Effect of Ado-Trastuzumab Emtansine on Autologous Platelet Kinetics and Function.

PURPOSE: Ado-trastuzumab emtansine (T-DM1) treatment results in grade 3-4 thrombocytopenia in 8%-13% of patients. Prior in vitro studies reported T-DM1 inhibition of megakaryocyte maturation as the cause of decreased platelet production. The current observational study was initiated to evaluate causes of thrombocytopenia in patients with metastatic breast cancer. MATERIALS AND METHODS: Patients with human epidermal growth factor receptor 2-positive metastatic breast cancer (N = 11) were enrolled in this postmarket safety study. 111-Indium- radiolabeled autologous platelet recoveries and survivals as well as serial platelet counts, bleeding time assays, and platelet aggregation responses to a wide range of agonists were performed at baseline (BL) and during two consecutive cycles of the drug (3.6 mg/kg IV once every 3 weeks). RESULTS: Platelet nadirs occurred earlier in cycle 2 than in cycle 1. Average nadir counts (% BL) in cycles 1 and 2 were 116,000/µL (53% ± 6%) and 115,000/µL (51% ± 9%), respectively, with return to BL by D15 in both cycles. BL platelet survival averaged 8.8 (± 0.3) days but progressively shortened to 5.5 (± 0.5) days during cycle 1 and to 4.6 (± 0.3) days during cycle 2 (P < .001 compared with BL for both cycles). Aggregation responses to all agonists decreased during the study, both in cycle 1 and cycle 2. CONCLUSION: Following T-DM1 administration, we observed statistically significant progressive decreases in platelet survivals and decreased platelet function from BL values. In distinction to published in vitro studies, these unexpected results indicate a direct toxic effect of T-DM1 on patients' autologous circulating platelets.

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.

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.

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.

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.

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.

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.

Review of in vivo studies of dimethyl sulfoxide cryopreserved platelets.

A literature review was conducted to assess the efficacy and safety of dimethyl sulfoxide (DMSO) cryopreserved platelets for potential military use. In vivo DMSO cryopreserved platelet studies published between 1972 and June of 2013 were reviewed. Assessed were the methods of cryopreservation, posttransfusion platelet responses, prevention or control of bleeding, and adverse events. Using the Department of Defense's preferred 6% DMSO cryopreservation method with centrifugation to remove the DMSO plasma before freezing at -65°C and no postthaw wash, mean radiolabeled platelet recoveries in 32 normal subjects were 33% ± 10% (52% ± 12% of the same subject's fresh platelet recoveries), and survivals were 7.5 ± 1.2 days (89% ± 15% of fresh platelet survivals). Using a variety of methods to freeze autologous platelets from 178 normal subjects, mean radiolabeled platelet recoveries were consistently 39% ± 9%, and survivals, 7.4 ± 1.4 days. More than 3000 cryopreserved platelet transfusions were given to 1334 patients. There were 19 hematology/oncology patient studies, and, in 9, mean 1-hour corrected count increments were 11 100 ± 3600 (range, 5700-15 800) after cryopreserved autologous platelet transfusions. In 5 studies, bleeding times improved after transfusion; in 3, there was either no improvement or a variable response. In 4 studies, there was immediate cessation of bleeding after transfusion; in 3 studies, patients being supported only with cryopreserved platelets had no bleeding. In 1 cardiopulmonary bypass study, cryopreserved platelets resulted in significantly less bleeding vs standard platelets. In 3 trauma studies, cryopreserved platelets were hemostatically effective. No significant adverse events were reported in any study. In summary, cryopreserved platelets have platelet recoveries that are about half of fresh platelets, but survivals are only minimally reduced. The platelets appear hemostatically effective and have no significant adverse events.

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.

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.

New thoughts on the correct dosing of prophylactic platelet transfusions to prevent bleeding.

