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H57 Hematology Toronto Notes 2023

Bacterial Infection

• Gram-positive:S.aureus,S’

, epidermidis.Bacillus cereus

• Gram-negative: Klebsiella, Serratia, Pseudomonas, Yersinia

• overall risk is 1/100000 for RBC and 1/10000 for platelets

• neverstore blood >4 h after bag hasleft blood bank

• treatment:stop transfusion, blood cultures,IV antibiotics, fluids

Hyperkalemia

• due to K ’release from stored RBC

• risk increases with storage time and if blood isirradiated; decreases with fresh blood

• occursin 5% of massively transfused patients

• treatment:see Nephrology. NP14

Citrate Toxicity

• occurs with massive transfusion and in patients with liver disease - patients are unable to clear citrate

from blood

• citrate binds to Ca -

1

and causessigns and symptoms of hypocalcemia and exacerbates coagulopathy

• treatment IV calcium gluconate 1 g

Dilutional Coagulopathy

• occurs with massive transfusion (>10 units)

• pRBC contains no coagulation factors,fibrinogen, cryoprecipitate,or platelets

• treatment FP,cryoprecipitate,and platelets

Delayed Blood Transfusion Reactions

IMMUNE

Delayed Hemolytic

• due to alloantibodies to minor antigens such as Rh, Kell, Duffy, and Kidd

• level of Ab at time of transfusion is too low to be detected and to cause hemolysis; Ab levelsincrease

later due to secondary stimulus and causes extravascular hemolysis

• occurs 3-14 d after transfusion

• presentation:anemia and mild jaundice

• treatment no specific treatment required;important to note for future transfusion

• N.B.serologic transfusion reactions are the development of alloantibodies in the absence of frank

hemolysis

Transfusion-Associated Graft Versus Host Disease

• transfused T-lymphocytes recognize and react against “host" (recipient)

• occurs 4-30 d following transfusion

• most patients already have severely impaired immune systems (e.g. Hodgkin lymphoma or leukemia)

• presentation:fever, diarrhea, liver function abnormalities,and pancytopenia

• can be prevented by giving irradiated blood products

Allogeneic SCTGVHD

To reduce risk of GVHD development

after allogeneicSCI.administer

inhibitors of T-cefl activation,including

cyclosporin A or tacrolimus

NONIMMUNE

Iron Overload

• due to repeated transfusions overlong period of time (e.g. p-thalassemia major)

• can cause secondary hemochromatosis

• treatment iron chelators or phlebotomy if no longer requiring blood transfusion and not anemic

Viral Infection Risk

• HBV 1/7000000

• HCV 1/12000000

. HIV 1/20000000

• Human T-lvmphotropic virus (HTLV ) 1/600000000

• other infections include HBV, CM V, WNV (West Nile virus)

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H58 Hematology Toronto Notes 2023

Common Medications

Antiplatelet Therapy

• see iigurc 12a, H27

SS£

"'

h---0 -

ACTIVATED

PLATELET

Clopidogrel

Ticlopidine

Prasugrel

Ticagrelor

splltihllaR

0 2

S

! AggrenoV j

|

3

2

1/3

0 :

t

§

5

a

so

AMP DEGRANULATION

Adhesive proteins

a Prothrombotic tsctors

Proinflammatory factors

A Platelet agonists

1

-c

ACTIVATED

PLATELET

AC - adenylyl cyclase

PDE - phosphodiesterase ©

Figure 17. Mechanisms of action of antiplatelet therapy

Table 40. Antiplatelet Therapy

Mechanism of Action Typical Dose/

Route of

Administration

Onset/Peakf

Duration

Specific Side

Effects

Remarks

Aspirin5 Irreversibly acetylates COX,

inhibiting thromboxane A2|tXA2) 300 mgP0.followed Peak:0.25-3 h

synthesis,thus inhibiting platelet by dose of 75-100 mg Duration:3-6 h

P0 daily

Single loading 200- Onset:5-30 rain Gl ulceo'bleeding

Tinnitus

Bronchospasm

(platelet inhibition Angioedema

lasts 7-10 d) Reye's syndrome in

pediatric patients

Indicated for stroke/MI prophylaxis

Reduce incidence of recurrent Ml

Decrease mortality in post-MI patients

Contrandicated in patients with Glulcers

(ASA)

aggregation

Dipyridamole increases

intracellular cAMP levels.

