Interventions to reduce platelet prophylactic transfusions in patients with hypoproliferative thrombocytopenia: providing patients with the full benefit.

To reduce the infectious and immunologic complications of platelet transfusions in patients with hypoproliferative thrombocytopenia, three interventions have aimed to decrease the number of prophylactic platelet transfusions received by such patients for the prevention of bleeding. These are the reduction of the platelet count threshold triggering prophylactic transfusion, the administration of low-dose (as opposed to standard-dose) platelet transfusions, and the administration of therapeutic (as opposed to prophylactic) platelet transfusions. We demonstrate that--in terms of absolute risk reduction in all infectious and some immunologic complications of transfusion--patients can benefit more from the transition to all-apheresis platelet supply than from the reduction of the platelet count threshold from 20,000/microL to 10,000/microL (mean reduction in the number of donor exposures by 26.28 versus 9.6, respectively). Also, patients can benefit just as much from the transition to an all-apheresis platelet supply as from the transition to a new standard of care employing therapeutic platelet transfusions for selected patients with hypoproliferative thrombocytopenia (mean reduction in the number of donor exposures by 4.08 versus 3.24, respectively). Finally, policies of low-dose platelet transfusions can directly benefit patients with hypoproliferative thrombocytopenia, effecting a median reduction in the number of donor exposures by 12.5 compared with a setting transfusing platelet pools, only if they are combined with Patient Blood Management (PBM) and an all-apheresis platelet supply. Thus, whatever strategy is adopted from among these three interventions, the replacement of the current platelet pools with an all-apheresis platelet supply is necessary for providing patients with the full benefit.

Donor exposures in recipients of pooled platelet concentrates: a case-study in arithmetic, logic, "expert opinion", and the "peer review" process.

Advocacy for single-donor (rather than pooled) platelets has been based on the absolute increase in the risk of transfusion-transmitted infections (TTIs) from pooled (rather than single-donor) platelets in the population of platelet transfusion recipients. A recent study published in a prestigious medical journal advocated for pooled (rather than single-donor) platelets based on the relative increase in the risk of TTIs from pooled (rather than single-donor) platelets in patients transfused with any blood component. If this policy recommendation for use of pooled (rather than single-donor) platelets were followed in the US, there would be an annual increase in the risk of TTIs by 15-20 recipient infections for hepatitis B virus, 85-113 recipient infections for the next "West-Nile-virus-like" pathogen, and 528-704 recipient infections for the next "human-immunodeficiency-virus-like" pathogen to emerge in the future. We present the calculation of the increased risk and discuss the stark contrast between simple arithmetic and logic versus the end result of a process of "expert opinion" and "peer review".

Consistency and proportionality in policy decision-making in blood safety: the case for an all-apheresis platelet supply in Germany.

Recently, German investigators presented the first mathematical model finding a significant increase in the risk of HIV, HCV, and HBV transmission when pools of 4 whole-blood-derived buffy-coat platelets, rather than 1 single-donor (apheresis) component, are used to provide one platelet dose. Based, in both cases, on mathematical models employing the incidence/window-period method, the relative risk of transmission from pooled versus apheresis platelets (2.2 or 2.75 for HIV, 2.7 or 3.375 for HCV, and 3.2 or 4.0 for HBV, with pools of 4 or 5 concentrates, respectively) is similar to the difference in risk before (versus after) introduction of HIV-1 and HCV RNA screening. The absolute increase in the risk from pools (1 to 2 HIV-, HCV-, or HBV-infectious platelet doses annually) is much smaller than the yield from HIV-1 and HCV RNA screening projected in the 1990s, but it becomes similar to that yield (with up to 88 infectious platelet doses intercepted) when we consider the next transfusion-transmitted pathogen to emerge in the future. Although pathogen reduction (PR) of platelets would eliminate the difference in risk between pooled and apheresis platelets vis-a-vis viral transmission, PR is not ready for implementation because the safety of PR needs to be investigated further. German transfusion guidelines should be revised to indicate the difference in risk associated with pooled versus apheresis platelets, and transition toward an all-apheresis platelet supply should commence. These actions are consistent with and proportionate to the action taken in the 1990s when screening for HIV-1 and HCV RNA was implemented.

Meta-analysis of the studies of bleeding complications of platelets pathogen-reduced with the Intercept system.