PURPOSE OF REVIEW: Recent studies have evaluated the effects of platelet dose on hemostasis. RECENT FINDINGS: As long as a critical level of 5000  platelets/µl is maintained, platelet counts do not affect bleeding. The risk of WHO grade 2 or greater bleeding was 25% on days with morning platelet counts of less than 5000/µl and was 17% at platelet counts between 6000 and 80 000/µl (P < 0.001). Therefore, it is not surprising that platelet doses of half to twice the usual dose of 2.2 × 10(11)  platelets/transfusion/body surface area (BSA) do not affect any bleeding grade. However, the risk of grade 2 or greater bleeding is higher in patients receiving an allogeneic hematopoietic stem cell transplant (HSCT, 79%) versus those receiving chemotherapy for hematologic malignancies (73%) or those receiving an autologous HSCT (57%) (P < 0.001 for the latter versus the first two groups). In contrast, in children under 18, the risk of bleeding was higher in all treatment groups than in adults, particularly for children receiving autologous HSCT (93 to 83% based on increasing patient age). However, for none of these treatment categories did platelet dose affect bleeding risk. SUMMARY: Platelet doses in ranges between half to twice the usual dose of 2.2 × 10(11)  platelets/transfusion/BSA have no affect on WHO bleeding grades.

Persistence of lymphocytotoxic antibodies in patients in the trial to reduce alloimmunization to platelets: implications for using modified blood products.

Patients with acute myelogenous leukemia undergoing induction chemotherapy have significant decreases in alloimmune platelet refractoriness if they receive filter-leukoreduced or UV-B-irradiated vs standard platelet transfusions (3%-5% vs 13%, respectively; P ≤ .03) with no differences among the treated platelet arms (Trial to Reduce Alloimmunization to Platelets). Therefore, measuring antibody persistence might identify the best platelets for transfusion. Lymphocytotoxic (LCT) antibody duration was evaluated for association with patient age, sex, prior transfusion and pregnancy history, study-assigned platelet transfusions, and percentage LCT panel reactive antibodies. During the Trial to Reduce Alloimmunization to Platelets, 145 patients became antibody positive; and 81 (56%) of them subsequently became antibody negative. Using Kaplan-Meier estimates, projected antibody loss was 73% at 1 year. Major factors associated with antibody persistence were prior pregnancy and percentage panel reactive antibody positivity, whereas neither the assigned type of platelets transfused during the 8 weeks of the trial nor prior transfusion history was predictive. After 5 to 8 weeks, the number and type of blood products transfused had no effect on either antibody development or loss. A majority of patients with acute myelogenous leukemia who develop LCT antibodies during induction chemotherapy will lose their antibodies within 4 months regardless of the type or number of blood products they receive.

White blood cell inactivation after treatment with riboflavin and ultraviolet light.

Functional white blood cells (WBCs) in blood components may be responsible for a number of adverse transfusion effects, including transfusion-associated graft-versus-host disease (TA-GVHD), alloimmunization, and alloimmune platelet (PLT) refractoriness. TA-GVHD occurs when functional lymphocytes are transfused into a patient who is unable to mount an immune response to the human leukocyte antigen (HLA) due to HLA compatibility or immunosuppression. Alloantibodies against HLA antigens on donor WBCs and PLTs are the major cause of refractoriness to PLT transfusions in patients receiving repeated blood transfusions. Attempts to reduce these undesirable effects have included leukoreduction filters and gamma irradiation. Studies have shown that exposure of PLT concentrates to riboflavin and light (Mirasol pathogen reduction technology [PRT], CaridianBCT Biotechnologies) causes irreparable modifications of nucleic acids that result in inactivation of a wide range of pathogens as well as inhibition of the immunologic responses mediated by WBCs present in PLT concentrates. This article summarizes these studies and also reports on additional findings from the Trial to Reduce Alloimmunization to Platelets (TRAP) and Mirasol Clinical Evaluation (MIRACLE) trials. Data from in vitro studies and this clinical trial suggest that PRT treatment may be as effective as gamma irradiation in preventing TA-GVHD and more effective than leukoreduction in preventing alloimmunization.

Dose of prophylactic platelet transfusions and prevention of hemorrhage.

BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 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 cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)

Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production.

Chronic immune thrombocytopenia (ITP) is a haematological disorder in which patients predominantly develop skin and mucosal bleeding. Early studies suggested ITP was primarily due to immune-mediated peripheral platelet destruction. However, increasing evidence indicates that an additional component of this disorder is immune-mediated decreased platelet production that cannot keep pace with platelet destruction. Evidence for increased platelet destruction is thrombocytopenia following ITP plasma infusions in normal subjects, in vitro platelet phagocytosis, and decreased platelet survivals in ITP patients that respond to therapies that prevent in vivo platelet phagocytosis; e.g., intravenous immunoglobulin G, anti-D, corticosteroids, and splenectomy. The cause of platelet destruction in most ITP patients appears to be autoantibody-mediated. However, cytotoxic T lymphocyte-mediated platelet (and possibly megakaryocyte) lysis, may also be important. Studies supporting suppressed platelet production include: reduced platelet turnover in over 80% of ITP patients, morphological evidence of megakaryocyte damage, autoantibody-induced suppression of in vitro megakaryocytopoiesis, and increased platelet counts in most ITP patients following treatment with thrombopoietin receptor agonists. This review summarizes data that indicates that the pathogenesis of chronic ITP may be due to both immune-mediated platelet destruction and/or suppressed platelet production. The relative importance of these two mechanisms undoubtedly varies among patients.

