The Effect of Prophylactic Platelet
Transfusion Dose on The Hypoliferative
Thrombocytopenia Outcomes
Areej Al mugairi
Hematological Pathology (PGY4)
University of Alberta
Jan 25,2011
Background
• It has been standard of practice in most hematology/
oncology units to use prophylactic platelet transfusion for
severely thrombocytopenic patients.
• The circulating platelets has a basic role in endothelial
support and to maintain hemostasis in the healthy
individuals.
• The platelet loss from the circulation for endothelial
support has been calculated to be 7.1 x 109/L.
Background
• Several studies and the currently used guideline
provide the evidence that the threshold for
prophylactic platelet transfusion can be safely reduced
to 10 x 109/L.
• The optimal number of platelets in a prophylactic
platelet transfusion is controversial.
BJH 2003:122;10-23
N Engl J Med.1997;337:1870-1875
Blood 1998 ;91:3601-3606
Dose of Prophylactic Platelet Transfusions
and Prevention of Hemorrhage
(PLADO)
N.Engl.J.Med. 2010; 362:600-13
The Question (PICO)
• Population: Hospitalized patients of any age with
hypoproliferative thrombocytopenia (Chemo or
Hematopoietic Transplant) 10 x 109/L.
• Intervention: Low dose (110 x 109/m2) prophylactic
platelet transfusion.
• Comparison: Standard (220 x 109/m2) or high dose (440
x 109/m2) prophylactic platelet transfusion.
• Outcome: Incidence of WHO grade 2 or higher bleeding.
Study Design
• Multicenter (26) NHLBI Sponsored RCT, with
patients enrolled between 2004-2007.
• Exclusion Criteria:
▫
▫
▫
▫
▫
▫
▫
▫
▫
▫
▫
▫
Severe thrombocytopenia duration <5 days.
Extremes of Weight (<10 kg, >135 kg).
PT or PTT >1.3X Normal.
Fib <1 g/L.
Pre-existing bleeding (≥WHO Grade 2)
Platelet refractoriness within the last 30 days.
Acute promyelocytic leukemia .
ITP, TTP/HUS.
Drugs affecting Platelet number or function.
Major surgery within previous 2 week.
Pregnancy.
Planed prophylactic transfusion.
4% withdraw
from the study
N=1351
Patients enrolled
79 did not receive
platelet
*The attempted dose adherence
among 1162 patients.
**The attempted dose adherence for
5384 transfusions.
N=1272
Randomized
Medium dose
Low dose
109/m2
F/U 30 Days
(110 x
N=417
(220 x
N=423
)
Dose adherence* 79%
Dose adherence** 86%
Dose changed in 17%
Trigger changed in 32%
(440 x 109/m2)
N=432
Dose adherence* 92%
Dose adherence** 98%
Dose changed in 9%
Trigger changed in 26%
9 died
417
Analyzed
High dose
109/m2)
Dose adherence* 86%
Dose adherence** 93%
Dose changed in 7%
Trigger changed in 25%
7 died
(1 from Hge)
4 died
423
Analyzed
432
Analyzed
Validity?
1. Did the experimental and the control groups begin the
study with a similar prognosis?
• The patients were randomized.
• The randomization was concealed by means of
computer-generated permuted blocks.
• The patients was analyzed in the groups to which they
were randomized regardless of whether they actually
received the intervention (Intention-To-Treat Analysis).
Validity?
• The patients in the 3 treatment arms were equally
distributed in regard of demographics,primary diagnosis
and laboratory test results.
Baseline Characteristics
Primary Diagnosis and Stratification
Low Dose
( N=417)
Medium Dose
P value
Primary diagnosis-no.(%)
• Acute Leukemia
202(48)
• Lymphoma
91(22)
• Myeloma
39(9)
• Chronic Leukemia
24(6)
• Myelodyspalsia
16(4)
• Solid tumors
5(1)
• Others
40(10)
0.35
Stratification categories-no.(%)
• Allogenic HST
173(41)
• Autologous HST
138(33)
• Chemo or Radiation
104(25)
for hematologic cancer
• Chemo or radiation
2(<1)
for solid tumors
1.00
( N=423)
High Dose
P value
( N=432)
0.40
186(44)
89(21)
59(14)
24(6)
26(6)
6(1)
33(8)
0.45
185(43)
84(19)
56(13)
33(8)
14(3)
7(2)
53(12)
0.96
173(41)
142(34)
105(25)
3(1)
P value
0.97
177(41)
149(34)
104(24)
2(<1)
Baseline Lab Characteristics
Validity?
2. Did experimental and the control groups retain a similar
prognosis after the study started?
• The clinician may be aware of the group allocation :
▫
▫
•
The different size of the platelet bags( as the low dose is half of
the medium dose).
Some of the clinicians changed the platelet dose when the
patient bleeds.
The outcome assessor were not aware of the group
allocation
▫
Bleeding grade was calculated by computer based system.
Clinical Assessment
• Research staff Performed :
▫ Daily assessment of the bleeding (physical
examination).
▫ Patient interview .
▫ Chart reviews .
▫ Daily platelet count.
▫ Daily hemoglobin and hematocrit.
• 3 non study physician adjudicated whether
bleeding is the cause of death.
Validity?
• Patient follow up in the 3 arm considered complete when
one these conditions occurred( which ever occurred
first):
▫
▫
▫
▫
▫
At hospital discharge(71%).
