1. 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

2. Transfusion Support in Hematology/Oncology Patients
Platelet therapy
Leukoreduction
Transfusion transmitted CMV
Irradiated Blood Components: Prevention of Transfusion associated Graft vs Host disease

3. Blood Products Whole Blood Packed RBCs Platelet-rich Plasma Plasma
Platelets
Cryoppt-reduced Plasma
Cryoprecipitate
Plasma Derivatives
Albumin
IVIg

4. 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

5. Whole blood platelet concentrate

6. Apheresis Platelet Donation
hr donation
-Returns red cells and plasma
- Collects 1-3 full adult doses of plts

7. Apheresis Platelets 200-400 ml >3.0 x 1011 plts/bag
(equiv to 5-6 WBPCs)
Storage: 5 room temp, constant agitation
Dose: 1 apheresis plt product per transfusion
plt ct  20 – 40K

8. Apheresis Platelets 200-400 ml >3.0 x 1011 plts/bag
(equiv to 5 WBPCs)
Storage: 5 room temp, constant agitation
Dose: 1 apheresis plt product per transfusion

9. Single Donor Platelets

10. 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

11. Transfusion for Bleeding
Achieving hemostasis in bleeding
thrombocytopenic patients
Investigator
Observation
Freireich, Ann Int Med 1963;59:277
Djerassi, NEJM 1963;268:221
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

12. Transfusion for Surgery
Invasive Procedures
Investigator
Observation
Toy, 1990, 1991
Minor procedures: thoracentesis, line placement, etc.
Bishop, Am J Hematol 1987;26:147 - Major intra-abdominal/ intra-thoracic surgeries
No increase in bleeding complications w/ plt ct K vs. > 100K
No excess surgical bleeding when plt ct > 50K
Recommendation: Transfuse if < 50K

13. 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
100
300
Bleeding Episodes/1000 days
Minor Bleeding
Stool Blood Loss (ml/day) 75
n=280
Major Bleeding
n=805 50
150
n=642
n=3588
n=687 25 75 25 5 10 15 20 25
0 - 5
6-10
11-15
16-20
>20
Platelet Count/μL x 103
Risk Category by Plt Ct/μL x 103

14. Prophylactic Transfusion
Threshold for Prophylactic Plt Transfusion in Adult AML
225 new AML pts (not m3)
Random, prospective
A: (135) < 10K
B: (120) < 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.

15. DAYS WITH ≥ GRADE 2 BLEEDING (%)
PERCENT OF DAYS WITH ≥ GRADE 2 BLEEDING VERSUS EACH DAY’S MORNING PLATELET COUNT* 30 25 20
DAYS WITH ≥ GRADE 2 BLEEDING (%) 15 10 5
1-5
11-15
21-25
31-35
41-45
51-55
61-65
71-75
81-85
91-95
>100
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.

16. 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:

17. Baseline Characteristics
Stanworth et al NEJM 2013;368:

18. Prophylaxis vs No Prophylaxis
No deaths from bleeding
Stanworth et al NEJM 2013;368:

19. 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

20. 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
Usually not needed
Clopidogrel
P2Y ADP receptor inhibitor
Verify Now (Accumetrix), aggregometry
CP Bypass
Plt activation on membrane
YES
Uremia
Accumulation of metabolic inhib
Eg guanidino succinic acid
No, Use Dialysis
and DDAVP

21. Platelet Refractoriness
40K
Usual Response
30K
Disease-related platelet consumption:
Bleeding, Sepsis, DIC, Splenomegaly, VOD, Amphotericin B, etc.
Platelet Count
20K
Antibody Mediated:Plt crossmatching, HLA-matched
10K 3 6 12 24
Hours

22. 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

23. 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

24. 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?

25. Platelet Recovery and Survival
50K
Usual Response
Platelet Count
25K
Recovery CCI >7500
Survival CCI>4500
10K 3 6 12 24
Hours Post transfusion

26. OPTIMAL PROPHYLACTIC PLATELET DOSE STRATEGY TO PREVENT BLEEDING IN
“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:
Study was conducted at 26 participating hospitals
within the Transfusion Medicine/Hemostasis Clinical Trials Network
supported by the National Heart, Lung and Blood Institute
of the National Institutes of Health

27. STUDY DESIGN Three-Arm Prospective
Randomized Trial) Platelets / m2(BSA)**
 Medium Dose (MD)* 2.2 x 1011
 Lower Dose (LD) 1.1 x (½ MD)
 Higher Dose (HD) 4.4 x (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.

