-
Transfusion Medicine for the Clinician
Walter (Sunny) Dzik, MDBlood Transfusion Service, Massachusetts General Hospital
Associate Professor, Harvard Medical School [email protected]
-
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: [email protected]
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