Transfusion Support in
Hematology-Oncology
Patients
Darrell J. Triulzi, M.D.
Professor of Pathology
University of Pittsburgh
Medical Director
The Institute for Transfusion Medicine
Pittsburgh, PA
Transfusion Support in
Hematology/Oncology Patients
•
•
•
•
Platelet therapy
Leukoreduction
Transfusion transmitted CMV
Irradiated Blood Components: Prevention
of Transfusion associated Graft vs Host
disease
Blood Products
Whole Blood
Packed RBCs
Platelet-rich Plasma
Plasma
Cryopptreduced
Plasma
Cryoprecipitate
Platelets
Plasma Derivatives
Albumin
IVIg
Whole Blood Platelets
• 60 ml each (approx.)
• >5.5 x 1010 platelets/bag
• Storage: 5 days at room temp,
constant agitation
• Dose: 1 unit/10 kg up to 40 kg
Adults (>40 kg) - Pool of 4
(= 1 unit of apheresis plts)
•  plt ct  20 – 35K
Whole blood platelet concentrate
Apheresis Platelet Donation
-1.5 -2.0 hr
donation
-Returns red cells
and plasma
- Collects 1-3 full
adult doses of plts
Apheresis Platelets
• 200-400 ml
• >3.0 x 1011 plts/bag
(equiv to 5-6 WBPCs)
• Storage: 5 days @ room
temp, constant agitation
• Dose: 1 apheresis plt
product per transfusion
– plt ct  20 – 40K
Apheresis Platelets
• 200-400 ml
• >3.0 x 1011 plts/bag
(equiv to 5 WBPCs)
• Storage: 5 days @ room
temp, constant agitation
• Dose: 1 apheresis plt
product per transfusion
Single Donor Platelets
Clinical Indications for Platelets
• Significant bleeding in a patient with thrombocytopenia
• Planned invasive procedure in a patient with
thrombocytopenia
• Risk of spontaneous bleeding (eg CNS, lung) due to severe
thrombocytopenia
• Bleeding or invasive procedure and platelet dysfunction
Transfusion for Bleeding
Achieving hemostasis in bleeding
thrombocytopenic patients
Investigator
Freireich, Ann Int
Med 1963;59:277
Djerassi, NEJM
1963;268:221
Observation
Cessation of overt bleeding in 51/57
episodes when plt increment
exceeded 40K
Cessation of overt bleeding in 17/18
pts when plt increment exceeded
30-40K
Recommendation: Transfuse to > 50K
Transfusion for Surgery
Invasive Procedures
Investigator
Toy, 1990, 1991
Minor procedures:
thoracentesis, line
placement, etc.
Observation
No increase in bleeding
complications w/ plt ct 50100K vs. > 100K
Bishop, Am J Hematol
No excess surgical bleeding when
1987;26:147 - Major
plt ct > 50K
intra-abdominal/ intrathoracic surgeries
Recommendation: Transfuse if < 50K
Prophylactic Transfusion
Stool blood loss in 28 aplastic,
thrombocytopenic patients
Bleeding risk vs. plt ct
The Lancet, Vol. 338, 1991
300
50
150
25
75
n=687
75
n=3588
Minor
Bleeding
Major
Bleeding
n=642
Ann. Review of Med, Vol. 31, 1980
100
25
0
0
5
10
15
20
Platelet Count/μL x 103
25
0
0-5
6-10 11-15 16-20 >20
Risk Category by Plt Ct/μL x 103
Prophylactic Transfusion
Threshold for Prophylactic Plt
Transfusion in Adult AML
Safety & Cost-Effectiveness of 10K
vs. 20K Platelet Trigger
•
•
•
•
•
•
•
•
•
•
•
•
•
•
225 new AML pts (not m3)
Random, prospective
A: (135) Tx @ < 10K
B: (120) Tx @ < 20K
21.5% fewer plt Txs in 10K grp
No signif difference in RBC Txs
Major bleeding:
21.5% (10K) vs 20% (20K),p=0.41)
Risk similar 10 vs. 20K threshold
Rebulla et al. NEJM, 337:26:1872-5, 1997.
105 new AML pts (not M3)
Prospective, 17 centers
A: (110) 10K vs. B: (106) 20K
Less plt Txs (~60%) in 10K grp
No signif difference in RBC Txs
Bleeding (WHO grade 2-4):
18% vs. 17% (p=0.8)
One-third lower cost w/ 10K vs. 20K
trigger w/ no associated increase in
bleeding risk
Wandt H et al. Blood, 91:10:3601-6, 1998.
