Fecal blood loss: A quantitative method of evaluating hemostasis in patients with thrombocytopenia.

BACKGROUND: The purpose of our studies was to determine if fecal blood loss can provide a quantitative measure of bleeding at platelet counts of 20 000/µL or less in patients with hypoproliferative thrombocytopenia and to document the effects of different prophylactic platelet transfusion triggers on fecal blood loss. METHODS AND MATERIALS: Patients had an aliquot of their autologous red blood cells (RBCs) labeled with 51 Cr. Following reinjection of their radiolabeled RBCs, all feces and a daily blood sample were collected to determine fecal blood loss per day. Three different studies were performed in patients with thrombocytopenia: The first was in patients with thrombocytopenia with aplastic anemia who were not receiving platelet transfusions, and the other two trials involved thrombocytopenic patients with cancer who were receiving prophylactic platelet transfusions at platelet transfusion triggers of 5000/µL, 10 000/µL, or 20 000/µL. RESULTS: In patients with thrombocytopenia not receiving platelet transfusions, fecal blood loss does not increase substantially until platelet counts are 5000/µL or less. When platelet transfusions are given prophylactically to patients with cancer with chemotherapy-induced thrombocytopenia at platelet counts of 5000/µL or less, fecal blood loss and red cell transfusion requirements are the same as those for patients transfused prophylactically at higher transfusion triggers of 10 000 platelets/µL or 20 000 platelets/µL. However, the total number of platelet transfusions needed increases significantly, and the duration of the patient's thrombocytopenia tends to be longer at the higher platelet transfusion thresholds. CONCLUSION: A prophylactic platelet transfusion threshold of 5000/µL or greater is sufficient to maintain hemostasis in patients with thrombocytopenia.

Leukofiltration plus pathogen reduction prevents alloimmune platelet refractoriness in a dog transfusion model.

Human lymphocyte antigen alloimmunization to filter leukoreduced (F-LR) platelets occurs in about 18% of immunosuppressed thrombocytopenic hematology/oncology patients and represents a significant challenge for effective chemotherapy. In a dog platelet transfusion model, we have evaluated other methods of preventing alloimmune platelet refractoriness and demonstrated that successful methods in our dog model are transferable to man. In the present study, donor/recipient pairs were dog lymphocyte antigen DR-B incompatible (88% of the pairs), and recipient dogs received up to 8 weekly treated transfusions from a single donor (a highly immunogenic stimulus), or until platelet refractoriness. Continued acceptance of F-LR platelets occurred in 6 of 13 recipients (46%), but neither γ-irradiation (γ-I; 0 of 5) nor Mirasol pathogen reduction (MPR; 1 of 7) treatment of donor platelets prevented alloimmune platelet refractoriness. Combining γ-I with F-LR was associated with only 2 of 10 (20%) recipients accepting the transfused platelets. Surprisingly, F-LR platelets that then underwent MPR were accepted by 21 of 22 (95%) recipients (P < .001 vs F-LR + γ-I recipients). Furthermore, 7 of 21 (33%) of these accepting recipients demonstrated specific tolerance to 8 more weekly donor transfusions that had not been treated. In addition, platelet concentrates prepared from F-LR + MPR whole blood were also nonimmunogenic; that is, 10 of 10 (100%) recipients accepted donor platelets. Overall, 31 of 32 (97%) recipients accepted F-LR + MPR platelets; none developed antibodies to donor lymphocytes. These data are the highest rate of acceptance for platelet transfusions reported in either animals or man. This approach to platelet transfusion may be particularly important when supporting patients with intact immune systems, such as in myelodysplastic syndromes.

Laboratory predictors of bleeding and the effect of platelet and RBC transfusions on bleeding outcomes in the PLADO trial.

