Dose of Prophylactic Platelet Transfusions and Prevention ofHemorrhageSherrill J. Slichter, M.D., Richard M. Kaufman, M.D., Susan F. Assmann, Ph.D., JeffreyMcCullough, M.D., Darrell J. Triulzi, M.D., Ronald G. Strauss, M.D., Terry B. Gernsheimer,M.D., Paul M. Ness, M.D., Mark E. Brecher, M.D., Cassandra D. Josephson, M.D., Barbara A.Konkle, M.D., Robert D. Woodson, M.D., Thomas L. Ortel, M.D., Ph.D., Christopher D. Hillyer,M.D., Donna L. Skerrett, M.D., Keith R. McCrae, M.D., Steven R. Sloan, M.D., Ph.D., Lynne Uhl,M.D., James N. George, M.D., Victor M. Aquino, M.D., Catherine S. Manno, M.D., Janice G.McFarland, M.D., John R. Hess, M.D., Cindy Leissinger, M.D., and Suzanne Granger, M.S.From the Puget Sound Blood Center and University of Washington Medical Center, Seattle (S.J.S.,T.B.G.); Brigham and Women’s Hospital (R.M.K.), Children’s Hospital Boston (S.R.S.), and BethIsrael Deaconess Medical Center (L.U.) — all in Boston; New England Research Institutes,Watertown, MA (S.F.A., S.G.); Fairview–University Medical Center, Minneapolis (J.M.); Universityof Pittsburgh, Pittsburgh (D.J.T.); University of Iowa, Iowa City (R.G.S.); Johns Hopkins University(P.M.N.) and University of Maryland ( J.R.H.) — both in Baltimore; University of North Carolina,Chapel Hill (M.E.B.); Emory University, Atlanta (C.D.J., C.D.H.); University of Pennsylvania (B.A.K.)and Children’s Hospital of Philadelphia (C.S.M.) — both in Philadelphia; Blood Center of Wisconsin,Milwaukee, and University of Wisconsin–Madison, Madison (R.D.W., J.G.M.); Duke University,Durham, NC (T.L.O.); Weill College of Cornell University, New York (D.L.S.); Case Western ReserveUniversity, Cleveland (K.R.M.); University of Oklahoma, Oklahoma City ( J.N.G.); University ofTexas Southwestern Medical Center, Dallas (V.M.A.); and Tulane University Hospital and Clinics,New Orleans (C.L.).AbstractBACKGROUND—We conducted a trial of prophylactic platelet transfusions to evaluate the effectof platelet dose on bleeding in patients with hypoproliferative thrombocytopenia.METHODS—We randomly assigned hospitalized patients undergoing hematopoietic stem-celltransplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylacticplatelet transfusions at a low dose, a medium dose, or a high dose (1.1×1011, 2.2×1011, or4.4×1011 platelets per square meter of body-surface area, respectively), when morning platelet countswere 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. Theprimary end point was bleeding of grade 2 or higher (as defined on the basis of World HealthOrganization criteria).RESULTS—In the 1272 patients who received at least one platelet transfusion, the primary endpoint was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dosegroup, and the high-dose group, respectively (differences were not significant). The incidences ofhigher grades of bleeding, and other adverse events, were similar among the three groups. The mediannumber of platelets transfused was significantly lower in the low-dose group (9.25×1011) than in themedium-dose group (11.25×1011) or the high-dose group (19.63×1011) (P = 0.002 for low vs.medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelettransfusions given was significantly higher in the low-dose group (five, vs. three in the medium-doseCopyright © 2010 Massachusetts Medical Society.Address reprint requests to Dr. Slichter at Puget Sound Blood Center, 921 Terry Ave., Seattle, WA 98104-1256, or at sjslichter@psbc.org.NIH Public AccessAuthor ManuscriptN Engl J Med. Author manuscript; available in PMC 2010 October 7.Published in final edited form as:N Engl J Med. 2010 February 18; 362(7): 600–613. doi:10.1056/NEJMoa0904084.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptand three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurredon 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower,as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubicmillimeter (P<0.001).CONCLUSIONS—Low doses of platelets administered as a prophylactic transfusion led to adecreased number of platelets transfused per patient but an increased number of transfusions given.At doses between 1.1×1011 and 4.4×1011 platelets per square meter, the number of platelets in theprophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number,NCT00128713.)The optimal number of platelets in a prophylactic platelet transfusion is controversial.1,2 Astandard dose for adults is considered to be approximately 3×1011 to 6×1011 platelets.3 Higherdoses than these could potentially result in superior hemostasis,4 but a lower dose might beequally effective while conserving the platelet supply. Two randomized trials with limitedenrollment — one of 111 patients5 and the other of 119 patients6 — have compared a low doseof platelets to the standard dose. In both trials, the two doses prevented bleeding to a similardegree. We conducted a randomized trial of prophylactic platelet transfusions to determine theeffects of the dose of platelets on clinical signs of bleeding, the use of platelet and red-celltransfusions, changes in the recipient’s post-transfusion platelet count, days to next transfusion,and adverse events.7METHODSA subcommittee of the Transfusion Medicine/Hemostasis Clinical Trials Networkinvestigators designed the study and wrote the manuscript, which was reviewed by all authors.Site coordinators gathered the data and submitted the results electronically. (The studyinvestigators and staff are listed in the Appendix.) The data were analyzed with the use of SASsoftware (version 9.2).8 The lead author wrote the first draft of the manuscript and vouches forthe completeness and accuracy of the data. Institutional review boards approved the study.Adults provided written informed consent; and for children, a parent or legal guardian providedwritten informed consent. Children provided assent if required by local site policy. A data andsafety monitoring board reviewed the data twice a year. Stopping boundaries for comparisonof the primary end point between each pair of treatment groups were calculated with the useof an alpha spending function similar to O’Brien–Fleming boundaries.ELIGIBILITY CRITERIAPatients were eligible for the study if they were inpatients of any age undergoing hematopoieticstem-cell transplantation or chemotherapy for hematologic cancers or solid tumors and it wasexpected that they would