H

Hematology
James Kennedy, Danni Li and Eric Tseng, chapter editors Ray Guo and Arnold Jacob, associate editors Shauna-Dae Phillips, EBM editor Dr. Janey Hsiao, staff editor
Basics of Hematology Complete Blood Count Blood Film Bone Marrow Aspiration 2 Disorders of Secondary Hemostasis Hemophilia A (Factor VIII Deficiency) Hemophilia B (Factor IX Deficiency) Factor XI Deficiency liver Disease Vitamin K Deficiency Disseminated Intravascular Coagulation Venous Thrombosis Approach to Treatment Hypercoagulable Hematologic 28

and Biopsy 4

Common Prese.nting Problems Anemia Polycythemia Thrombocytopenia Throm bocytos is Pancytopenia Neutrophilia Neutropenia Lymphocytosis Lymphocytopenia Eosi noph ilia Agra n u locvtosis Leukemoid Reactions Approach Approach to Lymphadenopathy to Splenomegaly •.•...•...•.•.

(DIC) 30

of Venous Thrombosis 32 33 33

Disorders

Malignancies

Myeloid Ma.lignancies Acute Myeloid Leukemia (AML) Myelodysplastic Syndromes (MDS) 10 Myeloproliferative Neoplasms Polycythemia Vera (PV) Chronic Myeloid Leukemia (CML) Idiopathic Myelofibrosis (IMF) Essential Thrombocythemia (ET) Lymphoid Mal'ignancies Acute Lymphoblastic Leukemia Lymphomas Hodgkin's Lymphoma Non-Hodgkin's Lymphoma

35

'1
11

Microcytic Anemia Iron Metabolism Iron Deficiency Anemia Anemia of Chronic Disease Lead Poisoning Sideroblastic Anemia Thalassemia Normocytic Anemia Aplastic Anemia ,., ,

39 (ALL) 40

15

Hemolytic Anemia ......• , ........•.. , .. 16 Thalassemia Beta-Thalassemia Minor (Thalassemia Trait) Beta-Thalassemia Major AI pha-Thalassem ia Sickle Cell Disease Autoimmune Hemolytic Anemia (AIHA) Microangiopathic Hemolytic Anemia (MAHA) Hereditary Spherocytosis Hereditary Elliptocytosis G6PD Deficiency Macrocytic Anemia Vitamin B'.2 Deficiency Folate Deficiency Hemostasis Three Phases of Hemostasis 2.1

Malig.nant Clonal Proliferations of B Cells ... 43 Chronic Lymphocytic Leukemia (CLL) Multiple Myeloma (MM) Light Chain Disease Monoclonal Gammopathy of Unknown Significance (MGUS) Wa Idenstrom' s Macrog 10 buli n em ia Complications of Hematologic Hyperviscosity Syndrome Tumour Lysis Syndrome Malignancies .. 47

Blood Products and Transfusions Blood Products Red Blood Cells Platelets Coagulation Factors Acute Blood Transfusion Reactions Delayed Blood Transfusion Reactions Common Medications Antiplatelet Therapy Anticoagulant Therapy Chemotherapeutic Agents Landmark References Hematology Trials

47

23

51

Disorders of Primary Hemostasis 25 Immune Thrombocytopenic Purpura (lTP) Hepa rin-In duc ed Throm bocytopen ia (HIT) Thrombotic Thrombocytopenic Purpura (TIP) and Hemolytic Uremic Syndrome (HUS) Von Wi.ll.ebrand's Disease (vWD)

54 55

Toronto Notes 2010

Hematology HI

H2 Hematology

Basics of Hematology

Toronto Notes 2010

Basics of Hematology
Hematopoi sti c stem c el I

-

.

,

.• Pro ervt hro bl ast Lymphoblast Monoblast

~

0
Erythrocyte

10

0
Basophil
L__ __

.. " ,
Eosinophil Granulocyte
L__

y

Neutrophil ___j Leukocyte

Lymphocyte

Monocyte

I
Platelet

L Agranulocyte
----'

J

" -. ,-,

© Mich.lI. kui 2005

• over 10" blood cells are produced daily • sites of hematopoiesis in adults: pelvis, sternum, vertebral bodies • Lifespan of mature blood cells "" ~ I • erythocytes (120 days); neutrophile (-1 day); platelets (10 days); lymphocytes ~~------------------~. (varies - memory cells persist for years) ErythrOl:VlB - csrri as oxygen from • role of lymphoid organs ·Iungs to peripheral tissu es • spleen: part of reticuloendothelial system; removes aged RBCs, removes antibodyReticulocyte - immature erythrocyte coated bacteria/cells, site of antibody production Neutropb il - integ ral celli n in nate • thymus: site ofT-ceIl maturation, involutes with age immunity • lymph nodes: site of activation of BIT cells (adaptive immune response)
Eosin Dphi I " invD Ived in res p onse to parasites {especially he hninths I an d aile rgic response

Figure 1. Hematcpclesls

Basopll il - function is mostly unknown; likely involved in all erg i c re sponse
Lymph ocyte - integral cell in adaptive

Complete Blood Count
Table 1_'Common Terms Found on CBC Test
Red blood cell I R BG) co unt Hemoglobin (H b I Hematocrit IHctl Mean corpuscular volum elM CV] Definition Normal Values' of blood 4.2.-6.9 x lO"/mm3

immun~y Monocyte· involved in ,innate Immun ~y; can d ifferenti ate into mac rap hage or d endrili c cell Platel et . msd later of primary hemostasis

Th e numb er of RBGs per 1101 urns
Amount of oxygen-carrying

protein in the blood

130·180 gil (13·18 gldL) (male) 120·160 gil (12· 16 g1dll (female)
45%-62% I mele) 37%-48% Ifemelel

Percentage of a gillen voillm e of whole blo 0 d eccup ied by packed REGs Measurement of sill) ofRBCs Amount of oxygen-carrying Hb inside RBGs

80-100/Jm'
27-32 pg/cell 32%-36%

?~--------------------,

Meallcorpuscular

Hb 1MGH)

Clinical Use of RDW To distinguish the etiologies of microcytosis: Fe deficie ncV - increased ROW {du e to anisocytosis I Thalassemia minor - normal ROW

Mean corpuscular Hb concentration (MCHC) RBC distribution width (RDW) Wh ite blood cell (WB CI count WBC differential

Average concentration of Hbinside RBGs M easurernent of variance in RBG size Thenumber of waCs per volume of blood Includ es neutropILils, eosinophils, basopllils, Iymp hocytes alld monocytes

11.0%-15.0% 4.3-10.8 x 11)3/mmJ

... ~ I

Platelet count Thenumber of platelets per 1101 ume of blood ~~-------------------, Mean p latelst volume 1MPV) M 8asurement of platelet size Absolute Neutrophil Count IANCI = WBC count x I%PMNs + %bandsl Reticulocytes Immeture RBCs that conta in no nuel 8US out have Beware tever + ANC < 0.5 xt 0" / L = resi dual RNA FEBA ILE NEUTAO PENIA 'Eve~ lob has its own set of normalIfililles tho! mav d~rffer thew from

150-400 x lO'/mm;
Normally make up 1% of total RBC count

Toronto Notes 2010

Basics of Hematology

Hematology H3

Approach for Interpreting CaGs 1. consider abnormal values in the context of indivi dual's baseline • up to 5% of population without disease may have values outside "normal" range • all. individual may display a substantial change from their baseline without violating "normal" reference range 2. is one lineage affected or are several? • if all lines are down: consider pancytopenia (see PanC!)topenia, H7) • if RBCs and platelets are down: consider MAHA • if single lineage affected: see corresponding section in Common Presenting Problems, H4

Teardro p cell

Nucleate d RBG

Heinz bod ies

Spur cel[

Blood Film Interpretation
REO BLOOD CELLS
Size • microcytic (MCV<80), normocytic (MCV",80-100), macrocytic • anisocytosis: RBCs of variable and abnormal size • iron deficiency anemia, thalassemia, myelofibrosis (MCV>100)

~

V

.~.
Sickle cell

Schistocyte

~
Normal'RBC

Colour • hypochromic ~ increased in the size of the central pallor (normal = less than one third of the diameter of RBC) • iron deficiency anemia, anemia of chronic disease, hemolytic anemias, sideroblastic anemia • polychromasia ~ increased reticulocytes (pinkish-blue cells) . • increased RBC production by the marrow Shape (see Figure 2) • discocyte ~ normal (biconcave disc) • poikilocytosis: increased proportion of RBCs of abnormal shape • iron deficiency anemia, myelofibrosis • spherocyte ~ spherical RBC (due to loss of membrane) • hereditary spherocytosis, immune hemolytic anemia • elliptocyte! ovalcytes - oval-shaped, elongated RBCs •. elliptocytes: the RBC long ~x~s is :e:2xthe lenpth of the short ~xis • ovalcytes: the RBC long aXISIS <2x the length of the short aXIS • these are the predominant cell form in hereditary elliptocytosis; occasional cells can have these forms in megaloblastic anemia, myelofibrosis, iron-deficiency MDS • schistocytes (helmet cells) ~ fragmented cells (due to traumatic disruption of membrane) • microangiopathic hemolytic anemia (HU5/TTP, Die, pre-eclampsia, HELLP, malignant HTN), vasculitis, glomerulonephritis, prosthetic heart valve • sickle cell ~ sickle-shaped RBC (due to polymerization of hemoglobin S) • sickle cell disorders: HbSC, HbSS • codocyte (target cell) ~ looks like "hull's eye" on dried film • liver disease, hemoglobin SC, thalassemia, Fe deficiency, asplenla • dacrocyte (teardrop cell) - single pointed end, looks like a teardrop • myelofibrosis, thalassemia major, megaloblastic anemia • acanthocyte (spur cell) - distorted RBC with irregularly distributed thorn-like projections (due to abnormal membrane lipids) • severe liver disease (spur cell anemia), starvation! anorexia, post-splenectomy • echinocyte (burr cell) ~ RBC with numerous, regularly spaced, small spiny projections • uremia, HUS, bums, cardiopulmonary bypass, post-transfusion, storage artifact Distribution (see Figure 2) • rouleaux formation ~ aggregates of RBC resembling stacks of coins • cause: increased plasma concentration of high molecular Weight proteins • seen in pregnancy (most common cause; due to a physiological increase in fibrinogen), inflammatory conditions (due to polyclonal immunoglobulins), cell dyscrasias (due to monoclonal paraproteinemia; eg. multiple myeloma, macroglobulinemia), storage artifact

'VdJ

Hyp 0 chro mi c

microcytic

Spherocyte

Ell iptoc yte

Target cell

®
..
.

Howell-Jolly bodies

_A

Basophilic stippling

e
..

Burr cell

fROUI~X
figure 2.. Morphology

plasma

Inclusions (see Figure 2) • nucleus - present in erythroblasts (immature RBCs) • hyperplastic erythropoiesis (seen in hypoxia, hemolytic anemia), extramedullary hematopoiesis (seen with BM infiltration) • Heinz bodies ~ denatured and precipitated hemoglobin • G6PD deficiency • Howell-Jolly bodies ~ small nuclear remnant resembling a pyknotic nucleus • post-splenectomy, hyposplenism, neonates, megaloblastic anemia • basophilic stippling ~ deep blue granulations indicating ribosome aggregation • thalassemia, heavy metal (Pb, Zn, Ag, Hg) poisoning, megaloblastic anemia, hereditary (pyrimidine S'uucleotidase deficiency) • sideroblasts: erythrocytes with Fe containing granules in the cytoplasm • see Sideroblastic Anemia, H14

H4 Hematology

Basics of Hematology/Common Presenting Problems WHITE BLOOD CELLS

Toronlo Notes 2010

• lymphocytes: comprise 30-40% of white cells ~ Reed-Sternberg cell: giant, multinucleated B-Iyrnphocyte • seen in Hodgkin's lymphoma" other lymphoproliferative disorders, reactive nodes • smudge cells: lymphocytes damaged during preparation of the blood smear; indicating cell fragility; seen in Chronic Lymphocytic Leukemia (CLL) • neutrophile: • normally only mature neutrophile (with 2-4 lobed nucleus) and band neutrophil (immediate precursor with horseshoe-shaped nucleus) are found in circulation • hypersegmented neutrophil: >5 lobes suggests megaloblastic process (B12 or folate deficiency) • left shift: increase in granulocyte precursors (bands, metamyelocytes, myelocytes, promyelocytes, blasts) in circulation; seen in acute infections, pregnancy, hypoxia, shock • blasts • immature, undifferentiated cells; associated with leukemia • Auer rods: clum,lps of gran, ular materi,althat for,'m,long n,eedles i,n the cytoplasm of myeloblasts: pathognomonic for Acute Myeloid Leukemia (ANfL)

PLATELETS
• small purple anuclear cell fragments

Bone Marrow Aspiration and Biopsy
• sites: posterior iliac crest, sternum • possible analyses • asp ira lion ~ histology; flow cytometry, cytogenetics, molecular (C&5, AFB) • biopsy - for histology (keeps tissue structure intact) studies, microbiology

Indications • unexplained CBC abnormalities • diagnosis and evaluation of plasma cell disorders and leukemias • diagnosis and staging of lymphoma. or solid tumours • evaluate iron metabolism and stores • evaluate suspected deposition and storage disease (e.g, amyloidosis, Gaucher's disease) • evaluate fever of undetermined origin, suspected mycobacterial, fungal or parasitic infections, or granulomatous disease • unexplained splenomegaly • confirm normal bone marrow in potential allogenic hematopoietic cell donor Contraindications • absolute: hemophilia, severe DIe INR >1.5 • thrombocytopenia not a contraindication - may need to transfuse

platelets prior

Common Presenting Problems
Anemia
Definition • a decrease in red blood cell (RBC) mass that can be detected by hemoglobin concentration, hematocrit (Her), and RBC count • adult males: Hb <135 giL, (135 g/dL) or Hct <41% • adult females: Hb <120 gil, (12 gl dL) or Her <36%
Reticu locytes Relicu I ccvtes are you ng eryth rocvtes and are markers of ervthrocvte prod uction, Any tim e' the re' is a decrease in RBCs, the physiologic re spo nss is to increas e prod u ctl On which leads to ani ncreassd reticulocyt~ count. A person with low hemogl ob in and a normal erythropoe iIi c system would b e expected to have, a re lativelv h ighreliculocyte count, Therefor". a normal raticul Deytl! cOUnt in, an ernia should be interpreted: as a sign 01 decrees ed pro d uctlon,

(Hb)

EtiologV and Approach • differentiate anemia vs. pancytopenia (see Pancytopenia, H7) • look at the mean corpuscular volume (MCV) • microcytic (MCV <80), macrocytic (MCV >100), normocytic (MeV"" 80-100) • if normocytic, the reticulocyte count helps differentiate between decreased production (decreased retics) and increased destruction/loss (increased retics) • causes associated with decreased production can be • primary (i.e, bone marrow disorder aplastic anemia, myelophthisic! infiltrative process, hematologic malignancy) or • systemic [e.g chronic disease, hypothyroidism, chronic renal failure, liver disease, nutritional (iron, B12 folate decifiency)] • increased destruction/loss can be due to hypersplenism (sequestration and destruction), hemolytic disorders, blood loss

Toronto Notes 2010

Common Presenting Problems

Hematology

H5

I I

Low Hemoglobin

I
Normal

I I

Low MCV ,.. lron defir;ilwcy
~ Thelessema • Anemi.a(]f chronlc disease

MeV (see Figu'e 8)

I
Illgh reticu locyte

High MCV
Megalobl estlc
• Bl~ Deficiencv

• Siderobl';astk ..anemia • Lead Poi soni ng

I

I

Low reticulocyte

I

• Fol.," ~fici."cV • [JlU!;IS that impei rONA su Ifa, cnemo I • My.lodv",pl.,;. Non-megal tJo'!J.fastic
• Liver
[I isease

I
Bleeding • GI • GU • Other Pan oytop eni. t- Aplastic :anerl'lia • MUS
• ntyeltJfibrD$i~

svnthesis

~methotrexate,

Hem"lv,l, • ,Irnr.illsic .. Extrinsic

N Ol>-P'"cytopenia Anerl'li~{If CllTO[l[C disease ... Penal/liver diseese
to

• Alcol,olisll1 • R.ti ,"kJo\'losis Ise. Hien reti 0,100\'10, on loftl
• H~poltiyr{] idi sm

Figure 3. Approach to Anemia

Clinical Features
• history • symptoms of anemia - fatigue, malaise, weakness, dyspnea, decreased exercise tolerance, palpitations, headache, dizziness, tinnitus, syncope • acute vs. chronic, bleeding, systemic illness, diet, alcohol, fancily history • rule out pancytopenia (recurrent infection, musosal bleeding! easy bruisability) • physical signs • HEENT: pallor in mucous membranes and conjunctiva at Hb <90 gil «9 g/dL), ocular bruits at Hb <55 giL (<5.5 g I dL) • CVS: tachycardia, orthostatic hypotension, systolic How murmur, wide pulse pressure, signs of CHF • derrnatologic: pallor in palmar skin creases at Hb <75 giL «7.5 gf dl.), jaundice (if due to hemolysis)

Investigations
• • • • • rule out dilutional anemia (Iow Hb due to increased effective circulating volume) CBC with differential (pay special attention to MCV, ROW) reticulocyte count blood film additional laboratory investigations as indicated (see Microcytic Anemia, Hll, Normocytic Anemia, HIS, Hemolytic Anemia, HIS and Macrocytic Anemia, H21)

Polycythemia
Definition
• all increase in the number ofRBCs: Hb >180 giL or Hct >52% (males); Hb >160 or Hct >47% (females and black males)

Etiology
• relative / spurious erythrocytosis (decreased in plasma volume): diuretics, severe dehydration, burns, "stress" (Gaisbock's syndrome) • absolute erythrocytosis • primary • polycythemia vera (PV) (see PV, H36) • secondary • poor tissue oxygenation I hypoxia • high altitude • pulmonary disease: COPO, sleep apnea, congenital • cardiovascular disease: R ~ L shunt • hemoglobinopathies with increased O2 affinity • carbon monoxide poisoning • inappropriate production of erythropoietin • renal cell carcinomas, cerebellar hemangioblastoma, pheochromocytoma, hepatocellular cancer, uterine leiornyomas • local renal hypoxia • renal artery stenosis • benign renal cysts (compress vessels)

Clinical. Features
• secondary to high red cell mass and hypervisccsity • headache, dizziness, tinnitus, visual disturbances • symptoms of angina, CHF • thrombosis (venous or arterial) or bleeding (abnormal platelet function) • characteristic physical findings • plethora (ruddy complexion) of face (70%), palms

severe Bn! folate deficiency) • congenital (e. neonatal) • non-immune mediated: Disseminated Intravascular Coagulation (DIC).asti c anemia Ehemo.g.port'.ary bvpass Immune Mvelolibrosi' Nutrilional B.H6 Hematology Common Presenting Problems Toronlo Notes 2010 Investigations • principally directed at ruling out • RBC mass .platelet clumping (secondary to EDTA antibodies) • hemodilution (e.g.. pre-eclampsia and HELLP syndrome (see Obstetrics.nom"ll"lv Liver diseases Mal'ignil. myelofibrosis • failure: aplastic anemia • increased peripheral destruction (increase in megakaryocytes in 8M) • immune mediated: Immune Thrombocytopenic Purpura (rTP).g. toxins.j M. Penconi's 001 'M. CPAP for sleep apnea.~lasia non-irrmens ITP ViraIIHIV) System lc {SLEI AlkJimmune me TTP HUS Pre-eclemps HE~LP ia un Orug In~LICe~ APlAS Figure 4. abdominal u/s. niles out decreased plasma volume • serum erythropoietin (Epo) . Heparin Induced Thrombocytopenia (HIT). e. lyrnphoproliferative disorders (e. CMV. CLL. Alpert's syndrome.g. drugs (e. Approach to lhrombocytllilenia Adapted Irom Cecil's E:ss<lntials of Med ie in. sulfa. alloimmune destruction (e. SLE).treat underlying cause • O2 for hypoxemia. viral infections (e. massive transfusion) • decreased production (disease process occurs in bone marrow) • nutritional (e.decreased suggests hypoxic etiology • sleep studies if history suggestive of sleep apnea • carboxyhemoglobin (hemoglobin-carbon monoxide complex) level.g.. leukemia.I Seque!Slr~ti{ln .Fanconi's anemia) • marrow • injury: drugs.1 AI.noy MI"'I. EBV). Antiphospholipid Ab Syndrome (APLAS). post-transfusion. blasts. Hadialion Drug·induoe.g. m'g. hypersegmented PMNs.normal suggests relative erythrocytosis: confirms increased red cell production.g./I'olol. systemic diseases (e.'Iilln. OBIS) • platelet sequestration • any disease process that leads to splenomegaly (up to 30% of circulating platelets are normally in the spleen at any given time) I Th romboeytopenja I .~o~i lutioll Spl. Apl. Thrombotic Thrombocytopenic Purpura (TIP). HIV. surgical for EPO-secreting • phlebotomy tumours Thrombocytopenia Defi nition • platelet count <150 xlO~ IL Etiology and Approach • factitious . lymphoma). leukoerythroblastic changes • increased destruction: large platelets. schistocvtes (seen in MAHA.IlCV trar. post-transplantation. CT head) • arterial p02 .g. Hemolytic Uremic Syndrome (HUS). DlC) . Investigations • CBC and differential • blood film • decreased production: possible other cell line abnormalities. chemotherapy and radiation (acute or chronic damage) • infiltrative: malignancy. Cong.I I Desnuction Increased I H."il.g. hemoglobin O2 affinity Treatments • if secondary .g.sfusiOfl Carrli{]pu[llliJr1. HCV.increased suggests autonomous production or hypoxia and niles out PV • search for tumour as source of Epo as indicated (e. thiazides.dys. rrow d. quinidine).

premvelocvtes. surgery. bone marrow biopsy may be required to distinguish among the differenct causes of au tonomous thrombocytosis Pancytopenia Definition • a decrease in all hematopoietic cell Jines Clinical Features • anemia . many cI i n iclan s use the.acute phase reactant (e. atypical chest pain. If prese Ill. diagnosis of exclusion • history: trauma. surgery.Toronto Notes 2010 Common Presenting Problems Hematology H7 Thrombocytosis Definition • platelet count >500 xl O?!L • reactive thrombocytosis . App ro 1Ich to P1Incyto pe n ia PNH = Paroxysm. neoplasms) • autonomous thrombocytosis .7 x 10~!L) Left Shift Refetl. m~tamyelocytes. lightheadedness. livido reticularis. CML. primary myelofibrosis. CRp. myelodysplastic syndrome (MDS). . plasma fibrinogen.infecti ons (a. ESR. splenectomy. inllarnrnati 0 11. RBC folate. infection. constitutional symptoms indicating malignancy • physical exam: primary thrombocytosis more likely to cause vasomotor symptoms (headache. syndromes Ac ute myeloge nou s leu kemia Overwh el mi ng . bact eria/viral) Toxic depression 01 BM Ano rexla nervosa + 1" BM disease • Mye 10 dysplas ia ~~ 2" to system ic eli sease • SlE • Hype rs pi eni s m • Vit B12/folate deficiency • Alcoholism • TB • PNH • Myelofibrosis • lymphoma • S arco idosi s • AIDS Fig u re 5.fatigue • leukopenia +recurrent • thrombocytopenia . bleeding. inflammation. aquagenic pruritus) • clotting risk and rarely bleeding risk Clinical Features .g. acral dysesthesia. blasts]. trauma. AMLJ • essential thrombocythemia . serum Bn. prior diagnosis of chronic hematologic disorder. i rnplies in creased rna "OW producti on of gran u lccvtss Ie. blood film • investigate secondary cause: HIV test. inflammation.g. j nfeCli on.q. serum ferritin concentration • non-specific markers of infection or inflammation (e. visual disturbances. However. erythromelalgia. G·CSF Etiology • primary neutrophilia • hereditary neutrophilia (autosomal dominant) • chronic idiopathic neutrophilia in otherwise healthy patients • chronic myelogenous leukemia (CML) adrn inistration.Investigations • CBC. ferritin) • if a reactive process has been ruled out. term to refer to a relati ve neutroph il i a.g.l Nocturnal Hemoglobinuria Neutrophilia Definition • increase in absolute neutrophil count (ANC) above normal range (>7. bleeding.one of the myeloproliferative disorders. eM L). to an i ncrea sa in granulocyte precursors in the pariphero I smear (myelocytes.mucosal bleeding and ecchymoses Investigations • CBC and differential. iron deficiency.g. infection. peripheral blood smear.thrombocytosis due to myeloproliferative or myelodysplastic disorders [e. ANA • often requires bone marrow biopsy to distinguish among di fferen! causes Pel n cytop en ia infections ~ Hypocellular BM Cellular BM • • • • • • • Acquired aplastic anemia I nh anted apia stic a n em ia Some myelodysplasia. iron deficiency. polycythemia vera (Pv).