1capsuleP0 810 Peak:75 min More effecbve than ASA in secondary prevention of stroke

Dipyridamole potentiates antiplatelet action of ASA

Aggrenox H/A

(ASA *

Dipyridamole) which inhibits TXA2 synthesis,

leading todecreased platelet

aggregation

Dyspepsia

N/V

Abdominal pain

Cardiac failure

Kemorrboids

Clopidogrel

(Plavix )

Onset:2 h

(loading dose)

Peak:6 h

(loading dose)

Duration:5 d

Irreversibiity inhibits ADP

binding toplatelets,thus

decreasedplatelet aggregation

loading dose 300

mg PO.then 75 mg

URI Prevention of cardiovascular events inhigh-risk patients

Clopidogrel is a prodrug icquiring two- step activation lo active metabolite

CYP2C19 poor metabolirers have diminished response to clopidogrel

Caution with hepatic/renal impairment

Chest pain

daily HA

Flu-like syndtome

Depression r T

Utl ij

Gl hemorrhage

Pancytopenia

May cause TIP

Onset:30 min Oiaainess

(loading dose) HA

Peak:4h (loading Nervousness

dose)

Duration:5-10 d

Sameasclopidogiel loading dose 60

mg.then5-10mg

P0 daily

Alternative loclopidogrel for prevention of cardiovasculai events in high-risk

patients

Higher potency compared to clopidogrel

No significant drug-drug interactions,although more data is required

Prasugrel

(Effient | +

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H59 Hematology Toronto Notes 2023

Table 40. Antiplatelet Therapy

Mechanism of Action Typical Dosel

Route of

Administration

Onset/Peak/

Duration

Specific Side

Effects

Remarks

Ticagrelor

(Brilinta )

Reversibly inhibits ADP binding

to platelets

Loading dose180

rag.then 90 rag

P0 BID

Onset 30 nun

(loading dose)

Peak:1.5 h for

prodrug.2.Sb for

active metabolite

Difficulty or laboured Alternative todopidogrel for prevention of cardiovascular events inhigh-risk

patients

Shortness of breath Higher potency compared to dopidogrel

lightness in chest

Oneness

breathing

Ticagrelor does not need metabolic activation to serveits antiplatelet

function

Drug-drug interactions with CYP3A4 inhibitors and inducers

Prasugrel is a prodrug requiring metabolic actnrabon mainly by CYP3A5 and

CYP2B6

Glycoprotein

llb/llla

Inhibitors

Reopror

(abciiimab).

Integrilin'

(eptifibatide)

BockingGPblti'HIa receptor

inhibits fibrinogen and VWF

binding,leading to decreased

platelet aggregation

Variable IV Used most commonly in cardiac catheteruaton

Contraindicated in PUD

Monitoring aPTT/activated dottingtime

Variable Hypotension

Back pain

NY

Chestpain

Abdominal pain

Thrombocytopenia

Anticoagulant Therapy

Table 41. Anticoagulant Therapy

Dose/Route of Onset/Peak/ Reversing Monitoring

Administration Duration Agent

Specific Side

Effects

Mechanism of

Action

Remarks

Heparin Inhibition of factor Variable,depends Onset:

Xa and factor on indication:can

lla.mediatedvia be used IV or SC

antithrombin

Warfarin VitaminIf

antagonist inhibits dosing by

production of monitoring

Factors IUVII.DC.X. PT/INR:P0

proteins C and S

Mainly fador Xa

(enoiaparin. inhibition,some

dalteparin. Ftla inhibibon.

tinzaparin) both mediated via

antithrombin

Fondaparinui Selective factor

Xa inhibition,

mediated via

antithrombin

Rivaroiaban Dired factor Xa

inhibitor

Protamine

Immediate (IV): sulfate

20-30 min (SC)

aPTT (intrinsic Hemorrhage

pathway).UFH (anti- HIT

Xa)levels

Pregnancy:sale (does not cross placenta)

Increased liver

enryraes

Hemorrhage

Cholesterol embolism

syndrome

Intraocular

hemorrhage

Individualized Onset:24-72 It Vitamin K

Peak:5-7d PCC

Duration:2-5 d fP

INR:maintain 2-3

(2.5-3.S for certain

mechanical valves)