BACKGROUND: The eligibility criteria of a previously reported meta-analysis (Transfusion 2011;51:1058-1071) of randomized controlled trials (RCTs) of pathogen reduction of platelets in patients with hypoproliferative thrombocytopenia were modified to examine the impact on the findings of: (1) inclusion of a (previously excluded) RCT; (2) restriction of eligibility to RCTs of the Intercept (amotosalen-HCl/ultraviolet-A-light) system; and (3) differences in the methods used to assess bleeding complications. MATERIALS AND METHODS: Five RCTs comparing the risk of all, clinically significant (grades 2 through 4) and/or severe (grades 3 and 4) bleeding complications between recipients of platelets treated with Intercept vs. standard unmanipulated platelets were included. Odds ratios (ORs) of bleeding complications of similar severity recorded during similar periods of observation were calculated across all studies and across homogeneous subsets of studies by random-effects methods. RESULTS: Treatment with Intercept increased all bleeding complications when four RCTs meeting the eligibility criteria of the previous meta-analysis were integrated, but not across all the five currently available studies [summary OR=1·24; 95% confidence interval (CI), 0·79-1·93]. Clinically significant bleeding complications increased when the results of the SPRINT RCT were based on the expanded safety analysis (summary OR=1·52; 95% CI, 1·09-2·12)--but not the initial report (summary OR=1·30; 95% CI, 0·54-3·14)--of that study. CONCLUSIONS: Treatment with Intercept may increase the risk of all and clinically significant (albeit not severe) bleeding complications in RCTs maintaining a platelet count of ≥10×10(9) or ≥20×10(9)/l through increased platelet transfusions.

Rationale for randomized controlled trials and for intention-to-treat analysis in transfusion medicine: are they one and the same?

Articles on the appropriateness of intention-to-treat (ITT) vs. as-treated (AT) analyses of randomized controlled trials (RCTs) have highlighted issues relevant to drug trials, such as approaches suitable for 'explanatory' vs. 'pragmatic' RCTs. These considerations are less relevant to transfusion medicine RCTs, especially those of red blood cell transfusion therapies where the main issue is whether to include in the analysis randomized patients who did not receive transfusion. This article discusses issues pertinent specifically to transfusion medicine RCTs, and the thesis presented here is that the primary analysis of any transfusion medicine RCT must be based on the ITT principle. This is because the rationale for randomization is to avoid selection bias and to generate experimental arms that are comparable with respect to all, known and unknown, confounding factors. Only the entire arms produced by random allocation of subjects are so comparable, and only an ITT analysis of these entire arms fulfills the purpose of randomization. Withdrawals of randomized patients compromise the comparability of the groups and the rationale for randomization. Deviations from the ITT principle may be valid only when other conditions are met to ensure that non-adherence to ITT will not bias the results. For RCTs of red blood cell transfusion therapies, such conditions include that the RCTs be double-blind and that transfusion criteria should be applied consistently. Nonetheless, the rationale for ITT can be reversed in equivalence and non-inferiority trials where the finding of no difference is the objective of the research; thus, both ITT and AT analyses should be presented in these settings.

Why have meta-analyses of randomized controlled trials of the association between non-white-blood-cell-reduced allogeneic blood transfusion and postoperative infection produced discordant results?

Intention-to-treat analyses of randomized controlled trials (RCTs) of the association between non-white-blood-cell (WBC)-reduced allogeneic blood transfusion (ABT) and postoperative infection were reported as the reason why meta-analyses of RCTs of this association have produced discordant results. We examined three possible reasons for disagreements between meta-analyses: (i) sources of medical heterogeneity and integration of RCTs despite extreme heterogeneity; (ii) reliance on as-treated (vs. intention-to-treat) comparisons; and (iii) inclusion (or not) of the three most recent RCTs. When nine RCTs reported up to 2002 were combined despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found an association between non-WBC-reduced ABT and postoperative infection [summary odds ratio (OR) = 1.38, 95% confidence interval (CI) 1.03-1.85, P < 0.05; and summary OR = 1.56, 95% CI 1.06-2.31, P < 0.05, respectively]. When 12 RCTs reported up to 2005 were integrated despite extreme heterogeneity, both intention-to-treat and as-treated comparisons found no association of non-WBC-reduced ABT with postoperative infection (summary OR = 1.24, 95% CI 0.98-1.56, P > 0.05; and summary OR = 1.31, 95% CI 0.98-1.75, P > 0.05, respectively). In both analyses, the separate integration of four RCTs transfusing red blood cells (RBCs) or whole blood filtered after storage showed an association between non-WBC-reduced ABT and postoperative infection, whereas the separate integration of six (or nine) RCTs, reported through 2002 or 2005, and transfusing prestorage-filtered RBCs showed no association, whether intention-to-treat or as-treated comparisons were used. Thus, the published meta-analyses have produced discordant results because they did (or did not) investigate medical sources of heterogeneity and did (or did not) include the most recent RCTs. Intention-to-treat and as-treated comparisons produced concordant results.