C!>F.e. cytoplasmic vacuoles if infection • review for abnormalities in other blood counts Neutropenia Proph)'lactic Hematopoie~~ Colony-Slimulating "'cW~~n MO~lIlityind. BM infiltration • infection . ~' G-CSF = N~upog8n"" = Fligrastim GM-CSf = Leukine ~ = Sargramostim .<ll~ dor:umented inrec~oos IMR t:l:5% VS. malignancy to determine further investigations • examine oral cavity. but has no effect Definition • mild: ANC 1.9% vs.chronic gingivitis and recurrent stomatitis major sources of morbidity • febrile neutropenia (see Infectious Diseases.e. myelofibrosis.11). chills (only if infected) • infection by endogenous bacteria (i. steroids. Comp. people of African descent commonly have mild neu tropenia Clinical Features • fever.J% vs.5~1.high dose radiation. ID44) • in severe immune-mediated neutropenia. Prophylactic CSfs were given concurrently with or after initiation of cheroothe~.RA.0-1. inflammation. teeth.HS Hematology Common Presenting Problems Toronto Notes 2010 "" . i. acute Ie ukemias). viral hepatitis. S. aOO IeIlrile neutropeniB IMR 25. anus. benign cyclic neutropenia • peripheral destruction • antineutrophil antibodies • spleen or lung trapping • autoimmune disorders . chronic hepatitis.alkylaring agents.leukocytosis with left shift. can be as high as 100 due to marrow invasion and inflammation as well as solid tumours secreting substances with colony-stimulating activity) stress I exercise / epinephrine .(e. anticonvulsants.' the effecW 01 colOII\'" stimulating raG~r (CSf) (fn mortality.g. 18. range 12-30. a-methyldopa) • excessive margination (transient neutropenia) • idiopathic (most common) • overwhelming bacterial infection • hemodialysis • racial variation in normal range.2%: rate Illtio 0.e. neutmp!!ni' in paMnts undergoing ~h!roothe~ or stem·eel tJ1IIsIplBnt (Se1"j.l~biologiJ. myelofibrosis) • leukocyte adhesion deficiency • secondary neutrophilia • smoking . rate ratio 0. aureus. mil. antimetabolites. ET.5 x 109/L • moderate: ANC 0. negative organisms from GI and CU tract) • painful ulceration on skin. RA. MI.celJogrtlllPs. 44. cytoplasmic vacuoles in neutrophils OIl blood film • inflammation . malaria. aplastic anemia.v.g. skin for signs of infection appropriate Investigations • complete bJoodcount and blood film review • WEe differential .0 x 109 /L (risk of infection starts to increase) • severe: ANC <0.g.g. lithium Clinical Features • look for signs and symptoms of fever.constitutional neutropenia.lled toplocOOo omo therl!l1'/.most cornrnon cause of mild neutrophilia • infection . beta-agonists (e. 'rillE mtio 0. of CSF.Dohle bodies. Studv Seleclio~: 148 land'amimd control trials comparing the eifudl. inf~G~ns. peri-rectal area.TB.hematologic (i. tlll1c1usiooi: Prophylactic CSFs decreases inlectiJJn 'fates and episodes of febrile oautropenis in pa~ents und'ergoilg.BJoY folate • idiopathic . ~herootheFaP\' or SCT.1 %.idiopathic. lBO. genitals. epinephrine).6%. • other myeloproliferative disorders (rV.e.g. marrow invaded by tumour) and nonhematologic (especially large cell lung cancer.85 J. increase in inflammation. anti-inflammatory agents. R!:SIlI!s: Th~re were no diff~rence5 in all·cause moruiUty or infection·relined deoth between CSF andpl.5 x 109/L Etiology • decreased production • hematological diseases .movement of neu trophils from marginated pool into circulating pool • medications .g. anti-thyroid drugs toxic . to either placebo or no therl!l1'/ \Wreinduded. SLE • Wegener's granulomatosis • drugs as hap tens . The presence of predominantly blasts in the periphersl smear witholl1 cells 'between mature neutroph il an d bl ast su gg ests clonal cell dis 0 rd er (MDS. DDT) • nutritional deficiency . benzene. Dohle bodies (intra-cytoplasmic structures composed of agglutinated ribosomes). antipsychotics. burns • malignancy . and febri!.e.lnjedi~n !Inri irItem MOO.86). toxic granulation. ~O"I: 141:400·11 'PurP058: To revit. methotrexate) on ntl)ltlliiti. gram. ± toxic granulation. cyclosponne. mouth and throat following colonization by opportunistic organisms • avoid digital rectal exam Investigations • depends on degree of neutropenia and symptoms • ranges from observation with frequent CBCs to bone marrow aspirate and biopsy Treatment • regular dental care . reduoed inledion rale (median rate 38. C-CSF may increased neutrophil counts • if no response to C-CSF. I ?~--------------------. FE. typhoid fever. 43.mature neuttophils or left shift-bands >20% of total WBC suggesting infection I infl amrna tion • blood film . AIDS drug-induced . then immunosuppresion (e. glucccorticoids. chemicals (e. infectious mononucleosis.

rheumatoid arthritis) • neoplasm (e.. Treatment • treat/remove underlying cause • treat opportunistic infections aggressively (see InfectiousDiseases. lD32) disease 1030) and consider antimicrobial prophylaxis Eosinophilia • absolute eosinophil count >0. EM. Often ani nd lcater of Chronic Mye loid Leuk~mia. associated with pruritis due to ex" essive IJ lsta mine production. trauma. serum sickness) • autoimmune (e. eosinophils.Toronto Notes 2010 Common Presenting Problems Hematology H9 Lymphocytosis Definition • absolute lymphocyte count >4 x 1O\>L / Etiology • infection • majority are viral infections • IS. CNS . brucellosis. thionamidss (antithyroid drugs). Agra nulocytosis • severe depletion of granulocytes (neutrophils. ~ Basophilia ~~------------------~ . chills and weakness • oropharyngeal ulcers • high fatality without vigorous treatment ... basophils) from the blood and granulocyte precursors from the marrow • associated with drug use in 70% of cases: e. autoimmune • malignancy Clinical.g drugs. hepatitis C. toxoplasmosis • physiologic response to stress (e. pertussis.g.g. status epilepticus) • hypersensitivity (e. CLL. Features • opportunistic infections (see InfectiousOiseases.g. hepatitis B. sulfasalazine and ticlopidine • pathogenesis • immune-mediated destruction of circulating granulocytes by drug-induced antibodies or direct toxic effects upon marrow granulocytic precursors • abrupt onset of • fever.5 x 109/L • most common causes are parasitic (usually helminth) infections and allergic 'reactions • less common causes: • polyarteritis nodosa • cholesterol emboli • CML • Hodgkin's disease • adrenal insufficiency • Hypereosinophilic Syndrome • 6 months of eosinophilia with no other detectable causes • can involve heart.5 x 109/1 Etiology • idiopathic C04+ lymphocytopenia • chemotherapeutic agents • radiation • HIV / AIDS. clozapine. ALL.g. lymphoma) Investigations/Treatment • choice of investigations dependent on history and physical (see later sections) • example: • peripheral smear • smudge cells --> do flow cytometry • atypical lymphocytes --> suggestive of EBV infection • treat underlying cause Lymphocytopenia Definition • absolute lymphocyte count <1.

no"l<lnd'~r . RPR/VDRL. ANA. inguinal. night sweats • seen in TB. popliteal nodes • characteristics of lymph nodes (Table 2) • look for signs of infection in region which lymph nodes drain • determine if lymphadenopathy is localized or generalized • localized: typically reactive (i. cervical. Differentiating Inflammatory Inflammatory Nodes Rubl:tery Mobile Tfrnder <Zern vs.biopsy) • if generalized -7 lab workup.HI0 Hematology Common Presenting Problems/Approach to Lymphadenopathy Toronlo Noles 2010 Investigations/Treatment • • • • • discontinue offending pan-cultures if patient consider bone marrow initiate broad-spectrum G-CSF .g. Neoplastic Lvmph Nodes Neoplastic Firl11/hard Mattetl/lmmobile Non-tender " ?}-------------------. marked left shift (myelocvtes. other imaging • biopsy • if localized and no symptoms suggestive of malignancy. monospot/EBY. ticks (Lyme disease .y Allopurinol Atenolol Captopril Caibarnazepin e Cephelospori IlS Gold Kydrala<ine PeniciJlin Phenytoin Primidone Pyrim atharnin e Quinidine SuHo narnid es Feature Consistency Mobility Tenderness Size >2 em * note. epi trochlear. other malignancies • symptoms of infection or malignancy • exposures. high risk behaviors (HIV) • join t pain I swelling. th!)S<lclassificati~ns are not absolJl<l: Ivmphoma and ell nodes can feel 'rubbery and are frequently m~bile.. blood film • ± PPD. preauricular.e.weight loss.. cats (cat scratch .. Tbat Ca n Ca use LymphodanopiltII. can observe 3-4 weeks (if no resolution by then . supra/ in fra-clavicu lar. if negative -7 biopsy • if signs suggestive of malignancy biopsy immediately • excisiorial biopsy is preferred as it preserves node architecture (essential for diagnosing lymphoma) • FNA (helpful for diagnosing recurrence of malignancy) Table 2. fever. anorexia. ~ Drugs. submandibular. 2" to infection) • generalized: see Table 3 • a thorough examination is required to assess for systemic disease • labs • CBC and differential. lymphoma.growth factor drug is febrile (blood cultures x2. metamyelocytes. axilla ry. bands in peripheral blood) • important to rule out CML • myeloid leukemia mimicked by • pneumonia • other acute bacterial infections • intoxications • burns • malignant disease • severe hemorrhage or hemolysis • lymphoid leukemia mimicked by • pertussis • infectious mononucleosis • monocytic leukemia mimicked by • TB • IB Approach to Lymphadenopathy • history • constitutional IE-symptoms . HIV RNA.Bartonella henselae].Borrelia burgdorjeri). e.. rashes • pruritis (seen in Hodgkin's disease) • medications (can cause serum sickness -7 lymphadenopathy) • physical exam • basic assessment: occipital. urine culture as minimum) aspirate and biopsy IV antibiotics that stimulates neutrophil production Leukemoid Reactions • blood findings resembling those seen in certain types of leukemia which reflect the response of healthy BM to cvtokines released due to infection or trauma • leukocytosis >50 x 10~IL.

CMV. Monospot. haptoglobin. congestive and infiltrative causes Table 4. ideally..J:. petechiae • signs of CHF • labs • CBC and differential.J:.Neop!astic lymphoma ly. N ROW 1'1>15) N • Hypochromic.. • Normocytic/micro microcytic cytic ". Differential Hetnattdogical Spherocytosis H emo globinopathies Nutritional anemias Elliptocytosis Diagnosis of Splenomegaly Congestive CifThosis Spl eni c vei n obstrucfion Portal vei n obstruction CHF InCleased demand lui splenic hm ctiGB Infectious CMV EBV HIV/AIDS T8 Malaria Histoplasmosis leishmaniasis Autoimmune RAIFelty's) SlE Sarcoidosis Infiltrative Non-malignant Amyloi dosis Lysosomal storage diseases IGaucher's.Differential Re. H!V) Approach to LymphadenopalhyfApproach Diagnosis of Generalized l!lflammatory Autoimmune IRA. Causes TAILS of Microcytic Anemia NJ1' NJ1' Njl' Sidernblastic Anemia l' l' • Dual population • Ba sop hi Ii c stippli ng • Hypochromic.Toronto Notes 2010 Table 3. infectious and autoimmune workups CI inical Exam 1m Spl Bnomcg aly JAMA 1993. Niemann·Pick] Malignant Leukemia (CM Lymphoma Hoogkiri's diseese Myeloprolfferative diso rd ers Metastatic tumour u • history • constitutional symptoms • signs or symptoms of infection or malignancy • history of liver disease. microcytic • Bas 0 phi Ii c stippli ng • Poi ki I0 cytos is Thai assern ia An~ m ia of chronic disease Iron d etici encv lead Poisoning Siderobl astic anernia Thalassemia NJ-1' N NJ-1' Figure 6 . blood film • as indi cated: liver enzymes (liver function tests. these tests shou Id be don e togeth er. hemolytic anemia or high risk exposures • physical exam • percussion (Castell's sign. Iron Indices and Blood Film in Microcytic Anemia !MCV<BO) . LOH. reticulocyte count.mphocyti c leukemias Metastatic cancer Other Serum Sickness Amyloioosis Sarcoi des is DJUg hypersensitivity Sa rcoi des is. 2218·2. SLEj to SplenomegalyfMic[(Jcytk Anemia Hematology H11 lympbadenopathy ..J. amyloi des is Pa rasitic Itoxoplasmosis) FungalIII istoplasmosis] H istocytosi s X Approach to Splenomegaly • differential diagnosis • hyperplastic (increased demand for splenic function).. Siood Film TISe l' . Microcytic Anemia lab Tests Fenitin lron. Cat-scatch disease) Viral IEBV. Percuss i D n is m om sens~ive but less spec ific than palpati on as <I d iagn 0 stic test for splan omegaly .J:. Serum Iron .u:tive 8acteria! ITS.·Z7().1 The axa m ination for spl ~nomegal y is m est us efu I' to rul e in the diagnosis among patients in whom th ere is a cI incia 1 susp icion of at 1 east 10%. Traube's space) and palpation • signs of chronic liver disease • associated lymphadenopathy or hepatomegaly • jaundice. . lyme.Defi ciency Anemia Anemia of Chronic Disease -J.

g. and soy protein • males have a positive Fe balance • up to 20% of menstruating females have a negative Fe balance Iron Absorption and Transport • dietary Fe is absorbed in the duodenum • can be impaired by IBO. the majority of non-heme Fe is bound to transferrin which: • carries Fe from intestinal mucosal cell to RBC precursors in marrow • carries Fe from storage pool in hepatocytes ana rnacrophages to RBC precursors in marrow • binding ofthe circulating Fe-transferrin complex to the transferrin receptor in the cell membrane leads to the absorption of Fe and release of transferrin Iron Storage • Fe is stored in two forms: ferritin and hemosiderin • ferritin • ferric iron complexed to a protein called apoferritin • hepatocytes are main site of ferritin storage • minute quantities are present in plasma in equilibrium with intracellular ferritin • also an acute phase reactant so can be spuriously elevated despite low Fe stores • hemosiderin • aggregates or crystals of ferritin with the apoferritin partially removed • macrophage-monocyte system is main source of hemosiderin storage lron Indices (see Figure 6) • bone marrow aspirate is the gold standard test for iron stores • serum ferritin single most important blood test for iron stores • decreased in iron deficiency anemia • elevated in • infection. malignancy • liver disease. remainder is unsaturated • high specificity for decreased iron.g. expressed as a proportion or a percentage • low in iron deficiencv anemia • soluble transferrin receptor (STfR) • a new diagnostic tool that reflects the availability of iron at the tissue level • the transferrin receptor is expressed on the surface of erythroblasts and is responsible for iron uptake .g.some is cleaved off and is present in circulation as STfR • in Fe-deficiency states . low sensitivity • saturation • serum Fe divided by TIBC. H12) Iron Deficiency Anemia • most common cause of anemia in North America Etiology • increased demand • increased physiological need for iron in the body (e. in bran).more transferrin receptor is expressed on erythroblasts. leading to an increase in STfR • low in reduced erythropoiesis and iron overload • useful in determining Fe-deficiency in the setting of chronic inflammatory disorders (see Iron Deficiency Anemia. one third of the lIBC is saturated with Fe. dietary calcium. etc. hyperthyroidism and iron overload • serum iron • varies significantly daily • a measure of all non-heme Fe present in blood • virtually all serum iron is bound to transferrin. absorption of iron enhanced by citric acid and ascorbic acid! vitamin C and reduced by polyphenols (e. in tea). pregnancy) • decreased supply • dietary deficiencies (rarely the only etiology) • cow's milk (infant diet) • "tea and toast" (elderly) • absorption imbalances . celiac disease. • in circulation.Ht2 Hematology Microcytic Anemia Toronto Notes 2010 Iron Metabolism Iron Intake (Dietary) • "average" North American adult diet = 10-20 mg Fe! day • absorption = 5-10% (0. only a trace is free or complexed in ferritin • total iron binding capacity (TIBC) • measure of total amount of transferrin present in blood • normally. phyrate (e. inflammation.5-2 mg! day).

ang i odvsplasia etc.75:671·8 . Ap proa ch to interpreting Ad~ptedhon Killip et "I. serum ferritin <100 /lg/L in these settings is suggestive of Fe deficiency.menorrhagia in young women • occult . esophageal web.18 0.. nail changes [brittle.. dirt) Investigations • iron indices. '.. syrup) • ferrous sulphate 325 Illg tid. or ferrous fumarate 300 Illg od-bid • supplement until anemia corrects.]. including soluble transferrin receptor (Figure 7) • low ferritin «45 !-IgIL) is diagnostic of Fe-deficiency (Table 5) • ferritin is an acute phase protein and is elevated in the setting of in fI aITUTItory a conditions and liver disease. koilonychia (spoon-shapedf] • dysphagia (e. celiac disease. Hematology H13 • post-gastrectomy • malabsorption (IBD of duodenum. 9~------------------~ Ira n-d sflci e ncy an arnia is a com man presentati on 01 c:h ron ic lowe r G I :b leeds (ri g hI· si d ad colorectal can cer. GI tract cancer • intravascular hemolysis • paroxysmal nocturnal hemoglobinuria (PNH) • cardiac valve . paint. tinnitus. autoimmune • increased losses • hemorrhage • obvious causes .g." 100 ng/ml Sour~e: AIl1 J Med 1:900. palmar creases • glossitis • angular stomatitis (inflammation and fissuring at the corners of the mouth) • pica (appetite for non-food substances. dyspnea. postural dizziness. In males and . necessitating further workup (FigureZ) • peripheral blood film • hypochromic microcytosis: RBCs are under-hemoglobinized due to lack of Fe • pencil forms. palpitations.... weakness. ferrous gIuconate 300 mg tid... syncope. feeling cold. Th e Utility of Ferritin in the Diagnosis of Iron Deficiency Anemia ferritin (p!lll) l.12 41.ikelihooo ratio for iron deficiency anemia > 100 45·100 18·45 ". irritability. . 45 ng/ml Ferritin 46-99 ng/mI t Assess other Fe indi ee s t ~nBC~~ -J:. satu ration Any other resu It: Order StiR 1~"'"mF' l' saturati 0n 1.conjunctiva.g. confusion/loss of concentration • brittle hair.Toronto Notes 2010 Microcytic Anemia. Plummer-Vinson ring) • pallor .13 0.RBC fragmentation atrophic gastritis) Clinical Features • iron deficiency may cause fatigue before clinical anemia develops • symptoms due to anemia: fatigue.47 Treatment • treat the underlying cause • 5U P P I emen ta tion • oral (tablets. ice.. then continue for 3+ months until serum ferritin returns to normal • oral iron should be taken with citrus Juice to enhance absorption • IV (Venofert') can be used if patient cannot tolerate or absorb oral iron • monitoring response • reticulocyte count will begin to increase after one week • Hb normalizes by 10 giL per week • Fe supplementation required for 4-6 months to replenish stores Patient with microcytic anemia Ferritin.peptic ulcer disease.. e. 88:ZV5·9 .46 3. Ferritin". anisocytosis • target cells (thin) • bone marrow (gold standard but not commonly done) • Fe stain (Prussian blue) shows decreased iron in macrophages and in erythroid precursors (sideroblasts) • intermediate and late erythroblasts show micronormoblastic maturation I able 5. headache. exercise intolerance.. Am Film Phi'S'dan 21)(17.in po st -me nopau sal women a GI work-up is a'iways warranted.. 1(---- l' StfR ~~ Fe-deficiency anemia Fein di ces NOFe-deficiencv anemia Fig lire 7.

diabetes mellitus.HIli Hematology Micrecytic Anemia Toronlo Noles 2010 Anemia of Chronic Disease Etiology • infection.abnormal. • Abse nee 01 stai nabla iron on bone rna rrow a spiration/b i D pSV.normal or increased iron stores in bone marrow • decreased or absent staining for iron in erythroid precursors • anemia resolves if underlying disease is treated • only treat patients who can benefit from a higher hemoglobin level • erythropoietin may normalize the hemoglobin value (the required dose of erythropoietin is higher than the dose required for patients with renal disease) Treatment Lead Poisoning . alcohol. hypothyroidism . presenting a diagnostic dilemma (see Sidebar) • peripheral blood • mild: usually normocytic and normochromic .. chronic renal and liver disease.a subtype of MDS (see Myelodysplastic Syndrome. hypogonadism. randomly spread in the cytoplasm • found in healthy individuals • "ring": Fe deposits in mitochondria. • Hesp 0 nse to a th erepe uti c trial 01 oral iron. zinc toxicity. Su ggested bV: • S e ru rn I~rritin < 100 uglL in setting of a chronic inllamm atorv d isease • EI'evation 01 soluble transle rnh receptor. - ~}-------------------.. chloramphenicol). CRP. reflecting overall decrease in RBC production • bone marrow . H34) • may be a preleukemic phenomenon (10% transform to AML) • reversible • drugs (isoniazid..moderate: may be microcytic and normochromic if the anemia is • severe: may be microcytic and hypochromic • absolute reticulocyte count is frequently low.1 . fibrinogen) • "classic" serum iron indices (see Figure 6) • serum iron and TIBC low..ked. malignancy. ~~------------------~ . anemia of chronic disease often co-exists with Fe-deficiency.-.igations . fonning a ring around the nucleus . due to impaired Fe utilization • trapping of iron in macrophages -> reduced plasma iron levels making iron relatively unavailable for new hemoglobin synthesis • erythropoietin levels are normal OJ slightly elevated but the marrow is unable to respond with increased in erythropoiests • a mild hemolytic component is often present • red blood cell survival modestly decreased Invest. lead. inflammatory and rheumatologic disease.l. 1 Iren-d eficiencv An em la Common Iv Co-oxists with Anemia 01 Chronic Disease.g . endocrine disorders (e... hypothyroidism. median survival 10 years • idiopathic (acquired) • aka refractory anemia with ringed sideroblasts . • X-Ii. C ons i der Iead poison ing in anv child who lives in a house built before 1976 inC ansda or before 1977 in the US A ~ • • • • • L 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 Treatment: dimercaprol and EDTA are first line agents Sideroblastic Anemia • uncommon compared to iron deficiency anemia or anemia of chronic disease Sideroblasts • erythrocytes with Fe-containing (basophilic) granules in the cytoplasm • "normal": granules are small. % saturation normal • serum ferritin is normal or increased • however..J' • a diagnosis of exclusion • associated with elevation in acute phase reactants (ESR. hypopituitarism) Pathophysiology • an anemia of underproduction. large granules • the hallmark of sideroblastic anemia Etiology • due to defects in heme biosynthesis in erythroid precursors • hereditary (rare) .. copper deficiency.

basophilic stippling Treatment • depends on etiology • X~linked: high dose pyridoxine (vitamin 86) in some cases • acquired: Epo and G-CSF • reversible: remove precipitating cause • supportive transfusions for severe anemia Thalassemia • see Hemolytic Anemia. poikylccytosis.g. increased ferritin. Canses of Normocytic Anemia ABCD Acute blood Iass Bon" marrow failure Chronic disease Destruction I hemolysisI Figllre 8. H16 Normocytic Anemia Mev = 80·100 '". chloramphenicol. normo-. phenylbutazone) insufficiency) . increased soluble transferrin receptor (STiR) • blood film/bone marrow biopsy • ringed sideroblasts (diagnostic hallmark) • RBCs are hypochromic. chemotherapeutic agents) • idiosyncratic (e.Toronto Notes 2010 Microcytic Anemia/Normocytic Anemia Hematology H15 Clinical Manifestations • standard anemia symptoms • hepatosplenomegaly. can be micro-.g. or macrocytic • anisocytosis. normal lIBC. Approach to Normocytic Anemia Aplastic Anemia Definition • destruction of hematopoietic hypocellular bone marrow cells of the bone marrow leading to pancytopenia and Epidemiology • occurs at any age • slightly more common in males Etiology • congenital • Fanconi's anemia • Shwachman-Diamond syndrome (bone marrow failure and pancreatic • acquired • idiopathic • often T·cell mediated . Fe overload syndrome Investigations • serum iron indices • increased serum Fe.one half to two thirds of cases • drugs • dose-related (e.

but not a cause Clinical Features • can present acutely or insidiously • symptoms of anemia. pre-eclampsia/HELLI'.associated with aplastic anemia. thrombocytopenia • presentation of neutropenia ranges from infections: pallor and petechiae common findings to septicemia • absence of splenomegaly and lymphadenopathy Investigations • Cl3C • anemia or neutropenia or thrombocytopenia (any combination) • decreased reticulocytes (<1% of the total RBC count) • blood film • decreased number of normal RBCs • bone marrow • aplasia or hypoplasia of marrow cells with fat replacement • decreased cellularity • key: need to exclude other causes of pancytopenia first (Figure 5) Treatment • remove offending agents • supportive care (red cell and platelet transfusions. infection (e.50-60% of patients respond • cyclosporrne • allogenic bone marrow transplant are the most ± pancytopenia Hemolytic Anemia (HA) Classification • hereditary • abnormal membrane (spherocytosis. march hemoglobinuria (exertional hemolysis).H16 Hematology Normocytic Anemia/Hemolytic Anemia Toronto Notes 2010 • toxins • benzene and other organic solvents • DDT and insecticides • ionizing radiation • post viral infection (parvovirus B19.associated with DIe. mechanical heart valves • HA are also classified as intravascular or extravascular: • intravascular: G6PD deficiency. elliptocytosis) • abnormal enzymes (pyruvate kinase deficiency. cold agglutinins • non-immune • rrucroangiopathic HA (MAHA). antibiotics) • immunosuppression • anti-thymocyte globulin . hypersplenism. HHV6. SLE) . thrombus in blood vessel causes RBCs to be sheared . HrV) • autoimmune (e. vasculitides.g. HUS/TTP. PNH. EBV. malignant hypertension • other causes.rare • Paroxysmal Nocturnal Hemoglobinuria (PNH) .e. hemoglobinopathies) • acquired • immune • hemolytic transfusion reaction. HOY. BM suppression • iron overload with extravascular hemolysis • iron deficiency with in travascular hemolysis Investigations • screening tests • increased • decreased • increased • increased • increased in overwhelming infection) reticulocyte count haptoglobin unconjugated bilirubin urobilinogen LDH . penicillin).g. TTP. malaria). autoimmune HA (AIHA). G6PD deficiency) • abnormal hemoglobin synthesis (thalassemias.g. DIC and PNH • extravascular: AlHA and hereditary spherocytosis Clinical features Specific to HA • jaundice • dark urine • cholelithiasis (pigment stones) • potential £0J" an aplastic crisis (i. drugs (e. HEY.

cross-matching of recipient Serum with donor's RBC .blood group antibodies in pregnant women .5-3.212) switches to adult forms HbA «:X-:tBz) and HbA2 (0. Bera-Thalasaernia Minor (Thalassemia Trait) Definition • defect in single allele of beta gene (heterozygous) • common among people of Mediterranean and Asian descent Clinical Features • palpable spleen (rare) Investigations • Hb 90-140 giL or 9-14 gl dL.autoimmune hemolytic anemia (AlHA) .. abnormal shaped RBCs on blood film Pathophysiology • defect may be in any of the Hb genes • normally 4 a genes in total. 1 on each copy of chromosome 11 • fetal hemoglobin.~------------------~ .5%) • non-specific: 50% have slight increased in HbF Treatment • not necessary • genetic counselling " .hemolytic disease of newborn . test is positive if the RBCs agglutinate • indications . HbF (0. MCV<70.. M icrtll:ytos is in Beta Tha I Mi nor Microcytosi s much mare prolou nd and the ane m ia much milde r than that of Fe deli ci ency..Toronto Notes 2010 • tests • • • • • • tests • Hemolytic Anemia Hematology H17 specific for intravascular hemolysis schistocytes on blood film free hemoglobin in serum methemalbuminemia (heme + albumin) hemoglobinuria (immediate) hemosiderinuria (delayed) speci fie for extra vascular hemol ysis direct Coombs' test (direct antiglobulin test) • detects IgG or complement on the surface of RBC • add anti-lgG or anti-complement antibodies to the patient's RBCs.' ThalasSEAmia . Bilill.~------------------~ . 2 on each copy of chromosome 16 • normally 2[) genes in total.bin 'f t S8 Ig Thalassemia Definition • defects in production of the alpha or beta-chains of hemoglobin.hemolytic transfusion reaction • indirect Coomb's test (indirect antiglobulin test) • detects antibodies in serum that can recognize antigens on RBCs • mix patient's Serum with donor RBCs and then Coombs' serum (anti-human antibodies).microcytosis basophilic stippling • I-Ib electrophoresis • specific: HbAz increased to 2.atypical blood group . test is positive if RBCs agglutinate • indications . normal Fe • peripheral blood film .2132) at 3-6 months of life • HbA constitutes 97% of adult hemoglobin • HbA2 constitutes 3% of adult hemoglobin 0._' . the resulting imbalance in globin chains leads to hemolysis in the spleen or BM • clinical manifestations and treatment depends on specific gene and number of alleles affected • common features: • increasing severity with increasing number of alleles involved • hypochromic microcytic anemia • basophilic stippling. a-Thai --> prevalent in South East Asia [SEA).AlHA .5-5% (normal 1. llama Brca kdown Keme rlemeoxygen8se Bi. for patient and family .~·Thal --> prevalent in Mediterranean SEA.livemin Biliverdin reduct.

most commonly caused by a Glu -7 Val substitution at position 6 resulting in HbS rather than HbA • increased incidence of HbS allele in people of African or Mediterranean heritage thought to be protective against malaria • sickle cell disease occurs when an individual has two HbS genes (homozygous.most commonly HbS-[?.on • sickling disorders arise due to a. normal Hb. pigmented gallstones) • death can result from • untreated anemia (should transfuse) • infection (should identify and treat early) • iron overload: a late complication. normal Hb • 3 defective a genes: HbH W4) disease. Tha lassem.. and Definition • defect in both alleles of beta gene (homozygous.. defective a gene: clinically silent."thal and HbSC disease . decreased MCV. secondary to repeated transfusions erythropoiesis Investigations • Hb 40-60 g!L (4-6 g! ctL) • Hb electrophoresis• HbA: 0-10% (normal >95%) • HbF: 90-100% Treatment • lifelong regular transfusions • folic acid supplementation • Fe chelation to prevent iron overload (e.screen for HbH inclusion bodies with special stain • Hb electrophoresis not diagnostic for a-thalassemia • DNA analysis using a gelle probes Treatment • depends on degree of anemia.HIB Hematology Hemolytic Anemia Toronto Notes 2010 Beta . • no treatment required for carriers of 1 or :2 defective a genes • HbH disease: similar to fI-thalassemia major Sickle Cell Disease • see Pediatrics..g. presents in adults.. Clinical Features • initial presentation at age 6"12 months when HbA normally replaces Hbf • severe anemia.mutant fI-globin chain. P47 Definiti. decreased Hb. Pathophysiology • ineffective chain synthesis increase in HbF leading to ineffective erythropoiesis. Thalassemia Major autosomal recessive) hemolysis of RBCs. jaundice • stunted growth and development (hypogonadal dwarf) • gross hepatosplenomegaly (due to extramedullary hematopoiesis) • radiologic changes (due to expanded marrow cavity) • skull x-ray has "hair-on-end" appearance • pathological fractures common • evidence of increased Hb catabolism (e. HbSS) or one HbS gene + another mutant fi-globin gene (compound heterozygote) . deferoxamine) • allogeruc bone marrow transplantation and ineffective AI pha . normal MCV • :2 defective a genes: decreased MCV.ia Definition • defect(s) in alpha genes • similar geographic distribution and Africans as beta-thalassemia but a higher frequency among Asians Clinical Features • 1.g. splenomegaly • 4 defective a genes: Hb Barts (y4) disease (hydrops tetalis) not compatible with life Investigations • peripheral blood film .