Pregnancy:not used,can crossplacenta (teratogenic)

LMWH Variable,

weight-based

dose,depends on

indication;SC/IV

Onset1-2 h

Peak:3-5 h

Duration:

12-24h

Partial

reversibility

Anh-Xa levels in Hemorrhage

pediatrics,eitremes fever

of weight,or renal Increased liver

insufficiency

Higher bioavailability than heparin

Can accumulate in patents with low CrCl (<30mb'min)

Standard treatment of VTEinpregnancy and patients

with malignancy

with

protamine

sulfate

enzymes

«1% HIT

Onset:2 h

Peak:2-3 h

Long half-life(17-21h)

Contraindicated inrenal failure

Variable

SC daily

Hot reversible Hone Anemia

fever

Nausea

Rash

Onset1-3h

Peak:1-3 h

Syncope

Gt hemorrhage

Menorrhagia

Gastroenlritis

Indicated for treatment of acuteVTE.secondary

VIE prevention,thrombopropbylaiis inorthopaedic

patients and strokeprophylaiis m non-valvular Afib:

ensure CrCl>30ml,

‘

min:must be taken withlood:

contraindicated in mechanical heart valves

Indicated for treatment of acute VIE.secondary

VIE prevention,thrombopropbylaiis inorthopaedic

patients and strokeprophylaiis innon-valvular Afib;

ensure CrCl >25 ml/min:contraindicatedin mechanical

heart valves

Indicated for treatment of acute VIE.secondary VTE

prevention,stroke prophytans innon-valvular Afib;

contraindicatedinmechanicalheart valves;dose

reduction in renal insuffidency.avoidinCrCl <15 mL/min

Indicated for treatment ofheparin-induced

thrombocytopenia.PCI:contraindicated in mechanical

heart valves

Indicated for treatment of acuteVIE(after 5-10 d

parenteral therapy),secondary VIE prevention,

thrombopropbylaiisin orthopaedic patients and

stroke prophylaiis innoa-valvular Afib:ensure CrCl

>30ml/min:shouldbe storedinoriginal packaging:

conlraindicated in mechanical heart valves

Variable,depends

on indication:PO

Andeianet o Anti Xa levels

validated for

rivaroiaban may

be used todetect

presence of drug only Cough

Apiiaban Direct Factor Xa

inhibitor

P0 BID Onset:1-3 h

Peak:1-3 h

Andeianet a Anb-Xa levels

validated for

apiiaban may be

used to detect

presence of drug only

Andeianet a Hot typically

available

Hemorrhage

Nausea

Anemia

Direct factor Xa

inhibitor

P0 daily Onset1-2h

Peak:1-2h

Edoiaban Hemorrhage

Direct thrombin

inhibitor

Onset 5-10min Hot reversible aPTT

Duration:20-40

Dyspnea

Hypotension

fever

Idarucizumab Dilute thrombin G!upset

bme may be used to Dyspepsia

detect presence of

drug only:IIalso

sensitive lor drug

presence

Argatroban Variable

IV

min

Direct thrombin

inhibitor

150 mg P0 BID Onset:1-3h

Peak:1-3h

Dabigatran

Adverse Reactions to Heparin

• hemorrhage:depends on dose, age, and concomitant use of antiplatelet agents or thrombolytics

• HIT a hematologic emergency associated with venous or arterial thrombosis(see Table 22, H30)

• osteoporosis:with long-term use

Low Molecular Weight Heparin (enoxaparin, dalteparin,tinzaparin)

• increased bioavailability7

compared to unfractionated heparin

• increased duration of action

• SC route of administration

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H60 Hematology Toronto Xotes 2023

