This page is Part 2 of a two-part blog post on the impact of ABO matching for platelet transfusion. Part 1 provides provide an overview of the ABO system as it applies to platelets, definitions of ABO platelet matching terminology, and common endpoints for studies looking at the impact of ABO matching on platelet transfusions. If you are interested, you can go back to that page by clicking on this link: Understanding the Impact of Platelet ABO Matching – Part 1: The Basics

In Part 2 we will discuss the results from an extensive review of the evidence surrounding the impact of ABO incompatibility for prophylactic transfusions to hematology-oncology patients. Taken as a whole, the evidence suggests there is a relatively small impact on clinical outcomes from platelet ABO incompatibility (major mismatch), when compared to other product factors impacting transfusion success. We are very interested to hear your views on the cited literature. Please post a comment below the post to contribute to the discussion.

Overview of the available literature

The literature discussing the impact of ABO compatibility for platelet transfusions is relatively sparse considering the potential importance of the topic. A systematic review conducted by Shehata et al. covers the evidence up to January 2009.1 Shehata found 3 randomized controlled trials, 5 prospective studies, and 11 retrospective studies. In addition to this systematic review, and the articles referenced therein, three recent large retrospective analyses were also reviewed for this blog post.2-4

As discussed in Part 1, some sources were not explicit in defining their terminology, in these cases ABO compatible and ABO matched are assumed to refer to both ABO identical and minor ABO mismatch combined, while ABO incompatible or unmatched are assumed to refer to a major mismatch.

ABO impact on bleeding events

It is difficult to assess the impact of ABO compatibility on bleeding events during studies because severe bleeding events are typically quite rare. Additionally, the popular method for grading bleeding, the WHO classification, carries significant limitations due to the subjective nature of grading bleeds.5,6 Nonetheless, the prevention of bleeding is the primary goal of prophylactic platelet transfusion and thus, understanding the impact of transfusion practice on bleeding risk is a critical step.

To date, only the PLADO study provides a sufficiently large data set of bleeding data to draw an informed conclusion. To minimize biasing and maximize sample size, the investigators of the PLADO study chose time to bleeding event ≥ Grade 2 as the primary bleeding outcome. The dataset included 778 evaluable patients, almost half of the patients (383 of 778) experienced a bleeding event ≥ Grade 2.

Using the three categories of platelet ABO compatibility listed above it was concluded that ABO compatibility did not predict time to bleeding events ≥ Grade 2. A similar analysis for bleeding events ≥ Grade 3 was also conducted and similarly did not find an effect, however, due to the rarity of bleeding events ≥ Grade 3 the ability to detect an effect was very low.

ABO impact on platelet increment

Most of the data reviewed rely on platelet increment as the primary outcome. Nearly all studies that specifically compared ABO identical platelet transfusions with ABO major mismatched platelet transfusions have found a statistically significant reduction in platelet increment.2,4,7-17 Only a few, relatively small studies, were unable to find a difference between major mismatched and ABO identical platelets,18-20 and no studies found major mismatched platelets to be superior to ABO identical platelets.

A large prospective study by Heim et al. compared the mean corrected count increments (CCI) obtained with minor mismatched or identical transfusions and found the difference was not statistically significant.18 However, when comparing the rates of transfusions that failed to reach an “above median” CCI of 12.5—as opposed to the more widely used CCI threshold of 5—the Heim study found that minor and major mismatched platelets resulted in more below median CCIs compared to ABO identical platelet transfusions.

By contrast, a similarly sized study recently published by Seigeot et al. found that minor mismatched transfusions actually resulted in an improvement in platelet increment compared to ABO identical transfusions that was statistically significant.4 Yet, the majority of studies that made a distinction between ABO identical transfusions and minor mismatched transfusions, including the retrospective analysis of the PLADO database, did not find any difference in platelet increment.2,7,15,21

Impact of other factors on platelet increment

Many of the studies from the past two decades also assessed the impact of non-ABO product factors on platelet increment. Other product factors found to have a significant impact on platelet increments were platelet storage time,2,4,7,8,11 storage medium,7,8 cell separation technology,7,21 platelet source,2,4 irradiation,4,11 and washing.4 The table below summarizes the impact on platelet increment found for each of these factors with source publication.

Table 2 Comparison of factors influencing platelet increment

Source

Outcome Metric

Impact on Platelet Increment

(listed as Reference vs. Negatively Impacting Parameter)

ABO:

Identical 
vs.    Major
mismatch

Storage time:
Day 5
vs.
Day 0-2
Storage time:
Day 5
vs.
Day 3
Storage medium:
100% Plasma
vs.
PAS
Cell Separator:
Best
vs.
Worst
Platelet Source:
Apheresis
vs.
Whole blood
Irradiation:

No
vs.
Yes

Washing:

No
vs.
Yes

Seigeot, 2018

24 hr CCI

-0.79

-2.64

-1.76

NS

NS

2.28

Triulzi, 2012

4 hr CCI

24 hr CCI

-1.38

-1.77

-1.70

-1.03

-1.38

Julmy, 2009

1 hr OR

3.97

3.11

2.13

7.82*

7.82*

Heim, 2008

1 hr HR

1.52

1.92

1.60

1.59

Slichter, 2005

1 hr CCI

24 hr CCI

-4.6

-6.3

-1.9§

-2.0§

-2.8

NS

Balduini, 2001

16 hr CCI

NS‖,**

9.71¶,**

2.97**

Footnotes

–       Not reported by publication
*       Platelets with additive solution only conducted on an Amicus cell separator, non-Amicus cell separators used exclusively 100% plasma 
       Conducted using historical control of 100% plasma vs. more recent period of platelets in PAS
      ABO Identical vs. major mismatch not reported, combined identical and minor mismatch vs. major mismatched used instead
§          Day 5 vs. Day 0-2 not reported, instead, result reported as ≤ 48 hr storage time vs > 48 hr storage time
      ABO Identical vs. major mismatch not reported, ABO identical vs non-identical used instead
¶         Best cell separator was Apheresis System Technology 204, worst was Autopheresis-C
**    Results based on univariate analysis

Abbreviations

NS    Not significant
PAS  Platelet additive solution
CCI   Corrected Count Increment (x 1011), listed as reduction in CCI from negatively impacting parameter compared to reference
PPR  Percentage Platelet Recovery
OR    Failed transfusion Odds Ratio, Julmy defined a failed transfusion was as PPR ≤ 30%
HR    Below-median transfusion Hazard Ratio, Heim defined below-median as CCI < 12.5

Discussion

One feature unifying nearly of all the non-ABO factors listed above is that they can cause, or increase, platelet activation. Platelet aging and storage lesion have been shown to increase activation as measured by average CD62P expression.22 The storage of platelets in T-Sol additive solution has also been shown to have elevated CD62P expression.23 Whole blood derived platelets made from the PRP method, as was the case for the platelets in these studies, has been shown to have elevated expression of a host of surface markers for activation, including CD62P.24 The compacting and resuspension involved in washing platelets exerts stress on platelets.25 In two previous blog posts (here and here), we have gone into detail on the impact various cell separation technologies can have on platelet activation as detected by microparticle content.

From our previous studies, irradiation does not seem to substantially increase activation which may explain why it was not shown to have significantly different count increments for most of the outcome metrics it was tested against.26

The findings above are bolstered by the conclusion found in a small study published by Jimenez et al. They found that after ABO-identical apheresis platelets are transfused and when all recipient factors are randomized, that donor quality is the major determinant of platelet yield in circulation. When donor quality is factored out, ABO identity prevails.22

It is clear from this literature review that there is some room for debate on the impact of ABO matching. In terms of bleeding, it seems there is no evidence of any difference between the three levels of ABO compatibility. With regards to platelet increment the discussion is a bit more complicated. There is some past evidence suggesting minor ABO mismatched platelets can lead to a reduction in platelet increment, however, the two largest studies from the past ten years both concluded that minor mismatched platelets are as good or better than ABO identical transfusions. Thus, it is reasonable to conclude that ABO identical and ABO minor mismatched platelets can be treated as equivalent from a platelet increment perspective.

When looking at major ABO mismatch, it is relatively clear that there is a statistically significant reduction in platelet increment, especially in large studies. However, the impact from major ABO mismatch is either comparable or much smaller than the impact of platelet activating factors. It is likely that lower count increments in some ABO mismatched transfusions are due to a portion of donor platelets being rapidly removed from the recipient’s circulation because that portion of the donor’s platelets express high enough levels of A or B antigens, and the patient has high anti-A or anti-B titers (see Table 1 from Part 1). However, because the remaining portion of platelets tend to survive normally it is very likely that the patients receiving the major mismatched platelets still receive sufficient protection from hemorrhaging.

A critical piece to understanding the impact of platelet ABO matching is to compare ABO mismatch to other factors known to reduce platelet increments. The impact of using day 5 platelets was similar or substantially larger than the impact of a major ABO mismatch in all studies that specifically investigated storage lesion on a day-by-day basis. The same is true for the cell separator used, platelet source and platelet washing. These factors can all impact the level of platelet activation, which our studies have shown negatively impacts count increments of prophylactic transfusions.27 Consequently, a policy that prioritizes ABO matching can result in the transfusion of more activated platelets, which in turn, could result in lower count increments. Adding additional weight to these findings is the fact that a major ABO mismatch only removes the subset of high antigen expressing platelets, whereas the transfusion of activated platelets can lead to the removal of all, or nearly all, of the platelets transfused. The literature supports that a major ABO mismatch has less impact on platelet increments than the factors that activate platelets, but more studies are needed to precisely quantify the relative impact.

To properly inform transfusion practice, a direct comparison of the effects of ABO matching vs platelet activation status matching would need to be conducted. One such study is currently underway, where activation status is prioritized over ABO matching for a period of 4 months. The results will be compared to the baseline with strict ABO matching. This study will help our understanding of the relative importance of ABO matching and platelet activation status. We will share these results when they become available. Until then add to the discussion by commenting on how you have interpreted the cited literature in the comment section below the references.

References

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  3. Solves P, Carpio N, Balaguer A, et al. Transfusion of ABO non-identical platelets does not influence the clinical outcome of patients undergoing autologous haematopoietic stem cell transplantation. Blood Transfus 2015;13:411-6.
  4. Seigeot A, Desmarets M, Rumpler A, et al. Factors related to the outcome of prophylactic platelet transfusions in patients with hematologic malignancies: an observational study. Transfusion 2018.
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