DAYS WITH ≥ GRADE 2 BLEEDING (%)
PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING VERSUS
EACH DAY’S MORNING PLATELET COUNT*
30
25
20
15
10
5
0
PLATELET COUNT (x 103/L)
*Data from 1,272 patients with morning platelet counts on 24,309 days.
Data reported as percentage with 95% confidence intervals.
Prophylaxis vs No Prophylaxis
• 600 patients randomized to Prophylaxis at
10k/ul vs no prophylaxis
• Both groups given plt tx for bleeding or
procedures
• >15 yo with hematologic malignancy or
stem cell transplant
• Assessed daily for bleeding
• Primary endpoint rate of WHO ≥grade 2
bleeding
Stanworth et al NEJM 2013;368:1771-80
Baseline Characteristics
Stanworth et al NEJM 2013;368:1771-80
Prophylaxis vs No Prophylaxis
No deaths from bleeding
Stanworth et al NEJM 2013;368:1771-80
Indications for Platelet Transfusions
in Heme-Onc Patients
• To control or prevent bleeding due to
deficiencies of platelet number or function
• Plt ct <10K/μL – prophylaxis, stable pt
• Plt ct <20K/μL – prophylaxis in patient
with clinical factors such as sepsis,
DIC, high fevers, splenomegaly
• Plt ct <50K/μL – bleeding or
undergoing invasive procedure
Platelet Transfusions for
Platelet Dysfunction
Cause
Mechanism
Test
Role for Plt Tx?
Aspirin
Irreversible
inhibitor COX
Abn PFA eg
closure time
Yes
NSAIDS
Reversible
inhibitor COX
Abn PFA eg
closure time
Clopidogrel
P2Y ADP receptor Verify Now
(Accumetrix),
inhibitor
Usually not
needed
Yes
aggregometry
CP Bypass
Plt activation on
membrane
Abn PFA eg
closure time
YES
Uremia
Accumulation of
metabolic inhib
Eg guanidino
succinic acid
Abn PFA eg
closure time
No, Use Dialysis
and DDAVP
Platelet Refractoriness
40K
Platelet Count
Usual Response
30K
Disease-related
platelet consumption:
20K
Bleeding, Sepsis, DIC,
Splenomegaly, VOD,
Amphotericin B, etc.
Antibody Mediated:Plt
crossmatching, HLA-matched
10K
0
3
6
12
Hours
24
Indications for Apheresis
Platelets
• To control or prevent bleeding in
patients refractory to WBPCs (HLAmatched or cross-match compatible
platelets)
• To reduce donor exposures in patients
receiving a limited number of
transfusions
• Otherwise, same as for WBPCs
Contraindications to Platelet
Transfusion
• Plt ct >100K/μL w/o platelet dysfunction
• ITP or TTP unless bleeding is life-threatening
• Prophylactic use
with massive blood
transfusion
• Prophylactic use
following cardiac
bypass
Recent advances in Platelet Transfusion
Practice
Does the dose of platelets transfused affect
hemostasis in thrombocytopenic patients?
How important are the characteristics of the platelet
component such as the source, ABO matching, or
storage duration in prevention of bleeding?
Platelet Recovery and Survival
Platelet Count
50K
Usual Response
25K
Recovery
CCI >7500
Survival
CCI>4500
10K
0
3
6
12
Hours Post transfusion
24
“DETERMINATION OF THE
OPTIMAL PROPHYLACTIC PLATELET DOSE
STRATEGY TO PREVENT BLEEDING IN
THROMBOCYTOPENIC PATIENTS”
(PLADO Trial)
Slichter SJ, Kaufman RM, Assman SF, McCullough J, Triulzi
DJ, et al. Dose of prophylactic platelet transfusions and
prevention of hemorrhage. New Eng J Med 2010;362:600-13.
Study was conducted at 26 participating hospitals
ithin the Transfusion Medicine/Hemostasis Clinical Trials Network
supported by the National Heart, Lung and Blood Institute
of the National Institutes of Health
STUDY DESIGN
Three-Arm
Prospective
Randomized Trial)
Platelets / m2(BSA)**

Medium Dose (MD)*
2.2 x 1011

Lower Dose (LD)
1.1 x 1011 (½ MD)

Higher Dose (HD)
4.4 x 1011 (2x MD)
* Medium dose corresponds most closely to the current
standard transfusion dose of 6 pooled platelet concentrates
or 1 apheresis platelet collection.
** An acceptable dose was within 25% either above or below
the target dose. The transfusion service was given each
patient’s study dose but not the patient’s randomization
arm.
