1. Random Donor Pooled Platelets, Prophylaxis. Ofira Ben-Tal, MD. Director, Transfusion Medicine Tel-Aviv, Sourasky, Medical Center

2. Issues addressed : Patient population. Platelet product:  Leukoreduction.  ABO compatibility.  Platelet age.  Random pooled (RDP) Vs. single donor platelets (SDP).  Transfusion as prophylaxis

3. Patient population: Earlier studies 1-4 (3 level IA) performed on adult AML patients during induction. More recent (level IIB) studies performed on allogeneic BMT recipients 5,6. Therefore: the discussion will include both leukemic and transplant patients.

4. Platelet Product: Leukoreduction 1,7 Bedside leukoreduction of whole-blood derived RDP reduces the Rate of refractoriness 8 via alloimmunization 1, mainly to HLA. Rate of CMV infection 9. Rate of FNHTR (caused by cytokines secreted from WBC) reduced from >30% to ~5% 8. Therefore:Leucoreduction of cellular products is assumed (level IA).

5. Platelet product: ABO compatibility  Rate of refractoriness decreased x2-5 with ABO identical PLT, compared to unmatched 10,11..  Most studies since 1995 were performed using ABO-compatible platelets for all arms 1,6,12,13. Therefore: Recommended that patients receive ABO compatible PLT transfusions when feasible.

6. Aim to give <3d old. Platelet Age: Aim to give <3d old. Frequency of FNHTR increases from 9% to 18% with RDP storage time: =3d 14,15. 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 <2d 17.

7. 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.

8. RDP Vs. SDP: Issues  Effectiveness: increments, refractoriness, alloimmunization.  Donor exposure-viral transmission.  Transfusion Reactions: FNHTR.  Bacterial contamination.  Cost.

9. RDP Vs. SDP: Effectiveness Number of platelet per transfusion and yield/ increment 13 : ~3x10 11  Current separation procedures allow a pool of 4–6 RDP to contain the same number of platelets as did 10 in the past, ~3x10 11.  When patient size, number of platelets and storage time are accounted for, the increment of RDP & SDP is equivalent 13.

10. Effectiveness. RDP Vs. SDP: Effectiveness. TRAP 1 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.

11. RDP 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 HTLV 18.

12. FNHTR FNHTR from non-leukoreduced SDP in 1990 were 8.4% SDP Vs. 14.2% from RDP 19. Revisiting, those SDP had been stored for a shorter time 20. n FTNHR (rise in >=1 o c ± chills) using non- leuocoreduced SDP vs. RDP on a ‘older first’ basis vs. RDP <=3d: SDP & <=3 day old RDP gave similar FNHTR rates 16. RDP Vs. SDP: FNHTR and Storage time

13. 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 reported 20,22. Currently applied methods of donor skin cleansing and diverting the first aliquot into a side bag have reduced contamination by 50-75% 13,22.

14. RDP Vs. SDP: Bacterial contamination 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 similar 23.  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 reported 24.

15. RDP Vs. SDP: Cost In Israel: In Israel:  One leucoreduced SDP unit from MDA: NIS 2390.  Pheresis of 2 SDP units from a single donor: NIS ~1200/unit.  Pooled 6 units RDP, filtered at the bedside: NIS 900.

16. RDP Vs. SDP: Summary Using leucoreduced, ABO compatible, preferably <3d old RDP is equivalent to SDP in: Using leucoreduced, ABO compatible, preferably <3d old RDP is equivalent to SDP in:  Increment.  Refractoriness, Alloimmunization, FNHTR.  Risk of viral transmission.  Bacterial contamination rate.  Cost: RDP less costly.

17. Platelet loss in Non-Bleeding Leukemic & Normal 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 10 3 /  L/d 33. Therefore, as along as there are ~7x10 3 /  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 0.5x10 11 /d, equivalent to 1 unit RDP/day.

18. Prophylactic Vs.Therapeutic Platelet Transfusions ”The reasons prophylactic platelet transfusion became standard practice include its common sense appeal, the clinically serious, and visually and emotionally distressing effects of bleeding... The underlying clinical paradigm in hematology for three decades has been that prophylactic transfusion is safer than waiting for bleeding manifestations before initiating platelet transfusions. Clinical anxiety derives primarily from the risk of devastating intracranial hemorrhage in thrombocytopenic patients” 13.

19. Prophylactic Vs. Therapeutic Platelets: Direct Comparison. Actual comparison made 25-35 y ago 26-28 ; patient selection, supportive care and study methodology, currently considered inadequate; many patients received aspirin as anti pyretic drug 25. More recent data 29, employing currently acceptable methodology, have applied platelet transfusions prophylactically, studying the following issues:

20. Prophylactic Vs. Therapeutic Platelets: Issued examined. Relationship between Relationship between bleeding and platelet count. Platelet transfusion trigger: Platelet transfusion trigger: the threshold. Reducing the threshold to <5000 /  L? Reducing the threshold to <5000 /  L? Summary. Summary.

21. Relationship between Bleeding and Platelet Count Bleeding is hard to assess then as today, studies vary in definition 30. 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 <1x10 3 /  L. At 5-20x10 3 /  L, gross bleeding occurred on 3% of the days 32.

22. Relationship between Bleeding and Platelet Count Assessing daily blood loss in patients receiving no transfusions, at >10x10 3 /  L there was no difference from normal subjects. At counts 5- 10x10 3 /  L, blood loss was slightly increased. However, at platelet counts of <5x10 3 /  L, stool blood loss was ~x10 elevated 28. 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 20x10 3 /  L. Blood loss did not differ among the transfusion trigger groups 28.

23. Relationship between Bleeding and Platelet Count In a descriptive analysis 34 compiling data from 4 studies (900 AML patients and ~10 500 transfusions, 72% RDP, 28% SDP) it was found that (compared to the 20- 29x10 9 /L reference range):  For 0-4x10 9 /L, there was an x8 increase in bleeding risk;  For 5-14x10 9 /L, a x2 risk was observed  The increased rate of bleeding at low counts occurred despite PLT therapy 34.

24. Platelet Platelet Transfusion Trigger: The Threshold  Seven studies 31,35-40, 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 cases 13

25. Platelet 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 outcomes 3-5 :  Major bleeding - similar 3,5.  Transfusion requirement >20% lower among <10 000/  L recipients 3-5. Threshold <10 000 /  L  Therefore: Threshold <10 000 /  L accepted accepted

26. Can the Threshold be Further Reduced to <5000/L?! Can the Threshold be Further Reduced to <5000/  L?! Protocol instituted in chronic SAA patients 41 : Platelet transfusions given at 38°C, or at >10 x10 3 /  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 x10 3 /  L, 57% at <5x10 3 /  L. Three major nonlethal bleeds, all controlled.

27. In Summary : Data is convincing that bleeding risk does not increase substantially until counts are <10x10 3 and probably not until they are <5x10 3 /  L. Level IA studies have documented that the prophylactic platelet transfusion trigger level can safely be lowered to <10x10 3 /  L without substantially increasing bleeding risk. Currently not enough data to clearly establish a <5 x10 3 /  L trigger, but data suggest that this is a safe threshold 33,42. The lower the transfusion trigger, the greater is the reduction in platelets transfused, transfusion risks and costs.

28. References (click to open) References