1. Leukoreduction to Prevent Complications of Blood Transfusion
曾士賓

2. Agenda Introduction Clinical Indications for Leukoreduction（LR）
FNHTR
HLA Alloimmunization and PTR
CMV Transfusion-Transmitted Diseases（CMV-TTD）
Adverse Effects of LR
Pre-storage versus Post-storage LR

3. Introduction

4. Leukocytes are considered a contaminant of other cellular blood components.
= have increasingly been recognized as a contributor to, if not the cause of
UpToDate P1: Leukoreduction to prevent complications of blood transfusion, Literature review current through: May | This topic last updated: Mar 04, 2014.
The Peripheral Smear, P.4

5. Transfusion Therapy, Clinical Principles and Practice, 3e (2011)
Rossi's Principles of Transfusion Medicine, 4th edition (2009), P.241
= Several lines of evidence have suggested that recipient exposure to donor WBCs can result in improved survival of subsequent renal transplants.
= Because cyclosporine and tacrolimus have become widely adopted as immunosuppressive agents for organ transplantation, the contribution of transfusion to graft survival has
declined.
= there is no longer a routine role for pretransplant transfusions to prolong graft survival.
= Because the risk of HLA alloimmunzation associated with using leukocyte-rich blood components outweighs any benefi t from potential immune tolerance, LR components are indicated for organ transplant candidates.
= Leukocytes, while naturally collected along with other cellular elements in a whole blood collection, are considered a contaminant of other cellular blood components (red blood cells and platelets), and have increasingly been recognized as a contributor to, if not the cause of, a number of adverse consequences of blood transfusion:
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. Literature review current through: Nov Updated: Oct 30, 2014.
●Immunologically-mediated effects
●Infectious disease transmission
●Reperfusion injury
UpToDate
The immunosuppressive activity of allogeneic blood has been known since the studies on renal allograft survival were published in the 1970s. Increasing attention has been directed towards the impact of the immunosuppressive effect of allogeneic blood (particularly the leukocyte component) on postoperative infection, tumor recurrence, and nosocomial infection in critically ill patients [16-18]. This phenomenon has been termed "transfusion-related immunomodulation" (TRIM).
Rossi’s P.228: Both acute and long-term complications can result directly from exposure to donor leukocytes, prompting the adoption of leukocyte reduction as a highly effective and widely practiced prevention strategy.
Transfusion Therapy, Clinical Principles and Practice, 3e (2011)

6. Rossi's Principles of Transfusion Medicine, 4e (2009)
Rossi's Principles of Transfusion Medicine, 4e (2009), P.228
However, during refrigerated storage of Red Blood Cells (RBCs), a substantial proportion of donor leukocytes undergo cellular degeneration and apoptosis, and surface antigens on residual cells change. Thus, refrigerated storage itself may help prevent complications from transfused donor leukocytes to a degree not completely appreciated.
Buffy coat depletion is sufficient to prevent many FNHTRs to blood but is not considered sufficient to prevent HLA alloimmunization or CMV transmission.
Rossi's Principles of Transfusion Medicine, 4e (2009)

7. Requirements for Residual Leukocytes in LR Blood Components
CoE Guide, 17e (2013), P.280, 310, 331 7

8. Leukocyte Reduction by Filtration
Filtration: the most commonly used method of leukocyte reduction:
Early filters: 1～2 log
Current high-performance filters： 3～5 log
Component-specific filters
red cell components
platelet components
Rossi's Principles of Transfusion Medicine, 4e (2009), P.229
Filtration has emerged as the most commonly used method of leukocyte reduction.
Early leukocyte reduction achieved only 90% to 99% (1 to 2 log10) leukocyte reduction
Current high-performance leukocyte removal filters can reduce the residual white cell (WBC) content at least 3 logs and typically achieve 4 log or greater removal.
Until recently, component-specific filters were required for red cell components and platelet components. The filters designed for red cells removed unacceptable numbers of platelets.
Transfusion Therapy, Clinical Principles and Practice, 3e (2011), AABB. P.666
Current filters remove between 3 and 5 log10 ( %) of leukocytes in RBCs, producing components having leukocyte counts well below the threshold required for leukocyte reduction.
Rossi's Principles of Transfusion Medicine, 4e (2009)