have platelet counts of 10,000 per cubic millimeter or lower for 5days or more. Additional criteria were a weight of 10 to 135 kg, prothrombin and partial-thromboplastin times 1.3 times the upper limit of the normal range or less, a fibrinogen levelof 100 mg per deciliter or more, and no previous platelet transfusions for thrombocytopeniaduring the current period of hospitalization.Exclusion criteria were as follows: bleeding of grade 2 or higher, according to the World HealthOrganization (WHO) bleeding scale9 (ranging from grades 1 through 4, with higher gradesindicating worse bleeding; see below and the Supplementary Appendix, available with the fulltext of this article at NEJM.org) before or at the time of assessment; performance of bedsideplatelet leukoreduction; platelet refractoriness within the past 30 days, according to localcriteria; a panel-reactive HLA antibody level of 20% or more; acute promyelocytic leukemia,idiopathic or thrombotic thrombocytopenic purpura, or the hemolytic–uremic syndrome;planned prophylactic transfusion of platelets at platelet counts of more than 10,000 per cubicSlichter et al. Page 2N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptmillimeter10; major surgery within the previous 2 weeks; use of drugs intended to affect plateletnumber or function; pregnancy; and previous enrollment in this platelet-dose trial (PLADOtrial).STRATIFICATION AND RANDOMIZATIONBody-surface area was calculated from height and weight.11 Patients were randomly assignedin a 1:1:1 ratio, by means of computer-generated permuted blocks, to receive platelettransfusions of one of three doses — 1.1×1011, 2.2×1011, and 4.4×1011 platelets per squaremeter per transfusion (low-dose group, medium-dose group, and high-dose group,respectively) — according to four treatment strata12: allogeneic hematopoietic stem-celltransplantation, autologous or syngeneic hematopoietic stem-cell transplantation,chemotherapy for hematologic cancer, or chemotherapy for solid tumor. Treatment-groupassignments were balanced within trial sites with the use of dynamic balancing.12 For typicaladults, the medium dose is similar to a standard adult dose with regard to the number ofplatelets.TRANSFUSIONSThe blood-transfusion service was given each patient’s assigned dose and the allowable range,±25% of the assigned dose. Site staff were not told the patient’s assigned dose, but differencesin transfusion volume prevented complete blinding. Selection of platelets for transfusion toachieve the correct “attempted dose” was specified as follows. For apheresis platelets, theplatelet count at the time of collection was used to select a partial unit, a single unit, or multipleunits. For pooled platelet concentrates, the mean platelet count per concentrate, based onquality-control data, was used to determine the number of platelet concentrates to combine.For each transfusion, an “at-issue” platelet count was obtained to determine the actual dosetransfused. HLA-selected platelets were transfused completely to avoid product wastage,regardless of the patient’s assigned dose.Platelets were transfused prophylactically if the morning count was 10,000 per cubic millimeteror lower (the “trigger” threshold). The patient’s physician could change the transfusion triggerthreshold or dose if required by clinical indications, with a return to study guidelines as soonas possible. Local practice determined the indications for red-cell transfusion. Platelets and redcells were leukoreduced by means of filtration.CLINICAL ASSESSMENTSResearch staff performed daily assessments of bleeding using physical examinations,interviews with patients, and chart reviews for bleeding events. They also collected data on allbleeding described in the WHO criteria,9 except they did not perform urine dipstick or stoolguaiac tests. The bleeding data were used to calculate each patient’s daily bleeding grade. Dailyplatelet counts, hematocrit values, and hemoglobin levels were also measured.The primary end point was bleeding of grade 2 or higher. Grade 2 bleeding was defined asoropharyngeal bleeding or epistaxis for more than 30 minutes during a 24-hour period, purpuraof more than 1 in. (2.54 cm) in diameter, deep hematoma, joint bleeding, melena, hematochezia,hematemesis, gross hematuria, abnormal vaginal bleeding consisting of more than spotting,hemoptysis, blood in bronchopulmonary lavage specimens, visible blood in body-cavity fluidwithout symptoms, retinal bleeding without visual impairment, spinal-fluid specimenscontaining microscopic amounts of blood, or bleeding for more than 1 hour at invasive sites.9 (See the Supplementary Appendix for definitions of bleeding grades 0 through 4.) If aninvestigator indicated possible death from hemorrhage or if a deceased patient had had grade3 or 4 bleeding, three nonstudy physicians adjudicated whether bleeding was the cause of death.Slichter et al. Page 3N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptADVERSE EVENTSInformation was collected on all serious adverse events and on events commonly associatedwith transfusion that occurred during transfusion or within 4 hours afterward.STUDY COMPLETIONThe study was considered to be completed at 30 days after the first platelet transfusion, aftera 10-day period without a platelet transfusion, at hospital discharge, at death, or at withdrawalfrom the study — whichever occurred first.STATISTICAL ANALYSISThe primary end point was bleeding of grade 2 or higher; secondary end points were the highestgrade of bleeding, total number of platelets transfused, and number of platelet transfusions.Other analyses were exploratory. To account for the three pairwise comparisons among thethree treatment groups, two-sided P values of less than 0.017 were considered to indicatestatistical significance. No other adjustment was made for analyzing multiple outcomes. Thestudy was designed to have a statistical power of 85% to detect an absolute difference of 12.5%in the incidence of the primary end point for any pair among the three treatment groups, whichrequired 450 patients per group.Unless otherwise specified, all analyses were restricted to data for patients who received atleast one platelet transfusion. Results were analyzed according to the patient’s treatmentassignment, even if platelet transfusions were not received at the assigned