Presentation incl udes dysp Ilea> chest pa in. menses and alcohol 4. i nroction or pu Imono TV lot ernb olus from infarcted marrow.~----------. splenic sequestration crises • usually in children. Affects 3 D% of pati ents with si ckl e cell disease and may ba life threatening. rapid change in temperature. level at which sickling occurs is related to the percentage of If. with significant pooling of blood in spleen.g acute chest syndrome) • precipitated by infections.. )' Function 01 aspl enis m -1' susce pti bil ity to inlecti on by ..) • Hbelectrophoresis distinguishes HbAS..bS present • in heterozygotes (HbAS). P47 L folic acid to prevent folate deficiency 2.hildl. tachypnea.. abdomen and extremities). but is dictated by symptom severity • HbSS .. leading to rigid crystal-like rods that distort membranes ~ 'sickles' • the pO. increased CO. Investigations for Sickle Celillisease ItbAS . ' ·t~--------------. onlY HbS and HbF (proportions cllange with age) decreased Hb.3 5 (35%1 • sickle cell prep: determines the presence of a HbS allele (i. pneumoniae • N. stroke.o-OcdusivG Organ eBe Peri pheral . HbSC. imedion Leg lLk>lrs ..Toronto Notes 2010 Hemolytic Anemia Hematology Ht9 Pathophysiology (Figure 9) • at low pO". Investigations Table 6.. resulting in acute decreased Hb and shock • uncommon in adults because of functional asplenia from repeated infarction 3.3-DPG. fever.65 (65%1 HbS fraction of 0.svndrerne. common in West Africa • milder anemia than HbSS • similal: complica~ons ~s H?SS alth?ugh typically milder and less frequent.rn Gapsul ated nrqanis rns • S.. chronic hemolytic anemia • jaundice in the first year of life • may have retarded growth and development ± skeletal changes • spleen enlarged in child and atrophic in adult • often presents with crisis L aplastic crises • toxins and infections (especially parvovirus B19) transiently suppress bone marrow activity 2. Acute Chesl Syndrome. CNS crisis Intestines Plai:llntl Penis Digits Femoral heod Bone Ankle Hml<lturia: loss of reool oollCetllrating ability AC!Jte abdomen S~llhirtl1s Priapism Oactvlitis Avascular necrosls InfarctiQn. Sickled cells No HbA. they also block small vessels Clinical Features • HbAS (heterozygous): patient will appear normal except at times of extreme hypoxia and infection (sickle cell trait) • HbSS (homozygous) •. Caused by ~aso" occl usion.no treatment required • HbSC . HbSS.e.see Pediatrics. deoxy HbS polymerizes. dehydration. and leukocytosis (e. long~emJ PUImOllOry h\'P'lrtensio~ S1JJ~es Hyperdynamic flaw murmurs Enlarged I(. decreased Hct ' . )' t~--------------. sickling occurs at a pOz of 80 mmllg • sickling is aggravated by increased H'. Pathophysiology of Sickling . . pregnancy.0100d H b electrophoresis Normal Normal. hydroxyurea to enhance production of HbF • mechanism of action: stops repression of Hb-gamma chains and/or initiates differentiation of stem cells in which this gene is active • presence of HbF in the 55 cells decreased polymerization and precipitation of HbS • note: hydroxyurea is cytotoxic and may cause bone marrow suppression 3. with the exception of proliferative SIckle retinopathy • spleen is not always atrophic in adults Figure 9. vaso-occlusive crises (infarction) • may affect many different organs causing pain (especially in back. "trophic )' Organs AII. etc. blindrmss Infarcts.. Crisis Probillm SeizlJlflS. a nd pu Imona TV infiltrate on CXR. sickling occurs at a pO~ of 40 mmHg • in homozygotes (HbSS). increased 2. HIISS locreased reticulocytes. snoka H emGrrilage.. bone marrow necrosis. priapism. possib IV a lew target cells HbA fraction of 0. RUO syndrome Chest .treatment is the same as HbSS. meningitidis • N_ influentae • Salmonella [nsteornvelitls) . chest crises (see sidebar) • HbSC (most common compound heterozygote) • epidemiology: 1:833 live births in African-Americans.. positive in HbAS. fever.leukocytos is.Clod bV Va. HbSC and other variants G"~ bl"dd~r Heart S~le"n loou~) Treatment • genetic counselling • HbAS . treatment of vase-occlusive crisis • oxygen • hydration (reduces viscosity) • antimicrobials • correct acidosis • analgesics j narcotics • magnesium (inhibits potassium and water efflux from RBCs thereby preventing dehydration) • indication for exchange transfusion: acute chest syndrome. increased temperature and osmolality • sickle cells are fragile and hemolyze. chest. HbSS.

eli di$ease. schistocvtes • hemolytic work-up • urine: hemosiderinuria.rs [dilfutl!llW. !lnd to~city QIhyiJrllX\Mre.uverteSs. WITh ~ckle ~II disease is not associated with leukEmia. increased osmotic fragility (rarely done today). SlE penieill i n Type II .Hemolytic Anemia (MAHA) Definition • hemolytic anemia due to intravascular purpura fragmentation (TIPl/hemolytic of RBCs uremic syndrome (HUS) . Theil dbservati. mired evidem:e su~ests tOOt hy<lruX\lllre. HELLP syndrome • malignant hypertension • v ascu litis • malfunctioning heart valves • metastatic carcinoma Investigations • blood film: evidence of hemolysis. LFTs.l hydrnxyureoreatmeM it t aw!tJ.fu: In the single randomiZed trial.. R".duks repott.H2O Hematology An hideru. 3. creatinine) • urinalysis annually • transcranial doppler annually until 16 years old • retinal examinations annually from 8 years old • echocardiography every two years from 10 years old (to screen for pulmonary hypertension) Autoimmune Table 1.. . pneumococcus (heptavalent and 23"valent). macroglo bulinemia. o rug induced Blood Film Management Spherocvres Treat undertying cause Corticosteroids Immunosuppression Spl enectomy Agglutlr. vaccination in childhood (e. The eVidence suggests thar hyiJrox'l'um.. effe.g. Hib) • prophylactic penicillin from 3 months until 5 years of age . The paJcily gI :long. .. wilen usml in adults with sidle cell disease."true" anti·R BC Ab e. 2008 May 5 Objll<lij'e: To svntltesil<l the iXJbishedlitEra1ure en the effica.g. observational studies. and leg:'ul'cers are not associated in patients with sidle . HoiijJitai admissions declined by 18% to J2%.Classification _________________ Antibody Allotype Hemolytic Anemia (AIHA) ~_'_ld IgM .m l!'UidellCil ls insufficient to estimate the risk for skin :neoplBsm. meningococcus. molecular analysis for spectrin gene • treatment: splenectomy (immunize against pneumococcus. and social support 5. screen for potential complications • regular bloodwork (CBC.. m ethyldo pa Type I .1Ite hemo~bin level_ higher .in 'hydrQl:yurea recipients than plaoobQ rndpients"lter 1 ye. CLL Test testl Positive fur IgG Idiopathic SeGonmny to lymph oprol iferative disorder (dilect anti-g!obulin Etiology e.g. reticulocytes.y in awlts with sickle ~II disease.lopmenl Confe.d a rebtive rncm:l!m in Mal hemoglobin 014% to 21l% end a mlafiw ~clian in cris~ rates tIy re% to 84%.2%J. and case reports eva~ating oIIiCOO/ <lid toKicity oI'hydrOl<'/Ure~ in adu~. ClL Hodgkin's Secoml8lY to autoim mune disease e.g.g. til".brut to~city.lIhoulih th8se artcomes con be ottributedto hy<lruxl'IIreainotherconditions. irrlbe p~cebo arm. fever) .e.g. nutrition.&<b""ld Relliew fur the NIH ConSlIIsUS O. quinine Typ e III .mal studies thm ellQlled . but avoid in early childhood . BUN. establish diagnosis • avoid conditions that favour sickling (hypoxia.bapten-m adated e.~ of AIHA W __ar_m IgG Agglutination Temperature 37"C Direet Coombs 4-37'C Pos~ive for complem ent Idiopathic Secondary to infection e.Wid Fi!lU re 1o. acidosis.icity studies 01.. as \1f<IS IIllBI'hemoglobin [absolute difference. .g. prevention of crises is key . hernoglobinurla Hereditary Spherocytosis Thrombus RBC Figure 11. likewise. good hygiene. Study Selection: R<IIIlarrilOO uials. rem srudil!<S lirtits conclusions .i mmun e-COmplBX mediated 8. Limite< 8~dDnce indicilIEs th. The median number 01 painful crises was 44%00. Schistocyte • abnormality in RBC membrane protems (i. WITh sic'~ rell dIs~. dehydration. meningococcus and Hib first).cy. Hemolytic Anemia Toronto Notes 2010 4. Sphern cyte Vessel wall Etiology • thrombotic thrombocytopenic (see Table 14) • DIC • eclampsia.g. iron indices. mycopfasma p neurnona EBV Secondary to Iymp hoproliferative disDf(ler e. spectrin) • spleen makes defective RBCs more spherocytotic (and more fragile) by membrane removal and also acts as site of destruction • autosomal dominant with variable penetrance • most common type of heredi tary hemolytic anemia • lnvestigations: blood film shows spherocytes. and tm.ation Treat lin derlying cause Wann patient I mmun osuppressi on Plasmapheresis Microangiopathic ."nc" on ilvd'OXliUrea for till' Treatment of Adutts willi Sickle Cell Oisease Allllimem MerI.hydroxvul\!iI in Gtiler cooditions thar WDre published in English were inl:lud:ed. 6uA1. may impair spermatQg~is. Condusions: Hydroxyurea IIilSdenmnstrated dfi:aI.

H20 GSSG NADP' NADPH <c.:> ~ G6P ePG 6PGD I Investigations • neonatal screening • G6PD assay • should not be done in acute crisis when reticulocyte count is high since reticulocytes have high G6PD levels • blood film • Heinz bodies (granules in RBCs due to oxidized Hb).D Pathway Treatment • transfusion in severe cases • stop offending drugs or food and avoid triggers Macrocytic Anemia Causes • megaloblastic • vit B]2 deficiency • folate deficiency • drugs (methotrexate. Comparison Between Megaloblastic Megalob lastic Morphology LiJrge. azathioprine) • non-megaloblastic • reticulocytosis • myelodvsplastic syndromes • liver disease • alcoholism • hypothyroidism Table 8. more prevalent in black males Glucose of RBC to Clinical Features • X-linked form frequently presents as episodic hemolysis precipitated • oxidative stress • drugs (e.(cobalamin) • binds to intrinsic factor (IF) secreted by gastric parietal cells • absorbed in terminal ileum • total body stores sufficient for 3-4 years . antimalarials.ypersegmented nelJlrophils Failure ·of DNA synthesis resu ltingin asynchronous maturation of RBC rueleus and cytoplasm and Non-Megaloblastic Macrocytic Anemia Non. meningococcus.:1. and Hib first) G6PDDeficiency Definition • deficiency in glucose-6-phosphate dehydrogenase (G6PD) leads to a sensitivity oxidative stress due to a lack of reduced glutathione (Figure 12) Pathophysiology • X-linked recessive. oval.g. RBC fragments) / Pentose Phosphate lactate Figure 12. pathologic neonatal jaundice by: ~ ~ 2GSH ~ ~ G6P 0.Megalllblastic Large round R B C Normal neutrophils Reflects membrane ebnonnal ity with abnormal cholesterol mstabolsm Pathophvsiology Vitamin 812 Deficiency B.Toronto Notes 2010 Hemolytic Anemia/Macrocytic Anemia Hematology H21 Hereditary Elliptocytosis • • • • • abnormality in spectrin interaction with other membrane proteins autosomal dominant 25~75% elliptocytes hemolysis is usually mild treatment: splenectomy for severe hemolysis (immunize against pneumococcus. nucleated RBC precursor H. nitrofurantoin) • infection • food (fava beans) • in neonates: can present a prolonged. G6P. sulfonamide.g. passage through spleen results in the generation of bite cells • features of intravascular hemolysis (e.

• CBC. Pancytopen ta 2.. The other cerpaed 2000 j. hyperactive reflexes • peripheral neuropathy (variable reversibililty) • usually symmetrical. is severe~ . Insuffii. G16) Treatment • vitamin B12 100 fig IM monthly for life or 1000-1200 fig PO daily if intestinal absorption intact • Less frequent.1lI! is e~~alent to 1M vitamin B.was due to dietary deficiency) • auto-antibodies produced against gastric parietal cells leading to achlorhydria and lack of intrinsic facto!" secretion • intrinsic factor is required to stabilize B'2 as it passes through the bowel • decreased intrinsic factor leads to decreased ileal absorption of B'2 • may be associated with other autoimmune disorders (polyglandular endocrine insufficiency) • female.H22 Hematology Etiology Macrocytic Anemia Toronto Notes 2010 '"I ~ ~~--------------------. transcobalamin 11deficiency) • diet Pathophysiology Schi IIing Test of Pernicious Anemia Pan 1 dose (1 IJgl of radiolabsled B. 2 ReTs met inc~siOll ~rrteri.: High dooeomlvi!1min B1. reticulocyte count • anemia often severe ± neutropenia ± thrombocytopenia • MCV>1l0 fL • low reticulocyte count relative to the degree of anemia «2%) • serum Bn and RBC folate • caution: low serum B12 leads to low RBC folate because of failure of folate polyglutam. Characterislics of Mega loblastic Macrocytic Anemia 1..ate synthesis in the absence of B12 • blood film • oval macrocytes • hypersegmented neutrephils • bone marrow • hypercellularity • nuclear-cytoplasmic asynchrony in RBC precursors (less mature nuclei than what would be expected from the development of the cytoplasm) • bilirubin and LDH • elevated unconjugated bilirubin and LDH due breakdown of cells in BM • Schilling test can distinguish pernicious anemia from other causes (see Gastroenterology. sdledule.Iimijed iby omall sample sees <lid short -fullow-IUJ periods. 1000 fig 1M q3 months) • watch for hypokalemia and rebound thrombocytosis when treating severe megaloblastic anemia Folate Deficiency • • • • • uncommon due to extensive dietary supplementation in developed folate complexes with gastric R binder complex then binds to intrinsic factor in the duodenum this complex is absorbed in the jejunum folate stores are depleted in 3-6 months countries ..g. proprioception 2-point discrimination .posterior columns . Svstematic Teview. No si~cant difference was 'observed between \Jllups in either stlJdy.. N'eurological and hematological. Mega Ioblastic bone rna rrow • strict vegan (rare. stricture) • fish tapeworm • resection of ileum • rare genetic causes (e. .male= 1. This data. affecting lower limbs more than upper limbs Part 2..on 11m sane or less frequent dosi . Hyperseqrnented neutropf ils 3. 4months. celiac sprue.. tn!~rvlllldoo: One study evaklated 1OOD of oml j.Jg.ien! 'numbers 01 patients wi!l1 malabsorption .spastic weakness.g. R.B '" th us allowing • Tracer radioactive B 12 to be excreted in ur·ine • 24 hour urine radiolaheled B'2 measured • Normal > 5% excretion (a normal excretion will ani y be seen if the low B.B 12 1M 1 hr later to satu rate tissu e binders 01 .:romll (II! patients WITh follow-up rrom 9G days to. often >60 years old Clinical Features • neurological • cerebral (common: reversible with 612 therapy) • confusion • delirium • dementia • cranial nerves (rare) • optic atrophy • cord (irreversible damage) • subacute combined degeneration .. higher doses are probably as effective (e.!leficiency CodiJolill /Jotabase ~ I!e'I 2005.1lIIM B" 011 a.s Intramustulor Vitamin 8" for VitaminB.g..g.less freo:pJent dosing sclIedul-l.tt. given PO • FI uslling d nse (1 mg Iof unlab eHed .ordi~ons IWm includedto general~e ..th8S<1 msUns ttl !he entire primary care populltioo.!OI:lgicai and IlelJrabgical end·fIOints in both or. daly orol' B" to 1000 J.l.1 and 1M groops.13!:CD0046>5 Study:. 1100112000 J. end poims were wakJateli.. CcnGlusi1lrn. Crohn's.'lilmninl" Vllriu.Jg B" oompilT8d to 1000 iJIllM B" on the sam~ dosing scltedule. blind loop. more likely to present in infants and toddlers) • gastric • mucosal atrophy secondary to chronic gastritis • pemicicus anemia (see below) • post-gastrectomy • intestinal absorption • malabsorption (e. • Same a s part I.6:1. pancreatic disease) • stagnant bowel (e.nger slli(lies ~ in the primary cam pOpuiatiOll <we reIluirW.: M"!a'an~sis was no! atli!illp!ed dUll to study he!erog~neity. but fad iolabeled B 12 given with oral in !. Bam stud ~s reporte:l impJO'IBment..decreased vibration sense.pyramidal tracts .ins ic factor • Should be dane on Iy ff first stage shows rsdacsd excretion • Normal te st result ( > 5% excretion) • Abnonnal test result I<5% excretion) '" lntsstlnal causes (malabsorption! and '" pam lclous enern la Investigations Ct<l. in hem.

then 5 mg PO 00 maintenance if cause not reversible .nt • folic acid 15 mg PO 00 x 3 months. .. film. reticulocytes. Resol uti on 2. exfoliative dermatitis in Clinical Features • mild jaundice due to hemolysis of RBCs secondary to ineffective hemoglobin synthesis • glossitis and angular stomatitis • r.I ~~--------------------o l Ph ases of H emostasls 1.i n c lotlorrnatlon 3. Fibrin Stabilization and Fibrinolysis (resolution) • conversion from soluble to insoluble clot • once healing initiated..ts Hemo'slas is PT/1N A: Ten 11 is is pl~yed IExtrinsi c Pathway I outside PIT: Tallie Tennis is played inside (lntrinsic Pathway) ... however with universal supplementation foods it is now less frequent . RBC folate. . clot dissolution (anticoagulant pathway) "" of Se&onda.nageme. Primary Hemostasis • goal is to rapidly stop bleeding • vessel injury results in collagen / subendothelia 1 matrix exposure and release of vasoconstrictors • blood flow is impeded and platelets come in contact with damaged vessel wall • adhesion: platelets adhere to subendothelium via vWF • activation: platelets are activated resulting in change of shape and release of ADP and thrornboxane A2 • aggregation: these factors further recruit and aggregate more platelets resulting in formation of localized hemostatic plug . folate deficiency has no neurologic manifestations Investigations • similar to 6]2 deficiency (CBC. Secondary hemostasis • F ib..y Te..I Norma I hemostas is occ urs as a result 01 the bela nee between procoagul ent an d a nli C oaguJant factors. serum Bd • it is crucial to rule out 612 deficiency asthe cause of the decreased RBC folate Ma. ·elderly..I Neverg ive 101"le "lone to an ioo ividua I with megaloblastic an Bmia becau seit wi II mask B".Toronto Notes 2010 Macrocytic Anemia/Hemostasis Hematology H23 Etiology • diet (folate is present in leafy green vegetables. . .are • melanin pigmentation • purpura secondary to thrombocytopenia • Iolatedeficiency at time of conception an-d early pregna~ncy has been linked to neural tube defects • unlike 612 deficiency. ' ~~--------------------. d eficie ncy an d neu rolog ical degenerati Do wi II contiaue. ' ~.• seen mainly in infants.. Secondary Hemostasis • platelet plug (formed through primary hemostasis) is reinforced by production clot in secondary hemostasis • extrinsic pathway • the only way coagulation is initiated in vivo • intrinsic pathway • allows for amplification once coagulation has started of fibrin • Fibrinolysis 3. fortified cereals) • most common cause traditionally.~------------------~ . Hemostasis Three Phases of Hemostasis 1. Pri m all' h emosta sis • Vascular response and plate let pi ug fa rrnation vi" vWF 2. alcoholics • intestinal • malabsorption • drugs / chemicals • alcohol • anticonvulsants • antifolates (methotrexate) • birth control pills • increased demand • pregnancy • prematurity • hemolysis • hemodialysis • psoriasis..