9. Coral-reef-like structures of porous polyurethane（聚氨酯）
Rossi's Principles of Transfusion Medicine, 4e (2009), P.229
Depletion of leukocytes results primarily from barrier retention in which the pore size of the filter medium is large enough to allow passage of red cells and platelets but small enough to impede passage of leukocytes.
Rossi's Principles of Transfusion Medicine, 4e (2009)

10. Polyester（聚酯纖維）fiber filters
可以做衣服、逆滲透過濾
Rossi's Principles of Transfusion Medicine, 4e (2009), P.229
As blood passes through the layers of medium, the fi ber diameter becomes smaller, and the pore size decreases to approximately 4 microns.
Rossi's Principles of Transfusion Medicine, 4e (2009)

11. Rossi's Principles of Transfusion Medicine, 4e (2009)
Rossi's Principles of Transfusion Medicine, 4e (2009), P.229
Red cells, which are more deformable than leukocyte nuclei, can traverse these small pores. Differences in the viscoelastic properties of red cells and leukocytes are particularly pronounced at low temperatures. This accounts for the better performance of red cell leukocyte reduction fi lters used at refrigerated temperatures.
Rossi's Principles of Transfusion Medicine, 4e (2009), P.230
Because of the complex physical and biologic forces involved in leukocyte retention by the fi lter medium, it is not surprising that several factors have been shown to affect the degree of leukocyte reduction obtained.
A primary factor is the capacity of the filter itself.
The input load of WBCs to be filtered has a direct relation to the post-filtration WBC content.
The temperature of filtration has a dominant effect on the performance of leukocyte filtration of RBCs. Nearly all studies have found that the efficiency of filtration improves when the procedure is conducted at refrigerated temperatures. Beaujean et al and Sirchia et al showed that when RBCs were filtered under conditions that mimicked bedside filtration at room temperature, filtration became less efficient such that most units filtered under bedside conditions over 3 to 4 hours did not meet minimum standards for LR RBCs. Improved performance of filtration at refrigerated temperatures has been observed by other investigators and is associated with lower rates of hemolysis of stored RBCs.
Results of studies suggest that approximately 50% of units from donors with hemoglobin AS clog the filter and do not flow. Of the remaining 50%, approximately half of these flow normally but do not undergo adequate leukocyte reduction.
If temperature is held constant, faster flow rates result in decreased performance.
Rossi's Principles of Transfusion Medicine, 4e (2009)

12. Residual Leukocytes Threshold
For prevention of transfusion reactions:
Febrile Non-Hemolytic Transfusion Reactions: < 5 x 10^8
HLA alloimmunization < 5 x 10^6
CMV transmission < 5 x 10^6
FNHTR: Rossi’s P.232
HLA alloimmunization: Rossi’s P.233, 234. UpToDate: P.2
CMV transmission: Rossi’s P.233
Rossi's Principles of Transfusion Medicine, 4e (2009)

13. Universal Leukocyte Reduction（ULR）
Nearly all of Europe and Canada have implemented leukocyte reduction of all cellular blood components—termed “universal leukocyte reduction.”
The US Blood Safety and Availability Committee recommended in January 2001 that ULR be implemented as “soon as is feasible.”
Rossi’s P.
Rossi's Principles of Transfusion Medicine, 4e (2009)

14. Transfusion Therapy, Clinical Principles and Practice, 3e (2011)

15. WB/RBCs LR in United States （% of Total Units Leukocyte Reduced）
Data from: National Blood Collection & Utilization Survey

16. ULR in United States
Despite the heat of the debate, the following collection facilities committed to ULR:
American Red Cross (45% of the blood supply)
United Blood Services (10% of the blood supply)
> 1/2 of the remaining independent blood centers.
Thus, approximately 85% of blood in the United States is already leukoreduced.
UpToDate
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. UpToDate. Literature review current through: Nov last updated: Oct 30, 2014.