Bleeding remains a significant problem for many thrombocytopenic hematology/oncology patients in spite of platelet transfusions. Factors that might contribute to bleeding were analyzed for 16 320 patient-days on or after their first platelet transfusion in 1077 adult patients enrolled in the Platelet Dose (PLADO) trial. All patients had a greatly increased risk of bleeding at platelet counts of ≤5 × 109/L (odds ratio [OR], 3.1; 95% confidence interval [CI], 2.0-4.8) compared with platelet counts ≥81 × 109/L. Platelet counts between 6 × 109/L and 80 × 109/L were also associated with a somewhat elevated bleeding risk in patients receiving allogeneic stem cell transplants (SCTs) or chemotherapy but not in those undergoing autologous SCTs. Other significant laboratory predictors of bleeding were hematocrit ≤25% (OR, 1.29; 95% CI, 1.11-1.49), activated partial thromboplastin time (aPTT) 30 to ≤50 seconds (OR, 1.40; 95% CI, 1.08-1.81; P = .01), aPTT >50 seconds (OR, 2.34; 95% CI, 1.54-3.56), international normalized ratio (INR) 1.2 to 1.5 (OR, 1.46; 95% CI, 1.17-1.83), and INR >1.5 (OR, 2.05; 95% CI, 1.43-2.95). Transfusion of either platelets or red blood cells (RBCs) on days with bleeding was often not sufficient to change bleeding outcomes on the following day. Because bleeding occurred over a wide range of platelet counts among patients undergoing allogeneic SCT or chemotherapy and because platelet transfusions may not prevent bleeding, other risk factors may be involved. These may include low hematocrit and coagulation abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Transfusion-related immunomodulation: gamma irradiation alters the effects of leukoreduction on alloimmunization.

BACKGROUND: Adverse events following blood transfusion include allosensitization and generalized immunosuppression, collectively referred to as transfusion-related immune modulation. We evaluated the immunological effects of red blood cell (RBC) and platelet transfusions on alloantibody responses and on immunoregulatory cells in nonimmunosuppressed patients undergoing cardiovascular surgery. STUDY DESIGN AND METHODS: Patients were randomized to receive standard unmodified (STD), leukoreduced (LR), or leukoreduced and γ-irradiated (LRγ) RBCs. Patients received only apheresis platelets that were in-process LR and were γ-irradiated for the third arm. Nontransfused patients served as controls for the effects of surgery itself on immunologic changes. Antibodies to HLA were assessed with use of solid-phase assays. The effects of transfusion on adaptive and innate immunity were evaluated by assessing T regulatory cells (Tregs) and invariant natural killer T (iNKT) cells. RESULTS: LR of blood products reduced the development of human leukocyte antigen (HLA) alloantibodies, but only in patients without preexisting HLA antibodies. However, if LR blood products were γ-irradiated, HLA antibody production was not reduced. Compared to nontransfused patients, recipients of STD or LR transfusions showed a significant increase in CD4+CD25hi T cells expressing FoxP3 or CTLA4 and also of iNKT cells producing interleukin-4. In contrast, recipients of LRγ blood products showed markedly lower increases in all three cellular assays. CONCLUSION: LR decreased HLA alloantibody production in naïve recipients, but did not reduce the immunosuppressive effects of transfusion. LRγ reduced immunosuppression and was not associated with decreased HLA alloantibody production.

Platelets stored in whole blood at 4°C: in vivo posttransfusion platelet recoveries and survivals and in vitro hemostatic function.

BACKGROUND: Ordinarily, whole blood (WB) is separated into components before storage. We assessed the posttransfusion viability and function of platelets (PLTs) if they were stored within WB at 4°C. STUDY DESIGN AND METHODS: Whole blood was obtained from 30 normal subjects and stored at 4°C without agitation for 12 days and for 10, 15, or 22 days with agitation. After WB storage, a PLT concentrate was prepared, and a fresh PLT sample was obtained from each donor. The stored PLTs were labeled with 111 In and the fresh with 51 Cr, and both were simultaneously transfused into their donor. Blood samples were obtained after transfusion to determine PLT recoveries and survivals. PLT samples from WB before and after storage were also assayed for PLT function and biochemistry. RESULTS: After storage for 12 days without WB rotation, poststorage PLT counts averaged only 49 ± 12% of baseline values. After storage for 10, 15, or 22 days with end-over-end WB rotation, PLT counts averaged 76 ± 14% of baseline values. Fifteen-day poststorage radiolabeled PLT recoveries averaged 27 ± 11% (49 ± 16% of fresh), and survivals averaged 1.2 ± 0.4 days (16 ± 6% of fresh). in vitro assays demonstrated marked PLT activation after any storage time, and although PLT function decreased over time, stored PLTs were still considered acceptable. CONCLUSION: These data suggest that, during rotated WB storage at 4°C for up to 15 days, PLT yields, poststorage PLT recoveries and survivals, and PLT function should be sufficient to support the short-term hemostatic needs of traumatized patients.