After 10 day period without PLT transfusion(14%).
30 days after the first PLT transfusion(10% ).
At withdrawal from the study(4%).
At death(2%).
The Precision of The Results
Low Dose
( N=417)
>1Episode of
71%
Medium Dose
P value
0.60
( N=423)
69%
High Dose
P value
( N=432)
P value
0.71
70%
0.94
grad 2 bleeding
(% of patient)
Highest
Grade of bleed
• Grade1
• Grade2
• Grade3
• Grade4
>1 RBC transfusion
(% of patients)
0.30
30%
58%
9%
3%
95%
Total RBC units /patient
0.65
32%
59%
7%
2%
0.54
30%
60%
8%
2%
0.12
92%
1.00
4
0.62
(2-8)
4
(2-8)
0.70
92%
4
(2-8)
0.09
0.90
Low Dose
( N=417)
No. of Platelet
Transfusions/patient
5
(3-9)
Medium Dose
P value
<0.001
Total No. of platelet
925
0.002
Transfused( x10-9 ) (491-1791)
Death from
hemorrhage
0
( N=423)
3
(2-6)
1125
(699-2276)
0
High Dose
P value
0.09
<0.001
1.00
( N= 432)
3
(2-6)
P value
<0.001
1963
<0.001
(1061-3744)
1
1.00
Response to Platelet Transfusion
Low Dose
( N=417)
No. of transfusions
Medium Dose
P value
2193
( N=423)
High Dose
P value
1646
( N=432)
P value
1386
( all data available)
Pre transfusion PLT
count (x10-3 /mm-3 )
9(7-16)
0.48
9(7-19)
0.08
Post transfusion PLT
count (x10-3 /mm-3 )
22(16-30)
<0.001
34(24-48)
<0.001
50(33-68)
10(5-17)
<0.001
19(11-30)
<0.001
38(22-54) <0.001
0.08
10(6-16)
0.03
9(7-12)
0.21
<0.001
PLT increment
(x10-3 /mm-3 )
Post transfusion CCI *
(x10-3 /mm-3 )
10(5-15)
11(6-15)
0.98
Applicability of The Results
1. Were the study patients similar to the patient in my
practice?
• Yes.
• The medium platelet dose(220 x 109/m2 ) in the trial is
equivalent to the standard adult dose considering 70kg
adult has body surface area(BSA)of1.8 m2.
Applicability of The Results
2. Where all clinically important outcome considered?
• Primary end point:
Bleeding of grade 2 or higher .
• Secondary end point:
The highest grade of bleeding.
Total number of platelets transfused.
Number of platelet transfusion.
•
• Surrogate end points:
 Total number of RBC transfusion.
A randomized controlled trail comparing
standard and low dose strategies for
transfusion of platelets (SToP) to patients
with thrombocytopenia.
Blood 2009 113: 1564-1573
Study Design
• Multicenter international study(6 sites) conducted by
BEST collaborative .
• 129 Patients recruited ( Oct. 2003 and Jun 2007).
• A double blind randomized controlled trail (RCT).
• Non-inferiority study.
• Eligibility criteria similar to PLADO trial .
• 2 arm study:
• Low dose arm , platelet count (150-300x109/product).
• Standard dose arm ,platelet count ( 300-600 x109/product).
Study Design
• Primary outcome:
▫ Bleeding Grade 2 or higher.
• The study was terminated by March 2008 by the Data
Safety Monitoring Board( DSMB) because the difference
in grade 4 bleed reached the prespecified threshold of
5% in the low dose arm.
Validity?
1.Did the experimental and control groups begin the study
with a similar prognosis?
•
•
•
•
The patients were allocated through a secure central web-based
randomization system.
The randomization was concealed with block randomization .
The patients analyzed in the groups to which they were
randomized.
The 2 arms were similar with respect to the prognostic variable
except for the baseline platelet count (31x109 /l in low dose arm
vs 46x109 /l in standard dose arm).
Baseline Criteria
The Primary Diagnosis
Validity?
2.Did experimental and control groups retain a similar
prognosis after the study started?
• It is double blinded study as the clinician and outcome
assessor were not aware of the treatment allocation
but 7 patients were prematurely removed from the
study at the request of the treating physician (6 in the
low arm).
• The follow up was complete till the DSMB stopped the
trail .
The Precision of the Results
Standard Dose
Type of the bleeding
No. of patients with bleeding(%)
Grade1
Grade2
Grade3
Grade4
Grade 2 or higher
n=61
48(78.7)
28(45.9)
6(9.8)
0
30(49.2)
Low Dose
n=58
53(91.4)
28(48.9)
5(8.6)
3(5.2)
30(51.7)
Percentage of days with bleeding (proportion)
Grade2 or higher
Grade 4
8.5(73/854)
0
12.1(111/918)
0.5(5/918)
The Precision of the Results
• The proportion of patient with grade 2 bleeding was
52%(30/58)in the low dose arm and 49% ( 30/61) in the
standard dose arm ( RR=1.05;CI 0.73-1.50).
Conclusion
• After a trigger threshold of 10x109/l platelet is reached ,
the platelet dose has no significant effect on the
incidence of bleeding in patients of hypoprliferative
thrombocytopenia .
• The rate of bleeding seen in PLADO trial was higher
compared to other previous studies.
• The strategy of low dose platelet transfusion is effective
and can preserve the blood supply.