17. Clinical Indications for Leukocyte Reduction

18. Rossi's Principles of Transfusion Medicine, 4e (2009)
(Continued)
Rossi's Principles of Transfusion Medicine, 4e (2009)

19. Transfusion-Related Immuno-Modulation" (TRIM)
(Continued)
Transfusion-Related Immuno-Modulation" (TRIM)
(Continued)

20. (Continued)

21. Established Benefits of Pre-Storage Leukocyte Reduction
Leukocyte reduction reduce the following:
recurrent FNHTR （≧ 2 febrile reactions to transfusion）
alloimmunization to leukocyte antigens （transplantation or chronic transfusion therapy）
transmission of CMV （e.g., chemotherapy, HPSCT, solid organ grafts）
Guidance for Industry: Pre-Storage LR of WB and Blood Components Intended for Transfusion, FDA, 2012.

22. We believe that increased availability of pre-storage LR blood components for non-targeted recipients will support the treatment of recipients who may benefit from receiving leukocytes reduced components but have not been identified as falling within the indications identified in section II.B.
We suggest that consideration should be given to making LR blood components more widely available.
Guidance for Industry: Pre-Storage LR of WB and Blood Components Intended for Transfusion, FDA, 2012.

23. Febrile Non-Hemolytic Transfusion Reactions（FNHTR）
An FNHTR is defined as the occurrence of:
>1℃ rise in temperature above 37℃
associated with transfusion
no other cause is identifiable
Technical Manual, 17e (2011), AABB

24. FNHTR S/S: shaking, chills, RR↑, BP change, anxiety
usually occur during transfusion but may occur 1 to 2 hours later.
Most FNHTRs are benign,
But they may cause significant discomfort and even hemodynamic or respiratory effects.
Technical Manual, 17e (2011), AABB

25. When these blood components are not LR, FNHTR occurs in approximately:
1% of red cell transfusions
up to 30% of platelet transfusions
Transfusion Therapy, Clinical Principles and Practice, 3e (2011)
Heddle, N.M., et al., Transfusion, (10): p

26. FNHTR mechanisms (A) , (B) : donor leukocytes
(C) : cytokine generation during the storage
Rossi’s

27. 64 pairs of PLT-product components were administered to 12 patients.
Heddle, N.M., et al., The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med, (10): p
PLT concentrates
Plasma
Cellular
: Citing Articles (257)
FNHTR:
Most frequent adverse reactions t blood prodcuts.
The risk of these reactions is highest with platelets; they occur in 5% to 30% of PLT transufsion.
### 12 patients received 64 pairs ###
Patient AML x 9, MDS x 1, CML x 1, ITP x 1
Plasma supernatant vs. Cellular component = 31.3% vs. 9.4%, p =0.009
64 pairs of PLT-product components were administered to 12 patients.

28. Heddle, N.M., et al., The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med, (10): p
■ No reaction　　■ Mild　
■ Moderate　 　■ Servere
FNHTR:
Most frequent adverse reactions t blood prodcuts.
The risk of these reactions is highest with platelets; they occur in 5% to 30% of PLT transufsion.
### 12 patients received 64 pairs ###
Patient AML x 9, MDS x 1, CML x 1, ITP x 1
Plasma supernatant vs. Cellular component = 31.3% vs. 9.4%, p =0.009

29. Heddle, N.M., et al., The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med, (10): p
In vitro studies
N = 10

30. Heddle, N.M., et al., A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. Transfusion, (3): p
P < 0.008

31. Shanwell, A., et al., Generation of cytokines in red cell concentrates during storage is prevented by prestorage white cell reduction. Transfusion, (7): p

32. Shanwell, A., et al., Generation of cytokines in red cell concentrates during storage is prevented by prestorage white cell reduction. Transfusion, (7): p
Shanwell, A., et al., Generation of cytokines in red cell concentrates during storage is prevented by prestorage white cell reduction. Transfusion, (7): p PMID: 32

33. FNHTR in Universal pre-storage LeukoReduction Studies (1/2)
Rossi’s P.234, Table 16-5
Ref 39, PMID: , Canada. In February 1998, prestorage WBC reduction of all platelet components began in Canada
Ref 40, PMID: , Yale-New Haven Hospital
Ref 41. PMID: , Johns Hopkins Hospital

