Post on 13-Jan-2016
description
Transfusion Support in Hematology-Oncology
PatientsDarrell 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
Platelets
Plasma
Cryoprecipitate
Plasma Derivatives
Albumin
IVIg
Cryoppt-reduced Plasma
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
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
Investigator ObservationFreireich, Ann Int Med 1963;59:277
Djerassi, NEJM 1963;268:221Recommendation: Transfuse to > 50K
Transfusion for Surgery
Invasive Procedures
No increase in bleeding complications w/ plt ct 50-100K vs. > 100K
No excess surgical bleeding when plt ct > 50K
Toy, 1990, 1991
Minor procedures: thoracentesis, line placement, etc.
Bishop, Am J Hematol 1987;26:147 - Major intra-abdominal/ intra-thoracic surgeriesRecommendation: Transfuse if < 50K
Investigator Observation
Prophylactic Transfusion
Stool blood loss in 28 aplastic, thrombocytopenic patients
Ann. Review of Med, Vol. 31, 1980
Bleeding risk vs. plt ct The Lancet, Vol. 338, 1991
Platelet Count/μL x 103
255 10 15 200
50
100
25
75
Sto
ol B
lood
Loss
(ml /
day)
0 00 - 5
25
150
75
300
Ble
ed
ing
Ep
isod
es/1
00
0
days
6-10
11-15 16-20 >20
n=
28
0
n=
68
7
n=
80
5
n=
64
2
n=
35
88
Minor BleedingMajor Bleeding
Risk Category by Plt Ct/μL x 103
Prophylactic TransfusionThreshold for Prophylactic Plt
Transfusion in Adult AML• 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.
Safety & Cost-Effectiveness of 10K vs. 20K Platelet Trigger
• 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.
0
5
10
15
20
25
30
>10091-95
81-8571-75
61-6551-55
41-4531-35
21-2511-151-5
PLATELET COUNT (x 103/L)
DA
YS W
ITH
≥ G
RA
DE
2 B
LEED
ING
(%
)
*Data from 1,272 patients with morning platelet counts on 24,309 days.Data reported as percentage with 95% confidence intervals.
PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING VERSUSVERSUS EACH DAY’S MORNING PLATELET COUNT* EACH DAY’S MORNING PLATELET COUNT*
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
Stanworth et al NEJM 2013;368:1771-80No deaths from bleeding
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
Usually not needed
Clopidogrel
P2Y ADP receptor inhibitor
Verify Now (Accumetrix), aggregometry
Yes
CP Bypass
Plt activation on membrane
Abn PFA eg closure time
YES
Uremia Accumulation of metabolic inhibEg guanidino succinic acid
Abn PFA eg closure time
No, Use Dialysisand DDAVP
Platelet Refractoriness
Hours
0 12 24
Pla
tele
t C
ou
nt
40K
20K
10K
63
Usual Response
Disease-related platelet consumption:
Bleeding, Sepsis, DIC, Splenomegaly, VOD, Amphotericin B, etc.
Antibody Mediated:Plt crossmatching, HLA-matched
30K
Indications for Apheresis Platelets
• To control or prevent bleeding in patients refractory to WBPCs (HLA-matched 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
Hours Post transfusion
0 12 24
Pla
tele
t C
ou
nt
50K
25K
10K
63
Usual Response
Recovery CCI >7500
Survival CCI>4500
“DETERMINATION OF THE
OPTIMAL PROPHYLACTIC PLATELET DOSE
STRATEGY TO PREVENT BLEEDING IN
THROMBOCYTOPENIC PATIENTS”
(PLADO Trial)
Study was conducted at 26 participating hospitalswithin the Transfusion Medicine/Hemostasis Clinical Trials Network
supported by the National Heart, Lung and Blood Institute of the National Institutes of Health
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.
*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.
