RBC Transfusion
2014년년년년 혈액종양내과혈액종양내과혈액종양내과혈액종양내과 춘계춘계춘계춘계 연수강좌연수강좌연수강좌연수강좌
Won Sik Lee, M.D., Ph.D.
Division of Hemato-Oncology, Department of Internal Medicine, Inje University College of Medicine, Busan Paik Hospital
2014. 06. 21.
Background
Red Cell Transfusions are common medical intervention1 - to augment oxygen delivery to tissues
In 1997, 11 million units for transfused in the US2 - 60-70% of use in the surgical setting
Patients undergoing hematopoietic stem cell transplant ar e traditionally high volume users3
- 3.8 units/patient (autologous HSCT) - 6.4 units/patient (allogeneic HSCT)
1 Goodnough. Transfusion Medicine. NEJM 1999 2 Wallace et al. Transfusion 1996
3 Kekre et al. Transfusion 2011
Q1) What is your Hb threshold for RBC tra nsfuison in HSCT setting regardless of sympt om?
1. 6 mg/dl
2. 7 mg/dl
3. 8 mg/dl
4. 9 mg/dl
5. 10 mg/dl
There is no universal accepted threshold for red cell transfusion
Historically, thresholds of 100 g/L
- Early guidelines in the 1990s suggest levels between 60 and 100 g/L depending on situation and co-morbidities of the patient
A threshold of 70 g/L is appropriate and leaves some mar gin of safety over the critical level of 40-50 g/L.
• In patients with indications of cardiac disease, it may be safer to mai ntain the hemoglobin above 90 g/L.
• Transfusion at hemoglobin above 100 g/L is unlikely to be appropriat e unless there are specific indications.
Audet et al. Annals of Int Med 1992;
Calder et al. CMAJ; 1997
Royal College of Physicians of Edinburgh. Transfusion Medicine 1994 Stehling et al. Anesthesiology 1996
BC Transfusion Advisory Group 2002
A Clinical Practice Guideline From the AABB
Recommendation 1:
–The AABB recommends adhering to a restrictive
transfusion strategy (7 to 8 g/dL) in hospitalized, stable patients
(Grade: strong recommendation; high-quality evidence).
Recommendation 2:
–The AABB suggests adhering to a restrictive strategy in hospitalized patients with preexisting cardiovascular disease and considering transfusion for patients with symptoms or a hemoglobin level of 8 g/dL or less
(Grade: weak recommendation; moderate-quality evidence).
Carson JL et al. Transfusion 2012
A Clinical Practice Guideline From the AABB
Recommendation 3:
–The AABB cannot recommend for or against a liberal or restrictive transfusion threshold for hospitalized,
hemodynamically stable patients with the acute coronary syndrome (Grade: uncertain recommendation; very low-quality evidence).
Recommendation 4:
–The AABB suggests that transfusion decisions be influenced by symptoms as well as hemoglobin concentration
(Grade: weak recommendation; low-quality evidence).
Carson JL et al. Transfusion 2012
Transfusion Requirements in Critical C are : TRICC study
•To determine whether a
restrictive strategy (7-10g/L) of red-cell transfusion and a liberal strategy (10-12g/L)
–30 mortality
–Designed as an equivalence trial
• Enrolled 838 patients
–418 (restrictive strategy) –420 (Liberal strategy)
influenced by symptoms as well as hemoglobin concentration
(Grade: weak recommendation; low- quality evidence).
Hebert et al. NEJM 1999
TRICC Study: Results
1. Overall, 30-day mortality was similar in the two groups
–(18.7 percent vs. 23.3 percent, P= 0.11).
2. However, the rates were significantly lower with the restrictive transfusion strategy among patients who were less acutely ill — those with an Acute Physiology and Chronic Health Evaluation II score of ≤20 –(8.7 percent in the restrictive-strategy group and 16.1 percent in the liberal-strategy group, P=0.02)
Hebert et al. NEJM 1999
8.7% vs 16.1% 5.7% vs 13.0%
TRICC Study: Results
Hebert et al. NEJM 1999
2012 ASH guideline: RBC Transfuison
Are red cell transfusions harmful?
P
roposed mechanisms linking transfusion of red cells and adverse clinical consequences
1.Red cell storage leads to impaired ability of red cells to carry oxygen and stimulate the inflammatory cascade.
2.Red cell transfusion may trigger and even prime the host for subsequent inflammatory injury
3.The altered immune responses following red cell transfusions may predispose transfusion recipients to SIRS, sepsis syndrome, nosocomial infections and multiple organ dysfunction
Lacroix J et al. NEJM 2007 Kirpalani H et al. J Pediatr, 2006
Red Cell Transfusions: Cohort Studies
Marik et al. Critical Care Medicine 2008
Risk of Death
Acute Respiratory distress Infectious complications
Could transfusions be beneficial?
1. A more liberal transfusion strategy was superior1,2
• Cardiac Disease
2. Pre-HSCT Hemoglobin is associated with inferior transplant outcomes and increased toxicity3
• It remains unclear whether improvements in hemoglobin levels prior and/or during transplant would abrogate these negative outcomes.