34. FNHTR in Universal pre-storage LeukoReduction Studies (2/2)

35. Although FNHTRs are not serious, FNHTRs are:
discomforting for the patient
ultimately quite expensive
require that an infectious etiology be excluded.
an additional unit of blood be crossmatched and transfused.
UpToDate:
FNHTRs are not serious, as the fever responds to antipyretics and the rigors to meperidine. However, these reactions are discomforting for the patient and ultimately quite expensive, since they require that an infectious etiology be excluded and, in many cases, that an additional unit of blood be crossmatched and transfused. In some patients (eg, asplenia due to sickle cell disease), development of fever may necessitate hospitalization and empiric antibiotic therapy until an infectious etiology is eliminated.
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. UpToDate, Literature review current through: Nov Updated: Oct 30, 2014. 35

36. Transfusion Reaction Differential Diagnoses (1/2)
Practical Transfusion Medicine, 3e (2009)

37. Transfusion Reaction Differential Diagnoses (2/2)
Shanwell, A., et al., CMAJ, (2): p

38. FNHTR AHTR
1～4/ /12,000

39. Cost-effectiveness of blood transfusion and LR in elective colorectal Sx
Jensen, L.S., et al., Cost-effectiveness of blood transfusion and white cell reduction in elective colorectal surgery. Transfusion, (9): p PMID:
Conclusion: The use of WBC-reduced whole blood transfusions in elective colorectal surgery significantly reduces the frequency of postoperative infection, the length of hospital stay, and the total hospital charges for patients needing blood transfusion.
Jensen, L.S., et al.,Transfusion, (9):p PMID:

40. HLA Alloimmunization and Platelet Transfusion Refractoriness（PTR）
UpToDate, P.2
Clinical problems that result from such allosensitization include an increased risk of graft rejection in patients awaiting organ or bone marrow transplantation and platelet refractoriness in those requiring subsequent platelet transfusion support.
Patients who are alloimmunized and refractory to platelets are often difficult to manage, even with HLA-matched or cross-matched platelets, high-dose intravenous immune globulin, or Rh immune globulin

41. HLA Alloimmunization Clinical problems:
increased risk of graft rejection in patients awaiting organ or bone marrow transplantation.
platelet refractoriness in those requiring subsequent platelet transfusion support.
In 33 studies involving more than 3000 patients, the median reported incidence of HLA alloimmunization when unmodified components were used was 39% (range, 20% to 71%).
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. Literature review current through: Nov Updated: Oct 30, 2014.
UpToDate P.2
Rossi's Principles of Transfusion Medicine, 4e (2009)

42. PTR 的原因
Non-Immune (約2/3)，包括：sepsis, fever, bleeding, splenomegaly, DIC, hepatic VOD, GVHD, medications。 → 治療：針對 underlying disease 處理。
Immune，包括： Alloimmunization to HLA and/or HPA。
Combination of both immune and non-immune (約20%)。
Goldfinger, D., et al., Refractoriness to platelet transfusion therapy
UpToDate, Literature review current through: Nov Updated: Aug 01, 2013.

43. The TRAP Study (The Trial to Reduce Alloimmunization to Platelets Study Group)
The best evidence in support of this approach has come from the Trial to Reduce Alloimmunization to Platelets (TRAP) conducted under the sponsorship of the National Heart, Lung, and Blood Institute .

44. 對象：530 位 AML 患者。 接受引導化學治療(induction chemotherapy)。
沒有 HLA alloantibody。
多機構、隨機、單盲研究。
: Citing Articles (389)

45. 隨機分成四組，接受四種不同種類血小板：
Control: Random donors platelet concentrates (PC).
UVB-PC: Random donors PC + ultraviolet B–irradiated.
F-PC : Random donors PC + filter.
F-AP: Single donor apheresis platelets (AP) + filter.