White-blood-cell-containing allogeneic blood transfusion and postoperative infection or mortality: an updated meta-analysis.

BACKGROUND: Additional randomized controlled trials (RCTs) comparing recipients of non-white-blood-cell-(WBC)-reduced and WBC-reduced allogeneic red blood cells (RBCs) have been reported since the undertaking of previous meta-analyses of the association of allogeneic blood transfusion (ABT) with postoperative infection and/or mortality. Because no further RCTs are underway, a final meta-analysis of all available RCTs was conducted. METHODS: RCTs reporting on the association of ABT with postoperative infection and/or short-term (up to 3-month post-transfusion), all-cause mortality were retrieved. Twelve RCTs reporting on infection and 11 RCTs reporting on mortality were eligible for meta-analysis. Summary odds ratios (ORs) of infection or mortality in recipients of WBC-containing ABT vs. WBC-reduced ABT were calculated across the studies. RESULTS: An association of ABT with postoperative infection was demonstrated across RCTs transfusing RBCs WBC-reduced after storage [summary OR = 2.25; 95% confidence interval (CI), 1.12-4.25] but not before storage (summary OR = 1.06; 95% CI, 0.91-1.24). An association of ABT with mortality was demonstrated across RCTs conducted in cardiac surgery (summary OR = 1.72, 95% CI, 1.05-2.81) and across RCTs transfusing buffy-coat-reduced RBCs vs. RBCs WBC-reduced before storage (summary OR = 1.60; 95% CI, 1.14-2.24), but not across RCTs transfusing non-buffy-coat-reduced RBCs vs. RBCs WBC-reduced before storage (summary OR = 1.01; 95% CI, 0.73-1.40). CONCLUSIONS: An association between ABT and postoperative infection or short-term mortality is not detected across all clinical settings and transfused RBC products. An association between ABT and mortality is detected in cardiac surgery, but the other associations found in subgroup analyses contradict current theories about mechanism(s) of the ABT effect.

A survey of the demographics of blood use.

Epidemiological information was obtained by a series of questions to experts in the field of epidemiology of transfusion from the United States, England, Australia and Denmark. Although it became clear that the methods for collecting the data had differed between the countries, useful information was obtained for all questions. The data highlighted some major differences between the countries: the incident rate for red cell transfusion varied from 44.7 to 54.1 units, for platelets from 2.0 to 6.0 units and for plasma from 4.8 to 13.8 units transfused per 1000 population per year. Age and sex distribution of transfused patients was similar in all countries. Most of the red cell products are transfused to older recipients, and the distribution between men and women is approximately equal. The distribution for platelets is over a wider age range, and the difference between men and women is marked, with men predominating in all countries. The distribution for plasma is also directed to the elderly, and there is a predominance of men. The relationship between the disease or surgical procedure and the use of blood products was similar between countries. The use of red cells in cardiovascular surgery predominated. Neoplasms and digestive disorders were also prevalent. Neoplasms, including those relating to haematology, were the main use for platelets, but cardiovascular surgery was also important. In all countries, plasma is largely used in cardiovascular surgery. Two countries provided data relating to the number of units per transfusion episode including information relating to massive transfusion. In Australia, red cell use of >or=50 units per episode was largely associated with multiple traumas. In Denmark, it was associated with gastrointestinal bleeding and various medical requests.

White-blood-cell-containing allogeneic blood transfusion, postoperative infection and mortality: a meta-analysis of observational 'before-and-after' studies.