Pathogen reduction with amotosalen/UVA reduces platelet refractoriness in a dog platelet transfusion model.

BACKGROUND AND OBJECTIVES: Pathogen reduction of donor platelets with amotosalen/UVA has been shown to effectively inactivate pathogens and also contaminating white blood cells (WBCs). We wanted to determine whether WBC inactivation could also decrease alloimmune refractoriness to donor platelets. MATERIALS AND METHODS: Platelets were prepared from a donor dog's whole blood, and the platelets were either transfused without modification [standard (STD) platelets] or treated with amotosalen/UVA under conditions modelling the amotosalen/UVA Blood System for human platelets (APR) using either 4 or 3 J/cm2 of UVA exposure. Platelets were transfused weekly from a single donor dog for 8 weeks or until the recipient dog became refractory to their donor's platelets. Antibody samples were drawn weekly and tested against the donor dog's platelets and WBCs (CD8 and B cells). RESULTS: Only 1/7 (14%) dogs that received STD platelets accepted 8 weeks of donor transfusions. Following APR 4 J/cm2 donor transfusions, 3/9 (33%) recipients accepted their donor's transfusions, but only one recipient remained antibody negative. Following APR 3 J/cm2 donor transfusions, the same dose as used for human platelet transfusions, 7/10 (70%) recipients accepted their donor's transfusions, but only two remained antibody negative. CONCLUSION: As a very high percentage of recipient dogs (70%) accepted APR 3 J/cm2 donor transfusions, these data suggest that preventing alloimmune platelet refractoriness may be another benefit of pathogen reduction using amotosalen/UVA.

Safety evaluation of a lyophilized platelet-derived hemostatic product.

BACKGROUND: Hemorrhage causes significant morbidity and mortality in people aged <65 years. A lyophilized platelet-derived hemostatic agent (Thrombosomes) demonstrated hemostatic efficacy in animal models. We report the results of the first safety trial of autologous Thrombosomes given to normal subjects. STUDY DESIGN AND METHODS: Ten subjects received autologous Thrombosomes prepared from their apheresis platelets, and five control subjects received a buffer solution. There were five cohorts, with three subjects per cohort (two in the Thrombosomes group and one in the control group). Doses escalated from 1/1,000 to 1/10 of a proposed efficacious dose. Cohorts 4 and 5 received the highest dose, but in Cohort 5, one-half the dose was infused 2 hours apart. Cohorts 1 through 3 were monitored for 42 days, Cohorts 4 and 5 were monitored for 60 days using hematology, coagulation, and chemistry assays and antibody testing. RESULTS: There were no serious adverse events (AEs) and no subject withdrawals. There were eight treatment-related AEs (TRAEs) in 5 of 15 subjects (33%) (four in the Thrombosomes group and one in the control group). Of four subjects receiving the highest doses, three had TRAEs. One had elevated D-dimer, prothrombin fragment 1 + 2, and white blood cell count (subject had concurrent upper respiratory tract infection); one had T-wave inversions in precordial leads V2 and V3 without elevated troponin or symptoms; and one had a platelet autoantibody without change in platelet count. All subjects' TRAEs resolved by Day 21. CONCLUSION: There were no serious AEs in this small study. Thrombosomes were considered safe at the doses assessed. Future, larger trials will be needed to further assess safety and efficacy.

In vivo viability of extended 4°C-stored autologous apheresis platelets.