dose or were notadministered in accordance with the prophylactic transfusion trigger threshold of 10,000platelets per cubic millimeter.Dichotomous end points were compared among the groups with the use of Fisher’s exact test.The highest grade of bleeding was compared using an exact version of the Kruskall–Wallistest. The time to next transfusion and time to bleeding were compared among the groups bymeans of the log-rank test.13 Dose adherence for each transfusion, trigger-threshold adherencefor each study day, pretransfusion and post-transfusion platelet-counts, platelet increments,and corrected count increments were compared among the groups with the use of generalizedlinear models to account for possible correlations between results within each patient.14,15 (Theplatelet increment is defined as the post-transfusion platelet count minus the pretransfusioncount; the corrected count increment has a numerator of the platelet increment [in cubicmillimeters] multiplied by the body-surface area [in square meters] and a denominator of thetotal number of platelets transfused divided by 1011.) Other continuous variables were analyzedwith the use of the Wilcoxon rank-sum test. The post hoc subgroup analysis of data regardingthe primary end point, according to randomization stratum, used a logistic-regression modelwith an interaction term.RESULTSSTUDY POPULATIONBetween 2004 and 2007, a total of 1351 patients were enrolled at 26 sites. Seventy-nine patientsdid not receive a platelet transfusion; however, including these patients in the analyses had anegligible effect on the results. The baseline characteristics of the study patients were wellbalanced among the three treatment groups (Table 1).ADHERENCE WITH PLATELET DOSE AND TRANSFUSION TRIGGER THRESHOLDDose adherence was not required for 210 HLA-selected units of platelets and could not bereliably determined for an additional 331 volume-reduced units from which plasma wasSlichter et al. Page 4N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptremoved by centrifugation after collection. Among the 5466 prophylactic platelet transfusionswith neither characteristic, the attempted dose was known for 5384 transfusions in 1162patients — and there was dose adherence for 86% of these low-dose transfusions, 98% of thesemedium-dose transfusions, and 93% of these high-dose transfusions (P<0.001 for low dose vs.medium dose and medium dose vs. high dose) (Table 2). Among the 1162 patients, all knownattempted doses were in adherence for 79%, 92%, and 86% of patients in the low-dose,medium-dose, and high-dose groups, respectively (P<0.001 for low dose vs. medium dose, andP = 0.004 for medium dose vs. high dose).Platelet doses based on at-issue platelet counts were within the patient’s assigned range for71%, 80%, and 70% of transfusions in the low-dose group, medium-dose group, and high-dosegroup, respectively (P = 0.007 for low dose vs. medium dose, and P<0.001 for medium dosevs. high dose). This result confirms that the platelet-selection procedure usually resulted intransfusions of at-issue doses in the assigned range. All known at-issue doses were within theassigned range for 51%, 63%, and 55% of patients in the low-dose, medium-dose, and high-dose groups, respectively (P<0.001 for low dose vs. medium dose).Physicians ordered changes in the platelet dose for clinical reasons for 17% of patients in thelow-dose group, 9% in the medium-dose group, and 7% in the high-dose group (P = 0.003 forlow dose vs. medium dose and P<0.001 for low dose vs. high dose). Overall, only 3% of patientshad a dose change before the onset of bleeding of grade 2 or higher.The trigger threshold of 10,000 platelets per cubic millimeter was adhered to on 90%, 92%,and 94% of patient-days in the low-dose group, medium-dose group, and high-dose group,respectively (P<0.001 for low dose vs. high dose). The trigger was adhered to on all study daysfor 53%, 62%, and 61% of patients, respectively (P = 0.01 for low dose vs. medium dose).Physicians ordered changes in the trigger threshold for clinical reasons for 32%, 26%, and 25%of patients, respectively, but a total of only 7% of patients had a change in the trigger thresholdbefore the onset of bleeding of grade 2 or higher.PRIMARY AND SECONDARY END POINTSIn the 1351 patients who underwent randomization, the percentage with at least one episodeof bleeding of grade 2 or higher was 68% in the low-dose group, 67% in the medium-dosegroup, and 69% in the high-dose group, with no significant differences among the groups (P= 0.83 for low dose vs. medium dose and for low dose vs. high dose; P = 0.66 for medium dosevs. high dose). Among the 1272 patients who received at least one platelet transfusion, thepercentage of patients in each group with at least one episode of bleeding of grade 2 or higherwas not significantly different (71%, 69% and 70%, respectively) (Table 3).Overall, the highest bleeding grade observed was no bleeding or bleeding of grade 1 in 31%of patients, grade 2 in 59%, grade 3 in 8%, and grade 4 in 2%. In each group, the median numberof days of bleeding of grade 2 or higher was 1. The median time from randomization to onsetof bleeding ranged from 7 to 8 days. The median number of red-cell units transfused per patientwas 4. A total of 93% of patients received at least one red-cell transfusion. There were nosignificant differences among the three groups for any of these end points.Bleeding of grade 2 or higher occurred in 79% of recipients of allogeneic hematopoietic stem-cell transplants, 73% of patients who had hematologic cancers and were undergoingchemotherapy, and 57% of patients undergoing autologous or syngeneic hematopoietic stem-cell transplantation (P<0.001 for the comparison of the latter group with each of the first twogroups). However, within each of these treatment categories, the platelet dose had no significanteffect on bleeding.Slichter et al. Page 5N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptThe 1272 patients who received at least one transfusion were observed for a total of 24,309days. Figure 1 shows the percentage of days on which bleeding of grade 2 or higher occurred,according to the patient’s morning platelet-count category. Bleeding of grade 2 or higheroccurred on 25% of days with morning platelet counts of 5000 per cubic millimeter or lower,17% of days