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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

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Transfusion support in hematology oncology patients

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 patients1
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
Blood Products

Whole Blood

Packed RBCs

Platelet-rich Plasma

Plasma

Platelets

Cryoppt-reduced Plasma

Cryoprecipitate

Plasma Derivatives

Albumin

IVIg


Whole blood platelets
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



Apheresis platelet donation
Apheresis Platelet Donation

  • 1.5 -2.0 hr donation

  • -Returns red cells and plasma

  • - Collects 1-3 full adult doses of plts


Apheresis platelets
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 platelets1
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



Clinical indications for 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

Transfusion for Bleeding

Investigator

Observation

Freireich, Ann Int Med 1963;59:277

Djerassi, NEJM 1963;268:221

Recommendation: 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

Transfusion for Surgery

Investigator

Observation

Toy, 1990, 1991

Minor procedures: thoracentesis, line placement, etc.

Bishop, Am J Hematol 1987;26:147 - Major intra-abdominal/ intra-thoracic surgeries

Recommendation: Transfuse if < 50K


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

Prophylactic Transfusion

100

300

Bleeding Episodes/1000 days

Minor Bleeding

Stool Blood Loss (ml/day)

n=280

75

Major Bleeding

n=805

50

150

n=642

n=3588

n=687

25

75

25

0

0

0

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


Prophylactic transfusion1

Threshold 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.

Prophylactic Transfusion


Transfusion support in hematology oncology patients

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

0

1-5

>100

11-15

21-25

31-35

41-45

51-55

61-65

71-75

81-85

91-95

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
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


Transfusion support in hematology oncology patients

Baseline Characteristics

Stanworth et al NEJM 2013;368:1771-80


Transfusion support in hematology oncology patients

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

Indications for Platelet Transfusions in Heme-Onc Patients



Platelet refractoriness
Platelet Refractoriness platelet number or function

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

0

3

6

12

24

Hours


Indications for apheresis platelets
Indications for Apheresis Platelets platelet number or function

  • 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/ platelet number or functionμL w/o platelet dysfunction

ITP or TTP unless bleeding is life-threatening

Prophylactic use with massive blood transfusion

Prophylactic use following cardiac bypass

Contraindications to Platelet Transfusion


Transfusion support in hematology oncology patients

Recent advances in Platelet Transfusion Practice platelet number or function

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 Recovery and Survival platelet number or function

50K

Usual Response

Platelet Count

25K

Recovery CCI >7500

Survival CCI>4500

10K

0

3

6

12

24

Hours Post transfusion


Transfusion support in hematology oncology patients

“DETERMINATION OF THE platelet number or function

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

within the Transfusion Medicine/Hemostasis Clinical Trials Network

supported by the National Heart, Lung and Blood Institute

of the National Institutes of Health


Transfusion support in hematology oncology patients

STUDY DESIGN platelet number or function

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.


Transfusion support in hematology oncology patients

Platelet Dosing Study platelet number or function

Low 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.


Transfusion support in hematology oncology patients

How important are the platelet number or functioncharacteristics 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 platelet number or function

Apheresis

0.9

WBP

0.8

0.7

0.6

0.5

0.4

Probability of Remaining Event Free

0.3

0.2

0.1

0.0

0

5

10

15

20

25

30

35

Time Since First Platelet Transfusion (Days)

No. Patients at Risk

Apheresis

552

338

168

68

32

16

4

WBP

220

119

56

30

15

5

PLADO: Platelet Source as a predictor of ≥ Grade 2 bleeding

p=0.72


Transfusion support in hematology oncology patients

PLADO: ABO matching as a predictor of time to platelet number or function≥ Grade 2 bleeding

p=0.28



Plado analysis of platelet characteristics
PLADO: Analysis of Platelet Characteristics to

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 patients2
Transfusion Support in Hematology/Oncology Patients to