BACKGROUND: The current 5-day storage time of room temperature (22°C)-stored platelets (RSPs) severely limits platelet (PLT) availability. Extended cold (4°C)-stored PLTs (CSPs) are currently being investigated for actively bleeding patients. However, we currently do not know how to best store PLTs in the cold for extended periods of time. In this study, we investigate how storage in plasma and PLT additive solutions (PASs) affects PLT viability in vivo. STUDY DESIGN AND METHODS: Twenty normal subjects had a 2-unit hyperconcentrated apheresis PLT collection. One unit was stored at 4°C in plasma for 3 days ("control unit"), and the CSP "test" unit was stored for 10 or 15 days in plasma or 10 days in 35% plasma with either 65% Intersol or Isoplate. After storage, all units were radiolabeled and transfused into their donors. RESULTS: For 10-day storage, both the plasma and the Intersol units had significantly better PLT recoveries than the Isoplate units (24% ± 8% vs. 11% ± 3% [55% ± 11% vs. 21% ± 8% as percentage of control data], p = 0.002; and 18% ± 4% vs. 11% ± 3% [43% ± 6% vs. 21% ± 8% as percentage of control data], p = 0.004, respectively). There was a trend for lower PLT recoveries with Intersol compared to plasma (p = 0.056). PLT survivals and most in vitro measurements did not differ significantly among the units. CONCLUSIONS: While the in vitro variables suggest largely comparable results between plasma and PASs, in vivo recoveries were higher with plasma compared with both Intersol and Isoplate (p = 0.057 and p = 0.002, respectively). Whether this difference leads to clinically relevant differences in hemostatic efficacy remains to be determined.

Safety and efficacy of cryopreserved platelets in bleeding patients with thrombocytopenia.

BACKGROUND: The short dating period of room temperature-stored platelets (PLTs; 5-7 days) limits their availability at far-forward combat facilities and at remote civilian sites in the United States. PLT cryopreservation in 6% DMSO and storage for up to 2 years may improve timely availability for bleeding patients. STUDY DESIGN AND METHODS: A dose escalation trial of DMSO-cryopreserved PLTs (CPPs) compared to standard liquid-stored PLTs (LSPs) was performed in bleeding patients with thrombocytopenia. Within each of four cohorts, six patients received escalating doses of CPP (0.5 unit, 1 unit, and sequential transfusions of 2 and 3 units) and one received a LSP transfusion. Patients were monitored for adverse events (AEs), coagulation markers, PLT responses, and hemostatic efficacy. RESULTS: Patients with a World Health Organization bleeding score of 2 or more received from 0.5 to 3 units of CPP (n = 24) or 1 unit of LSP (n = 4). There were no related thrombotic or other serious AEs experienced. Mild transfusion-related AEs of chills and fever (n = 1), transient increased respiratory rate (n = 1), DMSO-related skin odor (n = 2), and headache (n = 1) were observed after CPP transfusion. Among CPP recipients 14 of 24 (58%) had improved bleeding scores, including three of seven (43%) patients who had intracerebral bleeding. CPP posttransfusion PLT increments were significantly less than those of LSPs; however, days to next transfusion were the same. After transfusion, the CPP recipients had improvements in some variables of thrombin generation tests and thromboelastography. CONCLUSION: Cryopreserved PLT transfusions appear to be safe and effective when given to bleeding patients with thrombocytopenia.

Red blood cells derived from whole blood treated with riboflavin and ultraviolet light maintain adequate survival in vivo after 21 days of storage.