' von WlI~tnod 1""1" (IiWI) GPlb.~ FCl'o'~~_ &. platelet dysru nctien High in hemophili as A and B 22-35 sec PT 11-24 sec 0..~ __ wc· aoA·T .1 ~ FI.. ~-J: ~ _C~APC-G-t _ Vtla 1XJ:..inoQ&n R(. Commonly Used Tests of Hemostasis Tvpe of Hemostasis Primary Secondary Tesl Platelet count Bleedi ng lime af'n Reference Ranlle 150-450 x 1091L N <8mins ~.. Signs and Symptoms of Disorders of Hemostasis Primary (Plateletl Suriaal Cllts Onset After InjUly Excess ive. h ered itary resistance to APe Tests of patholo gicinhib itors [a g... II . GU tract Excessive post-traumatic H ema I1hroses. H US/ITP.... GI tract.e Superlicial i. D·dim ers Spec ific factor assays 1 ssts of physiological inhibitors lantithrombin.2 High ill factor VII dBli cioocy INR Mixing studies Clotting fuctonsl deficiency if lest now nnnnal Inhibitors 01 dotting lactor{sl if test stilll abnormal Filllinlllysis Other Euglobulin lysis time N > 9 min looks lor sccelerated fibrinolysis May be accelerated in 0 IC low in heretiitary defic iencv 01 fibrinogen Fibrinogen Fibrinog en degradati on products lFD PsI.1)(a_ .!ivaled III • W GPllb/IU._.. muscles..j. XI.j.. Lab Values of Disorders of Hemostasis PT Hem ophilia AlB N N PIT Platelet CIIunt N RBC Count N N NJ.. Platelet Activation Cascade figure Table 9.I-v .exposed MUagen fLb'" in suben&ithelOJm .. fib. joints. gingival.9-1. protein S.binding domain 01 vwr GPlb 0 un. DIG Hhigh in severe Ihromboeytopen ia.. !>:~~ VI I XI-~· 1- I W'~~·t x-_.0000aled OPIIb/1JI. hemato mas Site of Bleeding Lesions TabIII 11. prolonged bleeding 1mmediat... XIII an d common patllway Used 10 men itor heparin Iherapy Measures extrinsic palhway {factor VIII in particular and co nmon patllwa.e.. ..y Penn~s determination of extrinsic pathway status independent of laboratory parfonning measurement Used 10 mo n itar warfarin tllerapy Differentiate inhib~oTs of clotting lactor(sl from a defioiencyin clotting facturts] Mix petient' s plasma with normal plasma in 1:1 ratio and rep eat abnormal test Examp les of Associate d Diagnoses low in 1fP. protein C.Coagulation Cascade Purpose To quantitate platelet number Platel et function and vessel waillunction Measures intrinsi c pathway {factors VIII. C!!l .lupus anticoagulant) I Table 10.H24 Hematology Hemostasis Toronto Notes 2010 'EXTRtNSlC PATHWAY II ImRlNSIC !'A1'HWl\Y JjJI ----""- ""'" XI!o TisaJoF!IdD< (1F) lum"n "' 'IOUIIv es ...._ --_"-~~ r~~~x. skin Petechiae.. vWD. GI tract. vWD DlC Live r Failure IfP TIP l' l' N N Nt1' N N + + + N N . llIerinel.e. mucosel (nasal. Kryiki200J HI_·>Ig"I"-"'''''''91~ c e Dian" figure 13a. I :110 ~-~&- 1~ I~~) {!mrnbIn) ~_l_Fim 'Crnssirbd' Rm all 13b. ecchymoses Sel:llndary (Coagulation) Norma Vslighdy prolonged bleeding Delayed [Jeep i. IX...

re stil locking.X HepOJin Vane"my.IIIV.Toronto Notes 2010 Disorders of Primary Hemostasis Hematology H25 Disorders of Primary Hemostasis Definition • inability to form an adequate platelet plug due to • disorders of blood vessels • disorders of platelets • abnormal function • abnormal numbers (thrombocytopenia) • disorders of vWF • characterized by superficial bleeding. NSAJDs A.9% of immuoo thrombocytopenic purpuJa cases treil1lid with rifiJllimati. AcqU~d • PuIpJr1l simplex [easy bruising) • Senil! purpura • . . . maintain pIt >100 fOJ:at feast 7 days post reH where pos-sible .[Jisorders of Primary Hemostasis Immune Thrombocytopenic Purpura (ITP) Table 12.tOlD"j in 1'atierrtl. EtOH.Norm.TYPE) ITP • most common cause of isolated thrombocytopenia • diagriosis of exclusion (i. Adllllrsee'ents related til the drug were usuaI~ mild or rnoderTI~ witltalaw inGidenc~ 01 inf!lCtions.. and clearance Investigations • thrombocytopenia.ssification l' Hemostasis Disorders I PLATElETS I vWD .Rendu • Conoocti\lli tissue dioorders Al:quired • Drugs [ASA. Deillhs have been reported far 2. P48 CHRONICfADULT.UBStJaoon • Spl~nomB~ • TIP. Som e antiretroviral s reduce platelet production ACUTE fCHILD-TYPE) • see Pediatrics. then prednisone 1. platelet dysfunction VASCULAR _J__I --. longcterm complete responses "'e oowl'ledin 1>-21)% cl cases.jmab as a OOOlnd~ine treatment cl !:IlIonic immuoothrombocytopenic purpUJa aut. Usually weeks 80% or more ITP destruction 3.1IUS HereOitary • Bern. isolated thrombocytopenia with no clinically apparent causes) Pathophysiology • anti-platelet antibodies bind to platelet surface ~ increased splenic destruction Shoold Rilulimab be lIied Bef~re or AIWr Splene. Decreased produ~tion • Aplastic anemia Inc_ed • ITP • HIT destruction $eq.ytQpenic purpura Hrrulimab produc~ an initi.e: To datennin. giant platelets • bone marrow: increased number of megakaryocytes • critical test to rule out other causes of thrombocytopenia myelodysplasia in people >60 years old.lplatelet.ide' a clinio._--------------------. Direct effect ot HIV on morrow 2. wi1JJ Immllll8 illrombiJG)'Iopenit PUlp"". or ilfter failul1l 01SjJleneclomv. petechiae. emergency splenectomy. 1'4:642<i Purpo. increased bleeding time • PT and aPTf normal • peripheral bloc. meningococcal.b th<m foI:lwing splenectomy.. ecchymoses • life-threatening bleeding sites in thrombocytopenia: intracranial . 1 pool q4-6h) • emergency splenectomy may be considered • management of intracranial bleeding should include: IV steroids. Immune Thrombocytopenic features Peak Age Purpura Chronic ITP 2[}-40 years F > M(3:1) Rare Insidious Months to years Uncommon Acute rrP 2-6 years None Gommon Abrupt Sex Predilection History of Recentlnlection Onset ·01 Bleed Duration S pnmaneous Remiss ions M achanlsrns tor .f I1lSIlOIISll iI ~proo:imorety SIl% of cases.~rone Emamblllol iluinidiD" Am~h~tericin B ilu injn~ o . Approach to . and then craniotomy.'" ssoeiirtud Thrombocytopenia 1.5 mg/kg! day • IVIC 1 g/kg! d x 2 days tranexarnic acid "I g TV q6h • vaccination (pneumococcal.al trial.in Dig~xin Rifampin Arniod. 1001.Dysproteinemios low platelet (VJnt thrombocytopenialree H6 ) Here~h'ry • Osler-W8b8r.e.ho'MlWI. Emergency Treatment (active bleeding or in need of emergency surgery) • methylprednisolone 1 g/d for 3 days.etaminophen Ethanol H1 -a nta(lOnislS ~ and retroperitoneal Cla.}---------------------. Immu n e-mediated platelet . lYIC.rd SruITer sl'lldrome [GPlb def~ienC'f1 • GlanlJmll5 syndrome [GP IIM~a deficienC'/J • H$P lwe MP251 NSAIDs) 'Srurvv • C!Jshing's syndranB • Infections. Non-Urgent Treatment (platelet count <20-30 x 109!L and no bleeding OR the patient is experiencing significant bleeding symptoms and the platelet count is less than 50 x 10") . Con elusion: Both the response rate and the response duralilln ilppear lower fullrrwtng ritIJxim. like Treatment A. platelets.long·mnn sofety dGta. B.' ClJrr ()pin f!8mIJt&. At the present time. but they co(jd IIIll be ottril:t!ted to the sludy drug. IhllE is insufficient 8~dence to support the' repiaooment 01 SjJlen!lCtomy wrth riw. mullS • Uremi'l'ORf • Myeklproiferillilill disorders Figure 14. Atthou~ the side effects mil\' 'be fewer.e lWethBr th80~lirnol timing for this themPI' is before spl8nectumy..d film: decreased platelets. Results: No Sl\Jdy has direct~ oomPilred rituximal) 10 splenectomy in jlilIients with ChTOrtiC immune thrQmi)!rr. theus~ of immunotherapy 'before spienBcIorrri can 'b! recommended only in patients at high risk far splen~ctomy and in thore not willing to undel9'J SUllieII'.I rugs Ass eclated wilh Thmmaa cytQPftuia TM P-SM. wim no significant differenoe !blllwm splenectomimd ond oonsplenectQrOOW patients. haemoplulus influenza B) for life-threatening bleeding platelet transfusions are appropriate (max.caurll".

30% (25% of events are arterial) Bleeding compli cati OilS UIlCO mmon Venous thrombosis: D\I1 PE Arterial Ulrombosis: M I. Danaparo id . but they OJuld not be attributed to the S1UdV orug..fevl:ff/chills.!ne thromOOcvtopenic pUrp. long-term saflll]' datll.jb..H26 Hematology .. .vents re~ted to the drug we". (HIT) Table 13. 0.utorontM~lassets/treatment+ po~cies.. AI the pmssnt tim!..nic Purpuril? C!IITapiIJH~miIIDI...I) . there is insufficient evid'enre to wppm the replacement of iP~nectlmy with :rilUxim.lJ'.14:M2·6 Purpuie: To determine whetlrertlre QlJlim. mortality 1-2% • major concern is cerebral hemorrhage at platelet counts <5 x 109!L Chromeill' Soo(Jld RitJ.b as a second-line treatm. meningococcal.g. etc. taper once response is seen (platelet >50 x 109) by 50% every 14 days • all patients should be vaccinated (pneumococcal.lable t Figure 15. rna nitored with aPTI. Deaths hal'll been raported fur. tire useDI iml('lJnotoorapy beJore spiensctomy can be recommended only in patients at high risk fur $plenec-tomvand in those not willing to undergo surgery. CnnclusioD: Both (h! re>pons8 rille and' Ihe rBspoose dwaiion 'PP8.rl Platelet < 1O.exametlrasooe ilIB roontlTs NO t Consider r.if Heparin-Induced Thrombocytopenia "I . haernophilus influenza B) • if steroids fail.) Transi em global amnss ia T4Cserotonin release assay (uses donor platelets with "C serotonin and heparin with patient's plasma) .lmmune. LMWH is also assoc lared w~h HIT b ut th e risk . I ~}---------------------. HIT·II (Heparin induced thrombocytopenia. HIT can develop ill hours) . Meohanisms for IIIV.b to iPlenectomy in patients with chronic irrmun~ thrombaqtopenic pUrplJl"a. Some antiretrovi rats reduce platel et production • platelet transfusion does not work • [VIC is not appriopriate for patients not actively bleeding • prednisone 1-2 mgll<g/ day. 20Gl.associated Disorders of Primary Hemostasis Toronto Notes 2010 Thmmb ocytop enla 1.mediated platelst d astructl 00 3. with a low incidenoe m mid inlecoons. ~~------------------~.. adrenal gland involvement Hepariuind uced skin necros is Acute platelet activation syndromes: acute inflammatory reactions (e.ira caooslreated willi riIIJ.ll timiPg for this therapy is before splooectomy.. or <it!! fuilura or iP~nectomv. Ll"lg-temn comp~ JespOllSeS ara obse'l'ed in 15-2fj% 01 cases.MIs witlrlmmulIIi Thmmbo&ytup. PatlropllvsiologV type II) Immurremediated Ab recognizes a complex othepsrin and platelet factor 4 (PF4 ) leading to platelet activatioll via platel ~ Fe receptor and activation 01 coagulation system Diagnosis Onset 01 deGflIasedplate lots 50% reduction in platelets wh ile on heparin w~hi n 5·15 days of in~iation 5·15 days I if previ ousty e~posed to Ilsparin. use with caution in liver disease J.. MG 1 WI:~. or require> prednisone 10 mg daily to maintain a platelet count of >20 x l()9 AND have a persistent severe thrombocytopenia «20 x 109!L or 20 x 109 to 50 X 109 with bleeding)... limb and mesenteric arteries. TPO agonists. octMl bleeding Pijst~sp1~e.r lower fol:lwing ritu~ab than Mowing SpI800ctOmy.ti. decreased specaic than serotonin assay) Flow c'{lometry Management Clin ical suspi cion of H IT should prompt discontinuation of heparin Ispecific tests take several days) Because 01 90% cross-reactiv.imlO. fiushing.nlimab be Used' Belur8 Of After SplooeGll)my in Pa.0811)1200 mg PO bid X 4 month ~ial 4.. qrclophospharride 1 !JIm q ~ dol'S x 2-4 cveles or 1-2 rrqikg. IlliG 1 ~g q hveeis and ~lataletlrm>fusion for severe bleeding BIJT -------------I Dexamelhason8 NO 40 mg x • days q 28 davs x 6 cycles t· Re:sjlllnse to d. Ritu~mab 375 rII. avoid in renal disease). Although the side effects "lIY be feWlll.q4W88ks 5. Rostllis:No study hasdireclll' compared riru~m. or patients relapse on taper.is less than unfractionated heparin.d PO x 3-6 months 2. where clinical trial """. \wh no signilir:ant dilferant1l tr-etween spleooctorrW.lidiopathic tthrombocytopenia+ purpUJa.jIm' crwk for 4 weeks '6.ity LMWH shaul d not be substiUJIed AHemative agents include: lepirudin (reC{lmbinant hirudin. Adv"s. 2. . Argatroban I effective thrombininhi bitor.i and nOllSjllenectomilEd pat~nts. Plmle! count <20 0 R c 50 and Bleeding W81purpur. 1Iowe1'll( are still :~cking..im. uSlJaliy or modero.9% of . Direct effect of HIV 011 marrow 2. I ~~------------------~ HIT TVIlell Hepa rln-assnclated thro mb ocytopenia) Risk of thrombosis Clinical feature·s • Direct heparin mediated plallll'ln • • • • a gg re gat ion In 0 11-'immun e I Platelets > 100 X 100IL Self -limited [rm th rorncone risk I May continu e with heparin th erapy Onset 24-72 hou rs Sp ecili e tests EUSA lor HIT·lg (increased sens~ive.nt m chronic ilM1Jne thmmOOcvtopenic pUljXJm outside a dinic<ll trial. splenectomy may be considered • if patient relapses post splenectomy (see Figure 15) Prognosis • fluctuating course • overall relatively benign.-tomy t YES TTane'-OO1icocid 500-1000 t~ lfor . Imuran 2 rrqikg x 4 months 3.. stroke. Rituxirllilb produces <It initial response in aPilroximatelv 61l% of cases. Suggestive Care Path for Patients with Post-Splenectomy RefractorylTP Adapted frllm www_hematdlogy..

(purpura.A MTS -13 protease • Congen ital TIP is deli c ient in AOAMTS-13 • Antibodies aga i nst ADAMTS-13 p resent in acq u ired TIP Clinical features 1.!l was 13% 195%. The DWTilIl pro.Fever IHI A. Sepsis DIC H8LLP Antiphcspholipid Ab syndrome E~a. coli stlrotype 0157.e IP= O. fillrinogen: normal Markers of hemolysis: increased unconj bili. hematuria. Microang iopathic. One hundrod and thirtyonewcmen weradiagnosoo to hove \ItIII Willebrood d~eose wrth pr8'lDIenres in ird~idll8l sludies ranging frilm 5%. decreased 11aptoglob in Negative Coombs' test Creatinill a. Thrombocytopenia. Severe thrombocyto penia. menorrhagia • moderate to severe • as above but more severe. epistaxis.6%1.mild quantitative defect (decreased amount of vWF) in 75% of cases • type 2 . . hemolytic. underlying . 11 1:734-40 Pmpo~.lnosis and use of reee. GI Investigations • increased bleeding time and PIT • decreased Factor vrrr (5-50%) • platelet count normal or rarely decreased • decreased ristocetin cofactor activitv (normally causes vWF to bind platelets tightly) • decreased von WUlebrand antigen types 1 and 3) • blood group (as antigen quantification reference range differs dependent on blood group) • analysis of vWF multimers to detect variants On P'l1ulalion. Testingf~r this disordershould be considered when iwestigating' women with mer1onbagia. 10cal defects.ooSilln a sma.. method 01assessing menstrual Mood loss. and is th. especi<il~ those of CllI!C8sion origin.H 7) TTP Predo minantly aduk Deli ciency of metallcprots nase that breaks down ukrn-Ia rg e vWF multmers • Gong entiall genetic absence 01 ADAMTS-13) • Acquired (drugs. GI bleed) 2. Renallailur€ 5. of which includemethod of rEcruitment III study (rare). petechiae bleeding. The prt'll.qualitative defect (dysfunctional vWF) in 20-25% of cases • type 3 .oangiopa tllic hemolytic anemia (MAHA) 3" Neurologi cal symptoms 4. an emia (MAHA) 3. malignancy. u rea. oliguria.1 dicated (increased microvascular thrombosis) Plasma infusion n plasmapheresis is not immediately sva ilable nPm altai itv . aPIT. transplant.ns syndrome lautoimmune he rnolvtic a n emi a + IIPI Von Willebrand Disease (vWD) Pathophysiology • heterogeneous group of defects • usually autosomal dominant (type 3 is autosomal recessive) • qualitative or quantitative abnormality of vWF • vWF needed fOT platelet adhesion and acts as carrier for Facto)" VIn. Conci'Usions: -nhe pre~alellUl of vonlMkbrand d~e<lSe is increasedin Wllmen with men(lrha". acute renal faflure) 2. easy bruising. often improves during pregnancy and with age . FFP is not useful • conjugated estrogens (increase vWF levels) P.e was hig~ in the £mJpmll5l!Jdie!F-I' 8% 195% GI t5-2l%1 cOOl]Jarod with tho! in North Americanstud~ 1~ 195% ..llow renal fUllction Stool C + S IH US) .and ABO blood group· specifi. abnormality vWF can affect both primary and secondary hemostasis • vWF exists as a series of multimers ranging in size • the largest ones are most active in mediation of platelet adhesion • both large and small complex with Factor VIII • usually mild in severity Classification • type 1 .CI J 1-15.rognosis • may fluctuate. Mic.al'n(.OOJ] ell is rike~ to be !be resU~ of differences in the stndies..5-13%1.-'*~------------------~ ~ Palll ophysio!ogy IIf TIP • vWF secreted by endothelial cells in avery large polymer rap id Iy cleaved by the AD. Treatment • desmopressin (DDAVP1:M)is treatment of choice for type I vWD • causes release of vWF and Factor VIII from endothelial cells • variable efficacy depending on disease type • need good response before using with further bleeding • not to be used in type lIB (will cause worsened thrombocytopenia) • transexamic acid (antifibrinolytic) to stabilize clot formation • high-purity Factor VllI concentrate containing vWF (Hemare PTM) in select cases and type. to 24% .~n.mrtitRlIliow BJGa 2OIJ4. T~dlllcllllin8 1h8 preW~nce of ItOn Wilebrond dsease in Wllmen prerenting with menorrklgia" SlUiIy Selection: SVSIen. crillnia lor diil. in woman with rrte'no~hagi a Results: Eleven studies were included.severe total quantitative defect (no vWF produced) rare Clinical Features • mild • asymptomatic • mucosal and cutaneous bleeding. to fa. Renal failure (abnormal. but significlllt groop of Wllmen with m!nOJlhagia across !be WOI~.This differom. epistaxis. totalling 988 women with rrJ8norrhilgia'.Toronto Notes 2010 Disorders of Primary Hemostasis Hematology H27 Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS) Table 14.8 i ncl udes. occasionally soft-tissue hematomas. seinres) Investigations GBG and bla od film. sell istocvtes and decreased platelets consider diagnosi s (b oth TTP. hemoptysis. increased WH..rtic rovi!!l'/ 01 stulfteS evaluilting the prnv"~n" 01 VOn WillQbrand di"". those wrrh no olwious pelvic pDtholo~ IJIl'Jith addition'" bbarling symptoms. IlIfIIic oomposition of 5l!JdV IIIlPuliltion. varIeS tor von: Wil~brand factor. HUS) Platelet transfusion is corrtrai 1.n Will~brand Di!>la!>l in Women with Menon11agi!: A Syst". urinalysis.90% n untreated magn 05. HiV-associated. co niuslon. TIP and HUS HUS ~"i demiolouv EtiologV I'redominamly child ren Shiga toxi n (E. id iopathicl 1:.. HUS) PT. hemarthroses 'I._' ~ *}-------------------~ Differential Ma nagamont Plasmapheresis is tha treatment of choice :t steroids (both TTP..

k. alcohol abuse • secondary hemostasis affected • elevated INR (PT). VII.Signs and Symptoms of Disorders of Hemostasis Investigations • prolonged aPTT. more common in Ashkenazi Jews usually mild. normal INR (PT) • decreased Factor VIII «40% of normal) • vWF usually normal or increased • desmopressin (DDAVpTM) in mild Hemophilia A • recombinant Factor VIII concentrate for • prophylaxis • minor but not trivial bleeding (e. X. protein C & S • antibiotics eradicating gut flora.g. IX. which provide 50% of vitamin K supply • poor diet (especially in alcoholics) . IX. fresh frozen plasma.g. often diagnosed in adulthood level of Factor Xl does not predict bleeding risk treatment: fresh frozen plasma. • platelet dysfunction: e. multiple • anti-fibrinolytic agents (e. InvllstigatiDns in l. tranexamic acid) Treatment trauma) Hemophilia B (Factor IX Deficiency) • • • • a. hemarthroses) • major potentially life-threatening bleeding (e.000 males clinical and laboratory features identical to Hemophilia A (except decreased Factor IX) treatment: recombinant Pactor IX concentrate and use of anti-fibrinolytic agents Factor XI Deficiency • • • • • a. Christmas disease X-linked recessive. severe «1 %) Five tis Hemarth roses Hematomas Hemaloch e'tia Hematuria He~d hernorrhaqs Clinical Features • See Table 10 . Rosenthal syndrome autosomal recessive.a.g.a.H2S Hematology Disorders of Secondary Hemostasis Toronto Notes 2010 Disorders of Secondary Hemostasis Table 15. folate deficiency. • pathophysiology • deficient synthesis of all factors except Vlll • aberrant synthesis: fibrinogen '. 1/5.000 males • mild (>5% of normal factor level). moderate (1-5%). Soviet X. VII. Classification of Secondary Hemostasis DisordErs Hereditary • Factor VIII: Hemophi lia A. I ?}-------------------. vWD • Factor IX: Hemophilia B {Christmas Disease) • Factor Xl • o1!1erfactor deficiencies are rare Acquired • Liver disease • DIG • Vitam in K deliei ency • Acq uired inhib imrs Hemophilia A (Factor Pathophysiology Hemo~hilia A vln Deficiency) • Xvlirrked recessive. treat liver disease DIe VitaminK ~' Deficiency Etiology facto rs V. VII.k. Factor Xl concentrate Liver Disease "" . alcohol intoxication.Jver Disease Factor V.g. VIII Expect d ecrees ed V and VlI because th ay Ita VB tit a 'shortest I I/"Faclo' VIII wi II be no rrnal Of increased because it is produced in endoth el i(Jm.itam in K Dependent 1972 Conada vs. II protein C&S • drugs • oral anticoagulants inhibit Factors II. DIe • miscellaneous: inhibition of secondary hemostasis by FDPs • investigations • peripheral blood film: target cells • primary hemostasis affected • thrombocytopenia 2° to hypersplenism. deficient clearance of hemostatic' debris' and fibrinolytic acti vators • accelerated destruction due to dysfibrinogenernias: increased fibrinolysis. aPTT and thrombin time • treatment: supportive. 1/30. platelets.

.. burns.iNRs between 45 and 10 and not bleeding (excludes hemorrhagic disease of the newborn) • if bleeding. '9~--------------------. hematologic malignancies especially acute promyelocytic leukemia AML-M3) • snake venom • fat embolism . malaria) • tissue injury (obstetric complications. ecchymosis.. • • . splenectomy • vascular stasis . give fresh frozen plasma (FFP) • note: excessive amounts of vitamin K will delay therapeutic warfarin anticoagulation once re-started . VII.V .ons • INR (PT) is elevated out of proportion to the elevation of the aPIT • decreased Factors II. RBC fragmentation . short euglobin lysis time (i.. accelerated fibrinolysis) • extent of fibrin deposition: urine output.~--------------------.... see Pediatrics.)eVil NVIII DlC -J. seizures skin: focal ischemia. superficial gangrene :renal: oliguria. TT. aPTI. S e rl~I f brin "g en levels shou Id be measured to see 'il there is a trending decrease along with an increase ill D·climer .. epistaxis. oozing from puncture sites renal: hematuria mucosal: gingival oozing.)eVil .)eVil 1'VIII ..e. urea.g. coma.. :Etiologies Important of Die Trauma Shock Infection Mal i g nancy Obstetric com p Iications Clinical Features • signs . coagulation factors and fibrinogen subsequently giving rise to risk of life-threatening hemorrhage Etiology • a 2" disorder that occurs as a complication of a number of other conditions • its unifying cause relates to widespread endothelial damage ± extensive inflammatory cytokine release • activation of pro coagulant activity • Antiphospholipid Antibody Syndrome • intravascular hemolysis (incompatible blood. I ' 9~--------------------' ole is a spectrum which may . extracorporeal circulation factor Coagulopathies Liver disease ~V . cortical necrosis pulmonary: ARDS GI: acute ulceration RBC: microangiopathic hemolysis of hemorrhagic diathesis bleeding from any site in the body is possible because decreased factor levels neurologic: intracranial bleeding skin: petechiae. hypotension . • signs .. . delirium..indude mrembosis or bleed i nn or both.. hypovolemia ... ... crush injuries) .Toronto Notes 2010 Disorders of Secondary Hemostasis Hematology H29 • biliary obstruction • chronic liver disease (decreased stores) • malabsorption (e. of microvascular thrombosis neurological: multifocal infarcts. malignancy (solid tumours. . P71 Investigati. • • • • • '" t~--------------------.. celiac disease) • hemorrhagic disease of newborn.. PT should improve within 24 hours 01 vitam in Kad min i stration Ions at is in 6· 12 h rs].)eVIIi . " Disseminated Intravascular Coagulation (Ole) Definition • uncontrolled release of plasmin and thrombin leading to uncontrolled intravascular coagulation and depletion of platelets. pulmonary embolus • other • acute hypoxia! acidosis .. • • . IX and X (because vitamin Kvdependent) Treatment • hoi d anticoagulant • vitamin K I mg PO for . heat stroke • endothelial injury • infecti ons I sepsi s • vascu litis • metastatic disease (adenocarcinoma) • aortic aneurysm • giant hemangioma • reticuloendothelial injury • liver disease ...... trauma. . ~ not sea rch 10 r other cause s. '" ~~------------------~ Levels of fibrinogen can still be norma I in ole as it is an acute phase raactant... azotemia.. platelet and dotting Investigations • primary hemostasis: decreased platelets • secondary hemostasis: prolonged INR (PT). decreased fibrinogen and other factors • fibrinolysis: increased FOPs or D-dimers. massive bleeding . give vitamin K 10 mg rv IPO and if life-threatening bleeding... t~vels in Acq!lillld VitKDef NV .

. PNH. Factor V an d Xd ef. mJlcomfS: Time (0 IhEropemic INR. lymphangitis or lymph obstruction. against increased hemocvsteine hyperviscosity (multiple myeloma. venous valvular ruptured popliteal cysts. femur. ? I + trauma (especially fractures of spine. polycythemia. tniti\!~ng W.~. and higher risk of disease . thoracic. £onclu~i'm: Ini~ationo! warfa. th:ifllPV with a 10 mg nOOlo(Jam alllJ\1fS fasteJ oohilNEment III a therapeu~o. Screening.. PIT Only Hem ophil ia A and B vWD Heparin AIltiphospllOl ipid Ab Facto r illhib itors F X!iF XH defici ency ractorVII inh iMors Venous Thrombosis Definition • the presence of a thrombus and subsequent inflammatory response in a superficial or deep vein • thrombi propagate in the direction of blood flow (commonly originating in calf veins) • more common in lower extremity than upper extremity • incidence -1 % if age >60 • the most important sequelae are pu lmonary embolism (-50% chance with proximal DVT) and chronic venous insufficiency Etiology (Virchow's Triad) • endothelial damage • leads to decreased inhibition of coagulation and local fibrinolysis . OCr.138191:114-9 Study: Mullicentre. HRT.~--------------------. PRY. pancreas. P. in Coagulopathies IncreasedBoth Prothrombin del. Gl and GU) . cryoprecipitate • in thrombotic phase: LMWH (controversial) Table 16. rand~mizedtrial. • venous stasis Virchow's Triad • immobilization (post-Ml. erythema. + prolonged immobilization (CHF. CHF.~------------------~ + neoplasms (especially lung. and fibrinogen inhiMors Excessive anti coagul ation Increased. kidney and prostate cancer) Folic acid 5 mg PO da i Iy wi II prole CI + blood dyscrasias (myeloproliferative disorders. warmth and tenderness • palpable coni (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 tear. rectum. Test Abnormalities Increased' INR On Iv Factor VII del.1 damaqa • Stasis coagulation factors • Hypercoaqu lability • hypercoagulability • inherited (see Hypercoagulable Disorders. SERMs) + antiphospholipid antibody syndrome (APLAS) + hyperhomocysteinemia + heart failure (risk of DVT greatest in patients with RHF and peripheral edema) • idiopathic (10-20% are later found to have cancer) Clinical features • absence of physical findings does not rule out disease • unilateral leg edema.nts: 101 patients with . MaW.> intheW mg ~wp reached 0 (h~~utlc t~ 1.cute VEnous thromboembobm In!el'l'en~on:5 mg: WlIrflIrtn iniliiltlon nomo(Jam VIlrSIJSWmg ~mogfllm. Results: Patient.rfarin TheraPl' Ann IIlIMr Met} 2003. post-op). but is expensive.001).4days filsmnJlOn b ilthe 5 R mg grQUp with no difference· in major bleed·. 'betlwen (h81WO groups Ip <:0.fiJO Hematology Disorders of Secondary Hemostasis/Venous Thrombosis Toronto Notes 2010 Treatment • recognize early • heat underlying disorder • individualized critical care support • in hemorrhage: replacement of hemostatic elements with platelet transfusion. invasive. arterial occlusive disease insufficiency. stroke. H32) • acquired + age (risk increases with age) + surgery (especially orthopaedic. pelvis. Hbrinogen del. esp. tlR withool increased tmJing rtsl Investigations • D-dimer test only useful ttl rule out DVT if negative and low clinical suspicion • doppler ultrasound 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. MI. protnrombin. stroke. Vitam in K del. leg injury) + hormone related (pregnancy. Warfarin Liver disease FFP. colon. or tibia and SCI) . ET). inhibits clearance and dilution of • Endothel i. sickle cell) levels. cellulitis. Severe liver disease Factor V and X.". leukemia..

