random donor pooled platelets, prophylaxis. ofira ben-tal, md. director, transfusion medicine...

Random Donor Pooled Platelets, Prophylaxis.Random Donor Pooled Platelets, Prophylaxis.

Ofira Ben-Tal, MD.Director, Transfusion Medicine

Tel-Aviv, Sourasky, Medical Center

Issues addressed:Issues addressed: Patient population. Platelet product:

Leukoreduction.ABO compatibility.Platelet age.

Random pooled (RDP) Vs. Random pooled (RDP) Vs. single donor platelets single donor platelets (SDP).(SDP).

Transfusion as Transfusion as prophylaxisprophylaxis

Patient population:Patient population:

Earlier studies1-4 (3 level IA) performed on adult AML patients during induction.

More recent (level IIB) studies performed on allogeneic BMT recipients5,6.

Therefore: the discussion will

include both leukemic and transplant patients.

Platelet Product: Leukoreduction1,7

Platelet Product: Leukoreduction1,7

Bedside leukoreduction of whole-blood derived RDP reduces the Rate of refractoriness8 via

alloimmunization1, mainly to HLA.Rate of CMV infection9.Rate of FNHTR (caused by cytokines

secreted from WBC) reduced from >30% to ~5%8.

Therefore:Leucoreduction of Therefore:Leucoreduction of cellular products is assumed cellular products is assumed (level IA).(level IA).

Platelet product: ABO compatibilityPlatelet product: ABO compatibility

Rate of refractoriness decreased x2-5 with ABO identical PLT, compared to unmatched10,11..

Most studies since 1995 were performed using ABO-compatible platelets for all arms1,6,12,13.

Therefore: Recommended that patients receive ABO compatible PLT transfusions when feasible.

Platelet Age:Aim to give <3d Aim to give <3d old.old. Platelet Age:Aim to give <3d Aim to give <3d old.old.

Frequency of FNHTR increases from 9% to 18% with RDP storage time: <3d Vs. >=3d14,15.

Frequency of FNHTR from <3d RDP equal that of SDP: <5%16.

Moderate-to-severe reactions (2.2% transfusions in 22% patient) significantly reduced when RDP were stored <2d17.

Pooled Random Donor Vs. Single Donor Platelets

Pooled Random Donor Vs. Single Donor Platelets

…“The arguments for use of pheresis platelets have mostly relied on theoretical advantages rather than direct evidence and have changed over time. Twenty years later these arguments should be re-evaluated in the light of new data as well as increasing concern about cost of the product and to the donor” 13.

RDP Vs. SDP: IssuesRDP Vs. SDP: Issues

Effectiveness: increments, refractoriness, alloimmunization.

Donor exposure-viral transmission.

Transfusion Reactions: FNHTR. Bacterial contamination. Cost.

RDP Vs. SDP: EffectivenessRDP Vs. SDP: Effectiveness Number of platelet per transfusion

and yield/increment13: Current separation procedures allow

a pool of 4–6 RDP to contain the same number of platelets as did 10 in the past, ~3x10~3x101111.

When patient size, number of platelets and storage time are accounted for, the increment of RDP & SDP is equivalent13.

RDP Vs. SDP: Effectiveness.Effectiveness.RDP Vs. SDP: Effectiveness.Effectiveness.

TRAP1 set the ground: ABO-matched unmodified RDP vs. F-RDP, UVB-RDP and F-SDP given to 530 adult AML patients during induction.

Refractoriness during 8 weeks: reduced by half in recipients of both F-RDP and F-SDP vs. controls.

Alloimmunization decreased from ~13% to ~4% by both F-RDP and F-SDP.

RDP Vs. SDP: Donor ExposureRDP Vs. SDP: Donor Exposure

In the 1980s, the most compelling reason for SDP use was a reduction in the number of donor exposures; data were scarce.

Currently, residual risk of viral transmission during the infectious window period is 1:488,000 for Hepatitis B, 1:2,135,000 for HIV, 1;1,935,000 for HCV and ~1:3 million for HTLV18.

FNHTRFNHTR from non-leukoreduced SDP in 1990 were 8.4% SDP Vs. 14.2% from RDP19.