BACKGROUND: Pathogen reduction (PR) of whole blood (WB) may increase blood safety when applied before component separation. This study evaluates the in vivo performance of red blood cells (RBCs) derived from WB treated with the riboflavin and ultraviolet (UV) light PR (Mirasol) system. STUDY DESIGN AND METHODS: This was a prospective, two-center, single-blind, randomized, two-period, crossover clinical trial designed to evaluate autologous 51 Cr/99m Tc-radiolabeled recovery and survival of RBCs derived from Mirasol-treated WB compared to untreated WB. RBCs were stored in AS-3 for 21 days at 1 to 6°C. In vitro RBC variables were characterized. Frequency and severity of treatment-emergent adverse event (TEAE) and neoantigenicity were determined. RESULTS: Twenty-four healthy adult volunteers (n = 12 per site) were evaluated. The Mirasol 24-hr RBC recoveries were 82.5 ± 3.9% with one-sided 95% lower confidence limit of 80.9%, meeting US Food and Drug Administration acceptance criteria, albeit at lower level than controls (91.7 ± 6.8%, p < 0.001). Mean RBC survival and T50 were reduced in the Mirasol group (61 and 23 days, respectively) versus controls (82 and 36 days, respectively; p < 0.001) with a mean area under the curve survival of treated RBCs of 83% of untreated controls. End-of-storage hemolysis in the Mirasol group was 0.22 ± 0.1% (control, 0.15 ± 0.1%; p < 0.001). No neoantigenicity or differences in TEAEs were found. CONCLUSION: RBCs derived from Mirasol WB and stored for up to 21 days in AS-3 maintained acceptable cell quality and recovery, albeit modestly reduced compared with untreated RBCs. Mirasol WB may represent a valid single WB PR platform that allows manufacture of RBC for storage for up to 21 days.

Exploratory studies of extended storage of apheresis platelets in a platelet additive solution (PAS).

To evaluate the poststorage viability of apheresis platelets stored for up to 18 days in 80% platelet additive solution (PAS)/20% plasma, 117 healthy subjects donated platelets using the Haemonetics MCS+, COBE Spectra (Spectra), or Trima Accel (Trima) systems. Control platelets from the same subjects were compared with their stored test PAS platelets by radiolabeling their stored and control platelets with either (51)chromium or (111)indium. Trima platelets met Food and Drug Administration poststorage platelet viability criteria for only 7 days vs almost 13 days for Haemonetics platelets; ie, platelet recoveries after these storage times averaged 44 ± 3% vs 49 ± 3% and survivals were 5.4 ± 0.3 vs 4.6 ± 0.3 days, respectively. The differences in storage duration are likely related to both the collection system and the storage bag. The Spectra and Trima platelets were hyperconcentrated during collection, and PAS was added, whereas the Haemonetics platelets were elutriated with PAS, which may have resulted in less collection injury. When Spectra and Trima platelets were stored in Haemonetics' bags, poststorage viability was significantly improved. Platelet viability is better maintained in vitro than in vivo, allowing substantial increases in platelet storage times. However, implementation will require resolution of potential bacterial overgrowth during storage.

C1q-binding anti-HLA antibodies do not predict platelet transfusion failure in Trial to Reduce Alloimmunization to Platelets study participants.

BACKGROUND: In the Trial to Reduce Alloimmunization to Platelets (TRAP) study, 101 of 530 subjects became clinically refractory (CR) to platelets (PLTs) without lymphocytotoxicity assay (LCA)-detectable anti-HLA antibodies. The LCA only detects complement-binding antibodies and is less sensitive than newer assays. Utilizing a more sensitive bead-based assay that does not distinguish between complement-binding versus non-complement-binding antibodies, we have previously shown that while many LCA-negative (LCA-) patients do have anti-HLA antibodies, these low- to moderate-level antibodies do not predict refractoriness. As complement can contribute to PLT rejection, we assessed if previously undetected complement-binding antibodies account for refractoriness among LCA- patients. STUDY DESIGN AND METHODS: Samples from 169 LCA- (69 CR, 100 non-CR) and 20 LCA-positive (LCA+; 10 CR, 10 non-CR) subjects were selected from the TRAP study serum repository. Anti-Class I HLA immunoglobulin (Ig)G and C1q-binding antibodies were measured in serum or plasma with bead-based detection assays. Levels of C1q-binding antibodies were compared between CR and non-CR subjects and correlated with corrected count increments (CCIs). RESULTS: While some of the LCA- subjects had detectable C1q-binding anti-Class I HLA antibodies, and some LCA+ subjects did not, levels were significantly higher among LCA+ subjects. C1q-binding anti-Class I HLA antibody levels did not differ significantly between CR and non-CR among either the LCA- or the LCA+ subjects. Furthermore, there was no significant correlation observed between CCIs and either C1q-binding or any anti-HLA IgG antibodies. CONCLUSIONS: This work confirms that low- to moderate-level anti-Class I antibodies do not drive PLT rejection, suggesting a role for antibody-independent mechanisms.