with morning platelet counts from 6000 to 80,000 per cubic millimeter, 13% ofdays with morning platelet counts from 81,000 to 100,000 per cubic millimeter, and 8% ofdays with morning platelet counts over 100,000 per cubic millimeter (P<0.001 for plateletcounts of ≤5000 per cubic millimeter vs. counts of 6000 to 80,000; P = 0.001 for platelet countsof 81,000 to 100,000 per cubic millimeter vs. counts of 6000 to 80,000; and P<0.001 for plateletcounts of >100,000 per cubic millimeter vs. counts of 6000 to 80,000) (Fig. 1).We could calculate the total number of platelets transfused per patient for 1000 patients. Themedian number of platelets transfused was 9.25×1011, 11.25×1011, and 19.63×1011 in the low-dose, medium-dose, and high-dose groups, respectively (P = 0.002 for low dose vs. mediumdose, P<0.001 for high dose vs. low dose and high dose vs. medium dose) (Table 3). The mediannumber of platelet transfusions administered was five in the low-dose group as compared withthree in the medium-dose group and three in the high-dose group (P<0.001 for low dose vs.medium dose and low dose vs. high dose).RESPONSES TO PLATELET TRANSFUSIONSThe low-dose, medium-dose, and high- dose groups differed significantly in the median post–transfusion platelet count (22,000, 34,000, and 50,000 per cubic millimeter, respectively), themedian increase in platelet count after transfusion (10,000, 19,000, and 38,000 per cubicmillimeter, respectively), and the median number of days until the next transfusion (1.1, 1.9,and 2.9, respectively) (P<0.001 for all comparisons for all end points) (Table 2). The median4-hour corrected count increment was 10,000 in the low-dose group, 10,000 in the medium-dose group, and 11,000 in the high-dose group, with no significant differences among groups.ADVERSE EVENTSThere were no significant differences among the three groups in the occurrence of any specificcategory of serious adverse events or in the percentage of patients who had one or more seriousadverse events (Table 4). Wheezing during or shortly after transfusion was significantly morecommon in the high-dose group than in the medium-dose group. Nine patients in the low-dosegroup died, as did four patients in the medium-dose group and seven in the high-dose group;the number of deaths did not differ significantly among the three groups.STUDY COMPLETIONCompletion of the study occurred at the time of hospital discharge for most patients (71%).Other causes of study completion were an absence of platelet transfusion for 10 days (in 14%of patients), the elapsing of 30 days from first platelet transfusion (10%), withdrawal from thestudy (4%), and death (2%). The three groups did not differ significantly with regard to reasonsfor study completion.DISCUSSIONThis study evaluated the effects of platelet dose on hemostasis and transfusion end points. Fora typical adult, the medium dose was equivalent to the standard dose currently used in clinicalpractice.16 The low dose was half the medium dose, and the high dose was twice the mediumdose. There were high rates of adherence for platelet doses and transfusion trigger thresholds.Physicians changed the dose to a nonstudy dose for patients in the low-dose group more oftenthan for those in the medium-dose and high-dose groups, but the changes were made primarilyafter the onset of bleeding of grade 2 or higher.Slichter et al. Page 6N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptThe percentages of patients who received at least one platelet transfusion and had bleeding ofgrade 2 or higher — 71%, 69%, and 70% in the low-, medium-, and high-dose groups,respectively — were not significantly different. The only death from hemorrhagic causesoccurred in the high-dose group (from pulmonary hemorrhage). The highest grade of bleeding,the number of days of bleeding of grade 2 or higher, the number of days before the occurrenceof bleeding of grade 2 or higher, and the occurrence and number of red-cell transfusions alsodid not differ significantly among the three groups. These findings confirm that the dose perprophylactic platelet transfusion, within the range of doses studied, did not significantly affectbleeding.The percentage of patients with bleeding of grade 2 or higher was significantly less amongthose undergoing autologous or syngeneic hematopoietic stem-cell transplantation (57%) thanamong those with hematologic cancers who were undergoing chemotherapy (73%) or thoseundergoing allogeneic hematopoietic stem-cell transplantation (79%), as has been describedpreviously.17 However, platelet dose had no significant effect on bleeding in any of thesetreatment categories.Patients had a 25% risk of having bleeding of grade 2 or higher on days on which the morningplatelet count was 5000 per cubic millimeter or lower, as compared with a 17% risk on dayswith counts from 6000 to 80,000 per cubic millimeter. Previous reports suggest that endothelialintegrity can be maintained with platelet counts of 5000 per cubic millimeter or higher.18,19Further reductions in the risk of bleeding at platelet counts of 80,000 per cubic millimeter orhigher are postulated to be due to an improved clinical status.The rates of bleeding seen in our trial are higher than those in several other platelet-transfusiontrials.20–22 The reported incidence of bleeding depends on factors that often differ amongstudies, such as assessment method, frequency of assessment, criteria used for bleeding grade,and population of patients.20 In our study, consistent data collection was achieved with the useof daily hemostatic assessments performed by research staff who were unaware of the treatmentassignments and who followed detailed instructions. Bleeding grades were ascertained on thebasis of objective criteria, thus reducing bias.To our knowledge, only two previously reported randomized trials, with limited enrollment,have evaluated the use of low-dose platelet transfusions as compared with standard-dosetransfusions.5,6 Neither trial showed any significant differences regarding bleeding of anyWHO grades — findings similar to those in our study.The Strategies for Transfusion of Platelets (SToP) study (NCT00420914)6 was halted becauseof grade 4 bleeding in three patients in the low-dose group (1.5×1011 to 3.0×1011 platelets pertransfusion), as compared with none in the standard-dose group (3.0×1011 to 6.0×1011 plateletsper transfusion). A stopping rule of a 5% absolute difference between the two groups in theincidence of grade 4 bleeding was reached after only 58 and 61 patients were enrolled in thelow-dose group and the standard-dose group, respectively. We did not find a significantdifference in the incidence of grade 4 bleeding in our similar, but much larger, cohort. Animportant difference between our study and the StoP study was that we adjusted the dose ofplatelets for body-surface area, whereas in the StoP study, the same dose range was used forall patients in each of the two groups.In our trial, the total number of platelets transfused — 9.25×1011 for the low dose,11.25×1011 for the medium dose, and 19.63×1011 for the high dose — was significantlydifferent among the three groups. However, the median number of transfusions per patient wassignificantly greater in the low-dose group (five transfusions) than in the medium-or high-dosegroup (three transfusions in each group) (P<0.001 for both comparisons). In the SToP study,Slichter et al. Page 7N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript6 the low-dose group also required significantly more transfusions than the standard-dosegroup.As expected, the median platelet increment after transfusion in the low-dose group (10,000 percubic millimeter) was approximately half the median increment in the medium-dose group(19,000 per cubic millimeter), and the median increment in the high-dose group (38,000 percubic millimeter) was approximately twice the increment in the medium-dose group. Thenumber of days until the next transfusion also differed significantly among the three groups:1.1 days in the low-dose group, 1.9 in the medium-dose group, and 2.9 in the high-dose group.These data, data from other, smaller studies, and mathematical models all suggest that largerdoses give higher increments and prolonged intervals until the next transfusion.3,23–27However, the corrected count increment did not differ significantly among the three groups(i.e., differences in the increment were explained by differences in the number of plateletstransfused).In conclusion, when prophylactic transfusions are given after a trigger threshold of 10,000platelets per cubic millimeter or lower is reached, the platelet dose has no significant effect onthe incidence of bleeding in patients with hypoproliferative thrombocytopenia, probablybecause few platelets are needed to maintain hemostasis.18,19 A strategy of low-dosetransfusion significantly reduces the quantity of platelets transfused, which could preservethese scarce blood components but could also increase the number of platelet transfusions.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgmentsSupported by grants from the National Heart, Lung, and Blood Institute of the National Institutes of Health to the DataCoordinating Center at New England Research Institutes (HL072268), Case Western Reserve University (HL072033),Children’s Hospital Boston (HL072291), Cornell University (HL072196), Duke University (HL072289), EmoryUniversity (HL072248), Johns Hopkins University (HL072191), Massachusetts General Hospital (HL072299), PugetSound Blood Center (HL072305), Tulane University (HL072274), University of Iowa (HL072028), University ofMaryland (HL072359), University of Minnesota (HL072072), University of North Carolina (HL072355), Universityof Oklahoma (HL072283), University of Pennsylvania (HL072346), University of Pittsburgh (HL072331), and theBlood Center of Wisconsin (HL072290).Dr. Slichter reports receiving grant support from U.S. Army Medical Research Acquisition Activity (Department ofDefense), Navigant Biotechnologies, and Pall Medical; Dr. Assmann, receiving grant support from Z-Medica; Dr.Triulzi, receiving consulting fees from Fenwal Laboratories and Cerus and lecture fees from Pall; Dr. Strauss, receivingconsulting fees from CaridianBCT; Dr. Ness, receiving consulting fees from Fenwal Laboratories and CaridianBCT;Dr. Brecher, receiving consulting fees from Fenwal Laboratories; Dr. Josephson, receiving lecture fees fromMediware; Dr. George, receiving consulting fees and grant support from Amgen; and Dr. Manno, receiving consultingfees and grant support from Baxter Healthcare, consulting fees from Bayer Healthcare, and lecture fees from EMDHealthcare Communications Scientific Communication Group. No other potential conflicts of interest relevant to thisarticle were reported.We thank all the patients who volunteered to take part in this study, all the study investigators and committee members,and Ginny Knight at the Puget Sound Blood Center for administrative assistance.APPENDIXThe following investigators and staff participated in the study: Case Western ReserveUniversity, Cleveland: K.R. McCrae (principal investigator), V. Exum, D. Hendrix;BloodCenter of Wisconsin, Milwaukee, and University of Wisconsin–Madison,Madison: J.G. McFarland (principal investigator), R.D. Woodson, N. Ruys, J. Werndli, K.Koenig, N. Turman, J. Stublaski; Froedert Memorial Lutheran Hospital, Milwaukee: M.Slichter et al. Page 8N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptLankiewicz, D. Miller-Metcalfe, S. Graminske, R. Dora, S. Heldke; St. Luke’s MedicalCenter, Milwaukee: A.B. Divgi, J. Boos, S. Beekman; Children’s Hospital of Wisconsin,Milwaukee: R. Punzalan; Children’s Hospital Boston, Boston: E.J. Neufeld (principalinvestigator), S.R. Sloan, T. Kang, J. Hedstrom, K. Harney; Beth Israel Deaconess MedicalCenter, Boston: L. Uhl, B. Malynn; Brigham and Women’s Hospital, Boston: R.M.Kaufman, M. Kelly, B. Rowe, K. Wallace, S. Slate; Weill College of Cornell University, NewYork: J. Bussel (principal investigator), D.L. Skerrett, E. Feldman, C. Nguyen, J. Cruz, M.Wissert; Duke University, Durham, NC: T.L. Ortel (principal investigator), S. Adams, T.Anderson, C. Higgins, C. Mette, E. Petzold, C. Pinaroc, C. Thornburg, M.J. Telen; EmoryUniversity, Atlanta: C.D. Hillyer (principal investigator), C.D. Josephson, M.