• do not need to monitor aPTT

• adverse reactionsless common than U1 H

• patients with renal failure (CrCl <30 mL/min) can accumulate LMWH,therefore may need to adjust

dose

• only partially reversible with protamine sulfate

• HIT isless common

Table 42. Recommended Management of a Supratherapeutic INR

INR Bleeding Present Recommended Action

^Therapeutic No

to 4.5

>4.5 to 10.0 No

Lowerwarfarindose or omit a dose andresume warfarin at a lower dose when INR isin therapeutic

range or no dose reduction needed if INR isminimally prolonged

Omit thenext1-2doses of warfarin,monitor INR more frequently and resume treatment at a lower

dose when INR isin therapeutic rangeOR omit adose and administer oral vitamin K1-2.5 mg in

patients withincreased risk of bleeding

Hold warfarinandadminister oral vitaminK 2.5 to 5 mg:monitor INR more frequently and

administer more vitamin K as needed:resume warfarin at a lower dose when INR is in therapeutic

range

Hold warfarin andadminister vitamin K 10 mgby slowIV infusion:supplementwith four-factor

prothrombin complex concentrate:monitor and repeat as needed

>10.0 No

Serious or life

threatening

Any

Adapted from:American Callage of Chest Physicians Evidence-Based Clinical Practice Guidelines.Chest 2012:(2suppq:e152S

Chemotherapeutic and Biologic Agents Used in Oncology

Table 43. Selected Chemotherapeutic and Biologic Agents

Class Example Mechanism of Action or Target

Damage 0NA via alkylation of base pairs

Leads to cross-linking of bases,abnormal base-pairing. DNA

breakage

chlorambucil,cyclophospham.de.melphalan

(nitrogen mustards)

carboplatin, cisplatin

dacarbazine.procarbazine

busulfan

bendamustine

Alkylating Agent

Antimetabolites methotrexate (folic acid antagonist)

6-mercaptopurine.Iludarabine(purine

antagonist)

5-fluorouracil (5-FU) (pyrimidine antagonist)

hydroxyurea

cytarabine

adriamycin (anthracycline)

bleomycin

mitomycin C

daunorubicin

Inhibit DNA synthesis

Antibiotics Interfere with DNA and RNA synthesis

Stabilize microtubules against breakdown once cell division

complete

Taxanes paditaxel

docetaxel

Vinca-alkaloids vinblastine

vincristine

vinprelbine

Inhibit microtubule assembly (mitotic spindles),blocking cell

division

Topoisomerase Inhibitors irinotecan,topotecan|topoI)

etoposide (topo II)

Interfere with DNA unwinding necessary for normalreplication

and transcription

Steroids prednisone Immunosuppression

dexamethasone

Purine Analogues fludarabine Interferes with DNA synthesis

cladribine

HER2 antagonist

VEGF antagonist

rituximab (Rituxan -

). olatumumab (Arzerra'

). CD20 antagonist

obinutuzumab|Gayzva:

) EGFR antagonist

cetuximab|Erbitux s)

daratumumab

Monoclonal Antibodies trastuzumab (Herceptm '

)

bevacizumab (AvasbnT)

CD38 antagonist

BCR-ASL inhibitor

BCR ASt inhibitor

BCR ASL inhibitor

BCRASL inhibitor

EGFR antagonist

EGFR antagonist

26S proteasorre inhibitor

VEGFR.PDGFR antagonist

BTK inhibitor

P13K inhibitor

JAK2 inhibitor

BCRABL inhibitor

Bcl-2inhibitor

Immunomodulators

imatinib mesylate (Gleevec !

)

dasatinib

nilotinib

bosutinib

erlotinib (Tarcevar)

gefitinib (Iressa -

)

bortezomib (Velcade;

)

sunitinib (Sutent1)

ibrutinib (Imbruvica '

)

idealasib (Zyedlig *)

nixolitinib (Jakavi - )

venetodax

lenalidomide.pomalidomide

Small Molecule Inhibitors

r

+

CARIcell therapy tisagenledeucel (Kymriahr) Target CD19

axicabtagene ciloleucel(Yescarta:

)

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H61 Hematology Toronto Notes 2023

Landmark Hematology Trials

Trial Name Reference Clinical TrialDetails

Hematologic Malignancies and RelatedDisorders

Long term outcomes of imatinib

treatment for chronic myeloid

leukemia

NEJM 2017;376:917-927 Title:Long-Term Outcomes of Imatinib Treatment forChronic Myeloid Leukemia

Purpose:To compare the efficacy of imatinib with that of IFN-aplus low-dose cytarabine innewly diagnosed chronic-phase CML.

Methods:T10 patients with Ph-positive CML in the chrome phase were randomized1:1to imatinib or interferon aplus cytarabine.

Crossover to matinrb were allowed if no response by 6mo or major cytogenetic response by12mo.

