The Effect of Variation in Donor Platelet Function on Transfusion Outcome: A Semi-Randomised, Double Blind, Controlled Trial (PROmPT)
Authors: Kelly Anne M , Garner Stephen F , Herbert Nina , Godec Thomas R , Kahan Brennan C , Deary Alison J , Bakrania Lekha , Foukaneli Theodora , Llewelyn Charlotte A , Ouwehand Willem H. , Williamson Lorna W , Cardigan Rebecca A 
Published: October 2019

Genetic variation is known to account for up to 70% of the wide variation in platelet function observed in healthy individuals. We have shown that platelet concentrates (PC) that are highly activated when collected by apheresis are produced from donors whose platelets are highly responsive to adenosine diphosphate (ADP) and collagen related peptide (CRP-XL) in vitro(high responder donors) with activation being measured by P-selectin expression and fibrinogen binding. The effect of this variation in donors on the outcome from platelet transfusion is unknown.

The aim of the PROmPT trial (Platelet Responsiveness and Outcome from Platelet Transfusion, ISRCTN 56366401) was to test the hypothesis that PC following transfusion from high responder donors are cleared more rapidly from the circulation than PC from low responder donors.

Method

We established a cohort of 1,000 blood donors phenotyped for responsiveness to CRP (0.1-0.5 µg/mL) or ADP (10-7M) by flow cytometry. A sub-set of these individuals (26 high and 19 low responder donors) who reproducibly had global responses, i.e. not outliers for just one agonist, in the top and bottom 10% of the cohort were selected to supply apheresis platelets collected on the Terumo Trima system for the trial.

The trial was designed as a parallel group, semi-randomised double-blinded trial in stable haematology patients who required prophylactic platelet transfusions. Based on 80% power, a 5% significance level, and a presumed 10% dropout, 100 patients (with the aim of 50 receiving a unit from high responders and 50 from low responders) were required to detect a mean difference of 7x109/L in the primary endpoint of the 1 hour (10-90 min) count increment (CI) between the high and low responder PC.

Patients were randomised to receive a single PC from either a high or low responder donor when both were available. If only one type of PC was available then patients received that PC. Patients with factors known to affect platelet CI were excluded. In addition, 30 patients acted as controls, receiving non-trial PC from random donors. PCs were ABO and Rh compatible. Patients were followed up for 5 days or until their next platelet transfusion.

Secondary outcomes included an assessment of bleeding score (modified WHO score) both by the patient and the clinician, 24 hour (12-36 hours) CI, as well as time to next platelet transfusion, and red cell transfusion requirements. CIs were adjusted for confounding factors that affect platelet increments, these were age and dose of PC, and body surface area.

Results

Baseline characteristics of patients were adequately balanced between groups. Fifty one patients received a PC from low responder donors, and 49 from high responder donors (47 of which were randomised and 53 non-randomised) and 30 patients received non-trial units (2 non trial transfusions were excluded from final analysis).

There was no significant difference in the adjusted 1 hour CI, in patients receiving platelets from high or low responder donors (high response 21.04 versus low response 23.34x109/L; difference 2.30, 95%CI -1.09 to 5.69, p = 0.18) or the 24 hour platelet CI (high response 12.9 versus low response 14.31x109/L; difference 1.41, 95% CI -1.96 to 4.78, p = 0.41).

There were no significant differences in all other secondary outcomes between patients receiving PC from high or low responder donors, including maximum bleeding scores (odds ratio 0.78, 95%confidence interval 0.29 to 2.16, p=0.64) and bleeding rates (number of days with Grade 2-4 bleed) (rate ratio was 0.70, 95% confidence interval 0.16 to 2.97, p = 0.63).

In addition, there was no significant difference in 1 hour CI between patients receiving non-trial units and those from high (p = 0.28) or low responders (p = 0.95) or in any secondary outcomes.

Conclusions

Results from this trial suggest that in a setting of prophylactic transfusion, the platelet responsiveness of the donor does not affect platelet count increments, bleeding scores, inter-transfusion interval or red cell usage in recipients. Further studies will be required to determine whether PC derived from high responders may be more efficacious in patients who are actively bleeding at the time of transfusion.

Disclosures

No relevant conflicts of interest to declare.