thrombocythemia) i In absence of recognizable stimulus (must rule out secondary Epidemiology ‘increases with age, FM = 24 but F-M at older age Diagnosis ‘+ WHO Criteria - Positive Criteria and Criteria for Exclusion + Positive Criteria * sustained platolet count >600 x 10°/L. + bone marrow biopsy ~ proliferation of megakaryocyte lineage with enlarged, mature megakaryocytes + acquired JAK2 mutation‘Toronto Notes 200 Myeloprlifeative Neoplasm/Lymphoid Maignances * Criteria for Exclusion * no evidence of PV, CML, IMF, MDS * no berabl fusion gene + no evidence of bone marrow collagen or reticulin fibrosis + no evidence of reactive thrombocytosis due to inflammation, infection, neoplasm, prior splenectomy Clinical Features + often asymptomatic * Sasomotoe symptoms (40%) headache (common), dizziness, syncope + erythromelagia (burning in of hands and feet dusky colour sally worse with Ipeat caused by ploteict activation » rnicrovasculae thrombosis) + thrombosis (arial and venows) + bleeding (often Gl associated with platelets >1000 x 10°/L) + constitutional 5x. splenomegaly pregnancy complications; inereased risk of spontaneous abortion ofbrosis Hileof transformation to AML (0,6-5'), my Investigations ‘+ CBC: increased platelets, may have abnormal platelet aggregation studies * bone marrow hypercellularity, megakaryocytic hyperplasia, giant megakaryocytes «increased K, increased PO, 2 to release of platelet eytoplacmic contents) * diggnosis: exclude other myeloproliferative disorders and reactive thrombocytosis ‘Treatment Tow dose asplein if thrombotic event, older or symptomatle + decreased platelets: hydroxyurea (Ist line therapy), anagrclide, interferon-alpha, or ™P (age =80 of lifespan <1 years) + plateletpheresis in emergencies * Splenectomy not recommended (Increased risk of bleeds, thrombosis) ymphoid Malignancies Acute Lymphoblastic Leukemia (ALL) Defini ‘malignant disease of the bone marrow in which ealy lymphoid precursors proliferate and replace the normal hematopoietic cells ofthe marrove + WHO subdivides ALL into two types depending on cel of origin B cell ~ precursor B lymphoblastic leukemia + Teall — precursar TIyemphoblastic leukemia Clinical Features * see Acute Myeloid Leukemia, H33 for full st of symptoms distinguish ALL from AMI based on Table 18 75%, ALL occurs in children <6 years old: second peak at age 40, + clinical symptoms usually secondary t0 * bone marrow failure ~ ancmiz, neutropenia (50% present with fo ‘of oropharynx, lungs, perianal region) dhrombocytopeni + organ infiltration ~ sender bones Iymphacenopathy, hepotosplenomegaly, ‘meningeal signs (headache, N/V, visual symptoms; especially in ALL relapse) also infections Investigations # CBC: increased leukocytes ~10 x 10°/L (occurs in 50% of patients); neutropenia, anemia, tr thrombocytopenia. ‘may have increased uric acid, K, POy Ca, LDH, + PT PTT, fibrinogen, D-dimers for DIC + leukemic lymphoblasts lack specific marphologs theres dlghosis depends On Immunophendpins + cytogenetics: Philadelphia (Ph) chromosome in ~25"" of adult ALL cases + CXR: patients with AEL may havea mediastinal mass 4 LP prior to systemic chemotherapy to assess for CNS involvement (no granules) or cytochemical features, Treatment +Climinate abnormal clone ‘imation ” Wo induce compete rion (ndeletabe leukemic Bast restore normal hematopolesis) og, Dana-Farber regimen ~ vincristine (Oncovin™), prednisone, methotrexate, Ichoovorin, L-aspanginase, intrathecal methotrexate and ara-e + in Pifadeiphia Chromosome positive ALL” can add imatinib mesylate {Gleevec a berabl tyrosine Kinase inhibitor), found to induce complete remission in up 10 95" canes Hematology 35 we a Elology of Seconary ‘iromneythonie Hiteton Inari 180, te) ones Hererage renaieey Hanoy nia Poatsaenectamy Putcbewborany [SA tpn eden or a FB Clsteston of ALL 1 at aa undo igh 12 at case etre, ‘ower 1B veritas, ge apes (asl ALLHo. Hematology “ontst ot ALL v= AML Die ‘ite portent ot marae hereto AML 2a CNS preps AML @ [jmphoid Maignandesitymphomas “Toronto Notes 210 2, consolidation and/or intensification chemotherapy ‘consolidation continuing same chemotherapy to eliminate further subclinical Teukemic cells + intensification — high doses of diferent (non-cross-reactive) chemotherapy’ drugs to eliminate cells with resistance to primary treatment 3. maintenance chemotherapy —low dase intermittent chemotherapy aver prolonged period (23 years) to provent relapse 4, prophylaxis: CNS with radiation therapy’ or methotrexate (intrathecal or systemic) «+ hematopoiotc stem cell transplantation - potentially curative (due to pre-implant snyloablative chemoradiation and postimplant grater elec but relapse tales and non-relapse mortality high Prognosis ‘depends on response to initial induction or if remission is achieved following relapse + good prognostic factors: young, WBC ~30 x 10?