STUDY DESIGNSTUDY DESIGNThree-Arm
ProspectiveRandomized 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)
Platelet Dosing StudyPlatelet Dosing StudyLow Med High Total
Number of patients enrolled 453 449 449 1351
Number of patients with 1 platelet transfusion* 417 423 432 1272
Primary Endpoint: At least one episode of Grade 2 bleeding 71% 69% 70% 70% (% of patients)
Secondary Endpoints: Highest grade of bleeding on study
(% of patients): None or Grade 1 30% 32% 30% 31% Grade 2 58% 59% 60% 59% Grade 3 9% 7% 8% 8% Grade 4 3% 2% 2% 2%
Hemorrhagic mortality (# of patients) 0 0 1 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?
p=0.72
Time Since First Platelet Transfusion (Days)
Pro
babi
lity
of R
emai
ning
Eve
nt F
ree
0 5 10 15 20 25 30 35
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ApheresisWBP
No. Patients at Risk
Apheresis
WBP
552 338 168 68 32 16 4
220 119 56 30 15 5
PLADO: Platelet Source as a predictor of ≥ Grade 2 bleeding
Time Since First Platelet Transfusion (Days)
Pro
ba
bili
ty o
f R
em
ain
ing E
vent F
ree
0 5 10 15 20 25 30 35
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
ABO IdenticalMinor MismatchMajor Mismatch
No. Patients at RiskABO Identical
Minor MismatchMajor Mismatch
467 215 78 31 10 3 175 30 8 2 1198 72 27 5
p=0.28
PLADO: ABO matching as a predictor of time to ≥ Grade 2
bleeding
Time Since First Platelet Transfusion (Days)
Pro
ba
bili
ty o
f R
em
ain
ing
Eve
nt
Fre
e
0 5 10 15 20 25 30
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0-2 Days3 Days4 Days5 Days
No. Patients at Risk0-2 Days
3 Days4 Days5 Days
48 13 5158 47 16 1223 69 13 1221 71 23 4 1
PLADO: Duration of platelet storage as a predictor of time to ≥ Grade 2
bleeding
p=0.87
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
Symptoms & Signs• Fever (temp rise at
least 1° C or 1.8° F)• Chills• Dyspnea• Tachycardia• Flushing• Hypertension“Fever-Chill” Reaction
Febrile, Non-Hemolytic TR
Etiology:• Recipient Ab’s to
transfused WBCs• Cytokines in
transfused product
Leukoreduction Reduces the Rate of FNHTR
Author Non-LR
RBC
LR
RBC
Non-LR
Plts
LR
Plts
Yazer*
2004
0.33% 0.19%
p<.001
0.45% 0.11%
p<.001
Paglino*
2004
0.34% 0.18%
p<.0001
2.18% 0.15%
p<.0001
King*
2004
0.37% 0.19%
p=.0008
NA 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)
05
10
15
2025
30
35
40
4550
Control UVB -PC F-AP F-PC
Perc
en
t A
lloim
mun
ized
F-AP = filtered apheresisF-PC = filtered pools
UVB-PC = Ultraviolet B irrad
New Eng J Med 1997; 337:1861-9.
530 patients with AML randomized to 4 platelet therapies
p<.001 for all 3 study arms
Trial to Reduce Alloimmunization to Platelets (TRAP): Refractoriness
02
4
6
810
12
14
16
1820
Control UVB -PC F-AP F-PC
Perc
ent
refr
act
ory
F-AP = filtered apheresisF-PC = filtered pools
UVB-PC = UVB irrad
New Eng J Med 1997; 337:1861-9.
530 patients with AML randomized to 4 platelet therapies
p≤.03 for all 3 study arms
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
TransplantationSeroneg
N=252
CMV safe
N=250 p valueCMV 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 Stem cell transplantation
Transfusion
Skin ++ ++++
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
Zou S et al Transfusion 2010;50:1495.
Virus
1996
2001 2013
HIV 1:493,000
1:1,326,000
1:1,470,000
Hepatitis C
1:103,000
1:237,0001:1,150,000
Hepatitis B
1:63,000
1:137,000<1:300,000
HTLV I, II
1:641,000
1:641,000 1:2,437,296
Estimated Risks of Viral Transmissions in US
62C O N F I D E N T I A L