Revisiting, those SDP had been stored for a shorter time20.

n FTNHR (rise in >=1oc ± chills) using

non-leuocoreduced SDP vs. RDP on a ‘older first’ basis vs. RDP <=3d: SDP & <=3 day old RDP gave similar FNHTR rates16.

RDP Vs. SDP: FNHTR and Storage time RDP Vs. SDP: FNHTR and Storage time

RDP Vs. SDP: Bacterial contamination


he risk was considered proportional to the number of units in the pool.

Data hard to compare; rate probably under reported20,22.

Currently applied methods of donor skin cleansing and diverting the first aliquot into a side bag have reduced contamination by 50-75%13,22.



Variable data/rates:Variable data/rates: 0.04-10%22 Patient events: In the BaCon (CDC)

study: bacteremia (events/million units) was 9.98 for SDP, 10.64 for RDP. Infection rate (1:100,000) and mortality (1:500,000) were similar23.

Product ‘events’: 1-7% RDP and 0.3–3% SDP ‘infected’; when a second culture required to confirm the first, a true positive rate of (1:3000) for RDP and (1:2000) for SDP was reported24.

RDP Vs. SDP: CostRDP Vs. SDP: Cost

In Israel: In Israel: One leucoreduced SDP unit One leucoreduced SDP unit

from MDA: NIS from MDA: NIS 23902390..Pheresis of 2 SDP units from Pheresis of 2 SDP units from

a single donor: NIS a single donor: NIS ~~1200/unit1200/unit..

Pooled 6 units RDP, filtered Pooled 6 units RDP, filtered at the bedside: NIS at the bedside: NIS 900900..

RDP Vs. SDP: SummaryRDP Vs. SDP: Summary Using leucoreduced, ABO compatible, Using leucoreduced, ABO compatible,

preferably <3d old RDP is equivalent preferably <3d old RDP is equivalent to SDP in:to SDP in:Increment.Increment.Refractoriness, Alloimmunization, Refractoriness, Alloimmunization,

FNHTR.FNHTR.Risk of viral transmission.Risk of viral transmission.Bacterial contamination rate.Bacterial contamination rate.Cost: RDP less costly.Cost: RDP less costly.

Platelet lossPlatelet loss in Non- in Non-Bleeding Leukemic & Bleeding Leukemic & Normal SubjectsNormal Subjects

Platelet lossPlatelet loss in Non- in Non-Bleeding Leukemic & Bleeding Leukemic & Normal SubjectsNormal Subjects

Using platelet recovery and survival, it was shown that platelets are lost by 2 mechanisms:

senescence with a lifespan of 10.5 days a randomly removed fixed fraction of ~7.1x 103/L/d33.

Therefore, as along as there are ~7x103/L/d to provide an endothelial supportive function, hemostasis may be maintained 28,31,32.

In a 70kg person with a normal spleen, the actual number of platelets required may be 0.5x1011/d, equivalent to 1 unit RDP/day.

Prophylactic Prophylactic Vs.Therapeutic Platelet Vs.Therapeutic Platelet TransfusionsTransfusions

Prophylactic Prophylactic Vs.Therapeutic Platelet Vs.Therapeutic Platelet TransfusionsTransfusions

””The reasons prophylactic platelet The reasons prophylactic platelet transfusion became standard practice transfusion became standard practice include its include its common sense appealcommon sense appeal, the , the clinically serious, clinically serious, andand visually visually andand emotionally distressing emotionally distressing effects of effects of bleeding... The underlying bleeding... The underlying clinical paradigmclinical paradigm in hematology for in hematology for three decadesthree decades has been has been that prophylactic transfusion is safer than that prophylactic transfusion is safer than waiting for bleeding manifestations before waiting for bleeding manifestations before initiating platelet transfusions. initiating platelet transfusions. Clinical Clinical anxietyanxiety derives primarily from the risk of derives primarily from the risk of devastating intracranial hemorrhagedevastating intracranial hemorrhage in in thrombocytopenic patients”thrombocytopenic patients”1313..

Prophylactic Vs. Therapeutic Prophylactic Vs. Therapeutic Platelets: Platelets: Direct Direct Comparison.Comparison.

Prophylactic Vs. Therapeutic Prophylactic Vs. Therapeutic Platelets: Platelets: Direct Direct Comparison.Comparison.