61). .. • Warfarin d eerees es Factor VII level s in tst 48 hrs -. prev ious VTE. ' ~~------------------~ Initiation of Warfario Therapv Requires Ove!:la p with H epari n lherapv lor 4·5 Davs • m mg loading dose of warfarin causes a p recipitous de din. sepsis. .e. ris~ f~r thromb?emb?lism (VTE <12 weeks. chronic recurrent embolism with pulmonary HTN. Factor Xa inhibitors (fondaparinux) • thrombolytic (e.Iu~oo. period. then weekly until INR stable.48·4.. Results.» INR is prolonged (most sensitive to Factor Vllievels).nosis. However. severe respiratory d is ease.Jdy: M~a·analVsis of B 'Rcrs [2994 patients) canparing: dilfarnm duraU. general a nesthetic IGAl < 30 m ins. and II are suff'iciently redu ced Ioccu rs after appro' 4 days).PTT with adjustment of dose to reach therapeutic level (-2x control valne): monitor platelet counts for development of thrombocytopenia (HIT) . warfarin should be discontinued for at least 4 days pre-operatively to allow INR to fall • avoid elective surgery in the first month of either a venous or arterial thromboembolic event • IV heparin may be used up to 6 hours pre-operatively intravenous heparin or LMWH (bridging) should be given before and after the erocedure while the INR is below 2. recurrent VTE. a 1 risk. ~f-------------------~ Prophyla)(. then warfarin for 4-6 weeks post-par tum. lab monitoring not required.rn. lsche m ic stroke an d lowsr limb pa ra Iys is.26).18. Contraindicationsand Adverse Reactions • see Anticoagulation Therapy.000 IU). stralified as either li'e~ or unlikelv tJJ have DIIT were . minor electiva.): 6-12 months or indefinite therapy (controversial) • recurrent DVT (2 or more episodes): indefinite therapy • rvc filters: useful in those with contraindications to anticoagulant therapy. during pregnancy. argatroban). lower risk of HIT. i. then every 2-4 weeks • recent evidence suggests that a therapeutic INR can be reached quicker by using a warfarin initiation protocol that starts with 10 mg dose rather than a 5 mg dose • UvfVVH shown to be more effective than warfarin at preventing recurrence of venous thrombosis in cancer patients • duration of anticoagulant treatment (with warfarin unless otherwise noted) • first episode DVT with transient risk factor: 3 months • first episode DVT with ongoing risk factor such as cancel.69). 0. . No spoof~ recorMlendation was rnade lllIJardQg opliRTal duration of treatment.li. direct thrombin inhibitors (hirudin. lepirudin. Corn. X. chronic venous insufficiency and chronic thromboembolic pulmonary HTN • unfractionated heparin (UFH) or low-molecular weight heparin (LMVI/H) • UHf • requires bolus (7500~ 10. acute n aurolnqic disease.I standi!rd diagnos~" WIlik~s set 0111 bV the investigators. mtagooist thel1lW lOR 114. however full antlth romb ntl c effect is not" chieved until F~ctor IX.g.men the till: of harm: from major bleeding Iwhich Illmains CCIIstlInt mor tiITFI is 01 gm. tPA) drugs reserved for limb/life-threatening thrombosis.0 for two consecutive days • warfarin should be dosed to maintain INR at2-3 except in select cases • monitor fNR twice weekly for 1-2 weeks.lllI>: kI patients treoted w~h vitEmin oK antagonists for a probnged. CI 0.. may need to adjust dose in patients with renal dysfunction • alternatives to LMWH and UFH: heparinoids (patients with HIT). safe and effective outpatient therapy • disadvantages: only partially reversible by protamine: renally cleared. or anti phospholipid antibody or more than one risk factor: consider indefinite therapy • first episode Dv'I' with no identifiable risk factors (idiopathic) or single inherited risk factor (i.teT concem man the .. there was no obselVlid excess QI VTE reclJrreooos Iollwing cessation of prolong.Vent fewer u~ . IiJEJM 2tlG3.<iI~ deemed to haw a OVT. at least as effective as UFH • advantages: predictable dose response and fixed dosing schedule. p'. the reduction in till: 01 reourrent lITE remai~ !:iJnsistEnl teganJless 01 the p~riod of time' since the in~ event lOR n. Factor V Leiden etc. no risk factors fo r VTE. ·LMWH • administered SC. long-term Treatment • standard treatment is warfarin" which should be initiated concomitantly with heparin overlap for at least 5 days and discontinue heparin after INR >2.I Low risks Hrgical petients: -c 40 vrs.> 30 m i ns High risk surgil)al patients: >40 vrs. GA . • perioperative: surgery safe when INR <1.Toronto Notes 2010 Venous Thrombosis O-DUTIer in Suspected Hematology HJ1 OVT Approach to Treatment of Venous Thrombosis Purpose • • • • prevent further clot extension prevention of acute pulmonary embolism (occurs in -50% of untreated patients) reduce the risk of recurrent thrombosis treatment of massive ileofemoral thrombosis with acute lower limb ischemia and / or venous gangrene (phlegmasia cerulea dolens) • limit developmentof late complications.4% of patients with a n!illative O'-<JirreTtest and III ultrasound PIlrtormed were bter elini. fa ctor for vn.18 t~ per patiants versus U4 rests per p1lliem..5. Potiems in the D~imer~ group undsr>.sounds than those in the ''''tmlyroop IG.lusion: i'lnli:rnged ttl!lllmenll'lith vitamin K antagonists reids to a ronsistam re:!ucu~nin the tis!: of recurrent lITE lOT <IS long is therapy is c(iII!inued.. followed by continuous IV infusion (1000-1500 IU /h) • weight-based heparin nomograms help to achieve proper dosing • advantages: rapidly reversible by protamine in case of bleeding • disadvantages: must monitor a..g. other rl sk factor. Main Re. In addition. D·dimer testing is uselul in ooWcing the n~ fur u~rasound in DVT di".. CI 0. tmdomizeO trial' with 1·6weak follow·up.oRmi lisk d recurrent WE Iwhich decines 01reT ti me).n~on~ts in pitients with symptomatic wnws throrTtoerTtolism 11ITE)..is • consider for those with a moderate to high risk of thrombosis without contraindications • non-pharmacological measures include: early ambulation: elastic compression stockings (TEDs).~ of !ivslemaridleview-r Z006. surgery for malignan cy or lower extremity orthopedic su"gery lasting . 18D). Thelapv shou~ be discontinued . active cancer.0 for patients at high.ons of treatment with ~tamin K.349113):I Z2l·35 Srudy: MII~centm. recent symptoms.91·1. patients who mCM prolonged mlOlment hada pmsismm increase in Ilwiririsk 01 m~r:bleedingl cOlI\plicotions lOR 1. in protein C levels in 1st 36 hours rs suIti ng' in a trsnsis nt l1yperc~agulable state . mechanical heart valve) • postoperately.>40 vrs.surgery. H52 Treatment of Pulmonary R19 of Anticoagulant Therapy Embolism (PEl H igb ri. achieving a minimum total anticoagulation time of 3-6 months .61'. atrial fibrillation With pnor stroke. or require emergent surgery without time to initiate anticoagulation • pregna~ncy: treat with LMWH.d vitatrin II.. conlin ed to bed and have" 1 addition a 1risk factor le. lupus anticoagulant. Intitial Treatment 111romboemboliml CodllOlJil. inh ibiters deficien cy or . 13·0. ndom~ed to :receive or n~t rece~e D~imer tEslingl inadditioll.OO8).0. recurrent thromboembolism despite adequate anticoagulation. p<fliculir~ inlow·tis!: p1l1iems. Patients: 595 patilnts with 5us~ted Ilg DIIT. postphlebitic syndrome. abdominal or thoracic . Cllrn.. low bleeding risk issue 1 SlJ. streptokinase.e. intermittent pneumatic compression (!PC) • UFH 5000 lU SC bid for moderate risk • UFH 5000 IU SC tid or enoxaparin 40 mg SC OD for high risk Moderato risk surgiGal patients: .sk modical pati ents: heart fa ilure. • see Respjrology. IV heparin or UvfVVH can be used for anticoagulation safely (12 hours after major surgery) until therapeutic INR levels are reached after restarting warfarin CII.. Oura1ioo of Treatment witl1 V"~amfn K Anta~O!listsm S'jrnptumatio 'ItlhllU.> 30 mi ns.

malignancy. heparin-resistant disease (AT deficiency).decreased AT functional.theophylline • folate 5 mg/ day can decrease plasma homocysteine by 50%.type Ill: decreased free Protein S levels aC. warfarin • antithrombin slowly inactivates thrombin in the absence of heparin.. t1.z.eII:. type .10-methylenetetrahydrofolate reductase) ?~------------------~. chronic renal failure.Juired: liver disease. post treatment • Protein C. systemic disease all decreased antithrombin levels) • deficiency may result in resistance to unfractionated heparin (LMWH must be used) • an independent marker of increased thrombotic risk • genetic basis for increased levels poorly understood • include congenital plasminogen deficiency. although effect on thrombosis risk reduction unclear • also increases risk of arterial thrombosis Protein C and Protein S Deficiency • Protein C inactivates Factor Va and VIUa using Protein S as a cofactor • Protein C deficiency • homozygous: neonatal purpura fulminans • heterozygous . • post acute event Althou gil lu pus anti-coaqulant prolongs . spontaneous abortions..sis • CXR • Mammogram and Pap 'in lema les • PSA in mal es • Colonoscopy • CI cs e fo'llow-u p • both a. • antithrombin (not on heparin) PH.its main el in ical feature is • FVlll (increased levels predictor of recurrence) th ro moos is.erstooa. also can interfere with action of protein 1:&5 Antibody Syndrome (APLAS) .. phenytoin.1 laboratory criteria clinical: thrombosis. age <50. DIC.P. tissue plasminogen activator deficiency Antithrombin Deficiency Elevated Factor VIII Levels Disorders of Fibrinolysis Antiphospholipid • • • • definition: . unusual site of DVT. protein S. B6. '. MaUgnancy is a Common Acquirod Cause of HI'P crcoagu lability.l_'th_ platelet mem_b_ rane phospholipid and increased adhesion and aggregation. methotrexate. • type I: decreased Protem C levels ". must be tested outside of this lime penod. heparin. premature birth before 34 wks laboratory: anticardiolipin or lupus anticoagulant antibodies mechanism: not well und. ?~------------------~. interact w.832 Hematology Hypercoagulable Disorders Toronto Notes 2010 ~' Hypercoagulable Disorders of Common Causes HypercOlIoulabilitv • workup for malignancy or hypercoagulable state may be indicated for idiopathic VTE in presence of the following features. ~ I ?~------------------~.FVL (factor V Leiden).Venous Thrombosis Protei n C. • diagnosis must be made outside window of acute thrombosis and anticoagulation treatment (acute thrombosis. inflammatory conditions. family history of VTE. MTHFR '"I ~ (5. nephrotic sydrorne. and folate deficiencies. • increased levels are found in vitamin B. • C 0 rnplete histoty and phI'S leal • Routine blood work • Uri nal\.. HERITABLECAUSES OF HYPERCOAGULABILITY LEADING TO VENOUS THROMBOEMBOliSM Activated Protein C Resistance (Factor V Leiden) • most common cause of hereditary thrombophilia • 5% of general population are heterozvgotes • point mu_tation in tt_leFactor V gene (Arg506Gln) results in resistance Factor Va by activated Protein C to inactivation of Causes of Both Venous and Anerial Thrombo'sis inclu de: • Anlip hospholipid amibodies • Hvperhemocvste inem ia • Myel opro Iiterative disorders • Heparin indu ced thombocvtopen i a ?~------------------~. and ATill are decrees ad during acute thrombosis til eretore to te st for daficien ey. recurrent VTE. warfarin-induced skin necrosis and neonatal purpura fulminans (Protein Cor S deficiency) • workup may include • initial • CBC • malignancy work up • APLA-ACA (anticardiolipin antibodies) and LA (lupus anticoagulant) • fastinz homocysteine • APCit' (activated protein C resistance) • DNA . Prothrombin G20210A • G -7A transposition at nucleotide position 20210 of the promoter region of the prothrombin gene results in increased levels of prothrombin subsequently leading to increased thrombin generation Hyperhomocysteinemia .. genetic and acquired abnormality . Workupinclude1. fetal loss. Die. warfarin • 1/3 of patients with warfarin necrosis have underlying Protein C deficiency • Protein S deficiency _ • type I: decreased free and total Protein S levels type II: decreased Protein S functional activity . '. S (not on warfarin) Protein C deficiency Antiphosphol ipi dAbs Factor V Le iden Malign"ncy Protein S d eficl e ney In creased Hom n cysteine Antith rom bin deticien ey Prothrombin G20210A In creasedFactor VIII CALMSHAP~ Hypercoagulable Workup . pregnancy. PT (prothrombin G20210A).1 clinical and . hypothyroidism.activity.IL decreased Protein C functional activity • acquired: liver disease. rapidly inactivates thrombin in the presence of heparin • autosomal dominant transmission or urinary losses in nephrotic syndrome • type I: decreased AT levels. sepsIs..

Neutrophil Myeloblast Maturation Definition • rapidly progressive malignancy characterized by failure of myeloid cell to differentiate beyond blast stage Epidemiology • incidence increased with age. radiation and alkylating agents for previous '. ~. 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 of a large tumour mass Clinical Features • anemia • thrombocytopenia (associated with DIC in promyelocytic leukemia) • neutropenia (even with normal WBC) ~ infections. especially sternum • organ infiltration with leukemic cells • gingival hypertrophy . vision changes (uncommon) • leukostasis (medical emergency) • patients with increased WBCs can present with symptoms of leukostasis (i. fever • accumulation of blast cells in marrow • skeletal pain. myeloproliferative disorders and MDS) or to previous chemotherapeutic agents (i.g. respiratory distress. median age of onset is 65 years old • accounts for 10-15% of childhood leukemias Risk Factors • myelodysplastic malignancy syndromes (MDS).Roth spots.40-60 yrs AML. Promyelocyte t Pathophysiology • etiology subdivided into • primary .e.Toronto Notes 2010 Hematologic Malignancies/Myeloid Malignancies Hematology H33 Hematologic Malignancies Hematologic Malignancies '" '.e.de novo • secondary .may present to dentist first • splenomegaly . of Acute Chronic Acute t Typical Age of Presentation leukemias ALL . bony tenderness. CLL . cotton wool spots. benzene.early satiety. LUQ fullness • hepatomegaly • lymphadenopathy (not marked) • skin . altered mental status.~--------------------.---------------------.Children CML .to hematologic malignancies (e.leukemia cutis • gonads • eyes . Overview of Hematologic Malignancies Myeloid Malignancies Acute Myeloid Leukemia (AML) -----------------------------'" 9. bleeding) Myelocyte Metamyelocyte Band Neutrophil l l l l .60+ years ALL Malignant Clonal Proliferation of B Cells • Cll • Plasma Cell Dyscrasias • Multiple Myeloma • MGUS • Waldenstrom's Macroglobulinemia t Lymphomas • Hodgkin's • Non-Hodqkin's t AML • Idiopathic Myelofibrosis Figure 16.

fibrinogen in case of DIC • increased LDH.g. thrombocytopenia. increased K after treatment Toronto Notes 2010 " '. normal clinical state) • several possible regiments. increased uric acid. Classification .. perianal area • fever . Refractory anemia with ringed sideroblasts (RARS) 3. decreased Mg • release of procoagulants --7 DIC • decreased K before treatment. gout • release of phosphate --7 decreased Ca. to induce differentiation • treatment strategy 1. increased P04 (released by leukemic blasts).C&S of all orifices. poor performance score before treatment. decreased Ca • order baseline RFTs. aggravated by treatment (rare) • increased uric acid --7 nephropathy. Leukemia Acute Definition .autologous or allogeneic (younger patients with better performance status) • consider acceleration with hematopoietic growth factors (e.H34 Hematology Myeloid Malignancies • metabolic effects. aPTT. catheter sites. Myelodysplasia unclassified (seen in those cases of megakaryocyte dysplasia with fibrosis and others) Myelodysplastic Syndromes (MOS) ------------------------~ Definition • heterogeneous group of malignant stem cell disorders characterized by dysplastic and ineffective blood cell production. G-CSF) if increased incidence of severe infection • supportive care • screening for infection via regular C&S of urine. ~}---------------------.syndrome (MD with del(5q)) 7.g. MUGA scan prior to chemotherapy (cardiotoxic) Treatment • mainstay of treatment is chemotherapy • cure: defined as survival that parallels age-matched population • all AML subtypes treated similarly • except promyelocytic variant with t(15:17) translocation .ineffective hematopoiesis despite presence of adequate numbers of progenitor cells in bone marrow (which is usually hypercellular) • intramedullary apoptosis (programmed cell death within bone marrow) • both processes leading to reduced mature cells in periphery • considered preleukemic: 30-70% develop AML . variable WBC • INR. WHO MOS Classification 1.50-60% cure rate • adverse prognostic factors: age >60. increased K. "~ MO MI M2 M3 M4 M5 M6 M7 . start antibiotics • platelet and RBC transfusions (irradiated to prevent transfusion-related GVHD) ± erythropoietin • prevention and treatment of metabolic abnormalities (allopurinol should be started for prophylaxis of hyperuricemia) Prognosis • achievement of first remission (no visible evidence of disease and normal blood counts) • 70-80% if 60 years old.poorer prognosis 2_Adjuvant Therapy (leukemia will recur if no further treatment given): • intensive consolidation chemotherapy • stem cell transplantation . WBC >20 000/ em". 5q.(WHO) Presence of 20+% blast cells in bone marrow at presentation. monosomy or deletion of chromosomes 5 or 7) " '.g.circulating blasts with Auer rods (azurophilic granules) • bone marrow aspirate • blast count: AML >20% (normal is <5%) • histologic classification (French-American-British (FAB) --7 MO-M7) . FDP. Freq <5% 20% 25% 10% 20% 20% 5% <5% Common Name Minimally differentiated Myeloblastic without maturation Myeloblastic with maturation Promyelocytic (APML) Myelomonocytic Monocytic Erythroleukemic Megakaryoblastic FAB Classifications Subtype Investigations • bloodwork • CBC . oropharynx. ~~--------------------. depending on whether blasts are myeloblasts or Iymphoblasts.divided into myeloid (AML) and lymphoid (ALL). Refractory anemia with excess blasts I and II 6. Refractory anemia (RA) 2. normal bone marrow with <5% blasts. AML secondary to chemotherapy or MDS / chronic myeloproliferative disorder. Refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS) 5.anemia.based on stage at which cell differentiation stops • cytogenetics. unfavourable cytogenetics (e.all-trans-retinoic acid (ATRA) added. immunophenotyping • CXR to rio pneumonia. example regimen is cytarabine with anthracycline (e. resulting in peripheral cytopenias • syndromes defined according to French-American-British (FAB) or World Health Organization (WHO) classifications Pathophysiology • disordered maturation .chemotherapy to induce complete "remission" of AML (normal peripheral blood film. daunorubicin) • patients with poor response to initial induction therapy . Refractory cytopenia with multilineage dysplasia (RCMD) 4. LFTs • peripheral blood film . increased LDH. sputum. 50% if >60 years old • median survival 12-24 months • 5 year survival 40% • survival may be improved by BMT . Induction . respectively. ECG. stool. CXR.

(90+%) IMF -idjDpathic +++ +++ ++ JAK2 mut. GM-CSF) may decrease risk of infection • high risk (>5% blasts in marrow) • supportive care • single agent chemotherapy ..utiously with chemothm. J) ESA shOl.ii. 6) Use ESA. Prognosis • may develop marrow fibrosis with time • all disorders may progress to AML Table 17.g. PV " ~Iy.g.i.Jted anemia tQ dools.yth. '~~------------------~ / Disorders CML -J. weakness.roop"~tin in Patillnts wi1h Cinter f!Jaod l008./N 1'1' 1'/-J.) trl\'elofi lrosls ± + JAK2 mut.IireguideliJre _e iii tTmeril. of E~o~n ando.t1 1.mplicmions. and rarely weight loss.I-5rn1.Toronto Notes 2010 . dyserythropoiesis. benzene or radiation • occurs in 1 in SUOpatients aged 60-75 years old exposure Clinical Features • insidious onset • fatigue. pallor. epistaxis. infections. and platelet cells Neoplasms (MPNs) leading to qualitative and quantitative changes in Epidemiology • mainly middle-aged and older patients (peak 60-80 years) . 4) DisGtotinue EllAs when patient not "'!P¢nding Treatment • depends on whether MDS classified as "low risk" or "high risk" of transformation to acute leukemia • low risk «5% blasts in marrow) • supportive care: RBC and platelet transfusion.chemotherapy as in AML • stem cell transplantation . fever. as it increases III'Qmboembolic risKs . Myeloproliferative Definition • clonal myeloid stem cell abnormalities erythroid. or other agents • intensive chemotherapy .IIQ1l..15-41 Clla pm.on Stoles and suppleroonl fron intako fut ESA·lreirted potients wilen OOCeSSilI\'. 2) Same as # I fo' patients with 1000nsk rfl'I'llody:. ± IMf fT 1'1' Pit MarlOW fibrosis + + ± Splenomegalv Hepalomtlil alv Genetic Assoc. 10' throm()cembolic cr.mia vera + + JAK2 mut.1 rale. 5) Monit<l.s! ths nsed lortlilnsfusions. myeloid.gy 12007) ReCllmmendiiliOlls: Illnitjale an erytlrQPoiesis·s!imuliilingl agent IEllA) wilen homoglobin IHb) is near or beklw 10 ~dL in patients with cli::mothempv-asspei.m lowers oorvi. giant hypogranular platelets) • bone marrow aspirate and biopsy with cytogenetic analysis required for definitive diagnosis • bone marrow ~ normocellular I h ypercellular (but 10% hyp 0 cellular ). decreased reticulocyte count • WBC: decreased in granulocytes and abnormal morphology (e.ild not be use fu. mercaptopurine. and hepatosplenomegaly • infections and bleeding can occur out of proportion with peripheral counts . d ysthrombcpoiesis) • CBC and peripheral blood film • RBC: usually macrocytic with oval shaped red cells (macro-ovalocytes). or trisomy 8 Us. 3) roUIiW!he packllge 'inse~ lor dllSe initi..py 01 in patients with an eiellated . Y.Investigations • diagnosed by • anemia ± thrombocytopenia ± neutropenia • bone marrow hypercellularity with trilineage dysplastic changes (dysmyelopoiesis.(-50%) ET " essen~al thrombocythemia .. 10% have marrow fibrosis • also may see ring sideroblasts in varying proportion • cytogenetics ~ including partial or total loss of chromosomes 5. bruising.7.. antifungals • erythropoietin SC weekly may be effective in reducing transfusion requirements in some patients • hematopoietic growth factors (G-CSF.Risk Factors Myeloid MalignancieslMyeluproliferalive Neoplasms Hematology IDS • elderly. often with micromegakaryocytes.an SiJcilll& of HlMliillJ!!Jgy ilIld Cffnical 0nmJr. antibiotics. bilobed or unsegmented nuclei = Pelger abnormality) • platelets: thrombocytoperua.p~sia.often hydroxyurea.m modiiication. (95%) CML" chmnictrl\'eloidleul:emill +++ + Bcr·AhI mut. patients with cancer who allllIOI recei~ng th~mothe~. post-chemotherapy. Chronic Myeloproliferative PV Hct WBC Bas ophilia is uncommo n in other rnsd ical cond itions .may be curative tolreirtment oolllnd 610 s-_~. size and cytoplasm abnormalities (e. c.

am.e. an active tyrosine kinase . thrombophlebitis. low-oose aspirin can safely prevent thrombotic GOmpl~illions in pilli8nts wiill p~\I9IIherria\l1llli. p".rimary Outcom~: GumuliltiiB Jill! m III nonfatal MI. leukemic transformation (AML) Chronic Myeloid Leukemia (CML) Definition • myeloproliferative disorder characterized by increased proliferation cell line without the loss of their capacity to differentiate Epidemiology • generally presents in fourth or fifth decade of life of the granulocytic Pathophysiology • Philadelphia chromosome (Ph) • translocation between chromosomes 9 and 22 • the c-abl proto-oncogene is translocated from chromosome 9 to 'breakpoint duster region" (bcr) of chromosome 22 to produce bcr-abl fusion gene. hemorrhage.as needed Prognosis • 10-20 year survival with treatment • complicated by thrombosis. and GI bleeding •. rmdomilOO trial finicipants: 51'8 p. gum bleeding. IntmlQHon: Patients recM eithe< l(lW-dose a>!linn 100 mg daily In""S31 01 pl~baln"'2.4.as needed • antihistamines .~lind. especially after warm bath or shower (40%) • due to cutaneous mast cell degranulation with release of histamine • epigastric distress. DOllbl. alterations in gastric mucosal blood flow due to increased blood viscositv • gout (hyperuricemia) • •. hepatomegaly (40%) Investigations • see Polycythemia. arterial POz >92%) • palpable splenomegaly • donal genetic abnormality other than bcr-abl fusion gene • endogenous erythroid colony formation in vitro • B Criteria (Minor) • thrombocytosis (>400 x 109/L) • leukocytosis (>12 x 109 III • bone marrow biopsy revealing panrnyelosis with erythroid and megakaryocytic proliferation • low serum EPO level • JAK2 mutation identified in most cases Treatment • phlebotomy to keep hematocrit <45% • hydroxyurea (age >65.plus pumnnary embolism .51 and were follamd fur up to '5 '/Ilars. P. CooclusfGtI. increased incidence of stroke. Resuhs: Prim. MI •.H36 Hematology Myeloproliferative Neoplasms Toronlo Noles 2010 Polycythemia Vera (PV) Definition • stem cell disorder characterized by elevated RBe mass (erythrocytosis) increased white cell and platelet production accompanied by ~~------------------~ Erytllro mel algia is a pathogn 0 monic rn i crovascula r thmmbotic cornpl i cation in polycyth ernia rubra vera and esse ntlel th rom b ocvth emia Effieatv and Safety of low·dlse Aipiin in Pofy&ythemia. V!m N Eng! J MOO200~:J5G:114-2~ SWdy.tients with pci~emi8 vela wiill no cla<r indication for or con1r. or dl!Jth nom Gardiovascular causes ood the wmlilat~e le1am Iliithe previaus 3 . H5 • must rule out secondary polycythemia • diagnosis (WHO) involves two required (') A criteria + 1 other A or 2 B criteria • A Criteria (Major) • elevated red cell mass' (>25% above mean predicted value) • no cause of 2° erythrocytosis * (i. H5) • bleeding complications: epistaxis. increased platelet number and / or activity • erythromelalgia (burning pain in hands and feet) •.41: P"'O!lJ9 ood frR 0. PUD • due to increased histamine from tissue basophils. due to increased blood viscosity. 32p (age >80 or lifespan <10 years) • low-dose aspirin (for erythromelalgia and / or antithrombotic primary prophylaxys) • allopurinol . prior thrombosis or symptoms). placebo·rontrolled. PE.nd major lfetrOOs thrombosis. associated with platelets >400 x 109/L • pathognomonic microvascular thrombotic complications • pruritus. palms • splenomegaly (70%). nonfatal snoke. There were no ditleflillCes in overall or Cilrdi:l'lascular mOltillIty and ~or bleeding ~pisudes.lindicatioo m aspirin therapy. due to platelet abnormalities • thrombotic complications: DVT.s II] and II~ were ~uc'd with treatment compared to placebo IRA 0.ry outmm. due to increased cell turnover • characteristic physical findings • plethora (ruddy complexion) of face (70%). ecchymoses. Clinical Features • those secondary to high red cell mass and hyperviscosity (see Polycythemia. ">!leclirlelyl.

