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Transfusion Medicine

Everything a Medical Oncologist should know about blood

Jeannie Callum, MD, FRCPC, CTBSDirector Of Transfusion MedicineAssociate Professor, University of Toronto

Which of the following is true about premedication?

A. Results in a 50% reduction in FNHTRB. Results in a 50% reduction in urticarial

reactionsC. Only prevents reactions from platelet

transfusionsD. Is of no value in preventing both FNHTR

and urticarial reactionsE. Should be administered to all patients

after the first transfusion reaction

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Which of the following are true regarding platelet transfusions?A. Administered as pools of 5 unitsB. The total volume per pool of

platelets is 200 mLC. All apheresis donors are maleD. ABO compatibility is not important

for platelet transfusionsE. Indicated for prophylaxis if the

platelet count is below 20

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Which of the following is an appropriate indication for plasma?A. A non-bleeding patient with an INR of

13 from warfarinB. A patient booked for lymph node

biopsy with an INR of 1.57C. A patient with a GI bleed and an INR

of 1.4D. A patient needing emergency

surgery for ICH on warfarin INR 3.2E. None of the above

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The Medical School Basics

What you should already know

This should be a review

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ABO and Rh D Grouping

There are four major ABO blood groups: O, A, B and AB

All recipients are also tested for Rh D: Rh D Positive or Rh D Negative

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O

AB

BA

RBC Compatibility

Universal Donor

Universal Recipient

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O

AB

BA

Plasma Compatibility

Universal Donor

Universal Recipient

Platelets

There is no such thing as a universal donor

We try for ABO-identical always but 30% of the time we can’t due to supply issues

Platelet incompatibility for A or B results in poorer increments and reduced plt survival

Plasma incompatibility can RARELY cause life-threatening ABO mediated hemolysis

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Blood Grouping

Rh D not detectedA & B not detected Anti-A & Anti-Bpresent

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Antibody ScreenPicks up Alloantibodies

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RBC Panel – Identify the antibody(s)

00400400000

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RBC Panel – Identify the antibody(s)

00400400000

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Crossmatch - 3 kinds

Electronic Crossmatch: 2 minutes patient blood group tested twice, unit ABO retested,

and antibody screen negative the computer does the final ABO check only

Immediate Spin: 10 minutes patient plasma and donor red cells mixed for final ABO

check only

Full antiglobulin Crossmatch: 45 min patient plasma, donor red cells, and anti-IgG checks for compatibility for all red cell antigens only used for patients with red cell alloantibodies

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What are we going to cover?Hemovigilance dataInfectious risk updateNon-viral transfusion complications

Indications for components RBC, PLT, FFP

2001-2009Serious Reactions (n = 142 including 14 deaths)

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3

46

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6 6

16

2 1

13

05

101520253035404550

[1]

[10]

[1] [1]

[1]

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HIVHIV

HCVHCV

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Transfusion Transmitted Injury Surveillance System (TTISS) Canada’s National hemovigilance system Modeled on the French system You must report every transfusion

reaction to the hospital blood bank, including: Minor – including urticarial/febrile reactions Serious - obviously Circulatory overload

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What are we going to cover?Hemovigilance dataInfectious risk updateNon-viral transfusion complications

Indications for components RBC, PLT, FFP

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CBS disease prevention strategy HIV Ab, HIV NAT (minipool) HCV Ab, HCV NAT (minipool) HBsAg, HBcAb, HBV NAT (minipool) Syphilis HTLV-1/2 Ab WNV NAT (minipool) CMV Ab (selective inventory) Bacterial culture Parvovirus B19 (Fractionated products only) Leukoreduction Diversion pouch/arm cleaning Chagas’ testing Deferral of all female apheresis donors

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HIV 1 in 7.8 million

Hepatitis C 1 in 2.3 million

Hepatitis B 1 in 153,000

HTLV 1 in 4.3 million

O’Brien et al. Transfusion 2007;47:316-325.