46. 對於 HLA & HPA Ab 的 產生，三種減白血品都 可以有效的預防，而且 都有統計上的意義。
45%
21% (p < 0.001)
18% (p < 0.001)
17% (p < 0.001)

47. 對於異體抗體造成的血 小板輸注無效，三種減 白血品都可以有效的預 防，而且都有統計上的 意義。
13%
5% (p = 0.03)
3% (p < 0.004)
4% (p < 0.01)
對於異體抗體造成的血 小板輸注無效，三種減 白血品都可以有效的預 防，而且都有統計上的 意義。

48. 對於血小板輸注無效，減白血品雖有明顯 的下降，但只有 F-PC 有統計上的意義。
16%
10% (p=0.17)
7% (p=0.03)
8% (p=0.06)
對於血小板輸注無效，減白血品雖有明顯 的下降，但只有 F-PC 有統計上的意義。

49. The TRAP Study 結論
不論使用 filter 或 ultraviolet B irradiation 來進行減白，都可以同樣有效的預防異體抗體造成的血小板輸注無效 (alloantibody-mediated refractoriness to platelets)。
使用 single donor AP 當作減白血品的來源並未優於 random donor PC。

50. 加拿大自 1999 年 8 月起，血品全面儲存前減除白血球 (ULR) 的經驗。
〈Blood Jan 1;103(1):333-9〉
Mollison's Blood Transfusion in Clinical Medicine, 12e (2014), P.578
Universal pre-storage leucoreduction (ULR) of red cell and platelet products has been performed in Canada since August 1999.

51. Fewer patients in the post-ULR group received HLA-matched platelets.
Seftel, M.D., et al., Universal prestorage leukoreduction in Canada decreases platelet alloimmunization and refractoriness. Blood, (1): p PMID:
Fewer patients in the post-ULR group received HLA-matched platelets.
(14% vs 5%, P < .001)

52. Cytomegalovirus Transfusion-Transmitted Diseases (CMV-TTD)

53. CMV-TTD (1/2)
Most are self-limited, but can cause significant morbidity & mortality in immunocompromised patients such as:
hematopoietic or solid organ transplantation,
AIDS patients,
low-birth-weight neonates.
The reported rate was as high as 10% to 60% historically.
almost exclusively transmitted through leukocytes – UpToDate
most are self-limited, but can cause significant morbidity and mortality in immuno-compromised patients such as: transplant recipients, AIDS patients, low-birth-weight neonates. –
The reported rate was as high as 10% to 60% historically. –
Wu, Y., et al., Transfusion, (4): p

54. CMV-TTD (2/2) Almost exclusively transmitted through leukocytes.
Even though it is still under debate, these two methods have been considered operationally equivalent in many institutional policies:
CMV-seronegative cellular blood products
Leukoreduced blood products
Wu, Y., et al., Transfusion, (4): p

55. 502 marrow transplant recipients: Seronegative (n=252)
the first large RCT demonstrated similarly low rates (< 3%) of CMV infection.
502 marrow transplant recipients:
Seronegative (n=252)
Bedsie Filtration (n=250)
In [ ]:
In the mid 1990s, in the first large randomized controlled trial reported, Bowden et al. [17] demonstrated similarly low rates (< 3%) of CMV infection in patients receiving either bedside LR CMV-untested blood products or CMVseronegative products.
These results prompted the AABB to publish guidelines stating that leucocyte-reduction reduces TT-CMV to a level that is at least equivalent to that observed with the use of CMV-seronegative components [18].

56. CMV infection: identification by culture or antigen detection.
CMV disease: biopsy evidence with compatible clinical symptoms.
80% power to detect a difference of 5% or more at the 0.05 level by two-sided testing.
These results prompted the AABB to publish guidelines stating that leucocyte-reduction reduces CMV-TTD to a level that is at least equivalent to that observed with the use of CMV-seronegative components.
We projected a sample size of 250 in each arm to have an 80% power to detect a difference of 5% or more at the 0.05 level by two-sided testing. 56