. LUQ pain/fullness.Toronto Notes 2010 Myeloproliferative Neoplasms Hematology HJ7 Clinical Features • 3 clinical phases • chronic phase .v glOUp ip< O.. Spleen Size (ern] 3.mat"'o~.7%195% (. malaise.QOI'I. 2/3 AML) • large foci of blasts in bone marrow." ~nd Lowdose Cytaratrin.more aggressive course.: In telln$ gI d cytouenetic respenses. fever • secondary to splenic involvement • early satiety. respective~ ip<O. difficult to control • circulating blasts 10-19%.lillihood of prnglBssion !J..01 in the irn. WBe Investigations • high increase in WBC. 10.and rates of progressilllL Results:.211..inhibits proliferation and induces apoptosis by inhibiting tyrosine kinase activity in cells positive for bcr-abl • clinical success with imatinib (cytogenic remission) has resulted in fewer patients requiring bone marrow transplantation • dasatinib (tvrosine kinase and src "dual inhibitor") or nilotinib (selective bcr-abll inhibitor) for those who fail imatinib • interferon-alpha . based on lou r prognosti cfactors: 1. increased/decreased platelets. extramedullary blast proliferation • clinical presentation • 20-50% of patients are asymptomatic when diagnosed (incidental lab finding) • nonspecific symptoms • fatigue.reversion of bone marrow to Philadelphia-chromosome negatiVity • molecular .l cytllgenetic mspoose>.tiJih ~roop andl 34.virtually obsolete with advent of tyrosine kinase inhibitors • hydroxyurea (for initial stabilization if WBC counts >20) • bone marrow transplantation (curative) accelerated phase • Gleevec™ 600 mg PO daily blast crisis • Gleevec™ up to 800 rng PO daily stem cell transplantation may be curative .g.OGlI.Prognosls • survival dependent on response • those achieving complete cytogenetic response (CCR) on imatinib by 18 months of therapy . Patierm: r1 06 poOOi1tl. !oI:lw·up of 19 months.1. encephalopathy (rare) . lo~rebility.secondary to highly increased (rare) '"' '~ 9~------------------~ Detection of the bcr-ahl fusion gen" is a dis gn nstic test lor CML (present in over 90% 01 patients I.. IIll N-ewly . Aftar a madi . PUD . excessive sweating.phase dhrQllio m'l"'Didlruk~niia (eMU. with newl!r diognooed cltvnic.2% (95% CL 1Z. At 18 monlhs.impaired neutrophil differentiation. ConGiusinn. 2003.. reduced basophils • cytogenetic .to be considered in young patients who do not meet therapeutic milestones treatment success is monitored based on therapeutic milestones.disease process easily controlled (85% diagnosed here) • few blasts «5%) in peripheral film • slightly elevated eosinophils and basophile • no significant symptoms • accelerated phase . priapism. Age (Years I 2.kemi.. b.3 to 40.5 to 79. mild fibrosis • molecular and cytogenetic studies of bone marrow or peripheral blood for Philadelphia chromosome • abdominal imaging for spleen size (used in Sokal prognostic scoring system) Treatment • symptomatic • allopurinol • chronic phase • imatirub The Sobl SCOI~ is used to calculate prognosis in GML pati ems.5 tQ 18. II Eng! J MeIl..picture similar to AML • unresponsive to remission induction • 1/3 develop a picture similar to ALL • remission induction (return to chronic phase) achievable Imatillib Com~led with Inte~en.l to 90.6 year OS of 66% • acute phase (blast crisis .. blasts fail to differentiate • blasts >20% in peripheral blood or bone marrow • evolution to acute Leukemia (1/3 ALL. and: the li. Intervention: !Imatinib 1553 patientsl or interferonafa plus lo~.accelerated·phaSji qr tilast·crisis CMt imetinib Woo superior to interfBroo-a1fll pus bw·dD9J cytaTilbine as first·line theropv in new~ diagno.secondary to increased blood histamine • leukostasis. • hematologic ~ improved Wl3C and platelet counts. increased megakaryocyres.secondary to platelet dysfunction • pruritus.J ..348:994·1004 Study: Ran<iorrize:l.6 year OS >90% • those who did NOT achieve CCR on imatinib . with increasing peripheral basophils (pruritis) • worsening constitutional symptoms and splenomegaly (extramedullary hematopoiesis) • CBC: thrombocytopenia <100. WBC count unresponsive to therapy • cytogenetic evidence of clonal evolution • blast crisis .1% in the imatinib 'groop and 9l5%in the c~mbilatiolHher.O~11. mu~icenter tJi:l1.Di~gnosed Ct"oQio·I~ ia se Chro!lic Mv8l~id leu. The estimated m~ofwmplete q'tOgo'Onetic response were 76. % Myeloblasts in peripheral blood and antihistamines • • • • mesvlaie (Glee-uec™) . op<rn"labei.91 and 14'5%(95% CI.usually within 3-5 years) • 2/3 develop a. decreased/normal RBC.Imatirib was b~tter tolerete:l lbon wmbination therepy .Jose !l{tilrabine (553 patientsl. the estimated'rate of a mojor cytogenetic je~onse 10 to l5%m cells in m~hasB posililre for the Phihdelphia ctrrorrrmmeJ at 18 months was 87. Platelets 4. weight loss.reduction! absence of bcr-abl transcripts in periphery and marrow .{!(j chrolic·phase CMt.0) in the ~roup ~n inmlfarortillfil pkJs cytoTabine Ip < O. myelocytes and normoblasts) • presence of different mid-stage progenitor cells differentiates it from AML • bone marrow • myeloid hyperplasia with a left shift.5). the es1imatM rate of freedom from pmg~~i.1 % (9j%C1. Outcome: Potients were evoklated for !hematololjc all.on to ~Ie*phase or blast·qisis CMl was 96. truic effects. increased basophile • peripheral blood film • leukoervthroblastic picture (immature red cells and granulocytes present. M. e. shoulder lip pain (referred) • splenomegaly (most common physical finding) • anemia • bleeding .

hydroxyurea for splenomegaly. bone disease). increased uric acid (increased cell turnover).extramedullary hematopoiesis (hence hepatosplenomegaly) 0. erythropoietm= 30-50% of patients respond • danazol has shown transient response with response rates of <30% .. variable platelets.proliferation of megakaryocyte megakaryocytes • acquired JAK2 mutation stimulus (must rule out secondary lineage with enlarged. thrombocytosis.HJS Hematology Myeloproliferative Neoplasms Toronto Notes 2010 Idiopathic Myelofibrosis (IMF) Definition • excessive bone marrow fibrosis leading to bone marrow failure • characterized by anemia. Investigations • CBC: anemia. "I . increased LDH (2° to ineffective hematopoiesis). increased B12 (2° to increased neutrophil mass). and hepatosplenomegaly Epidemiology • rare.5 years • risk of transformation to AML (8-10%) Essential Thrombocythemia (ET) Definition • overproduction of platelets in absence of recognizable thrombocythemia) Epidemiology • increases with age..Positive Criteria and Criteria for Exclusion • Positive Criteria • sustained platelet count >600 x 109fL • bone marrow biopsy . IMF). thickening and distortion of the bony trabeculae (osteosclerosis) Treatment • allogeneic stem cell transplant is potentially curative • symptomatic treatment • transfusion for anemia •. symptomatic splenomegaly . leukoerythroblastosis.g. sol i d tumour metastases! or fibrosis {e. Clinical Features • anemia (severe fatigue is most common presenting complaint. F:M '" 2:1 but Fe. nucleated RBCs. extramedullary hematopoiesis. fever. variable polychromasia. may cause early satiety • hepatomegaly (70%) ~ may get portal hypertension • bone and joint pain ~ secondary to osteosclerosis. increased leukocyte alkaline phosphatase (LAP) • blood film: leukoerythroblastosis with teardrop-shaped RBCs. migration of precUJsors to other sites .5-5. median age at presentation is 65 Pathophysiology • abnormal myeloid precursor postulated to produce dysplastic megakaryocytes that secrete fibroblast growth factors stimulates fibroblasts and stroma to deposit collagen in marrow • increasing fibrosis causes early release of hematopoietic precursors to peripheral blood. pallor on exam in >60%) • weight loss. leuk~mias. mature . large platelets and megakaryocyte fragments • bone marrow aspirate: "dry tap" in as many as 50% of patients • bone marrow biopsy (essential for diagnosis): fibrosis. leukocytosis. the presence of teardrop-shaped red cells in peripheral blood.. variable WBC • biochemistry: increased ALP (liver involvement. gout • signs of extramedullary hematopoiesis (depends on organ involved) "I . ~~------------------~ 1MF is c haracterized by a dry B M aspirate and lear drop RSCs I"YDU ory trying to Q et sn aspirate"]. ~~------------------~ A "leu koerythrolJlastiC" blood Ii 1m I Be R and granulocyte precursorsjrnpl ias bone marrow infiltration with mal ignancy I s. night sweats ~ secondary to hyperrnetabolic state • splenomegaly (90%) ~ secondary to extramedullary hematopoiesis.q. atypical megakaryocytic hyperplasia. allopurinol Prognosis • median survival rOT patients with AMM is 3. systemic symptoms • alpha interferon (as second line therapy) • splenectomy (as third line therapy-associated with high mortality and morbidity) • XRT for symptomatic extramedullary hematopoiesis. leading to • leukoerythroblatrc blood film (primitive RBC and WBC present in blood) .-M at older age Diagnosis • WHO Criteria .

Infection lnfla rnrnation {IBD. heteroqeneou lower N: C ratio s. (age >80 or lifespan <10 years) • plateletpheresis -in emergencies • splenectomy not recommended (increased risk of bleeds. U va cuolated b lasts. . t~--------------------. L-aspariginase. fibrinogen.) Definition • malignant disease of the bone marrow in which early lymphoid precursors replace the norma! hematopoietic cells of the marrow • WHO subdivides ALL into two types depending on cell of origin • B cell ~ precursor B lymphoblastic leukemia • T cell ~ precursor T lymphoblastic leukemia proliferate and Clinical Features • see Acute Myeloid Leukemia. CML. also infections of oropharynx. found to induce complete remission in up to 95% cases - . methotrexate. D-dimers for DIC • leukemic Iymphoblasts lack specific m_o_ rpholog_kal (no granules) or cytochemical features. a bcr-abl tyrosine kinase inhibitor). arthritis I Malignancy Hsmorrhaqe Iro n deficien cy Clinical Features • often asymptomatic • vasomotor symptoms (40%) • headache (common).6-5%). H33 for full list of symptoms • distinguish ALL from AML based on Table 18 • 75% ALL occurs in children <6 years old. anemia. restore normal hematopoiesis) • e. Thera is an asvmptomatie "benign"' form 01 essential thrombocythemia with a stable or slowly ris ing platelet count treatment inclu d as observati on. induction . aPIT. LDH • PT. PO".tender bones. visual symptoms.anemia. hepatosplenomegaly.g. therefore diagnosis depends on lmmunophenotyplng • cytogenetics: Philadelphia (Ph) chromosome in -25% of adult ALL cases • CXR: patients with ALL may have a mediastinal mass • LP prior to systemic chemotherapy to assess for CNS involvement Treatment • eliminate abnormal clone 1. neutropenia (50% present with fever. MDS '. ASA. unno rm high :. megakaryocytic hyperplasia. splenomegaly • pregnancy complications.. Ca. lymphadenopathy. dusky colour.~------------------~ cation01 ALL L 1 blast cells small. thrombosis) or 3Zp Lymphoid Malignancies Acute Lymphoblastic Leukemia (ALL. IMF. ftiolo.Toronto Notes 2010 Myel opro Iifera Iive N eop lasllls/Lymphoid Malignancies "'"' Hematology H39 • Criteria for Exclusion • no evidence of r\l. caused by platelet activation ~ microvascular thrombosis) • thrombosis (arterial and venous) • bleeding (often GI. N IV. perianal region). giant megakaryocytes increased K. intrathecal methotrexate and ara-c • in Philadelphia chromosome-positive ALL.C N FAB CI a sslf ratio LZ hla st cells larg er. no bcr-abl fusion gene • no evidence of bone marrow collagen or reticulin fibrosis • no evidence of reactive thrombocytosis due to inflammation. associated with platelets >1000 x 109/L) • constitutional Sx. dizziness. Dana-Farber regimen . older or symptomatic • decreased platelets: hydroxyurea (1st line therapy). can add imatinib mesylate (GJeevec™. bas oph ilic cytoplasm (usually B ·ALL) Investigations • CBC: increased leukocytes >10 x 109/L (occurs in 50% of patients). t~--------------------. may have abnormal platelet aggregation studies bone marrow hypercellularity. anagrelide. especially in ALL relapse) "'"' . increased risk of spontaneous abortion • risk of transformation to AML (0. usually worse with heat. interferon-alpha. syncope • erythromelalgia (burning pain of hands and feet. neoplasm. lungs. second peak at a. or thrombocytopenia • may have increased uric acid..to induce complete remission (undetectable leukemic blasts. thrombocytopenia • organ infiltration . increased P04 (2° to release of platelet cytoplasmic contents) diagnosis: exclude other myeloproliferative disorders and reactive thrombocytosis Treatment • low dose aspirin if thrombotic event. Iencovorin.gy Se conda rv 01 Thrombocythemia infection.vincristine (Oncovin TM). myelofibrosis Hernolvti c anem ia Post sple nectornv Post chern oth erapV "'"' '.ge 40 • clinical symptoms usually secondary to • bone marrow failure . Investigations • • • • CBC: increased platelets. neutropenia. prednisone. K. prior splenectomy . meningeal signs (headache. sulflnpyrazone or dipyridamole.

Differentiate AMl From ALL t.• Stage II • involvement of two or more lymph node regions or an extralymphatic site and one Hodgkin's is distinguished Irom or more lymph node regions on same side of diaphragm non. No routi ne eNS prophjiaxi sin AML 2. but grade I histology is more important for non-Hodgkin's lymphoma because it tends to present at more advanced stages Staging (Ann Arbor Staging System) • Stage I • involvement of a single lymph node region or extra lymphatic organ or site "'. 2 activati on Philadelphia ci1romlJsome locr -<lbl hybri Overexpression protei n eyel in Dl follicular lymphoma CML. AM L • D.potentially curative (due to pre-implant myeloablative chemoradiation and post-implant graft-versus-leukemia effect) but relapse rates 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 109/L. Su dan black sta in Maturation delect. T-cell phenotype.18) 1(9. All ill ad uks 125% of the time I Ma nile ceU lymphoma . early attainment of complete remission • achievement of first remission: 60-90% • childhood ALL: 80% long tern] remission (>5 years) ~ higher cure rates in children because of better chemotherapy tolerance.H40 Hematology Lymphoid Malignancies/Lymphomas Toronto Notes 2010 .Hodgkin's lymphoma by the • Stage Ill presence 01 Heed-Sternbe rg ce lis. Dot 01 All vs.j' To Differentiate AML From ALL: Remember Big and SmALL [see Table 181 AML Big people (adults) Big blasts ALL Small people (kids) Small blasts lots 01 cytoplasm lots 01 nucleol i (3"5) Lots 01 granulesnd Auer ro ds a Big toxicity 01 treatment Big mortal ity rate Less cytoplasm Few nucleoli (1·3) No granules Uttl e toxic ity 01 treatment Small mo rtality rate Myeloperoxidase. ~ I ~~------------------~ Treat". extranodal disease. and constitutional symptoms • Ann Arbor staging can be used for both Hodgkin's and non-Hodgkin's lymphoma. leading to lymphadenopathy.~------------------~.22) 1(11.Chromosome Trallslocation t(8.14) Translocations Associated Neoplasm Burkitt's lymphoma d) Gene Activation c"mye activation bel.beyond myeloblast or promyelocyte PAS (peri odic acid schiff) Maturation defect beyond lympho blast Lymphomas Definition • collection of lymphoid malignancies in which malignant lymphocytes accumulate at lymph nodes and lymphoid tissues. No proven be neli! 01 maintenance ch emotherapy inA M L 2.' diffuse involvement of one or more extralymphatic organs including bone marrow • subtypes: • A = absence of B symptoms • B = presence of 13 symptoms • unexplained fever >38oC • unexplained weight loss (>10% of body weight in 6 months) • night sweats Table '19·.~ I .. lower prevalence of bcr-abl fusion gene (associated with chemotherapeutic resistance) • adult ALL 30-40% 5·year survival Table 18. absence of Ph chromosome. mayor may not be accompanied by single extra lymphatic site or splenic involvement • Stage rv .. consolidation and/or intensification chemotherapy • consolidation . prophylaxis: CNS with radiation therapy or methotrexate (intrathecal or systemic) • hematopoietic stem cell transplantation ..ifferences 1. maintenance chemotherapy -low dose intermittent chemotherapy over prolonged period (2-3 years) to prevent relapse 4.high doses of different (non-cross-reactive) chemotherapy drugs to eliminate cells with resistance to primary treatment 3. • involvement of lymph node regions on both sides of the diaphragm.continuing same chemotherapy to eliminate further subclinical leukemic cells • intensification .14) 1(14.

procarbazine. decreased in advanced disease biochemistry • LFTs (liver involvement) • RFTs (prior to initiating chemotherapy) • ALP. rarely hemolytic). CVA) • PFTs . may be symptomatic (cough) • rarely may present with SVC syndrome. BEACOPP).om from progres. which causes interstitial pneumonitis infertility . stage III or IV. CHI'. vin blasti n e.' ~}-------------------. vin cri stne. lymphocytopenia (lymphocytes <0. resistant to therapy: high dose chemotherapy. bulky disease or cytopenia) <0' Treatment • stage I-II:. mediastinal mass). pruritus • non-specific / paraneoplasti c •. Ca (bone involvement) • ESR.ioo at 5 ~eo~.06 x 109 /L or <8% of WBC count or both) • prognostic score • each additional adverse prognostic factor decreases freedom from progression 5 years o 1 2 3 451% 5·7 42% FA' = heed. usually within 8 years) • solid tumours of lung. during treatment -. platelets normal or increased early. Investigations • CBC • • • • • anemia (chronic disease. age <AS years 6.. PUD. or echocardiography for EF) for patients at high risk of pre-treatment cardiac disease (age >60. CT chest (lymph nodes.Toronto Notes 2010 Lymphomas Hematology H41 Hodgkin's Lymphoma Definition • malignant proliferation of lymphoid genninal center B-cells) cells with Reed-Sternberg cells (thought to arise from Epidemiology • bimodal distribution with peaks at the age of 20 years and >50 years • association with Epstein-Barr virus in up to 50% of cases Clinical Features • asymptomatic lymphadenopathy (70%) • non-tender. CT abdomen/ pelvis (liver or spleen involvement). ncntende r. ble ornvci n. • cardiac function assessment ~ (MUGA. smoking. LDI-I (monitor disease progression) imaging • CXR. dacarbazin e BEACO PP = blec myc in. prednisone VAD '" yin crisiine. bone marrow transplant CHOP '" eye Iophospha m ide.5 x 1O~/L) 7. . firm.secondary to bleomycin.post splenectomy (give Pneumovax. rubbery en largem en! of supertiicaf fymph n odes. dexamethasone A BV 0 '" adriemvcin. leukocytosis (WEe >1. AML (secondary to treatment. adriamycin. spreads first to adjacent nodes • disease progresses in contiguity with lymphatic system ~~------------------~ H odgki n's Lym phorna classically presents as a pain less. HiB. breast. nephrotic syndrome • starts at a single site in lymphatic system (node). rubbery consistency • cervical/supraclavicular (60-80%). axillary (10-20%). adriamycin is cardiotoxic pulmonary disease . stage IV disease 5. alcohol-induced pain in nodes.recommend sperm banking secondary malignancy in irradiated field • <2% risk of MDS.if history of lung disease (COPD. pleural effusion • systemic symptoms • B symptoms (especially in widespread disease. eosinophilia. CAD. at . previous radiation to lung) excisional lymph node biopsy confirms diagnosis bone marrow biopsy to assess marrow infiltration (only necessary if B symptoms.actDrs Factors FFP 84% 77% 67% 60% Prognosis • adverse prognostic factors: 1.secondary to XRT. most often in the cerv ical region.. male 4. l"ternationalPrognostic Proi ect IS 98 Prognnsticf. serum albumin <4 gil (4 gm/dL) 2. chemotherapy (ABVD) followed by involved field XRT • stage Ill-IV: chemotherapy (ABVD. etoposide. fever in 30%). vincristine {Oncovini. history of hypertension.5 gmt dL) 3. with XRT for bulky disease • relapse. hemoglobin <105 gil (10. hvdroxvdox orub icin IAdriamyc in I. MI. >10 years after treatment • non-Hodgkin's lymphoma • hypothyroidism . and prednisone Complications • • • • of Treatment cardiac disease . and pneumococcal conjugate vaccines). cyclophosphamide. gallium scan (assess treatment response). leukocytosis. inguinal (6-12%) • splenomegaly (50%) ± hepatomegaly • mediastinal mass • found on routine CXR. adriamyc in.post XRT • infection .

plus rituxirnab jf B-celllymphoma • radiation for localized /bulky disease • CNS prophylaxis with high-dose methotrexate (intrathecal or systemic) if certain sites involved • relapse. mantle cell lymphoma •. anaplastic large cell lymphoma • WHO/REAL classification system .s 01 CHOp·lib chetrHltheraw . liand(llllired controlled trial with a medi. lollol'MlJl 01 :l4 months.goal of treatment is curative • combination chemotherapy: CHOP is mainstay. n -413) or. BtvIT • highly aggressive lymphoma • Burkitt's Lymphoma.g_ Burkitt's lymphoma. Autoimmune diseasesle. brain. Immu nodef c iency (e _g.g_ follicular lymphoma.g. proJes'Jion under ther. aggressive (-50% of NHL) . and leukoerythroblastic anemia • peripheral blood film sometimes shows lymphoma cells • biochemistry • increase in uric acid .ivol. bone. ResuHi: Patients leceiving CCR :had anincrmed 3-ye<18\11lm-free suro~al rompared willi the CLC groop [J9% ~ 59%.. cycl.tor.l)1/erel ~r. ploJeSSion-free ~r..g GI.etOncm lOOil.s RttUJdmab versus £HOP-likB ChBmDlhomlpv Aions in F\l~onts willi Diffu. NHL: Associalc~ Conditions 1. retroperitoneal and mesenteric involvement (2nd most common site of involvement) • oropharyngeal involvement in 5-10% with sore throat and obstructive apnea • extranodal involvement . EBVI CHOI'-lll<eChemotherapv Plu.e. P". kidney • CNS involvement in 1% (often with HIV) Investigations • CBC . '~}---------------------.q. usually >1 lymph region • usually presents as widespread disease • constitutional symptoms (fever.(15%) cells •..e. poor prognostic factor) • CXR and CT for thoracic involvement • cr for abdominal and pelvic involvement • gallium scan is useful for monitoring response to treatment and evaluation of residual tumour following therapy • diagnosed by • lymph node biopsy • fine needle aspiration occasionally sufficient..ry outwmas indudOO: response. autoimmune hemolvtic anemia .lllY. P <0_0001) and ill irn.s!i large-B-ceillymphDm~ IMl.nTl Iam.e.H42 Hematology Lymphomas Toronto Notes 2010 Non-Hodgkin's Lymphoma (NHL) Definition • malignant proliferation of lymphoid cells without Reed-Sternberg cells Classification • multiple classification systems exist at present and may be used at different centres • can originate from both B. B cell NHL . hepatosplenomegaly •. H IVI 2..most commonly GI tract. indolent (35-40% of NHL) ..gooi-j.. P'rticipants: au P'Dents WITh. increased LDH (rapidly progressing disease.dilfusel''lI'I-B-wIl~mphQma Iraatmeut of HLdepends on staqe.00 extranodal sites :received OOditional: rad"lIltheraP\'. Frequency of adV'lfse e\l1lnts did not differ belwwn groups. [ntlll'e!lti(lO: Patients receNed eIThe< 6 cycles 01 CHOf'. T cell NHL . excisional biopsy preferred • bone marrow biopsy Treatment • localized disease (e.goal of treatment is symptom management • watchful waiting • radiation therapy for localized disease • chemotherapy (single agent.OOOll. weight loss. SLI"I 3_ Infe ctions I e.(85%) and T.Iogn'lSis diffuse 'Iinge-8-celljrmphoma' who ha:l no OJ on~ one' risk flIi. mantle cell lymphoma. bone. ~ short bursts of intensive chemotherapy • "CODOX-M" chemotherapy regimen also often used ± IVAC • CNS prophylaxis and tumour lysis syndrome prophylaxis ." =4111. abnormal LFTs in liver metastases •.or NK.Je 1 disease willi bulk 18ge: 18 to .3 categories of NHLs based on natural history •.Ione [GLC.nd frequency 01 trrxic elIl!d$. sl. . £oncil!Sion: RitwimaIJ OOded'to si' qrcles of CHOP is ill effecthre treiltnmnt far young patients wITh gooi-prognl)Sis .e_g Burkitt's lymphoma Clinical Features • painless superficial lymphadenopathy..i"'l . all anti-CD20 antibody) • aggressive lymphoma .reased: 3VBar01/!r. BUltv . also testes.@yea!'!l. Prim illY Outccm~: Ewnt·ftee. normocytic normochromic anemia •. combination or ntuximab/Rituxan!". head and neck) • surgery (if applicable) • radiotherapy to primary site and adjacent nodal areas • adjuvant chemo-therapy • indolent lymphoma . small lymphocytic Iymphoma/CLL.1 sUlviVall!l3%¥s 84%. neutropenia.g_ diffuse large B-celllymphoma • highly aggressive (-5% of NHL) ..e. night sweats) not as common as in Hodgkin's disease • cytopenia: anemia ± neutropenia ± thrombocytopenia if bone marrow fails • abdominal signs .g_ mycosis tungoides. follicular lymphoma .O.urvivaL Second.l319-91 Studv. advanced disease: thrombocytopenia.like chemolhBlaP\' and ditu~mab [eeR. ~~------------------~ . resistant to therapy: high dose chemotherapy. treatment of N HL depends on h istobg ic subtype.o:Je 11-1\1 dioo'ire or sla.