Residual viral risks

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Year Emerging Pathogen

1995 HGV

1996 vCJD

1997 TTV

1999 WNV

2001 Monkeypox

2002 Chagas

2003 SARS

2004 Avian Flu

2005 Simian Foamy Virus

2006 Chikungunya

2007 HHV-8

2008 Dengue virus

2009 Plasmodium knowlesi

2010 XMRV

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What are we going to cover?Hemovigilance dataInfectious risk updateNon-viral transfusion complications

Indications for components RBC, PLT, FFP

LitigationLitigation

PreventabPreventablele

MeasuraMeasurableble

HAZARDS OF TRANSFUSION

ARDSARDS

MOFMOF

ThrombosThrombosisis

TRIMTRIMCMVCMV

FeveFeverr

Allergic Allergic ReactionsReactions

AnaphylactAnaphylactoid oid

ReactionsReactions TRALITRALI

Transfusion Transfusion 1:1 Causation1:1 Causation

Transfusion Transfusion as risk factoras risk factor

Transfusion 1:1 Transfusion 1:1 Causation + other Causation + other

factor/sfactor/s

GVHDGVHD

CompatibilityCompatibility

HIVHIV

HepatitiHepatitissEndotoxaemiEndotoxaemi

a a

Technical Technical errorerror

UNIFACTORIALUNIFACTORIAL

DefiniteDefiniteOLIGOFACTORIAOLIGOFACTORIA

LL

ProbableProbable

MULTIFACTORIAMULTIFACTORIALL

PossiblePossible

Minor reactions to expect

Most common cause ofdeath from transfusion

Sepsis

Most common causeof morbidity

Other infectious risks(Risk of vCJD if patient expected to live >15-30 years)

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Case

37F, healthy, G3P3 MVC head on collison – 78/50 on scene ER

CT abdo revealed active liver bleed 2 units of blood in ER -> 114/80, P84

OR laparotomy: splenic lac, liver lac, IM nail Rt

femur 6 RBCs, 4 FFP

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ER CXR

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Post-op

CRCU on admission, extubated 98/64, P98, SaO2 100% 2L nasal prongs Hgb 116, Plt 95, WBC 9.6, INR 1.33

POD 1 uneventful with plan to d/c to floor Hgb 93, Plt 68, INR 1.2, not bleeding 5 units platelets that afternoon 2 hours post transfusion develops dry

cough by 2400 intubation required for hypoxia

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Post-transfusion

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TRALI - Presentation

All ages – premature neonates to elderly Dyspnea Cough Hypoxia Fever Hypertension/Hypotension Leukopenia ++ secretions from the endotracheal

tube Normal BNP (pre to post correlation)

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Leukopenia

0

2

4

6

8

10

12

14

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0 1 2 3 4 5 6 7 8 9 10 11 12

Time (Days)

x10^9/L

WBC count

Neutrophils

Lymphocytes

Monocytes

RBC

Total white cell and differential counts.

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TRALI - Presentation

Popovsky & Moore - Transfusion 1985 First case series of 36 patients from the Mayo

Clinic with TRALI over a 2 year period 72% required mechanical ventilation All <6 hours from end of transfusion Bilateral infiltrates in all patients Rapid resolution <96 hours in 81% Mortality 6% No long-term sequelae

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Definition - Probable TRALITRALI Consensus Conference No prior acute

lung injury &

New ALI within 6 hours of transfusion &

No other risk factors for ALI

Acute lung injury = Acute onset PaO2/FiO2 <300 or

saturation <90% on room air

Bilateral lung infiltrates

No evidence of circulatory overload

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1 in 5,000 risk? Sick patient Antigen-

antibody reactions

HLA, class IHLA, class IIGranulocyte antibodies

TRALI - Etiology

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Kopko et al., JAMA 2002; 287: 1968-71 Female donor implicated in a fatal TRALI

case (anti-5b) 290 donations in a 10 year period Lookback investigation on 36 of 50

transfusions (14 charts unavailable) over 2 year period

15 were associated with hypoxic transfusion reactions, and of these 8 were severe enough to require mechanical ventilation

Transfusion Related Acute Lung Injury Under-recognition & Under-reporting

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TRALI - Management

MANAGEMENT Supportive care 80% recover in <4 days (compares to 50-60%

mortality from ARDS)

PREVENTION Reporting & donor deferral Female-free plasma products RBCs 2 mL plasma Apheresis platelet/plasma donors = male only