Actual comparison made 25-35 y ago26-28; patient selection, supportive care and study methodology, currently considered inadequate; many patients received aspirin as anti pyretic drug25.

More recent data29, employing currently acceptable methodology, have applied platelet transfusions prophylactically, studying the following issues:

Prophylactic Vs. Therapeutic Prophylactic Vs. Therapeutic Platelets: Issued examined.Platelets: Issued examined.Prophylactic Vs. Therapeutic Prophylactic Vs. Therapeutic Platelets: Issued examined.Platelets: Issued examined.

Relationship between Relationship between

bleeding and platelet countbleeding and platelet count.. Platelet transfusion trigger: Platelet transfusion trigger:

the the thresholdthreshold.. Reducing the threshold to Reducing the threshold to

<5000<5000//L?L? Summary.Summary.

Relationship between Relationship between Bleeding and Platelet Bleeding and Platelet CountCount


Bleeding is hard to assess then as today, studies vary in definition30.

The risk of serious bleeding in untransfused patients was assessed in the 50’s-early 60’s in NCI among leukemic children & adults. Gross bleeding occurred on 33% of the days in patients with <1x103/L. At 5-20x103/L, gross bleeding occurred on 3% of the days32.



Assessing daily blood loss in patients receiving no transfusions, at >10x103/L there was no difference from normal subjects. At counts 5-10x103/L, blood loss was slightly increased. However, at platelet counts of <5x103/L, stool blood loss was ~x10 elevated28.

A prospective randomized follow-up study compared prophylactic 6 RDP 4-5 days old (reflecting the least effective platelets) given at counts of 5, 10, or 20x103/L. Blood loss did not differ among the transfusion trigger groups28.



In a descriptive analysis34 compiling data from 4 studies (900 AML patients and ~10 500 transfusions, 72% RDP, 28% SDP) it was found that (compared to the 20-29x109/L reference range):For 0-4x109/L, there was an x8

increase in bleeding risk; For 5-14x109/L, a x2 risk was

observed The increased rate of bleeding at

low counts occurred despite PLT therapy34.

Platelet Platelet Transfusion Trigger: The ThresholdPlatelet Platelet Transfusion Trigger: The Threshold

Seven studies31,35-40, 748 patients: for stable patients, a threshold of 10,000/L was equivalent to 20,000/L.

Major bleeding occurred in median 17% of patients at each threshold in four studies reporting major bleeding on a per-patient basis.

Platelet transfusions decreased significantly, 20–25% in some cases13

Platelet Platelet Transfusion Trigger: The ThresholdPlatelet Platelet Transfusion Trigger: The Threshold

Three prospective, randomized level IA studies on AML and BMT patients:

Threshold reduced from <20 000/L to <10 000/L with similar outcomes3-5:

Major bleeding - similar3,5.Transfusion requirement >20% lower among <10 000/L recipients3-5.

Therefore: Threshold Threshold <10 000<10 000//L L

acceptedaccepted

Can the Threshold be Can the Threshold be FurtherFurther Reduced to <5000/ Reduced to <5000/L?!L?!

Can the Threshold be Can the Threshold be FurtherFurther Reduced to <5000/ Reduced to <5000/L?!L?!

Protocol instituted in chronic SAA patients41: Platelet transfusions given at <5000l in

stable patients, at 5-10 x103/L in recent hemorrhage and/or fever >38°C, or at >10 x103/L in case of major bleeding.

Progressively-lengthening the interval up to >7 days initiated; achieved in 78% of transfusions.

Of 1135 transfusions, 88% were at <10 x103/L, 57% at <5x103/L.

Three major nonlethal bleeds, all controlled.

In Summary:In Summary: Data is convincing that bleeding risk does not

increase substantially until counts are <10x103 and probably not until they are <5x103/L.

Level IA studies have documented that the prophylactic platelet transfusion trigger level can safely be lowered to <10x103/L without substantially increasing bleeding risk.

Currently not enough data to clearly establish a <5 x103/L trigger, but data suggest that this is a safe threshold33,42.

The lower the transfusion trigger, the greater is the reduction in platelets transfused, transfusion risks and costs.

References (click to open)

random donor pooled platelets, prophylaxis. ofira ben-tal, md. director, transfusion medicine...

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