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The Platelet Limbo:How Low Can You Go?
Susan Montgomery
Discussant: Dr. Terry Gernsheimer
History: Lots and lots
Harker LA & Slichter SJ. New Engl J Med 1972;287:155-9
Mucosal Blood Loss and Platelet Count
History: Lots and lots
• K.D Heckman; J Clin Oncol, 15 (1997), pp. 1143–1149 (Acute Leukemia)
• H Wandt; Blood, 91 (1998), pp. 3601–3606• P Rebulla; N Engl J Med, 337 (1997), pp. 1870–
1875• M.S Zumberg; Biol Blood Marrow Transplant, 8
(2002), pp. 569–576
1970’s: favorable results for therapeutic approach to plttransfusions not relevant now given change in treatment strategies
A substantial number of studies showed safety of lowering platelet transfusion threshold from 20K to 10K in pts with AML or undergoing stem cell transplant.
History: Lots and lots
Prophylactic Platelet Transfusion Triggers: 10,000/l vs. 20,000/l in Acute Leukemia
10,000/ l 20,000/ l
Patients Major Hemorrhagic Patients Major Hemorrhagic(N) Bleeding Deaths (N) Bleeding Deaths
(%) (%) (%) (%)
Rebulla et al, 135 22 1 120 20 01997
Wandt et al, 58 18 0 47 17 01998
Heckman et al, 37 0 41 01997
• K.D Heckman; J Clin Oncol, 15 (1997), pp. 1143–1149 (Acute Leukemia)
• H Wandt; Blood, 91 (1998), pp. 3601–3606• P Rebulla; N Engl J Med, 337 (1997), pp. 1870–
1875• M.S Zumberg; Biol Blood Marrow Transplant, 8
(2002), pp. 569–576
1970’s: favorable results for therapeutic approach to plttransfusions not relevant now given change in treatment strategies
A substantial number of studies showed safety of lowering platelet transfusion threshold from 20K to 10K in pts with AML or undergoing stem cell transplant.
German group: 2 studies in mid 2000’s Small, single center studies showing safety of ppx vs
therapeutic plt transfusions in pts with AML or those undergoing stem cell transplant
History: Lots and lots
Therapeutic vs. prophylactic platelet transfusion
Lancet article, German study:
Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with hematologic malignancies: an open-label, multicenter randomized study
Wandt, et al; Lancet Vol 380, Oct 13, 2012
Abstract at ASH
The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematologic malignancies and severe thrombocytopenia (TOPPS trial)
Simon Stanworth; UK non-inferiority study
Lancet: Therapeutic vs. prophylactic platelet transfusion
German multi-center study b/w 2005-2010; n = 391 Patients had either any subtype of AML (group A) or
were undergoing autologous PBSCT (group B) Group A patients were undergoing
induction/consolidation at standard dosing: n = 190 Group B were underdoing standard high dose
chemotherapy for transplant: n = 201 60% for MM; 30% lymphoma; 10% AML
Exclusion criteria: Refractory to platelet transfusions
Previous major bleeding
Plasmatic coagulopathy
In group B: patients with pulmonary or cerebral lesions
Randomized within each group on a 1:1 basis to receive ppx plt transfusion for plt # <10 or a therapeutic transfusion at any sign of WHO gd 2 bleeding or higher
Platelets: pooled or apheresed, leukocyte reduced Ppx group were transfused one unit if plt count <10
Therapeutic group transfused with one unit at first, then additional units if the treating physician thought necessary
Petechiae or skin purpura of any size not considered clinically relevant and therefore not included
Retinal bleeding without visual impairment not included
Any new headache or neurologic symptoms prompted CT to assess for CNS hemorrhage
WHO bleeding scale
WHO bleeding scale
WORLD HEALTH ORGANIZATION (WHO)Bleeding Grades
BleedingGrade Type of Bleeding
0 None
1 Petechiae, ecchymosis, occult blood, mild vaginal spotting
2 Gross hemorrhage not requiring RBC transfusion
epistaxis, hematuria, hematemesis
3 Hemorrhage requiring transfusion of ≥ 1 unit RBCs
4 Life‐threatening hemorrhage massive bleeding causing hemodynamic compromise bleeding into a vital organ
Primary outcome:
Number of platelet transfusions given during a standardized observation period of 14 days per patient
Secondary outcomes:
Clinically relevant bleeding
# of RBC transfusions required
Days with platelet count <20
Side effects of transfusions
Length of hospital stay
Survival
Results Primary endpoint: 33.5% less plt transfusions in the
therapeutic gp across Groups A & B (p = <0.0001).
Secondary Endpoints: no statistically significant difference b/w therapeutic and ppx groups, including overall survival
Exception: clinically relevant bleeding
Clinically relevant bleeding:
Risk of grade 2+ bleeding higher in therapeutic group in both groups A & B Group A: p = <0.0001
Group B: p = 0.0005
Group A: more grade 4 bleeding in therapeutic group vs the prophylactic group; 7% vs 2%, p = 0.0095
Group B: no evidence of grade 4 bleeding
Group A; AML Overall, bleeding
risk higher in AML group vs SCT gp 37% vs 18%,
p<0.0001
More grade 2 and 4 bld in therapeutic gp
13 gd 4 blds 11 controlled by
timely transfusions
7 w/plt >10
2 died of cerebral hemorrhage 1 with plt ~11;
pulm fungal infxn, ? Cerebral lesion
1 with plt >10; thrombocytopenia
Group B; transplant Overall, bleeding
risk higher in AML group vs SCT gp 37% vs 18%,
p<0.0001
No grade 4 bleeds
More grade 2 bleeding in therapeutic gp vs ppx gp
Take home for Lancet Article
Decreased # of plt transfusion in the therapeutic gp (by 1/3)
Increase risk of grade 2 or higher bleeding in therapeutic vs ppx platelet transfusion across AML and transplant pts
Grade 2 or higher bleeding was roughly 2x higher in the therapeutic vs the ppx approach
~93% of bleeds were only grade 2 bleeds, therefore Bleeding was tolerated
Most were controlled by timely platelet transfusions
Grade 4 bleeding only seen in the AML (group A) group, and of those, majority in therapeutic group
Conclusion: OK for therapeutic approach in stable transplant patients but should continue ppx approach for patients with AML undergoing induction or consolidative chemotherapy
TOPPS trial: UK non-inferiority study
The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematologic malignancies and severe thrombocytopenia (TOPPS trial)
Primary outcome: proportion of patients with clinically relevant bleed, gd 2 or higher, up to 30days after randomization
No ppx: n = 301; ppx: n = 299; 70% of patients in each gp undergoing autologous SCT
Fewer plt transfusions in the no ppx group
TOPPS results
Grade 2-4 bleeding occurred in 50% of patients in the no-ppx groups vs 43% in the ppx group; p = 0.06
Negative trial: did not prove that a no-ppx approach is non-inferior to a ppx approach No-ppx gp had more days with gd 2 or high bleeding
and shorter time to first bleed 6/300 gd 3-4 blds in the no-ppx group vs 1/298 in ppx
group: not statistically significant Only 2 of 7 of these pts had a plt count <10
Both pts receiving induction chemotherapy for AML
Needs further subgroup analysis
Thank you
Dr. Terry Gernsheimer
Dr. Mazyar Shadman
Dr. Aaron Gerds