28. Platelet Dosing Study
Low Med High Total
Number of patients enrolled
Number of patients with 1 platelet transfusion*
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)
*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:

29. How important are the characteristics of the platelet component such as the source, ABO matching, or storage duration in prevention of bleeding?

30. PLADO: Platelet Source as a predictor of ≥ Grade 2 bleeding
Time Since First Platelet Transfusion (Days)
Probability of Remaining Event Free 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
Apheresis
WBP
No. Patients at Risk
552
338
168 68 32 16 4
220
119 56
PLADO: Platelet Source as a predictor of ≥ Grade 2 bleeding
p=0.72

31. PLADO: ABO matching as a predictor of time to ≥ Grade 2 bleeding

32. PLADO: Duration of platelet storage as a predictor of time to ≥ Grade 2 bleeding

33. 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

34. Transfusion Support in Hematology/Oncology Patients
Platelet therapy
Leukoreduction
Transfusion transmitted CMV
Irradiated Blood Components: Prevention of Transfusion associated Graft vs Host disease

35. Leukoreduction: Definition
AABB Standards
“ 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…”

36. Leukoreduction by Filtration
Filter Generation
Filter composition
Mechanism
Filter efficiency
Log10
First
u nylon mesh
barrier -
Second
40u polyester 1
Third
Nonwoven synthetic fibers
Barrier and adsorption
3-6
>99.9%

38. 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

39. 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

40. Febrile, Non-Hemolytic TR
Etiology:
Recipient Ab’s to transfused WBCs
Cytokines in transfused product

41. Leukoreduction Reduces the Rate of FNHTR
Author
Non-LR
RBC LR
Plts
Yazer*
2004
0.33%
0.19%
p<.001
0.45%
0.11%
Paglino*
0.34%
0.18%
p<.0001
2.18%
0.15%
King*
0.37%
p=.0008 NA
*Transfusion Jan 2004 Vol 44.

42. 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

43. Trial to Reduce Alloimmunization to Platelets (TRAP)
530 patients with AML randomized to 4 platelet therapies
F-AP = filtered apheresis
F-PC = filtered pools
UVB-PC = Ultraviolet B irrad
p<.001 for all 3 study arms
Percent Alloimmunized
New Eng J Med 1997; 337:

44. Trial to Reduce Alloimmunization to Platelets (TRAP): Refractoriness
530 patients with AML randomized to 4 platelet therapies
F-AP = filtered apheresis
F-PC = filtered pools
UVB-PC = UVB irrad
Percent refractory
p≤.03 for all 3 study arms
New Eng J Med 1997; 337:

45. 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

46. Transfusion Transmitted Cytomegalovirus

47. 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

48. CMV in Auto or Allo BMT

49. 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

50. CMV Safe Auto BMT

51. Randomized Trial of CMV Safe vs Seronegative Blood in Allogeneic Stem Cell Transplantation
p value
CMV infection
Day
Day 0-100 2 4 3 6
1.0 .5
CMV disease
.25
.03
Mean RBC units 18 NS
Mean plt units 83 85
Bowden R, et al Blood 1995;86:3598

52. Indications for CMV Seronegative Components
Seronegative recipient of a seronegative allogeneic stem cell transplant
Seronegative allogeneic stem cell transplant candidate

53. 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

54. Transfusion Associated Graft versus Host Disease (TAGVHD)

55. 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%!

56. Organ Involvement in TAGVHD
Site
Stem cell transplantation
Transfusion
Skin ++
++++
Liver
GI tract
pancytopenia -

57. 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

58. Cell Irradiator

59. Irradiation Confirmation Sticker: “NOT” should not be visible

60. 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

61. Irradiated
CMV Negative
Leukoreduced

62. Estimated Risks of Viral Transmissions in US
Virus
1996
2001
2013
HIV
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
HTLV I, II
1:641,000
1:2,437,296
Zou S et al Transfusion 2010;50:1495.
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