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TRALI FatalitiesHolness et al. TMR 2004; July

TRALI fatalities reported to FDA (USA) Jan 1997 - Jul 2002 - 58 TRALI of 416

(14%) fatalities in USA FFP most frequently implicated

product (>RBC>PLT>cryoprecipitate) 83% positive for anti-HLA or anti-PMN

antibodies 75% of donors female

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Ladies first, what next?Wright SE, et al. CCM 2008; 36: 1796-802

211 patients undergoing open repair of a ruptured abdominal aortic aneurysm between 1998 and 2006

Less ALI following the change to male fresh frozen plasma (36% before vs. 21% after, p = .04)

At 6 hrs after surgery, fewer patients were hypoxic (87% before vs. 62% after, p < .01)

Change to male plasma was associated with a decreased risk of developing ALI (odds ratio 0.39; 95% CI, 0.16-0.90)

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TRIM – Transfusion-related immunomodulationReal or imagined? Retrospective series have found an

association of transfusion with many bad outcomes: Pneumonia Blood stream infections Multiorgan failure Death Thrombosis Tumour recurrence

Death and TransfusionMarik & Corwin. CCM 2008; 36: 2667-74.

ARDS and TransfusionMarik & Corwin. CCM 2008; 36: 2667-74.

Infection and TransfusionMarik & Corwin. CCM 2008; 36: 2667-74.

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How / why might transfusions cause harm?

2,3 DPG depletion RBC deformity and

deformability loss aberrant RBC –

endothelial cell adhesivity

NO scavenging vasoconstriction,

platelet aggregation supernatant changes

inflammatory mediators

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Nitric Oxide Binding & SNO-Hb

free Hb scavenges NO

SNO-Hb-depletion reduces delivery of NO from RBCs under hypoxic conditions

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CaseCase

37 year woman with cervical cancer Presents to a peripheral hospital ER with SOBOE Hemoglobin 67 g/L She is transfused 4 RBC over 4 hours At the end of the fourth unit the patient

develops light headedness, back pain and has hematuria

Patient told that ‘red urine’ is common after transfusion and is sent home

Feels very unwell at home and family brings patient to Sunnybrook ER

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Transfusion error ratesTransfusion Error Reporting System

Location Rate Denominator

Operating room 1 in 32 18,203

Emergency 1 in 46 6,829

Intensive care 1 in 71 30,546

Medical/surgical ward 1 in 99 36,546

Out patients 1 in 134 669

Out patient procedures

1 in 341 32,690

Obstetrics 1 in 1,369 1,369

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What causes acute hemolytic transfusion reactions? ABO mistake

Usually group O patient given non group O

anti-A and anti-B are naturally occurring antibodies and hemolysis is immediate

Non-ABO antibody Either due to the use of emergency

‘uncrossmatched’ blood or antibody not detected on antibody screen

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CaseCase

39 year old man AML, platelet count 9 x 109/L, tongue edema NYD, for ‘elective’ intubation in OR transfused with 5 units of platelets over 10 minutes

immediately before intubation within minutes - sBP <70 mmHg, HR 150, ST

depression Taken post-op to CRCU – temp 41C Blood cultures taken 1 hr, 4 hrs, 8 hrs post-op Serratia

marcescens despite iv cipro & tobramycin Patient expires at 18 hrs of septic shock 20 days later severe ‘febrile’ reaction to red blood

cells at a peripheral hospital – all other components recalled – including 1/5 above PLT

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Platelets - Beware

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BACTERIALCONTAMINATION

INCIDENCE Risk of septic shock:

1 in 10,000 PLT pools 1 in 100,000 RBC

Risk of death from septic shock: 1 in 40,000 PLT pools 1in 1,000,000 RBC

Key Message – Run PLT slowly for the first 15 minutes

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BACTERIAL CONTAMINATIONETIOLOGY donor bacteremia, skin plug, processing Most common organisms

Yersinia enterocolitica Serratia marcescens/liquefaciens Staph aureus/epidermidis

PRESENTATION fever, rigors, hypotension, renal failure,

DIC PLT more common; RBC more severe

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Bacterial Sepsis Prevention - Canada Donor history Donor vitals Optimal skin cleaning with 2

agents (timed) 40 mL diversion pouch Bacterial culture of all platelets Refrigeration Don’t leave RBCs out of the

fridge!