BACKGROUND AND OBJECTIVES: An association of white blood cell (WBC) reduction with decreased mortality was reported by one observational, before-and-after study. A meta-analysis was undertaken to examine whether this finding is supported by all the evidence currently available from before-and-after studies, and whether these studies support an association of WBC reduction with a decreased risk of postoperative infection. MATERIALS AND METHODS: Observational, before-and-after studies were retrieved that reported on postoperative infection and/or mortality between January 1997 and June 2003. Six studies met the criteria for meta-analysis. Unadjusted summary odds ratios (ORs) of postoperative infection or mortality in patients transfused after (compared with before) WBC reduction were calculated across the studies if the hypothesis of homogeneity was not rejected. Adjusted summary ORs were calculated across three studies that had reported multivariate analyses. RESULTS: There was an unadjusted association of WBC reduction with a decreased risk of postoperative infection [summary OR = 0.93; 95% confidence interval (95% CI), 0.88-0.99; P < 0.01] that did not persist following adjustment for confounding factors (summary OR = 0.94; 95% CI, 0.85-1.04; P > 0.05). There was neither an unadjusted nor an adjusted association of WBC reduction with decreased mortality (summary OR = 0.94; 95% CI, 0.71-1.23; P > 0.05; and OR = 0.92; 95% CI, 0.80-1.05; P > 0.05, respectively). CONCLUSIONS: An association of WBC reduction with decreased mortality was not detected across the results available from all before-and-after studies. An unadjusted association of WBC reduction with a decreased risk of postoperative infection exists, but this was not detected across the three studies that reported multivariate analyses.

Meta-analysis of randomized controlled trials comparing the risk of postoperative infection between recipients of allogeneic and autologous blood transfusion.

BACKGROUND AND OBJECTIVES: A previous meta-analysis of randomized controlled trials (RCTs), comparing the risk of postoperative infection between recipients of allogeneic blood or autologous blood obtained by preoperative autologous blood donation (PABD), did not detect an immunomodulatory (TRIM) effect of allogeneic blood transfusion (ABT). If such a TRIM effect was mediated by white blood cell (WBC)-derived soluble mediators accumulating during storage, however, stored autologous blood obtained by PABD would not prevent the TRIM effect, whereas unstored autologous blood obtained by acute normovolemic haemodilution (ANH), intraoperative blood recovery (IBR), or postoperative blood recovery (PBR), would abrogate the TRIM effect. MATERIALS AND METHODS: RCTs reported through January 2002 were retrieved, and five studies met the criteria for meta-analysis. Summary odds ratios (ORs) of postoperative infection in recipients of allogeneic vs. autologous blood were calculated across studies. RESULTS: No difference in the risk of infection between the comparison arms was detected across all five RCTs [summary OR = 1.22, 95% confidence interval (95% CI): 0.75-1.98], or when the results of studies using PABD or ANH/IBR/PBR were integrated separately (summary OR = 1.35; 95% CI: 0.45-4.08; and summary OR = 1.49; 95% CI: 0.69-3.22, respectively). CONCLUSIONS: The finding of no TRIM effect of ABT across RCTs using ANH/IBR/PBR to obtain autologous blood does not support the hypothesis that a TRIM effect of ABT is mediated by WBC-derived soluble mediators accumulating during storage. The null finding of the overall meta-analysis also does not support a TRIM effect of ABT mediated by other blood constituents.

Allogeneic blood transfusion and postoperative duration of mechanical ventilation: effects of red cell supernatant, platelet supernatant, plasma components and total transfused fluid.

BACKGROUND AND OBJECTIVES: In patients undergoing open-heart surgery, allogeneic blood transfusion (ABT) may be related to an enhanced inflammatory response and impaired pulmonary function, resulting in a need for prolonged mechanical ventilation. Transfused red blood cell (RBC) supernatant, platelet supernatant or plasma components, may exercise varying effects on pulmonary function, because these fluids differ in their content of soluble biological-response modifiers. MATERIALS AND METHODS: The records of 416 patients undergoing coronary artery bypass graft operations at the Massachusetts General Hospital were reviewed. Possible predictors and the number of days of postoperative ventilation, as well as the number of all transfused blood components, were recorded. The association between mechanical ventilation past the day of operation and the volume of transfused RBC supernatant, platelet supernatant, or plasma components, was calculated by logistic regression analyses. RESULTS: The volume of each transfused fluid differed (P < 0.0001) among patients ventilated for 0, 1, 2, 3, or > or = 4 days after the day of the operation. After adjusting for the effects of confounding factors, the volume of administered RBC supernatant was associated (P = 0.0312) with the likelihood of postoperative ventilation past the day of operation, but the volume of platelet supernatant, plasma components, or total transfused fluid was not (P = 0.1528, P = 0.1847, and P = 0.0504, respectively). CONCLUSIONS: These results are congruent with the hypotheses that ABT may impair postoperative pulmonary function and that any such adverse effect of ABT is probably mediated by the supernatant fluid of stored RBCs. Both hypotheses should be examined further, in future studies of the outcomes of ABT.