Ultraviolet B irradiation in the prevention of alloimmunization in a dog platelet transfusion model.

BACKGROUND: Alloimmune platelet (PLT) refractoriness remains a significant problem for chronically transfused patients with thrombocytopenia. STUDY DESIGN AND METHODS: In a dog PLT transfusion model, we evaluated ultraviolet B irradiation (UV-B) of donor PLTs-either alone or in combination with centrifuge leukoreduction (C-LR) or filtration leukoreduction (F-LR)-to prevent refractoriness to donor PLTs and to induce tolerance to standard (STD) PLTs from the same donor or to tertiary donors. RESULTS: Recipient acceptance rates for C-LR donor PLT transfusions were 14%, F-LR were 33%, and UV-B irradiated were 45% with no significant differences among the treatments given to the donor's PLTs. Adding UV-B irradiation to C-LR or F-LR PLTs increased acceptance rates to 50 and 68% (p = 0.02 and p = 0.05), respectively, comparing single treatments to the combined treatments. After a recipient had accepted any type of UV-B-treated donor PLTs, specific tolerance to subsequent transfusions of the same donor's STD PLTs averaged 65%. Nonspecific tolerance to third-party donor's STD PLTs averaged 36% if they had accepted their initial donor's treated PLTs but was only 4% (p < 0.001) if they had rejected these PLTs. CONCLUSION: Combining UV-B irradiation with a method of leukoreduction produces additive effects on prevention of alloimmune PLT refractoriness.

Low-level HLA antibodies do not predict platelet transfusion failure in TRAP study participants.

In the Trial to Reduce Alloimmunization to Platelets (TRAP) study, 101 of 530 participants became refractory to platelet transfusions without evidence of HLA or human platelet antigen (HPA) antibodies. We used a more sensitive bead-based assay to detect and quantify HLA antibodies and a qualitative solid-phase enzyme-linked immunosorbet assay for HPA to determine whether low-level antibodies could predict refractoriness in longitudinal panels from 170 lymphocytotoxicity assay (LCA)(-) and 20 LCA(+) TRAP participants. All TRAP recipients who previously tested LCA(+) were HLA antibody(+), using the bead-based system. Levels of HLA or HPA antibodies did not predict refractoriness among LCA(-) recipients, although higher levels of HLA antibodies were associated with refractoriness among LCA(+) recipients. These data demonstrate that weak to moderate HLA antibody levels detectable by modern binding assays are not associated with platelet refractoriness.

Transfusion-related adverse events in the Platelet Dose study.

BACKGROUND: How platelet (PLT) product characteristics such as dose, source (whole blood derived [WBD] vs. apheresis), storage duration, and ABO matching status affect the risks of transfusion-related adverse events (TRAEs) is unclear. Similarly, more information is needed to define how recipient characteristics affect the frequency of TRAEs after PLT transfusion. STUDY DESIGN AND METHODS: In the multicenter Platelet Dose ("PLADO") study, pediatric and adult hematology-oncology patients with hypoproliferative thrombocytopenia were randomized to receive low-dose (LD), medium-dose (MD), or high-dose (HD) PLT prophylaxis for a pretransfusion PLT count of not more than 10 × 10(9) /L. All PLT units (apheresis or WBD) were leukoreduced. Post hoc analyses of PLADO data were performed using multipredictor models. RESULTS: A total of 5034 PLT transfusions to 1102 patients were analyzed. A TRAE occurred with 501 PLT transfusions (10.0%). The most common TRAEs were fever (6.6% of transfusions), allergic or hypersensitivity reactions (1.9%), and sinus tachycardia (1.8%). Patients assigned HD PLTs were more likely than LD or MD patients to experience any TRAE (odds ratio for HD vs. MD, 1.50; 95% confidence interval, 1.10-2.05; three-group comparison p = 0.02). PLT source and ABO matching status were not significantly related to overall TRAE risk. Compared to a patient's first PLT transfusion, subsequent PLT transfusions were less likely to have a TRAE reported, primarily due to a lower risk of allergic or hypersensitivity reactions. CONCLUSION: The most important PLT unit characteristic associated with TRAEs was PLT dose per transfusion. HD PLTs may increase the risk of TRAEs, and LD PLTs may reduce the risk.