57. Smith, D., et al., Vox Sang, 2010. 98(1): p. 29-36.
Smith, D., et al., Survey of current practice for prevention of transfusion-transmitted cytomegalovirus in the United States: leucoreduction vs. cytomegalovirus-seronegative. Vox Sang, (1): p PMID:
A web-based survey was designed and administered to AABB physician members in April 2007 to collect information regarding current blood banking and clinical practices for prevention of TT-CMV in the United States.
Individuals representing 183 different institutions completed the entire survey (an institutional response rate of 32.5%).
Smith, D., et al., Vox Sang, (1): p

58. The Council of Europe, the AABB and the BCSH（British Committee for Standards in Haematology） all consider that components leucocyte-reduced before storage are equivalent in safety to those tested as CMV seronegative.
英國血液病標準委員會，BCSH（British Committee for Standards in Haematology）。
Practical Transfusion Medicine, 4e (2013), P211.
Practical Transfusion Medicine, 4e (2013)

59. Although some physicians prefer to use units that test seronegative for CMV for CMV (-) hematopoietic progenitor transplantation (HPT) recipients, neither testing nor leucoreduction eliminates transmission and both result in equivalently ‘safe’ components.
Mollison's Blood Transfusion in Clinical Medicine, 12e (2014)

60. Improved Outcomes in Cardiac Surgery
UpToDate, P.2
Clinical problems that result from such allosensitization include an increased risk of graft rejection in patients awaiting organ or bone marrow transplantation and platelet refractoriness in those requiring subsequent platelet transfusion support.
Patients who are alloimmunized and refractory to platelets are often difficult to manage, even with HLA-matched or cross-matched platelets, high-dose intravenous immune globulin, or Rh immune globulin

61. Circulation, 2004. 109(22): p.2755-60. PMID: 15148271.

62. 全民健康保險醫療服務給付項目及支付標準 2-2-8第二部第二章第八節-102.02.01
Available from [cited 2016 Apr-13] :

63. Adverse Effects of Leukocyte Reduction

64. Little evidence suggests a serious clinical disadvantage of LR.
Rossi's Principles of Transfusion Medicine, 4e (2009)

65. Loss of the therapeutic blood element
Cost
Loss of the therapeutic blood element
Bedside LR has been associated with hypotensive reactions, especially among recipients treated with ACE inhibitors.
Very small proportion of patients:
acute conjunctivitis,
pain at the site of blood infusion, or the
sudden onset of back pain
hypertension
【Transfusion Therapy, Clinical Principles and Practice, 3e (2011), P.666】
 = However, filtration does result in the loss of up to 15% to 25% of red cells and platelets, thereby reducing the dose administered and potentially incurring the costs and risks of additional transfusion.
【Practical Transfusion Medicine, 4e (2013), P.211 】
= LR results in a 10-15% loss of volume of whole blood or processed component, but has minimal adverse effects on the quality of blood components.
【Mollison's Blood Transfusion in Clinical Medicine, 12e (2014), P.579】
= Filters … and result in a 10-15% loss of the processed component.
【Rossi's Principles of Transfusion Medicine, 4e (2009), P.242】
= 1.
The technology is expensive—estimated at more than $1 billion every 2 years for the United States alone.
Concern has been raised that this cost will divert resources from other initiatives of greater consequence to safe transfusion practice.
= 2.
First, filtration results in a substantial loss of the therapeutic blood element intended for transfusion
= 3.
Second, bedside leukocyte reduction has been associated with hypotensive reactions, especially among recipients treated with ACE inhibitors.
= 4.
Third, reports of allergic reactions characterized by acute conjunctivitis, pain at the site of blood infusion, or the sudden onset of back pain and hypertension have been observed in some patients undergoing transfusion of LR blood.
Rossi's Principles of Transfusion Medicine, 4e (2009)

66. 高雄捐血中心 102 年分離術血小板QC

67. Hypotension with Bedside LR
There are over 80 reports of patients developing significant hypotensive events while receiving blood products transfused through a bedside LR filter.
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. UpToDate. updated: Mar 04, 2014.