Platelet Dosing Study
Number of patients enrolled
Number of patients with 1 platelet transfusion*
Primary Endpoint:
At least one episode of  Grade 2 bleeding
(% of patients)
Secondary Endpoints:
 Highest grade of bleeding on study
(% of patients):
 None or Grade 1
 Grade 2
 Grade 3
 Grade 4
 Hemorrhagic mortality (# of patients)
Low
453
417
Med
449
423
High
449
432
Total
1351
1272
71%
69%
70%
70%
30%
58%
9%
3%
0
32%
59%
7%
2%
0
30%
60%
8%
2%
1
31%
59%
8%
2%
1
*All data reported will be based on patients who received 1 platelet transfusion.
There were no significant differences among the arms for any
of these study endpoints. NEJM 2010;362:600-13.
How important are the characteristics of the
platelet component such as the source, ABO
matching, or storage duration in prevention of
bleeding?
PLADO: Platelet Source as a predictor
of ≥ Grade 2 bleeding
1.0
Apheresis
WBP
0.9
Probability of Remaining Event Free
0.8
0.7
0.6
p=0.72
0.5
0.4
0.3
0.2
0.1
0.0
0
5
10
15
20
25
30
4
Time Since First Platelet Transfusion (Days)
No. Patients at Risk
Apheresis
552
338
168
68
32
16
WBP
220
119
56
30
15
5
35
PLADO: ABO matching as a predictor of
time to ≥ Grade 2 bleeding
Probability of Remaining Event Free
1.0
ABO Identical
Minor Mismatch
Major Mismatch
0.9
0.8
0.7
p=0.2
8
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
10
15
20
25
30
Time Since First Platelet Transfusion (Days)
No. Patients at Risk
ABO Identical
467
Minor Mismatch
75
Major Mismatch 198
215
30
72
78
8
27
31
2
5
10
1
3
1
35
Probability of Remaining Event Free
PLADO: Duration of platelet storage as a
predictor of time to ≥ Grade 2 bleeding
1.0
0.9
0.8
p=0.87
0.7
0.6
0.5
0.4
0.3
0-2 Days
3 Days
4 Days
5 Days
0.2
0.1
0.0
0
5
10
15
20
Time Since First Platelet Transfusion (Days)
No. Patients at Risk
0-2 Days
48
3 Days
158
4 Days
223
5 Days
221
13
47
69
71
5
16
13
23
1
1
4
1
25
30
PLADO: Analysis of Platelet
Characteristics
Summary
• Although the source of platelets, ABO
matching, and duration of storage have a
measureable effect on platelet increments,
there is no discernable effect of these
platelet characteristics on a bleeding
outcome when platelet transfusions are used
prophylactically in hematology and
oncology patients
Transfusion Support in
Hematology/Oncology Patients
•
•
•
•
Platelet therapy
Leukoreduction
Transfusion transmitted CMV
Irradiated Blood Components: Prevention
of Transfusion associated Graft vs Host
disease
Leukoreduction: Definition
• AABB Standards
5.7.4.1 “ Leukocyte reduced blood and
components shall be prepared by a method
known to reduced the leukocyte number to
<5x106 for apheresis platelets and Red Blood
Cells…”
Leukoreduction by Filtration
Filter Generation
Filter
composition
Mechanism
Filter efficiency
Log10
First
170-240u nylon
mesh
barrier
-
Second
40u polyester
barrier
1
Third
Nonwoven
synthetic fibers
Barrier and
adsorption
3-6
>99.9%
Accepted Indications for
Leukoreduction
• Reduce the risk of fever chill non-hemolytic
reactions
• Prevent or delay alloimmunization to HLA
antigens
• Reduce the risk of CMV transmission
Febrile, Non-Hemolytic
Transfusion reactions
“Fever-Chill” Reaction
Symptoms & Signs
• Fever (temp rise at
least 1° C or 1.8° F)
• Chills
• Dyspnea
• Tachycardia
• Flushing
• Hypertension
Febrile, Non-Hemolytic TR
Etiology:
• Recipient Ab’s to
transfused WBCs
• Cytokines in
transfused product
Leukoreduction Reduces the Rate of
FNHTR
Author
Yazer*
2004
Paglino*
2004
King*
2004
Non-LR
RBC
0.33%
0.34%
0.37%
LR
RBC
0.19%
p<.001
0.18%
p<.0001
0.19%
p=.0008
Non-LR
Plts
0.45%
2.18%
NA
LR
Plts
0.11%
p<.001
0.15%
p<.0001
NA
*Transfusion Jan 2004 Vol 44.