The impact of platelet transfusion characteristics on posttransfusion platelet increments and clinical bleeding in patients with hypoproliferative thrombocytopenia.

Platelet characteristics, such as platelet dose, platelet source (apheresis vs pooled), platelet donor-recipient ABO compatibility, and duration of platelet storage, can affect posttransfusion platelet increments, but it is unclear whether these factors impact platelet transfusion efficacy on clinical bleeding. We performed secondary analyses of platelet transfusions given in the prospective randomized Platelet Dose Study, which included 1272 platelet-transfused hematology-oncology patients who received 6031 prophylactic platelet transfusions. The primary outcome of these analyses was time from first transfusion to first World Health Organization ≥ grade 2 bleeding. Platelet transfusion increments were assessed at 0.25 to 4 hours and 16 to 32 hours after platelet transfusion. There were 778 patients evaluable for analysis of time to bleeding. Adjusted models showed that randomized dose strategy, platelet source, ABO compatibility, and duration of storage did not predict this outcome. Platelet increments were generally higher for transfusions of apheresis platelets, ABO-identical platelets, and platelets stored 3 days versus 4 to 5 days. Thus, although platelet source, ABO compatibility, and duration of storage exert a modest impact on both absolute and corrected posttransfusion platelet increments, they have no measurable impact on prevention of clinical bleeding. This trial was registered at www.clinicaltrials.gov as #NCT00128713.

Bleeding risks are higher in children versus adults given prophylactic platelet transfusions for treatment-induced hypoproliferative thrombocytopenia.

Age-group analyses were conducted of patients in the prophylactic platelet dose trial (PLADO), which evaluated the relation between platelet dose per transfusion and bleeding. Hospitalized patients with treatment-induced hypoproliferative thrombocytopenia were randomly assigned to 1 of 3 platelet doses: 1.1 × 10(11), 2.2 × 10(11), or 4.4 × 10(11) platelets/m(2) per transfusion, given for morning counts of ≤ 10 000 platelets/µL. Daily hemostatic assessments were performed. The primary end point (percentage of patients who developed grade 2 or higher World Health Organization bleeding) was evaluated in 198 children (0-18 years) and 1044 adults. Although platelet dose did not predict bleeding for any age group, children overall had a significantly higher risk of grade 2 or higher bleeding than adults (86%, 88%, 77% vs 67% of patients aged 0-5 years, 6-12 years, 13-18 years, vs adults, respectively) and more days with grade 2 or higher bleeding (median, 3 days in each pediatric group vs 1 day in adults; P < .001). The effect of age on bleeding differed by disease treatment category and was most pronounced among autologous transplant recipients. Pediatric subjects were at higher risk of bleeding over a wide range of platelet counts, indicating that their excess bleeding risk may be because of factors other than platelet counts.

Extended storage of buffy coat platelet concentrates in plasma or a platelet additive solution.

BACKGROUND: Platelet (PLT) concentrates (PCs) prepared from whole blood in the United States are made using the PLT-rich plasma method. The PCs must be made within 8 hours of blood collection and stored for only 5 days. In Europe and Canada, PCs are made using the buffy coat (BC) method from whole blood held overnight at 22 °C and storage times may be up to 7 days. Our studies were designed to determine how long BC PLTs can be stored in plasma or Plasmalyte while meeting the FDA's poststorage viability criteria. STUDY DESIGN AND METHODS: Normal subjects donated whole blood that was stored at 22 °C for 22 ± 2 hours before preparation of BC PLTs. PLTs were stored for 5 to 8 days in either plasma or Plasmalyte concentrations of 65 or 80%. Radiolabeled autologous stored versus fresh PLT recoveries and survivals were assessed as well as poststorage in vitro assays. RESULTS: BC PLTs stored in either plasma or 65% Plasmalyte met FDA poststorage PLT recovery criteria for 7 days but survivals for only 6 days, while storage in 80% Plasmalyte gave very poor results. Both stored PLT recoveries and survivals correlated with the same donor's fresh results, but the correlation was much stronger between recoveries than survivals. In vitro measures of extent of shape change, morphology score, and pH best predicted poststorage PLT recoveries, while annexin V binding best predicted PLT survivals. CONCLUSION: BC PLTs stored in either plasma or 65% Plasmalyte meet FDA's poststorage viability criteria for 6 days.