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What are we going to cover?Hemovigilance dataInfectious risk updateNon-viral transfusion complications

Indications for components RBC, PLT, FFP

Basics

RBCs in non-bleeding, non-urgent situations are ordered 1 at a time 2 units okay if topping up for d/c for chronically

transfused to buy time till they need an outpt transfusion appt

PLT are ordered as POOLS There are no longer any sets of 5 or 6

FFP should be ordered as 15 ml/kg 2 units FFP is a completely inappropriate order

NEVER order pre-medication unless at least 2 episodes of FNHTR or urticaria

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RCT of premedication vs. PlaceboKennedy LD, et al. Transfusion 2008; 48: 2285-91.57

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RBC - TRICC Study

NEJM 1999; 340:409-17 - Hebert et al n=838 non-bleeding, ICU patients, Hb <90 g/L RCT - transfusion Hb <70 vs 100 Stratified by APACHE 2 score Those who were not enrolled were:

Older (mean age, 58 vs. 59) Less cardiac disease (26 vs. 20%)

Groups equal with respect to baseline characteristics Classic patient: 58 year old male, with 1-2 organ

failure, mechanically vented, admitted to the ICU from the OR

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Outcome - Mortality

Outcome <70 g/L <100 g/L P value

30-day 18.7% 23.3% P=0.11

Hospital 22.2% 28.1% P=0.05

NNT = 17 patients to prevent one in-hospital death

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What seemed to harm the patients in the liberal transfusion group?

Complication <70 <100 P value

Cardiac (all) 13% 21% <0.01

MI 0.7% 2.9% 0.02

CHF 5.3% 10.7% <0.01

ARDS 7.7% 11.4% 0.06

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Survival to 30 days – All patients

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All ‘cardiovascular’ patients (n=357)

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FOCUS Study

1300 Fractured hip patients, over age 50 (median age 82 years)

Hemoglobin <100 g/L Randomized to 1 unit for <100

vs <80 g/L Primary outcome:

Ability to walk 10 feet at 60 days Secondary outcomes:

MI/stroke, death, functional status at 30 & 60 days

NO DIFFERENCES FOUND!

Transfusion in Acute Coronary Syndrome

(Myocardial Infarction, Unstable Angina)

Publication Result

Wu et al. NEJM 2001 Transfusion : decreased mortality

(Hb 110 g/L: OR 0.22-0.69; Hb 120 g/L: OR ↑)

Rao et al. JAMA 2004 Transfusion : increased mortality

(Hb 83 g/L: OR 3.94)

Yang et al. J Am Coll Cardiol 2005

Transfusion : increased mortality

(Hb 87 g/L: OR 1.67)

Singla et al. Am J Cardiol 2007

Transfusion : increased mortality / MI

(Hb 90 g/L: OR 2.57)

Conflicting evidence from four retrospective studies…

OR = odds ratio for mortality at this trigger

Keep in mind it might be bleeding that kills you and not the bloodCirculation. 2006;114:774-782

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Bottom line for ACS/AMI patients We don’t know when to transfuse Probably ok with hemoglobin <80 g/L Hemodynamic instability is part of the

problem Don’t use an arbitrary hemoglobin level Stop transfusing when the patient is no

longer symptomatic (ie. no chest pain, no tachycardia) even if hemoglobin less than 100 g/L

Transfuse to a maximum of 100 g/L

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FFPAmerican Society of Anesthesiologists Task Force on Blood Component Therapy. Anesthesiology 1996; 84: 732-47.

The dose is: 15 ml/kg (approximately 3-5 U per adult patient)

Indications: Significant bleeding with PT/PTT

more than 1.5 times normal Microvascular bleeding, massive

transfusion, AND patient’s clinical status precludes waiting for laboratory test results

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Penalty AvoidanceDon’t do this...

