Transfusion Medicine for the Clinician

Walter (Sunny) Dzik, MDBlood Transfusion Service, Massachusetts General Hospital

Associate Professor, Harvard Medical School sdzik@mgh.harvard.edu

I have no disclosures

Pharma

Transfusion occurred on: September 26, 1818

James Blundell: transfusion devices

TransfusionComponent production

Plasma derivatives

Blood storage & preservation

Matching: Immunohematology

HLA

Stem cell

Apheresis

Clinical use of blood Adverse

effectsDonor Services

Medicine

Adverse effects of RBC transfusion 1 in 100 million

1 in 105

1 in 106

1 in 104

1 in 107

1 in 103

1 in 102

1 in 10

Risk

TACO

HIV

Death by medical error

HCV

TRALI

Carson et al. Ann Intern Med 2012; 157: 49-58

1-A 1-B

A 60 yo man for cardiac surgery, pre-op INR = 2.44 units of FFP are transfused...

TRALI or TACO ?

• Donor antibodies directed at HLA or Neutrophil antigens (multiparous female blood donors);

• React with pulmonary endothelium and WBCs, fix complement, flood alveolus.

• Host susceptibility varies.• Incidence on the decline (parous females excluded)

TRALI (Tx related acute lung injury)

• Donor antibodies directed at HLA or Neutrophil antigens (multiparous female blood donors);

• React with pulmonary endothelium and WBCs, fix complement, flood alveolus.

• Host susceptibility varies.• Incidence on the decline (parous females excluded)

TRALI (Tx related acute lung injury)

TACO (Tx associated circulatory overload)• 100-1,000 x more common than TRALI !• Risk factors: age, heart disease, renal failure, pre-

transfusion positive fluid balance; multiple units.• 1% of transfused patients; 5% of transfused ICU

Part 2: RBC Transfusions….

12 million per year in the USA….

The majority of US blood centers have a stock lasting < 3 days !

Oxygen Delivery depends on Heart and Hgb level

0 200 400 600 800 1000O2 Delivery mLO2/min/m2

Hem

oglo

bin

15

10

5

0

Normal

n= 1958

Lancet. 1996;348:1055-60

No Cardiovascular Disease

Yes Cardiovascular Disease

Transfusion in Critical Care (TRICC trial)

Randomized, controlled multicenter trial (Canada)Critically ill patients in the non-cardiac ICU

Not actively bleeding

Liberal StrategyHgb 10 - 12 g/dL

Restrictive StrategyHgb: 7 - 9 g/dL

Hebert et al. NEJM 1999; 340: 409 - 17

33% avoided Tx 0% avoided Tx

NEJM, 1999

Results: Transfusion in Critical Care

Hébert P, et al. NEJM 1999;340:409-17

Liberal: Hgb: 10-12 g/dL

P = 0.10

Restrictive: Hgb: 7-9 g/dL

Randomized Trials of RBC transfusion thresholdAuthor Name Setting Trigger ‘n’

Hebert, 1999 TRIC Adult ICU 7 vs 9 838Kirpalami, 2006 PINT Infants

Part 3: Fresh Frozen Plasma

Mild-moderately elevated INR does not represent a clinical coagulopathy.

“Stop treating INRs”

% Coagulation Factors

PT (sec)

50 %

30 %

100 %

21.81915.51312 3024 32

Normal hemostasis

INR 1.0 1.7 2.0 2.2 3.01.3

therapeutic

Zone of

Zone of

anticoagulation

INR and Coagulation Reserve

April 2006 ISI reagent

Closed Liver Biopsy: Abnormal Coags

• 200 patients: liver biopsy• All had abnormal coags• No pre-procedure FFP

• Insert Laparoscope.. biopsy..watch liver bleed !• Measure the time the liver bleeds

Ewe. Digestive Dis Sciences 1981; 26: 388

Ewe. Digestive Dis Sciences 1981; 26: 388

Coagulation time (% activity)

4.5 min Average

No correlation between pre-biopsy Platelet count or PT and duration of bleeding after liver biopsy.

Ewe. Digestive Dis Sciences 1981; 26: 388

4.5 min Average

Bled = 5No = 502

Bled = 0No = 41

Platelets

% Coagulation Factors

PT (sec)

50 %

30 %

100 %

21.81915.51312 3024 32

Normal hemostasis

INR 1.0 1.7 2.0 2.2 3.01.3

Zone of

therapeuticZone of

anticoagulation

INR and Coagulation Reserve

Feb 2007

20 %10 %

Toward Rational FFP Transfusion: Effect on Coagulation Test Results

• Retrospective cohorts at U of Oklahoma.

• Test group:179 patients receive 295 units of FFP

• Control group: Patients with INR < 1.6 who were not transfused

All patients get follow-up INR @ ~ 4-8 hrs

Holland and Brooks, Am J Clin Path 2006; 126: 133.

INR Change per 2 units FFP

r2 = 0.82

Decrease = 0.37 [pre-Tx INR] – 0.471.7

Holland and Brooks, Am J Clin Path 2006; 126: 133.

FFP take away• Let go of the INR.