-I. Castillejo, J.Newman, J. Ieong, J. Johnson; Johns Hopkins University, Baltimore: P.M. Ness (principalinvestigator), R. Case, A. Fuller, A.K. Fuller; Puget Sound Blood Center and University ofWashington Medical Center, Seattle: S.J. Slichter (principal investigator), T.B.Gernsheimer, A. Deyle, J. Corson, A. Hirata; Virginia Mason Medical Center, Seattle: D.Aboulafia; Children’s Hospital Medical Center, Seattle: D. Matthews; Tulane UniversityHospital and Clinics, New Orleans: C. Leissinger (principal investigator), R. Kruse-Jarres,H. Safah, C. Schmidt; University of Iowa, Iowa City: R.G. Strauss (principal investigator),B. Link, T. Raife, J. Swift, D. Schrock; University of Maryland, Baltimore: J.R. Hess(principal investigator), M. Mitrou, J. Spanfelner; Fairview–University Medical Center,Minneapolis: J. McCullough (principal investigator), T. Carr, T.Chlebeck, S. Malcolm, S.Pulkrabek; University of North Carolina, Chapel Hill: M.E. Brecher (principal investigator),A. Tsui, M. Miller, S. Hay; University of Oklahoma, Oklahoma City: J.N. George (principalinvestigator), D. Terrell, X. Li; University of Texas Southwestern Medical Center, Dallas:G. Buchanan (principal investigator), V.M. Aquino, J. Cox, T. Hoffman, G. Paranjape;University of Pennsylvania, Philadelphia: B.A. Konkle (principal investigator), E.A.Stadtmauer, I. Tarng, M. Kelty, M. Einarson, K. Hinkle; Children’s Hospital of Philadelphia,Philadelphia: C.S. Manno (principal investigator), A. Parker, A. Wade, J. Nathanson, M.Braun; University of Pittsburgh, Pittsburgh: D.J. Triulzi (principal investigator), P.D’Andrea, L. Blanker; Dartmouth–Hitchcock Medical Center, Lebanon, NH: J. AuBuchon(medical monitor); New England Research Institutes (Data Coordinating Center),Watertown, MA: S.F. Assmann (principal investigator), D. Brambilla, A.S. Corbett, E.Devlin, J. Erickson, E. Gerstenberger, S. Granger, K. Hayes, J. Miller, J. Scott; National Heart,Lung, and Blood Institute, Bethesda, MD: G. Nemo (project officer), S. Glynn, L. Harvath,E. Leifer, T. Mondoro, E. Wagner; Data and Safety Monitoring Board: S. Geyer, T. Lane,J. Lusher, B. McLeod, A. Reitsma, P. Roberson, A. Shapiro, C. Whitsett.REFERENCES1. Tinmouth AT, Freedman J. Prophylactic platelet transfusions: which dose is the best dose? A reviewof the literature. Transfus Med Rev 2003;17:181–193. [PubMed: 12881779]2. Heddle NM. Controversy concerning platelet dose. ISBT Sci Ser 2007;2:220–225.3. Stanworth SJ, Hyde C, Brunskill S, Murphy MF. Platelet transfusion prophylaxis for patients withhaematological malignancies: where to now? Br J Haematol 2005;131:588–595. [PubMed: 16351634]4. Norol F, Bieling P, Roudot-Thoraval F, et al. Platelet transfusion: a dose-response study. Blood1998;92:1448–1453. [PubMed: 9694735]5. Tinmouth A, Tannock IF, Crump M, et al. Low-dose prophylactic platelet transfusions in recipientsof an autologous peripheral blood progenitor cell transplant and patients with acute leukemia: arandomized controlled trial with a sequential Bayesian design. Transfusion 2004;44:1711–1719.[PubMed: 15584985]6. Heddle NM, Cook RJ, Tinmouth A, et al. A randomized controlled trial comparing standard-and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood2009;113:1564–1573. [PubMed: 19109560]Slichter et al. Page 9N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript7. Slichter SJ. Background, rationale, and design of a clinical trial to assess the effects of platelet doseon bleeding risk in thrombocytopenic patients. J Clin Apher 2006;21:78–84. [PubMed: 16619231]8. SAS/STAT software, version 9.2. Cary, NC: SAS Institute; 2000–2008.9. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer1981;47:207–214. [PubMed: 7459811]10. Rebulla P, Finazzi G, Marangoni F, et al. The threshold for prophylactic platelet transfusions in adultswith acute myeloid leukemia. N Engl J Med 1997;337:1870–1875. [PubMed: 9407153]11. DuBois D, DuBois EF. A formula to estimate the approximate surface area if height and weight beknown. Arch Intern Med 1916;17:863–871.12. Zelen M. The randomization and stratification of patients to clinical trials. J Chronic Dis 1974;27:365–375. [PubMed: 4612056]13. Cox DR, Oakes D. Analysis of survival data. London: Chapman & Hall. 198414. Hardin, JW.; Hilbe, JM. Generalized estimating equations. Boca Raton, FL: Chapman & Hall/CRC;2003.15. Liang K-Y, Zeger SL. Longitudinal data analysis using generalized linear models. Biometrika1986;73:13–22.16. Whitaker, BI.; Green, J.; King, MR., et al. The 2007 National Blood Collection and Utilization Surveyreport. (Accessed January 25, 2010, at.http://www.hhs.gov/ophs/bloodsafety/2007nbcus_survey.pdf.)17. Nevo S, Swan V, Enger C, et al. Acute bleeding after bone marrow transplantation (BMT ) —incidence and effect on survival: a quantitative analysis in 1,402 patients. Blood 1998;91:1469–1477.[PubMed: 9454780]18. Slichter SJ. Relationship between platelet count and bleeding risk in thrombocytopenic patients.Transfus Med Rev 2004;18:153–167. [PubMed: 15248165]19. Heddle NM, Cook RJ, Sigouin C, Slichter SJ, Murphy M, Rebulla P. A descriptive analysis ofinternational transfusion practice and bleeding outcomes in patients with acute leukemia. Transfusion2006;46:903–911. [PubMed: 16734806]20. Heddle NM, Cook RJ, Webert KE, Sigouin C, Rebulla P. Methodologic issues in the use of bleedingas an outcome in transfusion medicine studies. Transfusion 2003;43:742–752. [PubMed: 12757525]21. Wandt H, Frank M, Schaefer-Eckart K, Wilhelm M. Routine prophylactic platelet transfusions arenot necessary in patients with acute myeloid leukemia — a therapeutic transfusion strategy is safeand cost effective. Blood 2005;106:129a. abstract.22. McCullough J, Vesole DH, Benjamin RJ, et al. Therapeutic efficacy and safety of platelets treatedwith a photochemical process for pathogen inactivation: the SPRINT trial. Blood 2004;104:1534–1541. [PubMed: 15138160]23. Hersh JK, Hom EG, Brecher ME. Mathematical modeling of platelet survival with implications foroptimal transfusion practice in the chronically platelet transfusion-dependent patient. Transfusion1998;38:637–644. [PubMed: 9683101]24. Brecher ME, Hom EG, Hersh JK. Optimal platelet dosing. Transfusion 1999;39:431–434. [PubMed:10220274]25. Klumpp TR, Herman JH, Gaughan JP, et al. Clinical consequences of alterations in platelet transfusiondose: a prospective, randomized, double-blind trial. Transfusion 1999;39:674–681. [PubMed:10413273]26. Sensebé L, Giraudeau B, Bardiaux L, et al. The efficiency of transfusing high doses of platelets inhematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded endpoint (PROBE) study. Blood 2005;105:862–864. [PubMed: 15367427]27. Goodnough LT, Kuter DJ, McCullough J, et al. Prophylactic platelet transfusions from healthyapheresis platelet donors undergoing treatment with thrombopoietin. Blood 2001;98:1346–1351.