  • Platelet therapy

  • Leukoreduction

  • Transfusion transmitted CMV

  • Irradiated Blood Components: Prevention of Transfusion associated Graft vs Host disease


Leukoreduction definition
Leukoreduction: Definition to

  • 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…”



Accepted indications for leukoreduction
Accepted Indications for Leukoreduction to

  • 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 to

Fever (temp rise at least 1° C or 1.8° F)

Chills

Dyspnea

Tachycardia

Flushing

Hypertension

“Fever-Chill” Reaction

Febrile, Non-Hemolytic Transfusion reactions


Transfusion support in hematology oncology patients

Febrile, Non-Hemolytic TR to

  • Etiology:

  • Recipient Ab’s to transfused WBCs

  • Cytokines in transfused product


Leukoreduction reduces the rate of fnhtr
Leukoreduction Reduces the Rate of FNHTR to

*Transfusion Jan 2004 Vol 44.


Accepted indications for leukoreduction1
Accepted Indications for Leukoreduction to

  • 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

UVB-PC = Ultraviolet B irrad to

F-AP = filtered apheresis

F-PC = filtered pools

Trial to Reduce Alloimmunization to Platelets (TRAP)

530 patients with AML randomized to 4 platelet therapies

p<.001 for all 3 study arms

Percent Alloimmunized

New Eng J Med 1997; 337:1861-9.


Trial to reduce alloimmunization to platelets trap refractoriness

UVB-PC = UVB irrad to

F-AP = filtered apheresis

F-PC = filtered pools

Trial to Reduce Alloimmunization to Platelets (TRAP): Refractoriness

530 patients with AML randomized to 4 platelet therapies

Percent refractory

p≤.03 for all 3 study arms

New Eng J Med 1997; 337:1861-9.


Accepted indications for leukoreduction2
Accepted Indications for Leukoreduction to

  • Reduce the risk of fever chill non-hemolytic reactions

  • Prevent or delay alloimmunization to HLA antigens

  • Reduce the risk of CMV transmission



Cmv in blood donors
CMV in Blood Donors to

  • 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



Concept of cmv safe blood components
Concept of CMV “Safe” Blood Components to

  • 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



Randomized trial of cmv safe vs seronegative blood in allogeneic stem cell transplantation
Randomized Trial of CMV Safe vs Seronegative Blood in Allogeneic Stem Cell Transplantation

Bowden R, et al Blood 1995;86:3598


Indications for cmv seronegative components
Indications for CMV Seronegative Components Allogeneic Stem Cell Transplantation

  • Seronegative recipient of a seronegative allogeneic stem cell transplant

  • Seronegative allogeneic stem cell transplant candidate


Indications for cmv safe cellular components
Indications for CMV “SAFE” cellular components Allogeneic Stem Cell Transplantation

  • 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
Transfusion Associated Graft versus Host Disease Allogeneic Stem Cell Transplantation(TAGVHD)


Tagvhd
TAGVHD Allogeneic Stem Cell Transplantation

  • 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
Organ Involvement in TAGVHD Allogeneic Stem Cell Transplantation


Prevention of tagvhd
Prevention of TAGVHD Allogeneic Stem Cell Transplantation

  • 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
Cell Irradiator Allogeneic Stem Cell Transplantation


Irradiation confirmation sticker not should not be visible
Irradiation Confirmation Sticker: Allogeneic Stem Cell Transplantation“NOT” should not be visible


Indications for irradiated cellular blood components
Indications for Irradiated Cellular Blood Components Allogeneic Stem Cell Transplantation

  • 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


Transfusion support in hematology oncology patients

Irradiated Allogeneic Stem Cell Transplantation

CMV Negative

Leukoreduced


Estimated risks of viral transmissions in us
Estimated Risks of Viral Transmissions in US Allogeneic Stem Cell Transplantation

Zou S et al Transfusion 2010;50:1495.

C O N F I D E N T I A L

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