Utility of cross-matched platelet transfusions in patients with hypoproliferative thrombocytopenia: a systematic review.

BACKGROUND: Multiply transfused hypoproliferative thrombocytopenic (HT) patients with alloimmune transfusion refractoriness require specially selected platelets (PLTs). Cross-matching apheresis PLTs is a popular support option, avoiding requirements for large panels of typed donors for HLA-based selection. We undertook a systematic review of the utility of various cross-matching techniques on mortality reduction, prevention of hemorrhage, alloimmunization and refractoriness, and improvement in PLT utilization or count increments. STUDY DESIGN AND METHODS: A systematic review to December 2012 was conducted of MEDLINE, EMBASE, and Cochrane databases along with a bibliographic search of pertinent references. RESULTS: Of 146 retrieved citations, 20 met inclusion criteria. Eleven more were chosen from bibliographies, describing 29 unique cohorts. All but five enrolled transfusion-refractory, predominantly alloimmunized patients. Cross-match impact on mortality and hemorrhage could not be assessed from these studies. Two studies demonstrated durable corrected count increments and/or breadth of alloimmunization throughout cross-match support; none addressed development or persistence of refractoriness. In alloimmunized refractory patients and nonrefractory cohorts with greater than 25% alloimmunization, higher increments were seen with cross-match-compatible PLTs than incompatible or un-cross-matched units. In two nonrefractory, nonalloimmunized cohorts, the lack of utility of cross-match was reflected by test sensitivity of less than 20%. Comparison of cross-matched PLT success with that of HLA-identical units revealed inferior success rates for the former in one study and equivalent rates in another. No trend was observed regarding relative utility of the various commonly employed techniques. CONCLUSION: Cross-matched PLTs are useful in increasing PLT counts in alloimmunized, transfusion-refractory HT patients, but data about their impact on hemorrhage and mortality are lacking.

Leukoreduction and ultraviolet treatment reduce both the magnitude and the duration of the HLA antibody response.

BACKGROUND: Both leukoreduction and ultraviolet (UV) light treatment of blood products have been shown to reduce the incidence of HLA antibody development in recipients, but the impact of these treatments on the magnitude and persistence of the antibody response is less clear. STUDY DESIGN AND METHODS: Longitudinal samples from 319 subjects taken from four different study cohorts were evaluated for HLA antibodies to determine the effects of leukoreduction and UV treatment on HLA antibody generation and persistence. RESULTS: Subjects receiving leukoreduced or UV-treated blood products were less likely to generate Class I HLA antibodies, and those receiving leukoreduced blood were also less likely to generate Class II HLA antibodies. Among those receiving nonleukoreduced blood, 55% developed Class I HLA antibodies and 51% developed Class II HLA antibodies compared with 28% (Class I) and 15% (Class II) for those receiving leukoreduced blood and 36% (Class I) and 54% (Class II) for those receiving UV-treated blood. Among alloimmunized subjects, leukoreduction resulted in a significant twofold reduction in the magnitude of Class I HLA antibodies, and UV treatment resulted in a significant threefold reduction in the magnitude of Class II HLA antibodies. Both treatments resulted in shorter persistence of Class I HLA antibodies. CONCLUSIONS: These data demonstrate that leukoreduction and UV treatment of blood products results not only in a reduction in the incidence of HLA antibody production, but also in lower and more transient HLA antibody levels among sensitized transfusion recipients.