[PubMed: 11520781]Slichter et al. Page 10N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1. Days with Bleeding of Grade 2 or Higher in All three Treatment Groups, According toMorning Platelet-Count CategoriesThe percentage of days on which patients had bleeding of grade 2 or higher is shown, alongwith the associated 95% confidence intervals (dashed lines), according to the morning platelet-count category. Data are based on the 24,309 days during the study period on which patientshad both a morning platelet count and information on bleeding of grade 2 or higher. Eachpatient-day was treated as a separate unit of analysis. Analyses were adjusted to take intoaccount that for each patient, the results on various days may be correlated. The interactionbetween treatment group and morning platelet-count category was not significant, indicatingthat the effect of the morning platelet-count category did not differ significantly among thethree treatment groups; therefore, the data from all three groups are combined.Slichter et al. Page 11N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 12Table 1Baseline Characteristics of the Study Patients, According to Treatment GroupCharacteristicPlatelet Dose*LowDose(N = 417)P Value,Low vs. MediumDoseMediumDose(N = 423)P Value,Medium vs. HighDoseHighDose(N = 432)P Value,High vs. LowDoseAge — yr0.180.200.02 Median475051 Interquartile range30–5734–5832–62Sex — no. (%)0.440.830.33 Male243 (58)258 (61)267 (62) Female174 (42)165 (39)165 (38)Weight — kg0.340.820.43 Median807878 Interquartile range65–9260–9263–91Height — cm0.310.220.85 Median170170170 Interquartile range162–178160–177161–178Body-surface area — m20.360.740.54 Median1.91.91.9 Interquartile range1.7–2.11.6–2.11.7–2.1Previous pregnancy No./total no. of women (%)111/174 (64)0.09120/163 (74)0.11110/164 (67)0.69 No. of pregnancies0.330.970.32 Median323 Interquartile range2–42–42–3Previous transfusion — no. (%) Platelets244 (59)0.67240 (57)0.68240 (56)0.40 Red cells316 (76)0.62326 (77)0.13314 (73)0.32Spleen status — no. (%)0.410.430.75 Nonpalpable393 (94)390 (92)403 (93)N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 13CharacteristicPlatelet Dose* Enlarged15 (4)18 (4)20 (5) Splenectomized9 (2)15 (4)9 (2)Primary diagnosis — no. (%)0.350.400.45 Acute leukemia202 (48)186 (44)185 (43) Lymphoma91 (22)89 (21)84 (19) Myeloma39 (9)59 (14)56 (13) Chronic leukemia24 (6)24 (6)33 (8) Myelodysplasia16 (4)26 (6)14 (3) Solid tumor5 (1)6 (1)7 (2) Other40 (10)33 (8)53 (12)Stratification category — no. (%)1.000.960.97 Allogeneic stem-cell transplantation173 (41)173 (41)177 (41) Autologous or syngeneic stem-cell transplantation138 (33)142 (34)149 (34) Chemotherapy or radiation (i.e., non- transplantation) therapy for hematologic cancer104 (25)105 (25)104 (24) Chemotherapy or radiation (i.e., non- transplantation) therapy for solid tumor2 (<1)3 (1)2 (<1)Laboratory values Hemoglobin0.290.410.78 No. with data415421432 Median — g/dl9.79.99.8 Interquartile range — g/dl9.0–10.79.1–10.79.0–10.7 Hematocrit0.640.870.76 No. with data413419431 Median — %28.028.228.0 Interquartile range — %26.0–31.026.0–31.026.0–31.0 Platelet count0.430.0080.07 No. with data415421432 Median — ×10−3/mm3394035N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 14CharacteristicPlatelet Dose* Interquartile range — ×10−3/mm325–6226–6624–54 Prothrombin time†0.790.700.90 No. with data356369377 Median — ×ULN0.920.920.92 Interquartile range — ×ULN0.85–0.990.85–0.990.86–0.99 International normalized ratio0.830.820.99 No. with data411419428 Median1.01.01.1 Interquartile range1.0–1.11.0–1.11.0–1.1 Partial thromboplastin time0.640.780.52 No. with data411419430 Median — sec29.129.029.0 Interquartile range — sec26.6–32.926.3–32.226.0–32.9 Fibrinogen0.890.570.45 No. with data409417430 Median — mg/dl357355369 Interquartile range — mg/dl279–459276–465283–468 Positive for panel-reactive antibody0.970.980.95 No. with data389391410 Median — % of lymphocytes tested0.00.00.0 Interquartile range — % of lympho- cytes tested0.0–0.00.0–0.00.0–0.0* Platelet doses were as follows: low dose, 1.1×1011 platelets per square meter of body-surface area; medium dose, 2.2×1011 platelets per square meter; and high dose, 4.4×1011 platelets per square meter.† ULN denotes upper limit of the normal range.N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 15Table 2Platelet-Dose Adherence and Response to Prophylactic Platelet transfusions, According to Treatment GroupCharacteristicPlatelet Dose*LowDose(N = 417)P Value,Low vs.Medium DoseMediumDose(N = 423)P Value,Medium vsHigh DoseHighDose(N = 432)P Value,High vs.Low DoseDose adherence†Attempted dose‡ Transfusions that were neither HLA-selected nor volume-reduced and for which attempted dose was known No. of transfusions233317081343 Transfusions within assigned dose range — %86<0.00198<0.001930.06 Patients who received ≥1 transfusion that was neither HLA-selected nor volume-reduced and had ≥1 transfusions with data on attempted dose No. of patients395386381 All transfusions within assigned dose range — %79<0.001920.004860.02At-issue dose§ Transfusions that were neither HLA-selected nor volume-reduced and for which at–issue dose was known No. of transfusions227816691320 Transfusions within assigned dose range — %710.00780<0.001700.11 Patients who received ≥1 transfusion that was neither HLA-selected nor volume-reduced and had ≥1 transfusions with data on at-issue dose No. of patients392380380 All transfusions within assigned dose range — %51<0.001630.04550.19Response to prophylactic platelet transfusionsNo. of transfusions254719121572Days until next transfusion¶<0.001<0.001<0.001 Median1.11.92.9N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 16CharacteristicPlatelet Dose*LowDose(N = 417)P Value,Low vs.Medium DoseMediumDose(N = 423)P Value,Medium vsHigh DoseHighDose(N = 432)P Value,High vs.Low Dose Interquartile range0.7–2.10.9–3.11.2–4.7No. of transfusions with all data available to calculate 4-hr CCI‖219316461386Pretransfusion platelet count — ×10−3/mm30.480.080.21 Median999 Interquartile range7–167–197–12Post-transfusion platelet count — ×10−3/mm3**<0.001<0.001<0.001 Median223450 Interquartile range16–3024–4833–68Platelet increment — ×10−3/mm3 ‖<0.001<0.001<0.001 Median101938 Interquartile range5–1711–3022–54Post-transfusion CCI — ×10−3/mm30.080.030.98 Median101011 Interquartile range5–156–166–15* Platelet doses were as follows: low dose, 1.1×1011 platelets per square meter of body-surface area; medium dose, 2.2×1011 platelets per square meter; and high dose, 4.4×1011 platelets per square meter.