RBC alloantibody specificity and antigen potency in Olmsted County, Minnesota.

BACKGROUND: While RBC antigen frequencies for whites of Northern European ancestry are known, the relative frequencies of RBC antibodies within this population have not been determined. The distribution of RBC alloantibodies by sex and age was studied, as were the immunogenicity of RBC antigens and the occurrence of RBC alloantibody clusters in a geographically defined population. STUDY DESIGN AND METHODS: RBC alloimmunization among patients and donors in Olmsted County, MN, was determined for the period from 1975 to 1995. Alloantibody frequencies were used to calculate the potency of each antigen relative to K. Cluster analysis was applied to the data to identify natural groupings of antibodies. RESULTS: The frequency and potency of 33 alloantibodies from 1345 alloimmunized subjects were estimated. The most frequent alloantibodies were E (20.8%), Le(a) (18.6%), K (14.7%), D (12.9%), Le(b) (9.4%), M (7.2%), P(1) (6.7%), Fy(a) (6.3%), C (6.8%), and c (3.5%). The most potent antigens were Wr(a) (0.363), C(w) (0.078), Le(a) (0.03), E (0.028), V (0.025), Js(a) (0.023), Kp(b) (0.023), Go(a) (0.023), JMH (0.023), and Rd (0.023). Greater frequency of overall alloimmunization (M:F = 1:2.7), anti-D (p<0.0001), and anti-Le(a) (p = 0.003) was seen among females. Warm autoantibodies were more frequent among males with positive antibody screens (p<0.0001). No other gender differences were observed. Alloimmunization increased with age for K, Kp(a), Fy(a), D, C, E, and warm autoantibodies. Frequencies of alloimmunization to Le(a), Le(b), M, and P(1) decreased with age. The cluster analysis showed grouping of the antibodies to C and D as well as to Le(a) and Le(b), but the other RBC alloantibodies did not form clusters. CONCLUSION: Less than 1 percent of residents tested had positive antibody screens. Anti-E and anti-Le(a) were more common than anti-K. Wr(a) and C(w) were more potent antigens than K. Most antibodies showed an increase in frequency with increasing age. Except for anti-C and -D and anti-Le(a) and -Le(b), RBC alloantibodies did not occur in clusters.

Allogeneic blood transfusion and postoperative duration of mechanical ventilation.

BACKGROUND: In patients having open heart surgery, allogeneic blood transfusion (ABT) may be related to an enhanced inflammatory response and impaired pulmonary function, resulting in the need for prolonged mechanical ventilation. STUDY DESIGN AND METHODS: The records of 416 consecutive patients undergoing coronary artery bypass graft surgery at Massachusetts General Hospital were reviewed. Possible predictors and the number of days of postoperative ventilation, as well as the number of RBC units transfused and the length of their storage, were recorded. The association between mechanical ventilation after the day of operation and the number of RBC units transfused was calculated by logistic regression analysis. RESULTS: The number of RBC units transfused, but not the length of their storage, differed (p<0.0001) among patients ventilated for 0, 1, 2, 3, or 4 or more days after the day of operation. Patients taken off ventilation on the day of operation received (mean +/- SE) 2.01 +/- 0.14 RBC units; patients kept on ventilation for 4 or more days received 9.45 +/- 1.83 units. After adjusting for the effects of 18 confounding factors, the number of RBC units transfused was not a significant predictor of ventilation past the day of operation. There was, however, a trend suggesting that the likelihood of such ventilation might increase by 26 percent per RBC unit transfused (p = 0.0628). CONCLUSIONS: Future studies of the outcomes of ABT should examine further the possibility of a relationship between the number of transfused RBCs and the likelihood of postoperative ventilation after the day of operation.