/L, T-cell phenotype, absence of P Chromosome, early attainment of complete remission «achievement of first remission: 60.90% * childhood ALL: 80% long term remission (5 years) * higher cure rates in children because of better chemotherapy tolerance, ower prevalence of bcr-abl fusion gene (assoctated with chemotherapeuti resistance) + adult ALL: 30-10% Sear survival Tobe 18, Diffaremtiate AML From ALL ma a ‘itrentts AL From A: enon Bio SAL apenas Salo) ise Sgtass Sra Lesa olen Lassen asd nt 38) Fara) aso es a Aare Nagas Bi rosiy fees lide rey aren Sommaire Sra meaty 8 ype, Sin bck sin PRS pio ac shih axxo elt ted mei ems Necro dea tendo. or MO ety Definition ngs stg om roi rotamaby + collection of lymphoid malignancies in which malignant lymphocytes accumulate at Iymph nodes and iymphoid tissues, leading to lymphadenopathy extranodal disease, and constitutional symptoms ‘+ Ann Arbor staging can be used for both Hodgkin's and non-Hodgkin's lymphoma, but _gtade/ histology is more Important for non-Hodgkin's lymphoma because i tends t0 present at more advanced stages ‘Staging (Ann Arbor Staging System) = Segel * involvement of a single lymph node region or extralymphatic organ or site + Stage Il * involvement of two or more lymph node regions or an extralymphatic site and one ‘or more lymph node regions on same side of diaphragn + Stage I * involvement of lymph node regions on both sides ofthe diaphragm; may or may not be accompanied by single extra lymphatic site o splenic involvement Stage 1V * ditfuse involvement of one or more extealymphatic ongans including bone marrow «+ subtypes: + A absence of B symptoms = B= presence of B symptoms unexplained fever >38C ‘+ unexplained weight loss ( * night sweats 10% of body weight in 6 months) Table 19, Chromosome Translacations Trandocaion Gone Actnaion wi ye acaion 081) belzaciaton Felidae 13m Phinda ctrareson rsd) ALL nats (25% etre) amg Overepressin potin jin Maral para“Toronto Notes 20 ymphomas Hodgkin’s Lymphoma Definition ‘+ malignant proliferation of lymphoid cells with Reed Sternberg cells (thought to arise from ‘germinal conter B-clls) Epidemiology ‘bimodal distribution with peaks atthe age of 20 years and 254 years * association with Epstein'Barr virus in up to 50% of eases tna Fees * cervical/supraclavicular (60-80%), axillary (10-20%), inguinal (612%) seme Investigations CBC * anemia (chronic disease, rarely hemolytic), eosinophilia, leukocytosis, plat rhormal or increased early, decreased in advanced disease + biochemistry LFTs (liver involvement) FTs (prior to initiating chemotherapy) ALB Ca (bone involuement) ESR, LDH (monitor disease progression) + imaging "CXR, CT chest (lymph nodes, mediastinal mass), CT abdomen/ pelvis (liver or spleen Invoivement), gallium scan (assess treatment response), * cardiac function assessment ~ (MUGA, or echocardiography for EF) for patients at high risk of pre-treatment cardiac disease (age >6l, history of hypertension, CHE, PUD, CAD, ML CVA) + PETS ~it history of lung disease (COPD, smoking, previous radiation to lung) + excisional lymph node biopsy confirms diagnosis + bone marrow biopsy to assess marrow infiltration (only necessary if B symptoms, stage Ill or IV, bulky disease or eytopenia) Treatment «+ stage IE: chemotherapy (ABVD) followed by involved field XRT + Stage IT-IV: chemotherapy (ABVD, BEACOPP), with XRT for bulky disease + relapse, resistant to therapy: high dose chemotherapy, bone marrow transplant Complications of Treatment * cardiac disease ~ secondary to XRT, adriamycin is cardiotoxic + pulmonary disease ~ secondary to bleomycin, which causes interstitial pneumonitis, + Infertility ~ recommend sperm banking | secondary malignaney in irradiated field *# 2% risk of MD5, AML (secondary to treatment, usually within 8 years) + Solid tumours of lung, breast, >10 