Results:Assessing the imatinib arm after a median of11years of follow-upspecifically at the sixth year point,the complete

cytogenetic responserate was 83%.Among patients who attained a major molecular response after 18 mo olimatinib therapy,the

overall survival at 10-years was 93% and freedom from CML-related death 100%

Conclusions.This 116-year update ol IRIS demonstrates the efficacy and safety of imatinib as first !me therapy for CML patients.

Title:Ibrutmib Versus Ofatumumab in PreviouslyTreatedChronic Lymphoid Leukemia

Purpose:To evaluate the efficacy of ibrutinib inpatients with CLL and small lymphocytic lymphoma (SLL) atrisk for poor outcomes.

Methods:391patientswithrelapsed or refractory CLL or SLL were randomly assigned to daily ibrutmib or ofatumumab.

Results:Ibrutinib significantly improved progression-free survival (hazard ratio.0.22;P<0.001).overall survival (0.43;P -0.005)

with a higher overallresponse rate (42.6% vs.4.1%.P<0.001) as compared withpabents on ofatimumab.Overall survival was 90%

in the ibrutmibgroup and 81% in the ofatumumab group at 12 mo.

Conclusion:Ibrutinibsignificantly improved progression-free survival,overall survival,and response rate among patients with

previously treatedCLL or SLL.

Title: Daratumumab.lenalidomide.and Dexamethasone for Multiple Myeloma

Purpose: Toassess if daratumumab lengthens PfSwhen added tolenalidomide and dexamethasone therapyinpatients with

relapsed or refractory myeloma.

Methods:569patients with MM who had been previously treated were randomly assigned to either lerralidomide and

dexamethasone (control group) or daratumumab plus lenalidomide and dexamethasone (daratumumab group).The primary

endpoint was PFS.

Results:PFSat12mo was 83.2% in the daratumumab group and 60.1% in thecontrol group.Daratumumab had a significantly higher

overallresponse as compared to the control group (P< 0.001).Neutropenia was more frequent m the daratumumab group (51.9%

vs.37.0%).

Conclusion:PFS was significantly lengthened by addition of daratumumab to lenakdomide and dexamethasone for patients with

relapsed orrefractory MM but was associated withhigherrates of neutropenia.

Ibrutinib Versus Ofatumumab in

PreviouslyTreated Chronic Lymphoid

Leukemia.Byrd et al.2014

KJM2014:371:213-23

POLLUX NFJM 2016:375:1319-31

NEJM 2017:377:1331-44 Title:Obmutuzumab for the First-Line Treatment of Foi.

iculat lymphoma

Purpose: Tocomparerituximab-based chemotherapywith oii-utuzumab-based chemotherapy in patients withuntreated

advanced-stage follicular lymphoma.

Methods:1202patients were randomlyassigned toreceive induction treatment with obinutuzumab-based chemotherapy

(obinutuzumab) or rituximab-based chemotherapy (rituxiraab).

Results:Risk of progression,relapse,or death was significantly lower on obinutuzumab vsrituemab (estimated 3-yr PFS.80.0% vs.

73.3%;hazardratio for progression,relapse,or death.0.66:95% Cl.0.51-0.85;P-0.001|.There weremore adverse events in the

obinutuzumab group (grade 3-5: 74.6%vs.67.8%:seriousevents:46.1% vs.39.9%).

Conclusion:Obinutuzumab- based chemotherapy resultedinlonger PFS than rituximab-based therapy but more frequent high-grade

adverse events.

6AUIUM

Long-Term Follow-up of C019 CAR NEJM 2018:378:449 -59

Therapy inAcute lymphoblastic

Leukemia.Parket al. 2018

Title:Long-Term Follow-up of C019 CAR Therapy inAcute lymphoblastic leukemia

Purpose: To investigate the use of C A R T in relapsed 8-cellALL

Methods:Phase1trial including 53 adults withrelapsed B-cell ALLreceived an infusion of autologous T cells expressing the 19-28z

i.

:-1

Results:Severe cytokine release syndrome occurred in 26% of patients following infusion (95% Cl.15-40):1patient died.83% of

patients expenenced complete remission.At median 29 mo follow-up.median overall survival was129mo (8.7-23.4) and median

event-free survival was 6.1mo (5.0-11.5).