Accepted Indications for
Leukoreduction
• Reduce the risk of fever chill non-hemolytic
reactions
• Prevent or delay alloimmunization to HLA
antigens
• Reduce the risk of CMV transmission
Trial to Reduce Alloimmunization to
Platelets (TRAP)
Percent Alloimmunized
530 patients with AML randomized to 4 platelet therapies
UVB-PC = Ultraviolet B irrad
F-AP = filtered apheresis
F-PC = filtered pools
50
45
40
35
30
25
20
15
10
5
0
p<.001 for all 3 study arms
Control
UVB -PC
F-AP
F-PC
New Eng J Med 1997; 337:1861-9.
Trial to Reduce Alloimmunization to
Platelets (TRAP): Refractoriness
Percent refractory
530 patients with AML randomized to 4 platelet therapies
UVB-PC = UVB irrad
F-AP = filtered apheresis
F-PC = filtered pools
20
18
16
14
12
10
8
6
4
2
0
p≤.03 for all 3 study arms
Control
UVB -PC
F-AP
F-PC
New Eng J Med 1997; 337:1861-9.
Accepted Indications for
Leukoreduction
• Reduce the risk of fever chill non-hemolytic
reactions
• Prevent or delay alloimmunization to HLA
antigens
• Reduce the risk of CMV transmission
Transfusion Transmitted
Cytomegalovirus
CMV in Blood Donors
• 30-80% of blood donors are CMV seropositive
. Prevalence increases with age.
• CMV is transmitted in a latent non-infectious
state in the donor leukocytes.
• CMV is transmitted only by cellular blood
components eg. red cells, platelets
CMV in Auto or Allo BMT
Concept of CMV “Safe” Blood
Components
• Leukoreduction can substitute for CMV
seronegative components
– CMV exclusively WBC associated
– >3 log (99.9%) leukoreduction removes virus and greatly
reduces infectivity
• Conserves seronegative units for patients at highest
risk
• More readily available
CMV Safe
Auto BMT
Randomized Trial of CMV Safe vs
Seronegative Blood in Allogeneic Stem Cell
Transplantation
Seroneg
N=252
CMV safe
N=250
p value
CMV infection
Day 21-100
Day 0-100
2
4
3
6
1.0
.5
CMV disease
Day 21-100
Day 0-100
0
0
3
6
.25
.03
Mean RBC units
18
18
NS
Mean plt units
83
85
NS
Bowden R, et al Blood 1995;86:3598
Indications for CMV
Seronegative Components
• Seronegative recipient of a seronegative
allogeneic stem cell transplant
• Seronegative allogeneic stem cell transplant
candidate
Indications for CMV “SAFE”
cellular components
• Autologous stem cell transplant recipient
regardless of CMV serostatus
• All hem-onc patients who are not allogeneic
stem cell transplant candidates
• Any heme/onc or stem cell transplant
patients known to be CMV seropositive
Transfusion Associated Graft
versus Host Disease
(TAGVHD)
TAGVHD
• Results from engraftment of foreign T cells from
cellular blood components
• Clinically similar to GVHD from stem cell
transplantation except pancytopenia is a prominent
feature
• Usually presents with high fever and rash within 3-30
days of transfusion
• Unresponsive to therapy: mortality exceeds 90%!
Organ Involvement in TAGVHD
Site
Transfusion
Skin
Stem cell
transplantation
++
Liver
++
++++
GI tract
++
++++
pancytopenia
-
++++
++++
Prevention of TAGVHD
• Gamma irradiation of cellular blood
components (Cesium, Cobalt, X-ray)
• Minimum 2500 rads acheives 5-6 log
reduction in T cell mitogen response
• Does not cause clinically significant
damage to the blood component
• RBC experience some K+ leak, shelf life
shortened to 28 days
Cell Irradiator
Irradiation Confirmation Sticker:
“NOT” should not be visible
Indications for Irradiated Cellular
Blood Components
• Stem cell transplant recipients (auto or allo)
• Patients with congenital immunodeficiency
syndromes eg SCIDS, Wiscott-Aldrich, DiGeorge
• Patients with Hodgkins disease
• Patients receiving fludarabine
• Directed blood from blood relatives
• HLA matched platelets
• OPTIONAL for leukemia/lymphoma, usually done
• Not recommended for patients with solid organ
malignancy
Irradiated
CMV
Negative
Leukoreduced
Estimated Risks of Viral Transmissions
in US
Virus
1996
2001
2013
1:493,000
1:1,326,000
1:1,470,000
Hepatitis C 1:103,000
1:237,000
1:1,150,000
Hepatitis B
1:63,000
1:137,000
<1:300,000
1:641,000
1:641,000
1:2,437,296
HIV
HTLV I, II
Zou S et al Transfusion 2010;50:1495.
CONFIDENTIAL
62