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 By2 Deficiency Folate Deficiency Homostasis ..... cece BB ‘Three Phases of Hemostasis Disorders of Primary Hemostasis ..........25 Immune Thrombocytopenic Purpure (ITP) Heparin-Induced Thrambocytopenia (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 (ANAL) 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 (MIM) 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 Curing 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- os ie + thymus: site of T-cell maturation, involutes with age ‘ney baphi- reid resp fe epee etl aessinens Complete Blood Count Sapna 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 Sehecnss eee 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 eercnmncnn aa nom ee or Fei nemmatow | Reeth (ON) Masts 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 nanooo aus 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! oye Normal ABC Hypache Sypomi—tsen n the seth cent pallor normals than one tind | 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) + Ninoxplatned 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 cause * O, for hypoxemia, CPAP for sleep apnea, surgical for EPO-scereting tumours + phlebotomy Thrombocytopenia « platelet count <150x10°/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 differential * 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 2010 ‘Common Presenting Problems Hematology H 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 *hstory: ume, sngey planstomy nto nlammation besng 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 f+ 9 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 irra nga 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 rere of denne Eas in ‘eperyerl se wit als eowaor razr euoabl ar st Smet cra cel dsr 0S, ‘ealeuumash, Prt: nti a Sag Faso ese ‘one 0 071 Penida ‘rH ei Sete fant teewee mdteweth ane sy itera en “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™ = Fastin ‘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 (onty 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 undedying 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 Ter 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 Ditforentiating inflammatory vs. Neoplastic Lymph Nodes Featre Infants Modes Neoplastic Ge 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 Approach to Splenomega 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 eratlgical ‘acinus 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 ieaive Nowra ‘Arvedsas Iysosnra soroge dss (Gach Noman Pit Mgnt eke (OAL) byrpara Hokies dept ests Nexataic rox nol Exam tr Spenomensty thin 13'70 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 tab teste 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 (MICV- 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 on 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 Fevdeficoncy anemia Figure 7. Approach to interpreting Fe indices Agel pet, a yan 2078518HI Hematology ron detlency AnanisComesiy Chest wt Anam f 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 ‘Vatettn oma Reyes 2) i f —4 oan ¥ aus of Norm (ieee —] (Titan) (Fea) Rea) 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 Bhetetcae 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 Medtranean SEA; coThit— 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 eras rst mee 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 + Hp 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 ——— TWbl 6. Investigations for Sickle Col Dcease i aca SEE as es gm Faken 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 gga comealng 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 ‘abet oka te Cos {spre oes pee: be ‘fut Aom nn Serb Aton ‘hula catrs ct dee ‘Sha Sein end ‘Sate cnet ogee ‘Sey eee ante ce Soma toe sl ym ‘a wean ‘me ar syed seman ltueder site 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 oC 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 Aine engrave 0 sare Diet Comms ast Faso Poste cone (drt an-gbin est) Bion 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 20 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) G6PD 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! tesesive, more prevalent in black males Clinical Features + X-linked 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 CL 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 Megalablastic Macrocytic Anemia Mops Nor Mapltiastc Worbaoey Lae cal nce BC poor 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 Megleblse 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 nn ea aot este py Doe sme Sema Mere crns 03 8,0 ge, era ‘Sake arbalautenaedae ove eal Fete nonusers serpy eso 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 20 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 canna 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 offibvin | 2. scanary 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) Fiaceeaea 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, rokged 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 ABH 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 TPC 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 antibodies 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 Wes orn ADs orca yor atren ar Nese Ehen ental Oude aegis peace Die oy Mechta or abcd ‘Toromineyoperia bie ten arom 1 Inrne itd ptt desruan 2 See artrtonnds roc tet proueen Sta a ei are Nae Pine Crt HE 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 tomamee sna "asa ape eo 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 ‘hrombne pena Ore oe HY rene 2 ire madd aaoe 4. Some revo rue pave edu ‘Sembee oer Sleaze Pai e “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 Mepaiaseocied ‘tombcyepea "rete mcd is sapeastor hove) Petco > 0x10 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 Peta OR Bg Wea s Pa tic, Tria ‘at NS 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-Splenectomy Refractory ITP Na om wanlmayuon sna ape rte Heparin-Induced Thrombocytopenia (HIT) Table 13. HIT (Heparin induced thrombocytopenia, type Il) 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 decreased paelts 5:18 da pein expose then I can dase inka sk ftronbosis ~205 ek menswear) iia os ‘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 Manogoment 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 idensogy Parra cto Petar ast logy Shop texn cot seeype 01577) Dado of meters ht eas down sarge ‘i miners Conga genet secs of ADANTS 13) * Raut gs malay, arent Hae, ‘Goyatie) Giricsl ——|.Seaetiontnoynpena: puerta features “eisai hogy, ities) 2 Mizergopeic hrc rena (MAHAL 2 hlcrangopshichorays ama (HANA) 3. Newdegal syrpons| HA, cra cal os, ots) 5. Rallaue [aroma utes cgi, Rael faue eae aie) 5 eer Investinaons CBC nd fi: scissors tees asia 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 _Pasrephressis te wien ce = seis {hath TE HUS) Pacer enti contend reese icroeszue 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—qualitve detect (dstunctional VWF) in X25 af eae 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 Prthopyslogy of TP ‘Faery ens esa 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 ‘eb eee i ag ont mene Oise ‘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 Hooary ‘Reguiad +a ieFenaphile OSC Uf ‘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 Investigations «prolonged aPTT, 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 Vik + 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 Ie rnp ‘eau gmp ces ee als ne Onypap ecs eet 4S 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 Venous Thrombosis 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 frier 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 Nears ‘uy Abas ne Gua fi, aa pi dy See te roth ‘Sermimeio era ce Sep nd me ern dae See meres atl pap a prs ot ‘Sse M00 es ane arb waco ‘eine artes (het eg su ‘emt ironed arene pester ‘Teatro an ‘rapes a ‘ctr 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 (i ge mon ar ‘See eyed aca ‘Svein eo wlan ‘ato og Se coro, ‘eather ase ree gue oon (Bete ntdarn Vc ee fe ete ero ‘gard aracrcosrat “y Seacancn eames nos sere Een samen seen aia a popes eee Eectianeme a Soon Se ou a age patente <40 9, rove eta or IE grea Store Al 30 mpm ‘eit aber se sry Moderate sik supa paints: > 20 Ys stist ero VIEGAS rs igh i sien ptents: 40s, sare ke grey oon ‘xseiyochoped rey 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.