Conclusion:Median overall survival was12.9 mo in the entire cohort.More adverse events occurred inpatients with high disease

burden.

Thrombosis

NEJM 2003:349:146-53 Title:Low-Motecular-Neight Heparin Versus a Coumarin for the Prevention ol Recurrent Venous Thromboembolism in Patients with

Cancer

Purpose: To compare the efficacy of LMWH with an oralanticoagulant for preventing recurrent thrombosis in cancer patients.

Methods:Cancer patients with acute, symptomatic ptoumalDVT.PE. or both were randomly assigned to daHeparin (LMWH) for 5-7 d

plus a coumarin derivative for 6 moor dalteparin alone for 6 mo.

Results:A!6 mo.the rate of recurrent thromboembolism was17%in the oral-anticoagulant groupand 9% in the dalteparin group.

Rates ofmajor bleeding were not significantly differentbetween groups (6% vs.4%,respectively):any bleeding (14% vs.19%).

Conclusions:Dalteparin wassuperior to an oral anticoagulantin cancer patients for reducing recurrentthromboembolism rates

without increasing bleeding risk

3MJ 2011:342:d3036 Title:Influenceof Preceding length of Anticoagulant Ireatment andInitial Presentation of Venous Thromboembolism on Risk of

RecurrenceAfter StoppingIreatment:Analysis of IndividualParticipants' Data From Seven Trials

Purpose: To determine how length of anticoagulation of VIE influences recurrence risk after treatment isslopped.

CAR:Individual participants' data was pooled from 7 RCTs including 2925 men or women witha first VTE who did not have cancer

and had varying durations of anticoagulant treatment.

Results:Recurrence was higher if anticoagulation wasstoppedat1-1.5 mo vs.at >3mo (hazard ratio1.52.1.14-2.02) and similar if

treatment was stopped at 3 mo vs. >6mo (1.19.0.86-1.65).

Conclusion:Risk of recurrent VTE was similar when anticoagulation was stopped after 3 mo vs.stopping after a longer course of

treatment.

NEJM 2012:366:1287-97 Title:Oral Rivaroiaban for the Treatment of Symptomatic Pulmonary Embolism

Purpose:1o investigate the efficacy and safety of a fixed- dose rivaroiaban regimen for the treatment of PE.

Methods:4832 patients who had acute symptomatic PE e DVT were randomly assigned to rivaroiaban or standard therapy with

enoxaparm foUowed by a vitamin K antagonist.

Results: Rnraroxaban wasnoninferior to standard therapy for the primary efficacy outcome (symptomatic recurrent VTE),2.1% in

rivaroiaban vs.1.8% instandard-therapy (hazardratio.1.12:95% Cl.0.75-1.68).Clinically relevant bleeding occurred in10.3% of

patients on rivaroxaban and11.4% of those on standard-therapy (0.90:0.76-1.07:P-0.23).

Conclusion:For initial and long-term treatment of PE.fixed-dose rivaroxaban alone was noninfenor to standard therapy with a

potentially better benefit-risk profile.

CLOT

Influence olPreceding Length

of Anticoagulant Treatment and

InitialPresentation of Venous

Thromboembolism on Risk

of Recurrence After Stopping

Treatment Analysis of Individual

Participants' Data From Seven Trials.

Boubtie et al.2011

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H62 Hematology Toronto Notes 2023

Trial Name Reference Clinical Trial Details

AMPLIFY NEJM 2013;369:799-808 Title;Oral Apixaban for the Treatment of Acute Venous Thromboembolism

Purpose: To Investigate the efficacy and safely of fixed- dose apixaban for the treatment of VIE.

Methods:639S patients with acute VIE were randomly assigned to receive apixaban or conventional therapy (SC enoxaparin,

followed by wailarin).

Results: Apixaban was noninferior to conventional therapy lor the primary efficacy outcome (symptomatic recurrent VIE or death

from VIE)|P<0.001|. Major bleeding or clinically relevant nonmajor bleeding occurred in 4.3% of patients on apixaban vs. 9.7% ol

those on conventional-therapy ( RR . 0.44; 95%Cl.0.36-0.55;P'

0.001).

Conclusion:For the treatment of acute VIE.fixed-dose apixaban alone was noninferior toconventional therapy with significantly

less bleeding.