– Useful only at extremes: INR>6• No value to pre-procedure FFP in nearly all cases.• Local hemostasis for local bleeding.

• In advanced liver disease:– Dose Products by the clock (not INR)– MAIN hemostatic defect in cirrhosis is not addressed by

FFP, but rather by amicar.

Part 4: Platelets

ApheresisSingle donor

Whole blood derivedPooled

Leukoreduction & HLA alloimmunization

“What matters is the number of WBCs NOT the number of donors…”

Non-LR’ed Pooled Plts

(control) Pooled Platelets (Leukoreduced)

Single Donor Platelets

(Leukoreduced)

530 patients with AML

TRAP Trial: N Engl J Med 1997;337:1861-9.

p < 0.001

45 %

20 %

6 8420

50

100C

umul

ativ

e %

Allo

imm

uniz

atio

n

Weeks

Percent Alloimmunization

Pooled

Filtered Pooled DonorFiltered Single Donor

NEJM 1997; 337:1861.

same outcome

p < 0.001

45 %

20 %

6 8420

50

100C

umul

ativ

e %

Allo

imm

uniz

atio

n

Weeks

Percent Alloimmunization

Pooled

Filtered Pooled DonorFiltered Single Donor

NEJM 1997; 337:1861.

same outcome

Moms

The Threshold For Prophylactic Platelet Transfusion in Adults with Acute Myeloid Leukemia

Rebulla et al. N Engl J Med 1997; 337: 1870-5

AML (n=255)

10,000 /µL 20,000 /µL

RCT in 21 centers; Adults with AML for induction chemotherapy

10,000 thresholdN=135

20,000 thresholdN=120

Median Age 51 (16-70) 49 (17-70)Days in hospital 29 (3-64) 28 (4-54)Complete remission 76 (56%) 76 (63%)

Trigger: 20,000/µL vs 10,000/µL

Rebulla P, et al. NEJM 1997 337; 1870 - 75.

Prospective RCT in 255 patients with AML...

1 fatal CNS bleed @ platelets = 32,000/uL

Platelet Dose Trial (PLADO)Large multicenter RCT from NIH Transfusion and

Hemostasis Clinical Trials Network

Heme/onc patients, n = 1272

3 units 6 units 12 units

% of patients with WHO grade ＞ 2 bleeding

Platelets < 10,000 /µL

Slichter et al. NEJM 2010: 362; 600-13

71% 69% 70%

25%

17%

Based on 24,300 observation days.

2). Chance of bleeding is NOT related to platelet countData from prospective PLADO trial

Slichter et al. NEJM 2010: 362; 600-13

% of days > grade 2

You as consultant…

• A 32 year old female in the medical ICU has a platelet count = 30,000/uL and needs a biopsy.

• She is not bleeding.• You are asked to advise on platelet transfusion.

Think beyond the platelet count… Each of these patients has a plt count of 30,000/uL.The hemostatic lesion is entirely different.The appropriateness of Platelet Tx is entirely different.

“Reversing” Plavix– a fantasy

Platelet Transfusion does NOT reverse DAPT*

Cohn SM et al. Cureus doi 10.7759/cureus.3889

4º C 22º C

Day +1Pre Post Day +3 Day +7

*DAPT = dual anti-platelet therapy

PATCH RCT: Platelets versus No-platelets after CNS bleed on anti-platelet agents

No plateletsPlatelets

190 patients in 41 hospitals

n= 93n= 97Given within 6 hrs of symptomsIf aspirin: 5 unitsIf plavix: 10 units

Platelets No PlateletsAge 74.2 73.5Aspirin +/- Persantin 89% 91%Plavix 7% 2%ICH volume 13.1 (5 – 42) 8.0 (4 – 25)

Balanced by randomization

PATCH trial. Lancet 2016

PATCH RCT: Platelets versus No-platelets after CNS bleed on anti-platelet agents

Primary Outcome: Functional score at 3 months

Platelets n=97

No Platelets n=93

p -value

Poor functional score 72% 56% 0.01Alive at 3 months 68% 77% 0.15Median ICH growth at 24 hours 2 (0.3-9.3) 1 (0 – 4.4) 0.81Death in hospital 25% 16% 0.15

PATCH trial. Lancet 2016

Part 5: Pharmacologic adjuncts

PLASMIN

Fibrin / Fibrinogen

Lysine

Lysine binding sitesEnzymatic site

Fibrinolysis

Anti-Fibrinolytics

Amicar or TxA

Lysine Analogues: Don’t be afraid to use them…

RCT evidence:CRASH-II (trauma)WOMAN (OB bleeding)ATACAS (cardiac surgery)TICH-2 (neurosurgery)

Broad experience:Orthopedic surgeryCardiac surgery w/ bleeding

Case series:Cirrhosis Hemophilia w/ inhibitorsCancer thrombocytopenia

Amicar: 5 gm load and 0.25-1.0 gm/hr

Tranexamic acid: 1 gm load then 1.0 gm over 8 hrs

Use Vit K orally or i.v. NOT sub-cut

Lubetsky Arch Intern Med. 2003;163:2469. Raj Arch Intern Med. 1999;159:2721

Time (hours)

10

8

6

4

2

INR

2 4 6 12 24

2.5 mg oral

1 mg I.V.