68. Recommendations
Based on the current scientific knowledge, FDA recommends the following:
Watch for a precipitous drop in blood pressure. The primary clinical manifestation of the reaction is the sudden onset of a severe hypotensive episode within one hour of transfusing blood or blood components through a bedside leukocyte reduction filter. The hypotension may be associated with respiratory distress, facial flushing, abdominal pain and nausea, and loss of consciousness.  
Immediately stop the transfusion. Should the patient develop signs of a leukocyte reduction blood filter reaction, immediately stop the transfusion. A rapid resolution of the symptoms is usually seen once the transfusion is discontinued. Follow your institution’s protocol for treatment of transfusion reactions.
Use blood products leukocyte-reduced at the time of collection or during laboratory storage if available. Whenever feasible, should the patient’s condition require such products, use blood products leukocyte-reduced during the time it was collected or during its laboratory storage period.
Recommendations: Use blood products LR at the time of collection or during laboratory storage if available.
Hypotension and Bedside Leukocyte Reduction Filters. FDA. May 4, [cited 2014 Aug-26]; Available from:

69. Schmaier, A. H. , Am J Physiol Regul Integr Comp Physiol, 2003
Schmaier, A.H., Am J Physiol Regul Integr Comp Physiol, (1): p. R1-13. PMID:

70. Red eye syndrome 
In 1997 there were 159 reactions in 117 patients characterized by conjunctival erythema or hemorrhage, eye pain, photophobia, and/or decreased visual acuity.
Reactions were association with transfusion of red cells filtered with the LeukoNet filter which employed cellulose acetate membranes.
No reactions of this type have occurred after LeukoNet filters were withdrawn from the market.
【UpToDate】
Red eye syndrome — In 1997 there were 159 reactions in 117 patients characterized by conjunctival erythema or hemorrhage, eye pain, photophobia, and/or decreased visual acuity occurring one to 24 hours after initiation of transfusion, resolving within a median of five days (range: 2 to 21 days) [73]. A subset of patients also reported headache, periorbital edema, arthralgias, nausea, dyspnea, and skin rash.
Reactions were association with transfusion of red cells filtered with the LeukoNet filter which employed cellulose acetate membranes. A similar ocular syndrome was elicited in rabbits injected with cellulose acetate derivatives extracted from unused filters or filter precursors, as well as in some patients who developed red eye syndrome after hemodialysis with cellulose acetate-containing hemodialyzers [74-76]. No reactions of this type have occurred after LeukoNet filters were withdrawn from the market.
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. UpToDate. updated: Mar 04, 2014.

71. The only drawback of LR is the Cost.
Clinical and laboratory aspects of platelet transfusion therapy
Literature review current through: Nov | This topic last updated: Jun 12, 2015.
= The only drawback of leukoreduction is the cost. 71

72. Pre-storage versus Bedside Leukocyte Reduction

73. Timing of Leukocyte Reduction
Time of Filtration
Pre-storage
in the blood center shortly after blood collection
Laboratory
in the transfusion service laboratory before blood issue
Bedside
bedside
Rossi's Principles of Transfusion Medicine, 4e (2009), P.2302
Blood Transfusion Therapy: A Physician's Handbook, 10e (2011)

74. Definition of Pre-storage LR
LR blood components is completed prior to component storage while the cells are still intact, usually within 48 hours of donation.
Practical Transfusion Medicine, 4e (2013)
Prestorage LR is generally performed soon after WB collection and is always performed within 5 days of collection.
Technical Manual, 17e (2011)
Opinions differ as to the definition of prestorage LR, but the FDA has suggested that 72 hours be used as the time from collection to filtration.
Rossi's Principles of Transfusion Medicine, 4e (2009)
【Practical Transfusion Medicine, 4e (2013)】
= P.210 LR is completed prior to component storage while the cells are still intact, usually within 48 hours of donation.
【AABB Technical Manual, 17e (2011)】
= P.208 Prestorage leukocyte reduction is generally performed soon after WB collection and is always performed within 5 days of collection, per current manufacturers' instructions.
【Rossi's Principles of Transfusion Medicine, 4e (2009)】
= P.232 Opinions differ as to the definition of prestorage leukocyte reduction, but the FDA has suggested that 72 hours be used as the time from collection to fi ltration.