1 Wu et al. NEJM 2001 2 Herbert et al. NEJM 1999
3 Xenocostas et al. Transfusion 2003
Red cell Transfusions in HSCT
1995-2000 at PMH 519 allogeneic HSCT
1.Average of 6.8 ± 6.4 units of red cells between 0 – 60 days after HSCT.
2.Increased numbers of red cell transfusions were associated with the before-HSCT hemoglobin level.
3.The before HSCT hemoglobin level was also
associated with increased mortality within 6 months of HSCT.
Xenoscostas et al. Transfusion 2003
Could transfusions be beneficial?
3.Younger duration of storage of blood was associated superior cardiovascular outcomes1 4.Quality of Life
–A higher transfusion trigger may better facilitate a
“outpatient” transplant based program
–Correlations with better quality of life with a higher hemoglobin
•Cancer
•Heart Disease
•Chronic Kidney Disease
•Menorrhagia
•Patient knowledge of Hb
1Koch et al. NEJM 2008
Red Cell Transfusion Trigger Studies:
Randomized Controlled Trials
Red Cell Transfusion Trigger Studies:
Randomized Controlled Trials
Carson et al. Cochrane Database 2012 Issue 5
What should the red cell transfusion trigger be in Hematopoietic Stem Cell Transplant?
• The critical care population may be the closest to the HSCT population
• Perhaps 70g/L should be the standard in patients undergoing HSCT.
Transfusion practice and HSCT:
Survey of red cell transfusion triggers
• Canadian Bone Marrow Transplant Group (CBMTG) (n=15)- Programme Directors
• 14 centres used a red cell transfusion trigger of 80g/L
• 1 centre used a red cell transfusion trigger of 70g/L
• Preferences of individual transplant physicians not available.
• No clear rationale for stated red cell transfusion trigger.
Are there any transfusion trigger studi es in HSCT?
• 69 patients (from 3 Canadian Centres)
• 16 patients undergoing HSCT
• Groups were randomized to standard thresholds for red cell transfusion (<80 g/L) compared with an augmented red cell transfusion scheme to maintain Hb > 120 g/L.
• The primary outcome was bleeding.
Webert et al. Transfusion. 2008 Jan;48(1):81-91
Are there any transfusion trigger studi es in HSCT?
• They noted that patients randomized to the more liberal transfusion arm received greater number of red cell transfusions
• 0.233 vs 0.151 RBC transfusions/pt-day, p=0.003
• No differences in bleeding events or requirement for platelet transfusions.
• Did not report on toxicity, morbidity or mortality outcomes of HSCT.
Webert et al. Transfusion. 2008 Jan;48(1):81-91
Are there any transfusion trigger studi es in HSCT?
• Multicentre randomized Pediatric HSCT study
–Transfusion trigger of either 70g/L or 120g/L
• Primary Endpoint: Engraftment
• Enrolled 6 patients
–All 3 patients on the 120g/L arm developed VOD –2 requiring intensive care
• Study halted by DSMB
Robitaille et al. BBMT 2013
Transfusion of Red cells In Hematopoi etic Stem cell Transplantation (TRIST)
• Multicentre Canadian RCT (n=3)1,2
– Completed a pilot RCT of 100 patients receiving HSCT – 70g/L vs. 90g/L
• Now embarking on a Phase III study
– Non-inferiority study
– Aiming to recruit another 200 patients
– Primary endpoint of Quality of Life (FACT-BMT scale) – Secondary endpoints include: TRM, LOS hospital stay, ICU
admissions, GVHD, Incidence of Infections, Transfusion requirements Incidence and grade of bleeding , Incidence of adverse transfusion reactions, Bearman Toxicity Score, Sinusoidal Obstruction Syndrome and Cost effectiveness/utility
1 Tay et al. Trials 2011
2 Clinicaltrials.gov NCT01237639
Summary
Red cell Transfusion Thresholds
1.Red cell transfusions are integral part of the overall care of patients receiving HSCT.
2.A red cell transfusion threshold as low as 70g/L in recipients of HSCT is likely safe.
–Quality of life/Vitality remains unclear
–Hyper-transfusion using threshold of 120g/L in children is detrimental
3.The ongoing TRIST study will inform practice.
Q2) What kind of blood type of RBC do you transfuse for patient with postBMT D3 Hb 6.
0 mg/dl (Donor: type B, Recipient: type A)?
1. A
2. B
3. AB
4. O
5. Any blood type is OK!
ABO incompatible HSCT
ABO and Rh compatibility are not required for the successful outcome of BMT
Red cell-incompatible donors: 30–50%
Immediate and delayed hemolytic transfusion reactions ar e expected complications
Immunohematological consequences of red cell-incompati ble transplantation include delayed red blood cell recovery , pure red cell aplasia and delayed hemolysis from viable ly mphocytes carried in the graft (‘passenger lymphocytes’).