EBV·asso dated 2. BeI-6. 5()'!f.Hoe B-Cell Burkitt's Lymphoma <1% adult NHLs 30% ell ildhood NHLs c-myc activation Very aggress iva Manlle Cell lymphoma 5% Overexpression of cyclin 01 (Bel· 1 activation) Indolent Male (malefemale = 4:1) BcI·2..see H47 Prognosis • poor • • • • • • prognostic factors >60 years old poor response to therapy multiple nodal regions elevated LDH nodes >5 em previous history of low-grade disease or AIDS Table 20. n not artifact. de notes hvp erglobuli nemi".African origin. S po Tildic . Characteristics of B-Cell Mali!lnant Proliferation eLL Ma croglobulinemia Plasmacytoid IgM Common Common Myeloma Plasma cell IgG.no EBV 3.Toronlo Noles 2010 Com plications • • • • • lymphomas/Malignanl Oonal Proliferatinns of B Cells Hematology H43 hypersplenism infection autoimmune hemolytic anemia and thrombocytopenia vascular obstruction (from enlarged nodes) tumour lysis syndrome (particularly in very aggressive lymphoma) . 0 orE Rare Rare Common Common Common Rare '"'. 5-year survival 25% Malignant Clonal Proliferations of B Cells Table 21. massive jaw LAD with pal pable LAD • "Stany·sky" hi stology • Invotvem em 01 Gf tract • High risk of Tumour Lvsis (lymphomatosis polyposis). . Characteristics (If Selected Non-Hod!lkin's Lymphomas FolliC1llar Lymphoma Lymphoma (DlBCL) Diffuse 33% Genetic MutationS Classification Risk Factors c]':2 activation Indolent Middle-ag e . Syndrome upon treatmem Waldeye(s Ring • Extremely aggressive. widely disseminated cu 1 Endemic .I Bare Infrequent Roulea ux formatien smea r. MYC rsa rrange1nems Aggressive (high-grade) Previous (Richter's transi: 5% eLL pati ents progress to 0 LBC l) • Rapidly progressive LAO and extran odal inhl ~ratio n • 50% presem at stage till.elderly I. HIV·related AIDS ·delinin g illness Clinical Features • Widespread painless LAO' ± bone marrow involvement • FrequenllJansformation to aggressive lymphoma • Very [ESP onsive to chemoTild iation tx • Endemic fa rm • Often preseots Stage IV. A. Cell type PlOtein Lymph nodes Hepatosplenomegaly Bone lesions Hypercalcemia Renal fa ilurll Immu noglobulin Complications Lymphocyte IgMif p resent Very common Common Hare Hare Hare Common Bare Rare *~------------------~ on periphera I brood .

immune thrombocytopenia purpura (ITP).autoimmune hemolytic anemia (Coombs +).) Definition • indolent disease characterized by clonal malignancy of mature B-cells Epidemiology • most common leukemia in Western world • mainly older patient. immune deficiency (hypogammaglobulinemia.ith aggressive disease usually associated with chromosomal abnormalities (e. median age 65 years • M>F Pathophysiology • accumulation of neoplastic lymphocytes in blood.d of: unintentional weight loss . 19M 0. asymptomatic • intermittent chlorambucil or fludarabine • corticosteroids.u weeks without evidence of infection. Investigations • CBC: absolute lymphocytosis >5 x 109fL • peripheral blood film • lymphocytes are small and mature • smudge cells • flow cytometry • cytogenetics .5% . lVlG . bone marrow. extreme fatigue) • lymphadenopathy (50-90%). with slow progression. 19A 20%.especially for autoimmune phenomena • radiotherapy • chemotherapy . although biclonal myeloma has been reported Epidemiology • incidence 3 per 100. secondary to marrow involvement by CLL cells Q Smud ge cells ars artifacts of da rnaqed lymph ocvtes from slid B prepsration.000 • increased frequency with age. interstitial (30%).autoimmune hemolytic anemia. fevers >38 C or night sweats for.<:10%of bod y weight within previous 6 months..induding Ritxuimab (anti-C020 mAb) • small minority p. stable. but varies greatly Com pllcatlons • bone marrow failure • immune complications .H44 Hematology Malignant Oona! Proliferatinns B Cells Toronto Notes 2010 Chronic lymphocytic leukemia (Cll. immune thrombocytopenia (ITP). hepatomegaly (15-25%) • immune dysregulation .g.FlSH • bone marrow aspirate • lymphocytes >30% of all nucleated cells • infiltration of marrow by lymphocytes in 3 patterns: nodular diffuse (35%. splenomegaly (25-55%).aggreSSive transformation to Diffuse Large 8-Cell Lymphoma Multiple Myeloma (MM) Definition • characterized by neoplastic proliferation of a clone of plasma cells producing a monoclonal immunoglobulin • usually single clone of plasma cells. esent w. Natural History and Treatment • natural history . p53 deletion) • 9 year median survival. median their 20's and 30's) age of diagnosis is 68 (have had younger patients in Pathophysiology • malignant plasma cells secrete monoclonal antibody • 95% produce M protein (a monoclonal Ig = identical heavy chain + identical light chain) • 19G 50%.!.indolent but incurable. • bone marrow failure . or mixed (25%) (10%). thus select gentlest treatment that will control SylnptOIT1S • observation if early. 19D 2%. impaired T-cell function) • polyclonal or monoclonal gammopathy (often IgM) • hyperuricemia with treatment • 5% undergo Richter's Transformation . hypogammaglobulinemia ± neutropenia.late. lymph nodes and spleen Clinical Features • 25% asymptomatic (incidental finding) • 5-10% present with B symptoms (. worse prognosis).

SuT'lJiwlwa:.Ii1.1 ~~--------------------.69. pain. stroke.pain (usually back). spine. Coru:lU. rn!)nths ""lra 312 113.6iIot T!. _ived 'eithJr melphalan pkls p~ni!one (M I': ""'1961. .riy i'ollenll. n'" 1251. improvement in quality of life (improve anemia.59. ribs) • increased bone resorption secondary to osteoclast activating factors such as PTHrP • anemia . A outi ne urinelvs is wi II not detect light chains as dipstick detects albu m in. confusion. purplish colour • hyperviscosity .B·54.II. in 80% . Bone rna rrow > 30% plasma cells 2. Treatment: • treatment is non curative • treatment goals are '. Need suHosalicylic acid or 24 hour urine protein. P"'O. such as: • increased serum Ca • lytic bone lesions • anemia • renal fa ilure 10.lnls: <WJ previously untreated patienll.. MP p~s thalidomide (MPT.nth a media" follow up of 51. leukopenia • rouleaux formation on peripheral film • biochemistry • increased Ca. paresthesias • radiculopathy caused by vertebral fracture. Lytic bon e Iesi ens 4.demonstrates monoclonal protein spike in serum. extramedullary plasmacytoma • spinal cord compression (in 10-20% of pts) is a medical emergency Renal failure Anemia Bony lesions (lytic or osteoporosis 10 becaused by myeloma 1 felt ".61 for MEL 1011.~ . IntervwltiOll:Potient. ". 51:6 months i26. also identifies light chains • bone marrow biopsy • often focal abnormality. sigmntiy higher with the MPf thempythan MP IHR 0. Primary Outcome: SlJrvivalliIte Results: Median SUIl/~alrate. or a plasmacytoma 3_presence of end-organ damage related to plasma cell dyscrasia.1: months. pathologic fractures • lytic lesions are classical (skull.81 fOT M P.may manifest as headaches. orl i ght chain excretl 0 n 1 Minor Criteria 1_ Bone rna rrow plasmacytosis 1 0-30% 2. proteinuria (24 hour urine collection) • monoclonal proteins • serum protein electrophoresis (SPEPl .lambda ratio) • urine as Bence-jones Protein • <5% are non-secretors ~~--------------------. bony pains.igations • CBC • normocytic anemia. serum or urinary monoclonal protein 2.iIln: Thillid'ffmid . prednisone and bortezomib if 65-75 yrs . angina.tem wll trallliP~ntetion using fTIil~haloo 100 rTl'im' (MEL 100. and J. MRI if symptoms of cord compression • presence of lytic lesions and areas at risk of pathologic fracture • bone scans are not useful since they detect osteoblast activity • beta-2 rnicroglobulin.anspl. proximal long bones. with II1JltiplBIIl'(llloma (age 65 to 75 years). NP32) • bleeding • secondary to thrombocytopenia.demonstrates light chains in urine = Bence-lones Protein (20% only secrete light chains) • immunofixation shows M protein and identifies Ig type.Toronto Notes 2010 Malignant Donal Proliferations B Cell.us Melpfr.1 ~~--------------------.OO061 orMEL100 Diagnosis • International Myeloma working group criteria 1.fldomidB ~en. IgA. f'rticip. IWHOI 1.weakness. constipation.chlrll for MPT. may see petechiae. purpura • extramedullary plasmacytoma • soft tissue mass composed of monoclonal plasma cells. increased Cr. LDH and CRP are poor prognosticators Melphalah and Prednj. Manocional protein less than major criteria levels 3.0271. polyuria.. increased ESR. pallor • secondary to bone marrow suppression • weight loss • infecti 0 ns • usually S" pneumoniae and Gram-negatives • secondary to suppression of normal plasma cell function • hypercalcemia . ". prevent progression of disease and complications of disease) • increase in overall survival • autologous stem cell transplant if <70 year old • usually preceded by 4-6 months of tumour reducing therapy utilizing a regimen that includes steroids (prednisone or dexamethasone) • chemotherapy if >70 years old or transplant-ineligible • consier melpha Ian and prednisone alone if >75 yrs • melphalan. greater than 10% plasma cells. Oi a gnlNiis of M M: Major Criteria.e. bony tenderness. Reduced non-donal Ig lovels Invest. thrombocytopenia. M protein • urine protein electrophoresis (UPEP) . Plasmacvtorna on tissue biopsy 3_ Hi9h pareprutains (elevated serum I9 G. presence of donal plasma cells in bone marrow. P =0.muscle weakness. with MuI1iple Mye!liI1lil liJllCer 2001.N! V.i. abnormal morphology. Multipll) yeloma M CRAB Increased Ca lclum Clinical Features and Complications • bone disease .tla" a"d Redilced-intensitv Autpio i"'" Stem Cd T. polydipsia • secondary to increased bone turnover • renal disease/renal failure • most frequently causes cast nephropathy (see Nephrology. fatigue. or ~uced-intens!ty .3 months i13JJ.1 Hematology H45 • 15-20% produce only light chains.mn~ :t Ih.ntatWn in Bd. found in either: • serum as an increase in the quantity of ei ther kappa or lambda light chain (with an abnormal kappa.37G:1 209·18 Study: Rond'omillld: control trial. reverse renal failure.~ . n '" 1 ~61. MI • secondary to increased viscosity caused by M (monoclonal) protein • amyloidosis • accumulation of insoluble fibrillar protein (Ig light chain) in tissues • may cause Factor X deficiency if fibrils bind Factor X -7 bleeding • neurologic disease . clonal plasma cells • skeletal series (x-rays).• in cnmbinatioolWh m~halan ond prednirone is more effici!cioos for pteliouslV unneated eldl!i~ patien~ with II1Jltiple myeloma. prednisone and thalidomide or melphalan.

albumin. bortezomib if ARF • supportive management with • bisphosphonates for those with osteoporosis or lytic bone lesions • local XRT for bone pain. CHF (triad of anemia. Prognosis • median survival based on stage.Reynaud's phenomenon. hyperviscosity.H46 Hematology Malignant Clonal Proliferations B Cells Toronlo Notes 2010 • dexamethasone ± thalidomide. Significance (MGUS) Definition • presence of M protein in serum in absence of a. hepatomegaly. 5% of people >70 years of age • asymptomatic Diagnosis • presence of a serum monoclonal protein (M-protein) at a concentration <30 giL • <I 0% plasma cells in bone marrow • absence of hyperCalcemia. Anemia. high ESR if hyperviscosity not present anemia .of hyperlliscosity syndrome" Definition • proliferation of lymphoplasmacytoid cells (a hybrid of lymphocytes • secrete large quantities of monoclonal IgM paraprotein Clinical Features • chronic disorder of elderly patients.3-1% of patients develop a hematologic malignancy each year • patients with M protein peak :?:15giL. serum protein electrophoresis (considered pre-malignant) Waldenstrom's Macroglobulinemia and plasma cells) . recurrent infections.. ~. rouleaux. pamidronate) for severe hypercalcemia. hemolytic precipitated by cold weather • normocytic anemia. usually 16-70 months Light Chain Disease • malignant clonal plasma cells producing only light chains • 15% of patients with myeloma • diagnosis . spinal cord compression • kyphoplasty I vertebroplasty for vertebral fractures to improve pain relief and regain height (kyphoplasty) • treat complications: hydration for hypercalcemia and renal failure. neurological symptoms.rarely see hypercalcemia • cold hemagglutinin disease possible . splenomegaly. patient's comorbidities and preference. plasma volume expansion). erythropoietin for anemia • all patients will relapse.ammopathy of Unknown. physical. weight loss. bleeding (oronasal). peripheral neuropathy. Calcium. CBC.-------------------~ Wo Idenstrom's Ma croglobu lin ernia accounts for 85% of aU cases .. serum free light chains • urine immunoelectrophoresis • serum protein electrophoresis often non-diagnostic as light chains can pass through glomerulus • may be suggestive of light chain disease if there is a flattening of gamma region suggesting hypogammaglobulinemia • renal failure is a major problem • prognosis for survival: kappa> lambda Light chains Monoclonal G..ny clinical or laboratory evidence of a plasma ceil dyscrasia or lymphoproliferative disorders • incidence: 0.15% in general population. median age 64 • symptoms: weakness. dyspnea. lymphadenopathy. retinal lesions • key complication to avoid: HYferviscosity Syndrome (see H47) • because 19M (unlike TgG confined largely to intravascular space Investigations & Diagnosis • bone marrow shows plasmacytoid lymphocytes • bone lesions usually not present • blood work . and Renal insufficiency. OJ: patients with IgA or 19M MCUS are at higher risk of malignant transformation • patients with a normal free light chain ratio are at low risk • monitor with annual history. Bony disease related to the plasma cell proliferative process (absence of '·CRAB") • 0. Cr. organ involvement. bisphosphonates (e. ~ . fatigue. prophylactic antibiotics.g. cerebral dysfunction • signs: pallor. choice of retreatment regimen depends on duration of remission.

Complications of Hematologic Hyperviscosity Syndrome Malignancies Definition • refers to clinical sequelae of increased blood viscosity (when relative serum viscosity >5-6). rituximab. ataxia. absorption of soluble coagulation factors.g. oozing gums • ESR usually very low Treatment • plasmapheresis Tumour Lysis Syndrome Definition • group of metabolic complications that result from spontaneous or treatment-related breakdown of cancer cells • more common in diseases with large tumour burden and high proliferative rate (high grade lymphoma. e. dilutional anemia CNS symptoms due to decreased cerebral blood flow: headache.• aggressive IV hydration • alkalinization of the urine • allopurinol • correction of pre-existing metabolic • dialysis uric add. increased PO. blood products are te ukcdepleted via filtration immed iately after donar' on. "m~B Ami·B Anti·A Nil H A B A and B Blood Products and Transfusions Blood Products • RBCs. releasing K uric acid. nasal bleeding.P is thawed at low temperatures A B AS In Canada. lethargy. vertigo.Toronto Notes 2010 Complications of Hematologic MalignancresIBlood Products and Transfusions Hematology H47 Management • alkylating agents (chlorambucil). factor concentrates) are available for transfusion • donated blood (1 U '" 450-500 mL) is fractionated into these various components • centrifugation separates whole blood into RBCs and platelet-rich plasma • platelet rich plasma is further fractionated into platelets and plasma • need to pool together multiple units to obtain therapeutic amounts • FFP is plasma frozen within 8 hours of collection • cryoprecipitate is the high MW precipitate generated when FF. PO. or combination therapy • corticosteroi ds • plasmapheresis for hyperviscosity .acute reduction in serum IgM thalidomide. cryoprecipitate. headache. leukemia) Clinical Features • metabolic abnormalities • cells lyse.) abnormalities Blood Gmups Gmup 0 Amigen Anlib(Htv Ami-A. platelets and coagulation factors (fresh frozen plasma. resulting from increased circulating serum Igs or from increased cellular blood components in hyperproliferative disorders • Waldenstrom's macroglobulinemia accounts for 85% of cases Clinical • • • • Features hypervolemia causing: CHF. nucleoside analogues (f1udarabine). resulting 'in a lower incidence of febrile nonhemolytic transfusion reactions • CM \I n~gative (because C MV lou nd in leukocytesl . increased • P04 binds Ca (decreased Cal • complications • lethal cardiac arrhythmia (increased K) • acute renal failure (urate nephropathy) Treatment • prevention . (increased K. The rsfore it is consi d ered: • Low in l)yrnphokine s. stroke retina shows venous engorgement and hemorrhages bleeding diathesis • due to impaired platelet function.

W did net diflere ill a subgroup with clinic..:l4a:4fj9' 11 StudV: Muttioontre.l~ s~~ific.a"" ConclusioD: A RSaf md·ccll tr.5 years of age 15. • if an increase in the platelet count is not seen post-transfusion. otherwise cell lysis may result in hyperkalemia • transfuse within 7 days of collection if renal failure or hepatic failure is present to reduce solute load • infuse each unit over 2 hours.n R"~uimmonts in Critic.ute'r ill patients 18. max of 4 hours • Hb <70 gil (7g/ dL) • maintain Hb between 70 and 100 gil durinG: active bleeds (7g/ dL to 109/ dL) • consider maintaining a higher Hb for patients with • CAD/unstable coronary syndromes • uncontrolled. P"0.011. alloantibodies. ~~------------------~Packed Red Blood Cells • stored at 4"C • transfuse within 35 days of collection. the following should be ordered: • group and screen • determines the blood group and Rh status of the recipient as well as the presence cf autoantibodies vs.031 and . unpredictable bleeding ~ impaired pulmonary function • increased O2 consumption Transfusi.]% RS and 1 J% 1. used for immunocompromised patients • CMV~negative blood products • potential transplant recipients • neonates • AIDS patients • seronegative pregnant women Toronlo Noles 2010 or actual BMT recipients Red Blood Cells '"I / 1 unit of pRBe will" pproxrnate Iy increase H h by 10 giL of incraas ~ He! by 4%.blood for fertile females. triit Partitipants: 838 critic. Indications for pRBC Transfusion Frozen Red Blood Cells • used (or recipients with rare blood groups OJ: multiple auto-antibodies Selection of Red Cells for Transfusion • when a need for RBC transfusion is anticipated. di". Indications for Plawillt Transfusion Pit (K 10"11) Indications NOfl-im < 10 < 20 < 50 < 100 Any rruna thrombocytopenia Procedures not associated with Procedures associated Pre-neUTosurge ry or head trauma s iQn~ica nt b'lood loss with blood loss or major surgery (> 500 mL EBlJ Platelet dysiu retion and marked oleeding . major 1minor blood group antigens • crossmatch • involves mixing the recipient's blood with potential donor blood and looking for clotting • takes 30-45 min • when blood is required.possibl\r superi(J to .A matched platelets Indication Thrombocytopenia with bleeding.£.2.: Mmlliity rates at .andom donor Ipooled) SinQle donor platelets H l. l%in 1.msfused IT h8moglobin was Ie~ lh. 'n=4181 in which rod rel~ Wlife'tr. Platelet Products Product R.H48 Hematology Blood Products and Transfusions Specialized Products • irradiated blood products "' prevent proliferation of donor T-cells in potential . fully crossmatched blood (not always available in emergency situations) • 2nd line: donor blood of the same group and same Rh status as the recipient • 3rd line: 0.. several options are available • 1st line. Int"l'ilmion: Patient> receilring a \ransrosioo followed either II) a rnslrictil'll stliltO(Jl' IRS. sepsis or hypersplenism may be present Table 23. 0+ blood for all others Platelets Table 2.£ group.1.ndomil:ed: control.. roortilrty rates were signilirimt/y IOIWr with the RS among klss . r.0 gldland then m..2 hours lit ICU OOm~sioo.imain~d 8110 10 1'1 WdL Prim."! Oumom~:M()rtlitv at :Jil dal'S and oorerityol' wglll dysfunctiOlL R!lS1lh.n! Gardial.ro davs were simib b8lwoon group" HoweveI.I'r iIT palient5 whh ell'lolemia after initial treatment and hemoglobin ess than 9 glCl within 7. loss than .".£ 111lnsrosioo it critic<ljr il patients. . bleeding. this should increase the platelet count by at least 15 x lO"/L • single donor platelets (transfused as single units) should increase the platelet count by 40-60 x H1' /t .OWdl and then maintllined at J to 9 !lidL) 1I iii a iberalstrategy ILS: n" 420) in which transfusions oo::urrnd when the hern:lglobin was ess than 10. Transfusion strate~ io patients wlth OWIe myOC<ldial infarction and unsl<illeangina nood hmhsr study. p= 0.lnsfuslan is at least as effec~ve as and . Poterrtial BMT recipiellts Refractory to pooled or single donor platelets • stored at 20-24°C • random donor platelets are transfused in groups of 5 twits.7% and RS grwp and 16.n J .leam (TRICCI N Eng! J MeG 1999.mng tho".

give antipyretics and anti-histamine '. give IV diphenydramine. hemoglobinuria acute renal failure «24 hIS) and DIe treatment • stop transfusion • notify blood bank and check for clerical error • maiI{tain BP with vigorous IV fluids ± inotropes • maintain urine output with diuretics. crystalloids. epinephrine. VIII.LI. HIT. severe trauma.Indication Depletion of multiple coagulation factorsle. hypotension. HELLP Blood Products and 'Itansfusions Hematology H49 Coagulation Product fresh Fmzen Plasma (FFPi Cryoprec ipitate Ienriched Ii brinogen. vWF. post-transfusion purpura. Factor VIII inl1iMars Acute Blood Transfusion IMMUNE Reactions Acute Hemolytic Transfusion Heactions (AHTH) • • • • • • • ABO incompatibility resulting in intravascular hemolysis secondary to complement activation most commonly due to incorrect patient identification occurs immediately after transfusion risk per unit of blood is <1 ill 250... . hypotension • treatment • rule out fever due to hemolytic reaction or infection • if fever <38°C.000 presents with fever. myalgia. stop transfusion.. TIP/HUS. dopamine . headache. }------------. platelets or other donor plasma antigens and release of cytokines from blood product cells • occurs within 0-6 hours of transfusion • risk per unit of blood is 1 in 100 • presents with fever ± rigors. acute onset of pulmonary insufficiency • profound hypoxemia (Pa02/Fi02 <300 mmHg) • bilateral pulmonary edema on CXR • pulmonary artery wedge pressure <18 mmHg • no clinical evidence of left atrial hypertension . IV fluids and brouchcdilators Transfusion-Helated Acute Lung Injury (THAll) • new-onset acute lung injury that occurs during transfusion or within 6 hours of the completion of transfusion • insidious.1 • Aller9Y Ibroncno1. chills. Coagulation Factor Products .!l. DDx &f Post:Transfusioh Fever: • Acule hernol yti c Iran sfu sion reacti 0 11 • Feb rile no n-hemolvtic Iran stuslon raaction • Bacteria I co ntamin ali 0 n • Allergy DDx of Post-Transfusion Dyspnea: • C Ircul~to ry overload • frensfuslon-related acute lung injury ITR. back or flank pain. CNS bl eed 5. sepsis. [}IC. emergency reversal of Iffe threateni ng bleed ing secondarv to warfarin overdose Factor VIII deliciency von Wmebrand's disease Hypofihrino genemia von Wiflebrand' 5 disease Factor VIII deficiency I Hemoph ilia AI Factor IX deficiency ('H emop hilia B) Factor VIII deficiency.Toronto Notes 2010 Helative Contra-indications • TTP. Febrile Nonhemolytic Transfusion Heactions (FNHTH) • due to alloantibodies to WBC. facial flushing. dilution.. steroids.. or multiparous women • risk per unit of blood is 1 in 100 • presents mainly as urticaria and occasionally with fever • can present as anaphylactoid reaction with bronchospasm. continue with transfusion but decrease rate and give antipyretics • if fever >38"C. XIII I Hemate P Factor VIII concentrate Factor IX concentrate Recombinant Vila Factors Table 24. laryngeal edema. liver disease).g.pasm/anaphylaxisj Allergic Nonhemolytic • due to alloantibodies (IgE) to proteins in donor plasma which result in mast cell activation and release of histamine • occurs mainly in those with history of multiple transfusions. dyspnea. and hypotension but this occurs mainly in IgA deficient patients that have anti-IgA antibodies • treatment • mild: slow transfusion rate and give diphenhydramine • moderate to severe: stop transfusion.

epidermis. later the level of antibody increases due to secondary stimulus and causes extravascular hemolysis • occurs 5-7 days after transfusion • presents as anemia and mild jaundice • treatment: no specific treatment required. and cryoprecipitate cryoprecipitate. • treatment: FFP. important to note for future transfusion Transfusion-Associated Graft Versus Host Disease {GVHDl • transfused T-lymphocytes recognize and react against "host" (recipient) • occurs 4-30 days following transfusion • most patients already have severely impaired immune systems (e. fluids Circulatory Overload • due to impaired cardiac function and/or excessive rapid transfusion • presents as dyspnea. blood cultures. liver function abnormalities.g. Hodgkin's leukemia) • presents as fever. and pancytopenia • can be prevented by giving irradiated blood products or NONIMMUNE Iron Overload • due to repeated transfusions over long period of time (e. S. give diuretics and oxygen Hyperkalemia • due to K release from stored RBC • risk increases with storage time and if blood is irradiated • decreased risk if given fresh blood • occurs in 5% of massively transfused patients • treatment: see Nephrology. Pseudomonas. or platelets Delayed Blood Transfusion Reactions IMMUNE Delayed Hemolytic • due to alloantibodies to minor antigens such as Rh. fibrinogen. perhaps due to binding of donor antibodies to wBe of recipient and release of mediators that increase capillary permeability in the lungs • typically occurs 2-4 hrs post transfusion and resolves in 24-72 hrs • risk per unit of blood is I in 5000 • is currently the leading cause of transfusion-related morbidity and mortality • treatment: supportive therapy (oxygen) • inform blood bank. orthopnea. and Kidd • level of antibody at time of transfusion is too Low to cause hemolysis. platelets. diarrhea.opathy • occurs with massive transfusion (>10 units) • pRBC contains no clotting factors. tachycardia. Bacillus cereus • Gram negative: Klebsiella.1 Coagul.000 for platelets • never store blood >4 hours after a bag has left blood bank • treatment: stop transfusion.g. IV antibiotics.patients are unable to clear citrate from blood • citrate binds to Ca and causes signs and symptoms of hypocalcemia • treatment: IV calcium g11. NP19 Citrate Toxicity • occurs with massive transfusion in patients with liver disease .000 for RBC and "I in 10. beta-thalassemia • can cause secondary hemochromatosis • treatment: iron chelators after transfusion major) . and increased venous pressure • incidence is 1 in 700 • treatment: transfuse at lower rate.H50 Hematology BloOOProducts and Transfusions Toronlo Noles 2010 • pathogenesis uncertain. hypotension. patient and donor testing will be arranged NONIMMUNE Bacterial Infection • Gram positive: S. au reus. Yersima • overall risk is 1 in 100. crackles at base of lung. Kelt Duff. Serratia.1conate (10 ml of 10%) for every 2 units of blood Dilutiona.