1 mg sub-cut

4 Factor PCC (K-Centra) vs FFP for Coumadin Reversal

PCC n= 98

FFP n= 104

Age 69.8(29 – 96)

69.8(26 - 92)

Baseline INR 3.9 3.6

Non-visible GI 55 58

Visible 16 21

Intracranial 12 12

Other 15 13

200 patients on coumadin with acute bleeds.All patients receive vitamin K.

Sarode et al. Circulation. 2013;128:1234-1243

Results: K-Centra vs FFP

PCC N = 98

FFP N = 104

PCC - FFP

71 68 --

72%(64 to 81)

65 %(56 to 74)

7.1 %(-6 to 20)

PCC N = 98

FFP N = 104

PCC - FFP

62%(53 to 72)

10 %(4 to 15)

53 %(40 to 66)

Hemostatic Efficacy at 24 hours

INR < 1.3 at 30 min after start of Rx

PCC was “not inferior”to FFP for hemostatic

efficacy

PCC was superior to FFP for rapid correction

of laboratory test.

Sarode et al. Circulation. 2013;128:1234-1243

Prada PradaxaThis is This is

X

XaCa++V

PlateletProthrombin Thrombin

VIIa-TFVIIIIX

Dabigatran Pradaxa

Fibrinogen Clot

DOAC: Direct Thrombin Inhibitor

LAB: “thrombin time”

Idarucizumab (Praxbind)• Monoclonal antibody Fab fragment• Affinity for dabigatran = 350x higher than

dabigatran for thrombin.• Clinical study

– 51 patients with bleeding on dabigatran– 39 patients on dabigatran …going to O.R.

• 5 grams of idarucizumab in 30 min (1020 molecules)• Endpoints:In tra-op hemostasis

Pollack et al. NEJM 2015; 373: 511-20.

202 patients to O.R.: 93% had normal hemostasis.

Nearly 1 in 5 died (19% overall mortality).

X

XaCa++V

PlateletProthrombin Thrombin

VIIa-TFVIIIIX

Fibrinogen Clot

DOAC: Oral Xa InhibitorsRivaroxaban Xarelto Apixaban Eliquis

LAB: “anti-Xa assay”

Endoxaban Lixiana

Andexanet: Reversal of oral Xa inhibitor drugs

Andexanet

Xa inhibitor drug

Prothrombin

Thrombin

Andexanet is a decoy factor Xa molecule

Effect of Andexanet on anti-Xa activity:

Siegal DM et al. NEJM 2015; 373: 2413-2424.

Effect of Andexanet on anti-Xa activity:

Siegal DM et al. NEJM 2015; 373: 2413-2424.

$50,000

$50,000

Effect of Andexanet on anti-Xa activity:

Siegal DM et al. NEJM 2015; 373: 2413-2424.

$50,000

$50,000

10 Take Home Messages…

1. Blood is a shared national resource: use it wisely.2. Volume Overload is much more likely than TRALI.3. Don’t transfuse a Hct…think about cardiac output.4. Use FFP to treat actual bleeding, not an INR.5. HLA-sensitization occurs in multiparous females. 6. Platelets: think about turn-over rate.7. Platelet transfusions worsened outcomes after CNS

bleeds on aspirin + persantin.8. To reverse coumadin, use vit K+FFP; or vit K+PCC.9. Amicar / TxA is safe when used in bleeders.10. Reversal agents are here for DOACs.

Thank you !

Write with questions: sdzik@mgh.harvard.edu

Transfusion Medicine for the ClinicianSlide Number 2Slide Number 3Slide Number 4Slide Number 5Slide Number 6Slide Number 7Slide Number 8Slide Number 9Part 2: RBC Transfusions….Oxygen Delivery depends on Heart and Hgb levelSlide Number 12Slide Number 13Slide Number 14Randomized Trials of RBC transfusion thresholdPart 3: Fresh Frozen Plasma Slide Number 17Closed Liver Biopsy: Abnormal CoagsSlide Number 19Slide Number 20Slide Number 21Slide Number 22Toward Rational FFP Transfusion: Effect on Coagulation Test ResultsSlide Number 24FFP take awayPart 4: PlateletsLeukoreduction & HLA alloimmunizationSlide Number 28Slide Number 29The Threshold For Prophylactic Platelet Transfusion in Adults with Acute Myeloid LeukemiaSlide Number 31Slide Number 32Slide Number 33You as consultant…Slide Number 35Slide Number 36Slide Number 37PATCH RCT: Platelets versus No-platelets after CNS bleed on anti-platelet agents PATCH RCT: Platelets versus No-platelets after CNS bleed on anti-platelet agents Slide Number 40Slide Number 41Slide Number 42Slide Number 434 Factor PCC (K-Centra) vs FFP for Coumadin Reversal Results: K-Centra vs FFPSlide Number 46Slide Number 47Idarucizumab (Praxbind)Slide Number 49Slide Number 50Slide Number 51Slide Number 52Slide Number 5310 Take Home Messages…Slide Number 55