No deleterious effects on transplant outcomes, such as granulocyte and platelet engraftments, the incidences of acute or chronic GvHD, relapse risk or OS, have been consistently demonstrated.
Rowley et al. BMT 2011
ABO and SCT
Any allogeneic SCT will be one of:
– ABO-Identical
– Major ABO Incompatible – Minor ABO Incompatible – Bidirectional (Major/ Minor )
40-50% of MUD-recipient pairs are ABO incompatible (ABOi SCT)
– 25% sibling donor-recipient pairs are ABOi
Peri-transplant transfusion management of ABOi transplant is not standardized.
Worel et al Vox Sang 2010
Raimondi et al BMT (GITMO) 2004
Recipient- Donor ABO Compatibility
ABO Major Mismatch: Recipient is O-Donor is A
- Acute hemolysis at infusion.
- Delayed hemolysis from persistent patient antibodies.
- Delayed onset of hematopoiesis.
ABO Minor Mismatch: Recipient is A- Donor is O
- Acute hemolysis at infusion.
- Delayed hemolysis from donor antibodies.
ABO Major-Minor Mismatch: Recipient is A-Donor is B
Blood Group O A B AB
O Compatible Major Major Major
A Minor Compatible Major and minor
Major
B Minor Major and
minor
Compatibl e
Major
AB Minor Minor Minor Compatible
RECIPIENT
ABO Compatibility
DONOR
Does ABO Incompatibility impact SCT outcomes?
Contradictory studies
ABO incompatibility does not appear to affect graft failure or rejection
– Further, does not affect survival, although may be
related to prolonged RBC aplasia or delayed hemolysis Difficulty in analyzing quality of studies: many many
variables impacting patient outcomes with this complex therapy
– eg, baseline disease/stage/risk, conditioning, comorbidities,
SC dose, SC source, GVH prophylaxis,
supportive care regimens, transfusion support regimens
Worel et al Vox Sang 2010
Raimondi et al BMT (GITMO) 2004
Kanda et al Transfusion 2009
Kim et al BMT 2005
ABOi SCT impact on Outcome:
Nonmyeloablative Transplants
Seattle
503 NMA SCT No difference
Wang Z et al BJH 2010
BM source
– Major ABO mismatch – Red cell depletion – Minor ABO mismatch – Plasma depletion
– Bidirectional – Both RBC and Plasma depletion
PB HPC (Apheresis)
– Hct kept <2%, typically ~10ml
– Considered red cell depleted and plasma depleted
Cord HPC source
– Most often RBC and plasma depleted prior to cryostorage
– Otherwise, washed with dextran/albumin solution to remove lysed RBC ( and donor plasma) post-thaw
Stem Cell (HPC) product preparation
Red cell depletion and/or plasma depletion ONLY performed on BM collection.
Red cell depletion: Recipient has Ab against Donor red cells.
- To avoid hemolysis of donor red blood cells in HPC collection.
Plasma depletion: Donor has Ab against Recipient red cell .
- To avoid hemolysis of red blood cells in recipient’s circulation.
Marrow Processing
Rowley et al. BMT 2011
Recipient lymphocytes continue to produce IHA’s (against donor A and B Ag) for up to 3-4 months May delay RBC engraftment,
– Does not impact Platelet / Neutrophil lines
>40d post Major ABO incomp, v 20d RBC chimerism may exist for months
– Potential for delayed hemolysis
PRCA –risk varies
– NMA (8-38%) v MA transplant (16-29%) – A antigen incompatibility
– CSA-only
MAJOR ABOi SCT:
Risks delayed RBC engraftment
Yazer and Triulzi 2007 Curr Op Hem
Product Selection
Acute hemolytic transfusion reaction with SC infusion
– Usually little hemolysis compared to major ABO incompatible transplant
– Plasma reduce BM-derived SC product
Potential severe hemolysis post transplant
– Passenger Lymphocyte Syndrome
SCT - Minor ABO Incompatible
Graft’s viable lymphocytes produce IHA against recipient RBC
– 5-12d post HPC-A; 9-16d post HPC-M
– DAT positive, intravascular, abrupt onset, possibly severe, usually subsides <2wks
– Risks: PBSC, unopposed T cell suppression for GVHD prophylaxis, RIC
– Protect with appropriate RBC support selection and plasma selection
Incidence decreasing? :
– MTX for GVH prophylaxis is protective
Minor ABO Incompatible SCT:
Passenger Lymphocyte Syndrome
Rowley et al BMT 2001 Gajewski et al Blood 2008
Major Rh-incomp., patient anti-D antibodies against engrafted donor Rh+ RBCs.
Mismatches involving Rh system may cause hemolysis, do not affect survival.
Kidd,M,N and S.
NON-ABO MISMATCHES
Product Selection
Summary
ABO incompatibility in HSCT
1. ABO matching is not required for successful SCT 2. There are potentially significant consequences of
ABO mismatched transplant
– There is controversy about the impact of ABO mismatch on overall survival
3. Transfusion support of ABOi SCT recipients is not standardized