Title:Idarucizumab for Dabigatran Reversal

Purpose:toinvestigate the efficacy and safety of idarucizumab for reversing the anticoagulant effects of dabigatran.

Methods:90 patients with either a serious bleed or one requiring an urgent procedure secondary to dabigatran received

idarucizumab.

Results:Iddiuclrumabnoimalircd test results in 88 98% of patients,which was evident within minutes.Unbound dabigatran

concentrations remained *20 ng/ml at 24 h in 79% of patients.

Conclusion: Thcanticoagulant effect of dabigatran was completely reversed by idarucizumab within minutes.

Title:Anticoagulant Iherapy for Symptomatic Calf Deep Vein Thrombosis (CACTUS):A Randomised. Double-Blind.Placebo-Controlled

RE VERSE AD NEJM 2015;373:511-20

CACIUS lancet Haematol

2016;3:e556-e562 Trial

Purpose:To investigate the efficacy and safety of anticoagulant treatment inpatients with acute symptomatic DVT of the calf.

Methods:259 low-risk outpatients without active cancer or previous VTE with a first acute symptomatic call DVT were randomly

assigned to receive either nadroparin ( LMY/H) or placebo for 6 wk.

Results: No significant difference between groups was seen in the composite primary outcome (extension of calf DVT to proximal

veins,contralateral proximal DVT.and symptomatic pulmonary embolism at day 42).Bleeding occurredin 4% of patients on

nadroparin and no patients on placebo (risk difference 4.1,95% Cl 0.4-9,2;p‘0.0255).

Conclusion:Inlow risk outpatients with symptomatic call DVT. nadroparin was non-superior to placebo inreducing the risk of

proximal extension or VIE.but it did Increasebleeding risk.

Blood Products and Transfusion

fOCUS NEJM 2011:365:2453- Title:Liberal or Restrictive Transfusion in High-Risk Patients after Hip Surgery (FOCUS)

Purpose: To determine whether a higher threshold for blood transfusion would improve recovery in patients who had undergone

surgery for hip fracture.

Methods: 2016 patients >50 yr with a history of or risk factors for cardiovascular disease and Hb level below10 g/dlafter hip

fracture surgery were randomly assigned to a liberal transfusion strategy (a Hb threshold of 10 g/dl) or a restrictive transfusion

strategy (anemia symptoms or at physician discretion foi a Hb level less than 8 g/dl).

Results: The primary outcome was death or inability to walk across a room without human assistance on a 60 d follow-up. Primary

outcome rates were 35.2% in the liberal transfusion strategy group and 34.7% in the restrictive transfusion strategy group.Rates of

complications were similar in the two groups.

Conclusion:A liberal transfusion strategy did not reduce mortality rates or the inability to walk independently on 60 d follow-up

compared to a restrictive transfusion strategy inelderly patients with high cardiovascular risk factors after hip surgery.

NEJM 1999;340:409-17 Title: A Multicenter.Randomized,Controlled Clinical Trial of Transfusion Requirements in Critical Care.Transfusion Requirements in

Critical Care Investigators.Canadian Critical Care Trials Group

Purpose: To determineif equivalent results can be achieved by a restrictive strategy of red-cell transfusion and a liberal strategy in

critically ill patients.

Methods 838 critically illpatients with euvolcmia (after initial treatment and Hb <9 g/dlwithin 72 h of ICU admission) received

cither (1) a restrictive strategy (transfusion it Hb «7.0 g/dl.maintained at 7-9 g/dl) or|2) a liberal strategy (transfusions if Hb <10.0

g/dl,maintained al10-12 g /dl).

Results: Mortalityrates at 30 d were similar between groups.However,among less acutely illpatients and those <55 yr of age.

mortality rates weresignificantly lower in RS than IS:8.7% vs.16.1%,P-0.03 and 5.7% vs.13%,P~0.02.respectively.

Conclusion:In critically ill patients,a RS of red cell transfusion is as effective as a LS transfusion.

Lancet 2012;380:1309-16 Title:TherapeuticPlatelet Transfusion Versus Routine Prophylactic Transfusion inpatients With Haematological Malignancies:An

Open-label. Multicentre. Randomised Study

Purpose: To investigate the influence ola novel therapeutic platelet transfusion strategy on the number of transfusions and safety

in patients with hypoproliferative thrombocytopenia.