75. Bedside vs. Laboratory LR
Sprogoe-Jakobsen, U., et al., Transfusion, (5): p

76. Wang, R.R., et al., Am J Clin Pathol, 2012. 138(2): p. 255-9.
Wang, R.R., D.J. Triulzi, and L. Qu, Effects of prestorage vs poststorage leukoreduction on the rate of febrile nonhemolytic transfusion reactions to platelets. Am J Clin Pathol, (2): p PMID:
apheresis single-donor platelets (SDPs), prestorage-leukoreduced (PreSLR) pooled platelets, poststorage-leukoreduced (PostSLR) pooled platelets, nonleukoreduced (NonLR) pooled platelets
Prestorage leukoreduction (PreSLR) refers to removal of WBCs soon after component preparation (ie, before storage)
poststorage leukoreduction (PostSLR) usually occurs just before the products are issued for transfusion.
Single donor platelets (SDPs) are typically leukoreduced at the time of apheresis collection.
The difference between the nonleukoreduced (NonLR) and the other 3 types of leukoreduced platelets was P = .008 (for single-donor [SDP]), P = .382 (for prestorage leukoreduction
[PreSLR]), and P = .045 (for poststorage leukoreduction [PostSLR]).
Wang, R.R., et al., Am J Clin Pathol, (2): p

77. Safety Concerns Related to Bedside LR Filtration
Bedside filtration has been associated with precipitous hypotension in the transfusion recipient, an infrequent yet serious adverse effect not associated with pre-storage LR.
Medication with ACE inhibitors appear to be particularly susceptible.
Pre-storage LR allows the LR process to be monitored under controlled conditions that assure component purity, consistency, and safety and is therefore generally preferable to bedside filtration.
Guidance for Industry: Pre-Storage LR of WB and Blood Components Intended for Transfusion, FDA, 2012.

78. Preparation of LR components: best to avoid the bedside
Routine filtration at the bedside in unreliable.
Hypotensive reactions associated with post-storage LR.
One authour’s personal experience with bedside infiltration:
unused filters post-transfusion
use syringes to force blood through the filters
Mollison's Blood Transfusion in Clinical Medicine, 12e (2014), P.580
One authour’s personal experience with bedside infiltration:
= Discovery of unused filters in the nursing statin (post-transfusion)
= Some outpatient personnel use syringes to force blood through the filters to reduce trasnfusion time.
Mollison's Blood Transfusion in Clinical Medicine, 12e (2014)

79. Pre-storage vs. post-storage LR (1/4)
Pre-storage LR is the optimal method of LR:
lower levels of cytokine generation and result in a lower risk of FNHTR.
general more effective (consistently leave < 10^6 leukocytes/unit)
immediate available inventory
quality control of residual leukocyte content.
【Rossi's Principles of Transfusion Medicine, 4e (2009), P.232】
= For these reasons bedside leukocyte reduction is not generally recommended.
1. reduced performance and poor quality control.
2. In addition, there is evidence that febrile reactions to platelet concentrates may be more effectively prevented if leukocytes are removed before storage.
3. Moreover, for some recipients taking angiotensin-converting enzyme (ACE) inhibitors, bedside fi ltration has been associated with hypotensive transfusion reactions.
Blood Transfusion Therapy: A Physician's Handbook, 10e (2011)

80. Pre-storage vs. post-storage LR (2/4)
We believe it is advantageous to provide pre-storage LR components in preference to bedside filtered blood components based on quality and safety considerations
Guidance for Industry: Pre-Storage LR of WB and Blood Components Intended for Transfusion, FDA, 2012.

81. Pre-storage vs. post-storage LR (3/4)
Prestorage filtration in the laboratory or at the time of collection, rather than at the bedside, is more reliable for leukocyte reduction.
Modern Blood Banking & Transfusion Practices , 6e (2012)

82. Pre-storage vs. post-storage LR (4/4)
The only significant advantage of post-storage LR is that only units requiring LR will be treated, thereby limiting the extra expense of filtration .
Pre-storage LR has supplanted post-storage LR as the method of choice.
Arthur J Silvergleid, MD, Leukoreduction to prevent complications of blood transfusion. UpToDate. updated: Mar 04, 2014.

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