5 years. CMY.80.82 (95% CI 0. inhibiting TXA2 synthesis. provide sufficient evidence to prefer the combinatIOn regimen of aspirin plus dipyridamole over aspirin alone as antithrombotic therapy after cerebral ischaemia of arterial origin . Conclusion: The ESPRIT results. 95% CI 0. leading to decreased platelet aggregation • used most commonly in patients undergoing cardiac catheterization Aspirin Plus Dipyridamole versus Aspirin Alone After Cerebral Ischaemia of Arterial Origin (ESPRITI: Randomised Controlled Trial Lancet 2006. Intervention: Patients were assigned to aspirin (30325 mg daily) with (n~1363) or without (n~1376) dipyridamole (200 mg twice daily). non-fatal myocardial infarction. 367: 1665-73 Study: Randomised.000 • HTLV <1 in 1. leading to decreased platelet aggregation • hypothesized that these effects of dipyridamole potentiate antiplatelet actions of ASA • Aggrenox™ is more effective than aspirin in secondary prevention of stroke • ongoing clinical trials will determine the best indications for this agent Clopidogrel [Plavix'"] • ADP activates GP lIb/IlIa. Patients on aspirin and dipyridamole discontinued trial medication more often than those on aspirin alone (470 vs 184).000 • HIV <1 in 4.800. WNV Common Medications Table 25.11. Integrelin™ (eptifibatide). Drugs for Anemia Drug iron Common Formularv Iron gluconate Iron sulphate Iron fumarate Palafer'" Mechanism of Action Synthesis of hemoglobin Dosing Schedule Indications Iron deficiency anemia treatment and prevention Pregnancy Contraindications Iron overload Side Effects In children: acute iron toxicity Constipation 2-3 mg/kg/day of elemental iron in 3 divided doses PO Fernron" B'2 cyanocobalamin hydroxycobalamin Bedoz'" Cobex'M Folic acid Novo Folacid '" Folvite'M epoetin Epogen'M Eprex '" dabrepoetin Aranesp '" Synthesis of folic acid and DNA Up to 1000 pg/day PO B'2 deficiency Hypersensitivity Diarrhea folic acid Synthesis of purines and thymidylate.8).91).000.000 • HCV <1 in 2. combined with the results of previous trials. 3 times weekly Hypertension Antiplatelet Therapy ---------------------------------------- Aspirin (ASA) • irreversibly acetylates COX. thus inhibiting platelet aggregation • ASA is currently indicated for • stroke and MI prophylaxis • to reduce the incidence of recurrent Ml • to decrease mortality in post-Ml patients • dosage: single loading dose of 200-300 mg. controlled. Results: Primary outcome events arose in 173 (13%) patients on aspirin and dipyridamole and in 216 (16%) on aspirin alone (hazerd ratio 0. 95% CI 0. or malor bleeding complication. followed by daily dose of 75-100 mg PO OD Aggrenox™ • combination of ASA and dipyridamole • dipyridamole increase intracellular cAMP levels which inhibits TXA2 synthesis. WEPT Warfarin Extrinsic Increased Pathway PT/INR .66-0. whichever happened first. allowing platelets to bind to fibrinogen and aggregate • clopidogrel and ticlopidine (Ticlid™) inhibit ADP binding to platelets.0% per year.98. Patients: 2739 patients wtthin 6 months of a transient ischaemic attack or minor stroke of presumed arterial origin. auditing-blinded trial with mean follow-up of 3. open-treatment. non-fatal stroke.Toronto Notes 2010 Blood Products and Transfusions/Common Medications Hematology H51 Viral Infection Risk • HBV <1 in 82.000 • other infections include EBY.74-0. or myocardial infarction of 0. Primary Outcome: The composite of death from all vascular causes. Aggrastatt'" (tirofiban) • blocking GP Ilb / IlIa receptor inhibits fibrinogen and vWF binding. stroke. thus DNA Stimulation of RBC synthesis up to 1 mg/day PO Folic acid deficiency Pregnancy Renal failure Marrow failure Autologous blood donation Uncorrected pernicious anemia Uncontrolled hypertension Myelodysplastic syndrome Rash erythropoietin 50-1000 U/kg SC/IV.000. absolute risk reduction 1. Addition of the ESPRIT data to the meta-analysis of previous trials resulted in an overall risk ratio for the composite of vascular death. mainly because of headache. thus inhibiting aggregation • useful for prevention of cardiovascular events in high-risk patients • clopidogrel may cause TTP • ticlodipine (Ticlid™) is associated with a risk of agranulocytosis and is rarely used Glycoprotein lib/ilia Inhibitors • Reopro™ (abciximab).

2. ~}---------------------. p<. 3.4%). randomized. non-inferiority trial with follow up of 3 months.8%) vs. 3.OOI). subcutaneous unfractionated heparin is as effective as standard treatment with LMWH in patients with acute VfE. and concomitant use of antiplatelet agents or thrombolytics • heparin-induced thrombocytopenia: associated with venous or arterial thrombosis (see Table 13) • osteoporosis: with long term use Low Molecular Weight Heparin (enoxaparin. . 1. Intervention: Patients were randomized to receive either fixed-dose.162:1833-40 Purpose: To determine whether a subcutaneous 2. Conclusion: Fixed-dose. X. randomized. double-blind trials in patients undergoing elective hip replacement. the LMWH group (12 patients. VII. age. with a common odds reduction of 55.1%) vs. treatment was administered outside of hospital.5-mg. Interact with vit K Anticoagulant Therapy • see Approach to Treatment of Venous Thrombosis. Results: There was no significant difference in the rate of recurrent VfE in the unfractionated heparin group (13 patients. 2002. Enoxaparin for the Prevention of Venous Thromboembolism in Major Orthopedic Surgery: A Meta-analysis of 4 Randomized Double-blind Studies Arch Intern Med. Although major bleeding occurred more frequently in the fondaparinuxtreated group (p=. the LMWH group (5 patients.000/ mrn") • intracranial bleeding. H31 Absolute Contra indications • active bleeding • severe bleeding diathesis or platelet count <20 x 109 /L «20. the incidence of clinically relevant bleeding (leading to death or reoperation or occurring in a critical organ) did not differ between groups. this beneficial effect was consistent across all types of surgelY and all subgroups. 1.Adjusted Unfractionated Heparin and LMWH for Acute Treatment of Venous Thrombembolism JAMA 2006.2% (95% CI. Therapv lasted for a minimum of 5 days and continued until the INR was brought within the therapeutic range with the initiation of wartarin therapy. Resufts: Fondaparinux significantly reduced the incidence of VfE by day 11 (182 [6. TREATMENT Monitoring Pregnancy Adverse Reactions of Heparin • hemorrhage: depends on dose. tinzaparin) • increased bioavailability compared to normal heparin • increased duration of action • SC route of administration • do not need to monitor aPTT • adverse reactions less common than UFH • patients with renal failure (CrCl <30) can accumulate LMWH Heparin Alternatives Danaparoid • indicated for HIT. achieving an overall risk reduction of VfE greater than 50% without increasing the risk of clinically relevant bleeding. once-daily regimen of fondaparinux sodium starting 6 hours after surgelY was more effective and as safe as approved enoxaparin regimens in preventing VfE.H52 Hematology Common Medications Toronto Notes 2010 " '.8% to 63. elective major knee surgelY. open-label. stable patients • inhibits Factor Xa via antithrombin III • SC route of administration • monitor anti-Xa levels if renal failure or extremes in weight. starting 6 hours postoperatively. In 72% of patients receiving unfractionated heparin and 68% of patients receiving LMWH. Study Selection: Four multicenter. mean weight 83 kg) with acute venous thromobembolism (VfE). weight-adjusted. acidic Parenteral (IV. 55% male. There was also no signrricant difference in the incidence of major bleeding within 10 days of randomization in the unfractionated heparin group (4 patients. Conclusions: In patients undergoing orthopedic surgelY. protein C and S Chronic (days) IV Vitamin K + FFP PT/INR (extrinsic pathway) Not used (can cross placenta).7%) of 2703 patients). teratogenic Common Medications that with Warfarin Acetaminophen (interference metabolism) NSAIDS (GI injury) Fluconazole Metronidazole Sulfamethoxazole Comparison of Fixed-Dose Weight . neurosurgery or ocular surgery within 10 days Relative Contraindications • mild-moderate bleeding diathesis or thrombocytopenia • brain metastases • recent major trauma • major abdominal surgery within the past 2 days • GI or GU bleeding within 14 days • endocarditis • severe hypertension (sBP >200 or BP >120) • recent stroke Heparin and Warfarin Table 26_ Comparison of Heparin and Warfarin Heparin Structure Route Administration Site of Action Onset Mechanism Duration of Action Acute Overdose Large anionic polymer. inhibits production of II.4%). and surgelY for hip fracture (n= 7344). showed a major benefit over enoxaparin.8%) of 2682 patients) compared with enoxaparin (371 [13. IX. 45. cannot monitor aPTT Hirudin • indicated for HIT.008). SCI Blood (via Antithrombin) Rapid (seconds) Accelerates activity of Antithrombin Acute (hours) Protamine sulphate apn (intrinsic pathway) Safe (does not cross placenta) Warfarin Small lipid soluble molecule Oral (PO) Liver Slow ((imited by half-life of clotting factors) Vitamin K antagonist. dalteparin. unstable patients (ICU / CCU) requiring procedures • direct thrombin inhibitor (natural) • IV route of administration • monitor aPTT levels • risk of anti-hirudin antibodies (40-60%) • increases INR (difficulty switching to warfarin) Argatroban • indicated for HIT.1%. Primary Outcome: Recurrent VfE over 3 months of follow up and major bleeding within 10 days of randomization. renal failure and unstable patients • direct thrombin inhibitor (synthetic) • IV route of administration • monitor aPTT levels • increases INR (difficulty monitoring switching to warfarin) Fondaparinux • selective inhibitor of Factor Xa • heparin pentasaccharide analogue • one of the newer drugs for prevention and treatment of VTE Fondaparinux vs. adjudicator-blinded.5 mg of fondaparinux sodium once daily. Patients: 708 adult patients (mean age 60 vrs. 296:935-42 Study: Multicentre. weight-adjusted subcutaneous unfractionated heparin or LMWH (dalteparin or enoxaparin).

Recommended Management of a Supratherapeutic IN R Bleedin$ PreSilut No Reco mmended AGtion INR > Iher te 5. cisplatin • dacarbazine. melphala n (nITrogen mustardsl • carboplatin.Bilsed Clinical Flaeti&<)Guid~lines (8th EIliti~nJ.5 mg oral vi! K in patients with increased risk of bleeding Hoi d waliarin a~d administer 5 to 10 mg oral vii K. Selected Chemotherapeutic Agents Class Alkylating Agenl Example • chlorambucil. blocking cell division (nterfere witll 0 NA ullwi nding necessary for normal rep lication an d transcription Tapa i.IV infusion. or recombinant human factor VI ta.Toronto Notes 2010 Common Medications Hematology 853 Table 27. Recommended Therapeutic INR Ranges of Common Indications for Oral Anticoagulant Therapv Indication Prophylaxis oJ venous ijlrombosis (high-risk surgery) Treatment of venous tillombosis M nst cases oJ thrombosis with anfiphusphol ipid anti body syndrome Treatment of pulmonary embolism PTe\lention of systemi G ernbol ism Ti ssue heart valves AM I. 0 R No dose reduction needed ~ INR is minimally prolonged Omit th e next 1 to 2 doses of warfarin. E.0to9.0 lower warfarin dose. >5. o NAbreakage Antim etabol ites Inhibit DNA synthesis Antibiotics Interfere with 0 NA and RNA synthesis Taxan es lIinca-a Ikaloids • pacl~ax81 • docetaxel • vi~bfastine • vincristine • vinorelbine 'irinotecan. depending on clinical urg ency. et el. mon itor INR more frequ811tly. Chest 2008: (6 Suppl]:t5Qs.in tharnpeiJIi c ra nge.0 Table 28.(J. OR Omit a dow and resume warfa rin at a lower dose when INR is . Chemotherapeutic Agents Table 29.icians Eli dence. Hyle~. PO GFR . and resume treetm ent at a lower dose when INR is in therapeutic range. OR Om~ a dose and administer 1 to 2.somerase In hibitors Mon oclana I Antibodies • beva cizumab(Avastin '") • rituxirna b (R ituxjln '") • cetuxi meb (Erb~ux '" ) Small Molecule Inhibitors • • • • • imatinib mesylate (Gleevec e~otinib (Tarceva '" I gefitiniblliessa") bortezomib (Velcade '"I sunitinib (S utent '" I • HER2 • VEI3F • C020 • 'EGFR '"I • • • • Bcr·AbI EGFR EGFR 26S Proteasome • VEGFR. cyclophospham ide.0 No Any Serious or Iile threatening Soorce: Ansell. procarbazine • busulfan • methotrexate (Iolic acid anta gonist) • 6-mercaptopurine. M ooito! IN R more frequently and administer more vit K as needed. abnonnal base-pa iring.(to prevent systemic e mbol ism) Valvular heart disease Atrial fibrillation Bil eallet mochanical valve in aortic position Mechanical prosthetic mitral valves (high riskl Prophylaxis of recurrent ll1yo card ial infarcti on INR. tludarabin e (purinB antagonist) '5-fU (pyrimidine antagonist I • hydroxyurea • adriamycin (anthr8cycline) • bleomycin • mitornyci n C Me~ hanism of Action or Targel Oamage 0 NA via al k'(lation of base pairs Leads to cross~inking of bases. topotecan(topo • etopcs ide (tapo II) • trastuwmab(H erceptin "" ) I) Stabil ize rn icrotubules against breakdown once cell division complete Inhibit microtubule essembly (mitotic spindles). Hirsh" J. Resume wariarin at a lower dose when INR is in therapeutic range Hoi d waliarin and admi nister 1 0 mg vii K by slow . Range 2. supplement wrth prothrombi n complex concentrate. fresh frozen plasma. J. Monitor a11drepeat as needed. Pharmac~logy and management m III! vitamin K antagonists: AmeriGanCGlifjl8 ot Chest Phv:.3.0 No >9.

349. 328: 1002-5 CLOT NEJM 2003. MOPP CH OP I'n Hodgkin's lymphoma.org/ Hydroxyurea plus low-dose aspirin is superior to anagrelide plus low-dose aspirin for pati ents with essential thrombo cythemia at hig h risk for vascular events A restrictive strategy of red-rell transfusion (when Hb < 70) is at least as effective as and possitily superior to a lib eral transfusion strategy lwilell Hb < 100) in ICU patien ts. Use oltha lower threshold reduced platelet usage by 21. but less myelotoxicity. 327: 1478-&4 ABVD vs.146-53 lIP: Dexamethasone NEJM 2003.831-6 MRC NEJM 2005. IFN + Cytarab ine Hodgkin's Lymphoma: Reference Results NEJM 2003. 353. one possible exception is patients with an acute M I or unstable angi na The risk of major bleeding ill patients with AMl undergoing induction chemotherapy was similar whetllef tile platelet-transfusion threshold was set at 20 or 10. CHOP is the standard fo r advanced NH L In patients with cancer and ecuts venous thromboembolism. ABVO regimen has equal fa ilure-free and overall survival to M OPP + ABVD.85-6 TRICC NEJM 1999 340:409-17 Platelet transfusion tilreshold flJEJM 1997 337:1870-5 . 348:99~ 1004 In patients with chronc-phase CMt.hematology. CHOP has lowest incidence of fatal toxic reactions and shows no signili cant diffe reoce from 3 other regi mens in response or disease-freW' overall survival. please refer to American Society of Hemate logy (AS H) gu ideline at http://www. 349. imatinib was more effective tllan IFNC( + cytarabil1e in indue illg cyto gSl1lJtic response and freedom from progression to accelerated pllasetblast crisis NEJM 19 92.5 percent NE JM 1993. For more informalion. LWMH was more effective than coumad in in redu cing the risk of recurrent thromboemoolism without incress ing the ri sk of bleeding A four-day course of high-dose dexamethasone is effective in~ial therapy for adults with immune thrum oocytopenic purpura.H54 Hematology Landmark Hematology Trials Toronto Notes 2010 Landmark Hematology Trials Trial CML: Imatinib vs. ABVD is standard chemotherapy for Hodgkin's In NH l.

WH~ Floeo G~ Heil JA. 31!4: 581.339:00&-15.Toronto Notes 2010 References Hematology 855 References Approachl(llhe patielfl ~th tlrrorrilDGyIllSis. 2003.nih·uilV Idiopath ic ThTOmbocytopenia. Trensfus Cli.tic anemias.iBm H. i'lEJM... RIlSe.34(i: 995-1 OOO. NEJM. SA.l.hBmatoIO'JY. UpToDare. Smith B. use 01 h8paTin . Clinical: use or warfarin. 1991.lid mvel:lfibrosis. ThrombQ:..rusioo R. BO [Ed}. UploOati. Iiose.hingtm M.matoio91' and Oncology Suoopedalty CQnsultli:pincott Wtia"msand Wilkins. S'lVenlh ACCP oonfe"-"'Ce on antIThrombotic andllhrorrtolytic therapy. 143 111:1O.~aI. rec'ptor and fu~itin in . CrtIovther MA. 20114. 1995. Croig: Lehman ED. et aL Prevemion of venous thromboembolism. In Saindels Manual 01 Cli"icalLabOlOtory Sci~nce. 199J. Cana:li.er D. Usefulness 01 solubl. MA 2006. Sickle Cell DiooaSll. Cohen K. Chest 20114. Milj'O Cinic Pmc. B~od' Altemao. Walls 1'$.cpsc. ABC of cini. In: Up ToDate. The Was. BO [Ed). \\I!itham. MA 2006.l) 1hrorrtoc\'lhaemia . MA 2005.314:733.W. Chronic rrrye~id IaoJk!!JIlia. 19M. NEJM 1003.n Family Physician. Mackie IJ. Bottomloy SO.i.. et al. 2002:66. 33:8: 400415. Hosooeje. A clinic. ABC of clinic. CMAJ 20(14.E.ooicioe. Awte rnye~id IaoJk!!JIlia. Normal hoomo. Hypercoagul. 1999.trics and Chi~ Heath.349: 1227·1235.110:321-4. Ste!nsma DP.161!:243J. Rose.~ham. Hea~h Canada.prevention cI pUlmonary smbolism iI p. Walthlll1. I 993. http://Cilllcmnet.ry lessenti.vlead'1l~mb-eng. MA WOO. Up To!late. JulyJAiJg 2005. Stroll MB. Roo. Section 11. BI. Valentine KA wd HuE RD. Sunnybrook wd Women's ColleW' Health Selsncas Centre: Toronto. UpTilDate. TreotrrEnt and plD~sis QI~i<llathk: thrombocytop.nic putp1Jra.caJhl-lfS!iyh-vSl/!ell'li.USQ.lIJ~gv: Plirt!ilet disorders.llI._ ~ Semin 000011993. Il\IrneH A . 2001. et al.11 [3): 158-162.ln: UpToOate. H'<Illusseua J. 2ooG: 15[11. 2003. W: 5JO l'illot Ii. 19S9. KYle RA and Rajbmar SV: Cinical manirestations and .Ie D.nd low molecular I'o"€ight heparin.l\ld athttp://www. . LymphadGnopatl!y. ATmitag! Jo. Pangalis GA. E. liesner RJ and Madlin SJ_ ABC of clinical haem.314:1 Hl3.s1.ssets/trBatment + policiesJidiilpathi~ t thTOmoocytopeniat purpul1lcpdf Kovacs MJ et <II. Compalison. Thomas RH.utoronto. w.60. Myelodysplas.. ~rl:m1On PH. 'The diagnpsis and manag. Causes m the hetOOit<Iy and acq. Aleh Intern Moo. PurPIJra. BMJ.8:278. 'In: Up ToOare. MA ZOIMi. 1'998.tolo9Y'OncololJl'. Chemotherapy in multiple rrrye~m a In. SD [Eli). ZOOI'. NEJM. 1001 . arecls 01 lead 1)11 Hurmn 'Health. Mechanisms of severe \raIlsiusion reactions. UpToDale. Li~pinc~tt Williams and Witjns: Phib:lel~hi:!PA. Waltham MA 2006.ti~s witli prmimal dS!lI"'/ilin thrombosis.328: Tnn·1 030.nt Il'mpooma5 end chTDnic~phocyti:: IaoJkoomi a BMJ.Irron deficiency and chronic disease. Cines DB and H~nchette VS. Americ.php Heaney MOl" Goi. lIas.bility svndrorres.333:1~2. 1999. ABC 01 cii"icol hoematolll'J'f I'olycythilemia..i:lns. 314:651. 1995'. Low-d. Leonardi·Bre J. Waltham.fl1l)lecul.1 haimatolOQ'l: Chronic I11)'Eklid Id'!!JIli. ED [Ed).I. Coates TO and Boehner RL C. NfJM. UpToDate.errias. 2nd edition: The MiIssOOhusetts Gooerel: Hospileiliondbook of Internal Med. In Pooket Mooicioo. WG2. Smucker OR. tire eTa since Ih" Po~cythemia Vera: Study Groop: a SIfIVey of Ameti::an Society 01 H!!JIlatol:lgy m!!Jllbers' priclioo patlllrns". Imerwtional Prognostic Factors Project on Ad"nwd Hodgkin's Disease.~c Leulerria. Christiansen SC. Wallhlrn. g9·141: \ 144 . The acuteleuk. 65:511:-516. et at RlJllirlw: ~amole given with or without aspiril reduoos retlJrt1!nt stroke. 293113):2353-2'361. http:/Mrww. Phibdelphia. Sc.. SO lEd).romiped/tJJpic251lJ.723·732. Ras. 1~91. i'aliatrics in HevieJA\ 28:7 259 . Messinezy M ondPearson TC. Driswll MC. 2005. ChaptEr 131: pbteletdisomers. Boussiolis VA.n Pediatric Society.mg. Go~man J.e BD fEdl.rted intemational normali211d' ratios: a brief re.ytopenia. Rooe.hc-sc. ROlITlan . ~ ACP Joornallllb. Thrombophilia..nci.286 Goort. W<rfarin inrtiation mOJll)JOl'lS together withlow. and Bull ItA. US. Pedi. B~od. DlIOOusus et .mal H... M. trial m ~na c1l'lal fillErs in tire .uired siderobla. Trnnsfusion and risk 01 infuGtion in: Cmad" Updare 20M. Up To date.Blood Trmslu. Spi\lllk Jl. In: Up To !late. Coosumer Product Safety CorrmissiOIL B. ll?wnill!J JR. transl"ri.J:2. www. UpTbDite.. In: Up To!late.esand Tr1ln. lipTiJOate. 339:150&-14.mem Dr pofycythemia WJa in. Rose. '138: 11'4-119..1. \I~lIham. 20(1(. etal A. prim. ChanIB M. M8adi GM. Lymphadenupathv alld Mali~""ncv. 341 :1051'-62.e. c. 8MJ.. 1991. liesner RJ and Goldstone All. 1998. BioI. Kyle RA and Rajhmar f}I. Ross BD 1Ed).tI:o~c M.11-.2439. 8M'J.ia. SO lEd). EIOOation m D·dimer in the di<IJnosis 01 suspecred deep·win iIrombosis.h ttl tire adu~ patient with thrombocytopenia.340:13Jt]-4(]. UpToOare. MA 10[15. Clilieal Factors.y: Malign. EI/aluation of Bleedillg Disorders.MEM.ROSj1.210:>-2110. lreatment m Non·Hod~~n·s Il'mphorni.flagnoois of Waldmstmm's rmcro~burrnemi:!. Callum JL. N EJM. Pui C" E"n. Hem. el aI TEds).351 :26Hll. 1997.Monts8nmE. Castellone DO. Immuoe T:hrombocytopelic Purpura. Wilson SE. ~rO'Jnostit: _e for advanood Hodg~i"'s disease. 2004. 'NEJM. Scan J Clin-lab Invest 2005. Sabatine MS IEdI. 1Zlil 3365-4005_ Georg" IN. and RecuRent Thrombotic EIfeIfl" JAMA.~!BUSINFCllregsumleadpainlpdl vmen~ne KA wd Hull R0. Mu~iplerrrrelom" NEJM. Phiadalphia PA. Bataiile R. lrwtment m deep·vein thrombosis. lowelterg S. 011 O-rrQ and s.314:oo9. The Merck Manual. et al. Blood'! EaS'\':. M". WMham. ~: Up ToDate. NEJM.tes SM alld GiPSIJerg JS. .11. and treatment Canctl Treot Res.ood REfli.1 hoomatol:lgv. MA 10M..acoOhS. NEJM. Sa!ak~ Nand SakamotQ It Acute Lymphobl._. WIl4. UpToDare. 34(]:164~.. B. Witsoo HG. MA 100.icine. Waltham. Hal>emmn 1M. 8MJ. Bousser MG. ABC of clinical haemalOlog. Chronic ~ll1'hocyti:: Idemi a NEJM. 1~9g.il)l'I.104:201·203.gc. and it reyulation. Acute Il'mphOblastic 1aoJ'!!JIlia. of lead-Containill!J Paint and Certain COlliuuer Products Bearill!J Lead-Containing Paint http://v. Cds esselltials 01Medicine.8 I.r-l'rei~ nep<rin for out patient treatrrr<nt. WB Saunders CO.dden 01 Non-Hod{jkin's ~lJ1lhoma: pathogenesis. C~nic. landaw. 1991. of acute veoous thromboomb(lism An" lntem Med.html SawyeIS C.medicine ZOOOacce. Approa. BO [Ed). Dr neutroplilia. Balernore AW. Bath PM.336:1657·64. cinical pTBsentllion.il1l:0p0uloo ~.ose oral vitmin K therepy fa the manageroom olasym~!lJma!ic pati~ with elw. Diehl V. PA. W.

H56 Hematology Toronto Notes 2010 .

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