Methods:Patients (16- 80 yr) undergoing chemotherapy foi AMI or autologous haemopoictlc stem-cell transplantation were

randomly assigned to receive either platelet translusion when bleeding occurred (therapeutic strategy) or when morningplatelet

counts were <10<109/l(prophylactic strategy:current standard of care).

Results:In all patients,the therapeutic strategy reduced the mean number of platelet transfusions by 33.5% (95% Cl 22.2-43.1;

p<0.0001).Major haemorrhage was not increased inpatients who had undergone autologous transplantation.Risk of non-fatal

grade 4 bleedingwas increased in patients with AML.

Conclusion:The therapeutic strategy should be considered for patients followingautologous stem- cell transplantation but not for

patientswith AML.

NEJM 2013:368:11 21 Title: transfusion Strategies for Acute Upper Gastrointestinal Bleeding

Purpose: lo compare the efficacy and safely of a restrictive transfusion strategy with a liberal translusion strategy in patients with

acute upper Gl bleeds.

Methods:921patients with severe acute upper Gl bleeding were assigned to either a restrictive strategy (transfusion when Hb <7 g/

dl;target Hb ~ 7-9 g/dl) or a liberal strategy (transfusion when Hb <9 g/dl;target Hb 9-11g/dl).

Results:Survival at 6 wk was higher in the restrictive-strategy group than inthe liberal-strategy group (95% vs.91%:hazard rabo,

0.55;95% Cl.0.33*0.92:P’

0.02).Further bleeding was more common in patients on restrictive-strategy than liberal-strategy (10%

vs.16%;P-0.01):adverse events were also more common (40% vs.48%;

p-0.02).

Conclusion:A restrictive transfusion strategy led to better outcomes than a liberal strategy in patients with acute upper Gl bleeding.

2462

TRICCBP

Therapeutic Platelet Translusion

Versus Routine Prophylactic

Transfusion in Patients With

Haematological Malignancies:

An Open -Label,Multicenlie,

Randomised Study.Wandl et al. 2012

Transfusion Slralcgies for Acute

Upper Gastrointestinal Bleeding.

Villanueva etal. 2013

ri

L J

+

Activate Windows

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H63 Hematology Toronto Notes 2023

Trial Name Reference Clinical Trial Details

Anemia

CHOIR NEJM 2006:355:2085 08 Title:Correction of Anemia with Epoetin o in Chronic Kidney Disease

Purpose:Todetermine the optimal level of Hemoglobin correction by recombinant human erythropoietin (epoetin o) inanemic CKO

patients.

Methods:1432 patients with CKD were randomly assigned to receive a dose ol epoetin alfa targeted to achieve a hemoglobin level

of13.5 g/dl or a dose targeted to achieve a level of 11.3 g/dL.

Results: 125 composite events (death.Ml,hospitaliration tor CHf, or stroke) were seen in the high hemoglobin group,as compared

with 97 events in the low- hemoglobin group (harard ratio.1.34;95% Cl.1.03-1.74;P'0.03).

Discussion:In patients with anemia and CKO.targeting a lower Hb reduced incidence of death. Ml. CHf related hospitaliration.and

stroke.

Other

CRASH-2 Health Technot Assess

2013:17|10):1-79

Title:The CRASH-2 Trial:A Randomised Controlled Trial and Economic Evaluation of theEffects of Tranexamic Acid on Death.Vascular

Occlusive Events and Transfusion Reguirement in Bleeding Trauma Patients

Purpose:To assess how early administration of a short course of tranexamic acid (TXA) influences rates of death,vascular occlusive

events and blood transfusions in trauma patients.

Methods:20211adult trauma patients within8 h of injury that had,or were at risk for.significant bleeding were randomized to

receive TKAor matching placebo.

Results: TXA significantly reduced all-causemortality at 28 d (14.5% in TXA vs.16.0% inplacebo:p'0.0035).Death rates caused by

bleeding were significantly reduced (4.9% vs.5.7%;p'0.0077).the risk of death due to bleeding was increased by treatment given

alter 3 h (4.4% vs. 3.1%; p-0.004|.

Conclusion:The risk of death was safely reduced by early TXA in bleeding trauma patients.8cyond 3 h of Injury,treatment islikely

Ineffective.

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