Bleeding and INR <1.5 Procedure and INR <1.5 Massive transfusion and

you’re caught not knowing what the INR/PTT is

INR>1.5 but the patient is not actively bleeding

Warfarin reversal Heparin/LMWH reversal “2 units” = 33 kg patient Elevated PTT alone

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An INR of 1.5 is indistinguishable from 1.7

A physician is very comfortable doing a renal biopsy an INR of 1.49 but requires plasma for an INR of 1.51

This is utter insanity! The INR can not have such a strict cut-off

I will show you why There has to be some thought built into

the interpretation of the INR

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% coagulation Factors

50 %

30 %

100 %

INR 1 1.7 2.0 2.2 3.01.3

zone of normalhemostasis

zone of anticoagulation

15 ml/kg FFP

60 ml/kg FFP = 4 L FFP

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Pre-FFP INR 1.3-1.8

Abdel-Wahab OI, et al. Transfusion 2006; 46: 1279-85

The INR of FFP is 1.2-1.4

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iv vitamin K works much faster than oral

Gentle nudge back to 2-32 mg po

Emergency10 mg iv

Door #1 Door #2

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RCT iv vs. poArch Intern Med. 2003 Nov 10;163(20):2469-73

• INR of 6-10 (n = 47) received either 0.5 mg iv or 2.5 mg oral

• IV more rapid at 6 hrs (11/24 vs 0/23) & at 12 hrs (16/24 vs 8/23)

• Patients in the intravenous group tended to be more often overcorrected (INR<2)

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Oral Vitamin K for emergency reversalA common error that results in

delay in cessation of bleeding and getting a patient to a necessary

procedure

Note: If you have a patient with an elevated INR/PTT – you must figure

out why!

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Prothrombin complex concentrates2,7,9,10 & Protein C/S

INR <3 = 1,000 IUINR >3 (or >90 kg) = 2,000 IU

Why use PCCs vs. FFP?PCC FFP

Pooled, virally inactivated

Prion reduction process

Not virally inactivated

Lyophilized

Needs to be reconstituted

Needs ABO group (10min)

Needs to be thawed (30min)

Volume 40-80mL

Infused over 15-30min

Volume 15mL/kg (~1000mL)

Infused over hours

Less risk of transfusion rxns Risk of transfusion rxns: TRALI, TACO, anaphylaxis

$1150 for 1000 units1 $1050 for 6 units plasma2

Cost of Octaplex, Ahmed Coovadia, CBS, 2009-11-16Callum and Pinkerton. BloodyEasy2. 2005.

Why use PCCs vs. FFP?PCC FFP

Pooled, virally inactivated

Prion reduction process

Not virally inactivated

Lyophilized

Needs to be reconstituted

Needs ABO group (10min)

Needs to be thawed (30min)

Volume 40-80mL

Infused over 15-30min

Volume 15mL/kg (~1000mL)

Infused over hours

Less risk of transfusion rxns Risk of transfusion rxns: TRALI, TACO, anaphylaxis

$1150 for 1000 units $1050 for 6 units plasma

Only lasts 6-8 hours

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The European ExperienceJ Thromb Haemost 2008; 6: 622-31

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Platelets

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XY

Buffy coat platelet pool

XY or XX

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PLT CLINICAL SETTING SUGGEST<10 Immune thrombocytopenia Transfuse only with serious

bleeding<10 Thrombocytopenia (e.g. bone marrow

failure)Transfuse 1 pool

<50 Vaginal delivery or procedures notassociated with significant blood loss

1 pool of platelets on hold,transfuse only if seriousbleeding

<50 Periprocedure massive bleeding, majorsurgery, or pre invasive procedure

Transfuse 1 poolimmediately beforeprocedure

<100 Peri-neurosurgery Transfuse 1 pool<100 Head trauma Transfuse 1 poolAny Platelet dysfunction and marked bleeding

(e.g. post cardiopulmonary bypass,aspirin, antiplatelet agents)

Transfuse 1 pool

Platelet Indications

RCT – 20 vs. 10Rubella et al. NEJM 1997; 337:1870-5

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Pre-transfusion triggersB Cameron et al, Transfusion 2007; 47: 206-11

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Platelet Refractoriness1 hour post platelet count is <15 Is it non-immune refractoriness?

Hypersplenism Drug-related Fever DIC Infection

Is it immune refractoriness? ABO antibodies - match HLA antibodies - screen HPA antibodies - screen

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You do not need to remember anything!

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Thank You

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