† Adherence to the prophylactic platelet dose was defined as receipt of a dose that was the assigned transfusion dose ±25%.‡ The “attempted dose” for apheresis platelets was based on the platelet count at the time of collection. For pooled platelet concentrates, the mean platelet count per concentrate, based on quality-control data,was used to determine how many concentrates to pool.§ The “at-issue dose” was based on platelet counts obtained from all products just before distribution from the blood-transfusion service.¶ The analysis of days until next transfusion takes into account data censoring at the time of a granulocyte transfusion, a stem-cell transfusion, or study completion.‖ Calculations of the corrected count increment (CCI) require complete data on pretransfusion and post-transfusion counts and total platelet counts at issue. The unit of analysis is the transfusion. Here, actualmedians and interquartile ranges are presented for pretransfusion and post-transfusion counts, the platelet increment, and the CCI, but the results of statistical comparisons are from a generalized linear modelthat takes into account that for each patient, the results for various transfusions may be correlated.**The post-transfusion platelet count was obtained within 4 hours after transfusion.N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 17Table 3Primary and Key Secondary End Points, According to Treatment Group.CharacteristicPlatelet Dose*LowDose(N = 417)P Value,Low vs. MediumDoseMediumDose(N = 423)P Value,Medium vs. HighDoseHighDose(N = 432)P Value,High vs. LowDosePrimary end point ≥1 Episode of bleeding of grade 2 or higher — % of patients710.60690.71700.94Secondary end points Highest grade of bleeding during study — % of patients0.300.650.54 No bleeding or grade 1303230 Grade 2585960 Grade 3978 Grade 4322 Death from hemorrhage — no. of patients001.0011.00 No. of days with bleeding of grade 2 or higher0.900.910.99 Median111 Interquartile range0–40–40–4 Days from randomization to onset of bleeding of grade 2 or higher0.850.660.55 Median778 Interquartile range3–183–193–19 Red-cell transfusions ≥1 Transfusion — % of patients950.12921.00920.09 Total units per patient †0.620.700.90 Median444 Interquartile range2–82–82–8 Platelet transfusions‡ No. per patient<0.0010.09<0.001N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 18CharacteristicPlatelet Dose*LowDose(N = 417)P Value,Low vs. MediumDoseMediumDose(N = 423)P Value,Medium vs. HighDoseHighDose(N = 432)P Value,High vs. LowDose Median533 Interquartile range3–92–62–6 Total no. of platelets transfused, based on at-issue count — ×10−110.002<0.001<0.001 Median9.2511.2519.63 Interquartile range4.91–17.916.99–22.7610.61–37.44* Platelet doses were as follows: low dose, 1.1×1011 platelets per square meter of body-surface area; medium dose, 2.2×1011 platelets per square meter; and high dose, 4.4×1011 platelets per square meter.† Analysis of the number of red-cell transfusions per patient was limited to data for patients who had at least one red-cell transfusion and who had no missing data on the number of units transfused: 394 patientsin the low-dose group, 387 in the medium-dose group, and 397 in the high-dose group.‡ Analysis of the number of platelet transfusions per patient was limited to data for patients who had no missing data on the number of transfusion events and no missing data on the total number of plateletstransfused: 295 patients in the low-dose group, 346 in the medium-dose group, and 359 in the high-dose group. In these patients, the tradeoffs between number of platelets and number of transfusion events canbe assessed.N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 19Table 4Adverse Events, According to Treatment Group.*EventPlatelet Dose†LowDose(N = 417)P Value,Low vs. MediumDoseMediumDose(N = 423)P Value,Medium vs. HighDoseHighDose(N = 432)P Value,High vs. LowDoseSerious adverse event — no. of patients (%) Anaphylaxis000.502 (<1)0.50 Bleeding5 (1)0.503 (1)0.735 (1)1.00 Cardiac event3 (1)0.682 (<1)0.455 (1)0.73 Central nervous system event4 (1)0.211 (<1)1.001 (<1)0.21 Deep-vein thrombosis3 (1)0.12000.12 Graft-versus-host disease000.253 (1)0.25 Infection10 (2)0.114 (1)0.1211 (3)1.00 Pulmonary event12 (3)0.8414 (3)0.6912 (3)1.00 Renal failure3 (1)0.1200.253 (1)1.00 Veno-occlusive disease of liver6 (1)0.775 (1)0.282 (<1)0.17 Other5 (1)0.754 (1)0.723 (1)0.50 Any35 (8)0.2927 (6)0.3036 (8)1.00Event occurring during or ≤ 4 hr after a trans- fusion — no. of patients (%)‡ Allergic reaction or hypersensitivity37 (9)0.4245 (11)0.2957 (13)0.05 Sinus bradycardia4 (1)0.756 (1)1.007 (2)0.55 Sinus tachycardia44 (11)0.7341 (10)0.6437 (9)0.35 Hypertension39 (9)0.5434 (8)0.2046 (11)0.57 Hypotension33 (8)0.2825 (6)0.7828 (6)0.43 Dyspnea18 (4)0.7421 (5)0.8823 (5)0.53 Hypoxia14 (3)0.8516 (4)1.0017 (4)0.72 Wheezing7 (2)0.112 (<1)0.00414 (3)0.19 Cough3 (1)1.004 (1)0.388 (2)0.22 Hemolysis2 (<1)0.621 (<1)1.002 (<1)1.00N Engl J Med. Author manuscript; available in PMC 2010 October 7.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptSlichter et al. Page 20EventPlatelet Dose†LowDose(N = 417)P Value,Low vs. MediumDoseMediumDose(N = 423)P Value,Medium vs. HighDoseHighDose(N = 432)P Value,High vs. LowDose Rigors or chills37 (9)0.5643 (10)0.5150 (12)0.21 Fever149 (36)0.17132 (31)0.51144 (33)0.47 Infection5 (1)1.005 (1)0.777 (2)0.77 Any event listed193 (46)0.33181 (43)0.19205 (47)0.78* Patients could have had more than one event.† Platelet doses were as follows: low dose, 1.1×1011 platelets per square meter of body-surface area; medium dose, 2.2×1011 platelets per square meter; and high dose, 4.4×1011 platelets per square meter.‡ For events occurring during or within 4 hours after a transfusion, data were missing for one patient in each of the three treatment groups.N Engl J Med. Author manuscript; available in PMC 2010 October 7.

Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage

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