years ater treatment + non-Hodgkin's lymphoma hypothyroidism - post XRT ‘+ infection ~ post splenectomy (give Pneumovax, HIB, and pneumococcal conjugate ‘vaccines, during treatment Prognosis ‘adverse prognostic factors 1 serum albumin 1.5 x 10°/L) 7 lymphoestopenia (lymphocytes 0.06 » 10°/L or 1 Iymph region + Usually presents as widespread disease + conatitutianal symptoms (lever, weight fos, night sweats) not as comman as in Hodgkin's disoase + cylopenia: anemia + neutropenia + thrombocytopenia if one marrow fails + abdominal * hepatesplenomegaly + retroperitoncal and mesenteric involvement Gad most common site of involvement) + oropharyngeal involvement in 5-iF' with sore throat and obstructive apnea + extranodal involvement ~ most commonly Gl trac, also testes, bone, kidney + CNS involvement in 1% (often with HIV) Investigations CRC * normocytic normochromic anemia + autoimmune hemolgtic anemia + advanced disease: thrombocytopenia, neutropenia, and leukerythroblastc anemia + peripheral blood film sometimes shotes lymphoma cls + biochemistry ‘increase in uri acid * abnormal LFTS in liver metastases + increased LDH (rapidiy progressing, disease, poor prognostic factor) + CXR and CT for thoracic involvement + CT for abdominal and pelvic involvement + gallium scan is useful for monitoring response to treatment and evaluation of residual tumour following therapy + diagnosed by * Iymph node biopsy * fine ncedle aspiration occasionally sufficient, excisional biopsy preferred * bone marrow biopsy Treatment «localized disease (c.g. Gl, brain, bone, head and neck) surgery (i applicable) * radiotherapy to primary site and adjacont nodal areas * adjuvant chemotherapy ‘+ indolent lymphoma goal of treatment is symptom management * seatchtul waiting, * radiation therapy for localized disease * chemotherapy (single agent, combination or rituximab /Rituxan™, an anti-CD20 antibody) + aggressive Lymphoma — goal of treatment is curative * combination chemotherapy: CHOP is mainstay, * radiation for localized bulky disease * CNS prophylaxis with high-dose methotrexate (intrathecal ar systemic) if certain sites involved + relapse, resistant to therapy: high dase chemotherapy, BMT. «+ highly aggressive Iymphoma * Burkit’s Lymphoma short bursts of intensive chemotherapy + “CODOX-M" chemotherapy regimen also often used + IVAC * CNS prophylaxis and tumour iysis syndrome prophylaxis is rituximab if B-cell lymphomaToronto Notes 200 {gmphomasaligant Clonal Proliferation of B Calls Hematology 188 Complications = hypersplenism + infection + autoimmune hemolytic anemia and thrombocytopenia + vascular obstruction from enlarged nodes) + tumour lysis syndrome (particularly in very aggressive lymphoma) - see H47 Prognosis + poor prognostic factors El years old * poor response to therapy + Inultipie nodal regions * elevated [DH * nodes >5 em, + previous history of low-grade disease or AIDS ‘oble 20. Characteristics of Selected Non-Hodgkin's Lymphomas alia psptons Oise Large &-Colarki’s proms Wane Cal lymphoma Lymphoma L801 Pacontage of ils 220% we 30% ofall nicest cells = infiltration of marrve by Iymphocytes in 3 patterns: nodular (10%) interstitial (30), dltuse (35%, worse prognosis or mined (257) Natural History and Treatment «natural history ~ indolent but incurable, with slow progression; hus select gentlest timer at wnat * observation i early, table asymptomatic 4 intermittent chlorambuell or Audarabine ‘icosteroide, VIG especially for autoimmune phenomena radiolerapy 2 Ghemotherapy —including Ritsuimab (ant-CD20 mAb) + small minority present with aggresive disease usually sociated with chromosomal abnormaliies (eg po deletion) + Syear median survival but vaies greatly Eerewtona eee eens hee terior Sect 2 ph irene det yeep spores ee ase Multiple Myeloma (MM) Detinition * characterize by neoplastic proliferation ofa clone of plasma cells producing a ‘monoclonal immumoglobulin ® poses + {ually ingle clone plasma clls although biclonal msoma has been reported Epidemiology * incidence 3 per 100,000 * increased frequency with age, median age of diagnosis is 68 (have had younger patients in their 20's and 3's) Pathophysiology + malignant plasma cells secrete monoclonal antibody #°O5% produce M protein (a monoclonal Ig = identical heavy chain + identical light ids P lg y ih * IgG 50%, IgA 20%, Ig 2%, IgM 05%