New strategies for the optimal use of platelet transfusions.

Patients with severe thrombocytopenia are presumed to be at increased risk for bleeding, and consequently it has been standard practice for the past four decades to give allogeneic platelet transfusions to severely thrombocytopenic patients as supportive care. Platelet transfusions may be given either prophylactically to reduce the risk of bleeding, in the absence of clinical hemorrhage (prophylactic transfusions), or to control active bleeding when present (therapeutic transfusions). While no one would argue with the need for platelet transfusions in the face of severe bleeding, important questions remain about what constitutes clinically significant bleeding and whether a strategy of prophylactic platelet transfusions is effective in reducing the risk of bleeding in clinically stable patients. It is now uncommon for patients undergoing intensive chemotherapy or bone marrow transplantation to die of hemorrhage, but it is open to debate as to what degree platelet transfusions have been responsible for this change in outcome, given the many other advances in other aspects of supportive care. If a prophylactic strategy is followed, the optimal transfusion trigger or quantity of platelets to be transfused prophylactically per transfusion episode needs to be addressed in adequately powered clinical trials, but these remain highly controversial issues. This is because, until recently, there have been few high-quality, prospective, randomized clinical trial (RCT) data for evaluating the relative effects of different platelet transfusion regimens or platelet doses on clinical outcomes. Moreover, most of these RCTs have not used bleeding as the primary outcome measure. Two such studies on platelet dose have now been undertaken, the PLADO (Prophylactic PLAtelet DOse) and the SToP (Strategies for the Transfusion of Platelets) trials. Data from these RCTs are not contained in this overview, as these data have not yet been completely analyzed or submitted for peer review publication. In addition to the above, several recent observational studies have raised the possibility that there is not a clear association between the occurrence of a major clinical bleeding episode and the platelet count in thrombocytopenic patients. Such findings have led to the questioning of the efficacy of prophylactic platelet transfusions in all clinically stable patients, and whether a policy of therapeutic transfusions used only when patients have clinical bleeding might be as effective and safe for selected patients. At least two RCTs evaluating the relative value of prophylactic versus therapeutic platelet transfusions have been initiated in thrombocytopenic patients with hematological malignancies. One such study, known as the TOPPS (Trial of Prophylactic Platelets Study) study, is currently underway in the U.K.

Evidence-based platelet transfusion guidelines.

Transfused platelets (plts) are either pooled random-donor platelet (plt) concentrates or single-donor apheresis plts. When stored for 5 days, all of these products are equally efficacious. A 10,000/microL prophylactic plt transfusion trigger has been documented to be both hemostatically efficacious and cost effective in reducing plt transfusion requirements. The optimal plt dose/transfusion is being evaluated in an ongoing clinical trial. Therapeutic plt transfusions to control or prevent bleeding with trauma or surgical procedures require higher transfusion triggers of 100,000/microL for neurosurgical procedures and between 50,000/microL and 100,000/microL for other invasive procedures or trauma. Leukoreduction has been documented to reduce plt alloimmunization rates, cytomegalovirus (CMV) transmission by transfusion, and febrile transfusion reactions. Whether it reduces immunomodulatory effects of transfusion (i.e., decreases infection rates and cancer recurrence) is still controversial, as is universal leukoreduction. Poor responses to plt transfusions are often multifactorial. For alloimmune plt refractoriness, HLA matching, cross-matching, and identification of the specificity of the patient's antibodies with avoidance of mismatched donor antigens are all equally effective in identifying compatible plts for transfusion. Other causes of poor plt responses are splenomegaly, ABO mismatching, females with 2 or more pregnancies and males, use of heparin or amphotericin, bleeding, fever, graft-vs-host disease (GVHD), and vaso-occlusive disease (VOD).

Platelet transfusion therapy.

This article provides guidelines for the appropriate use of platelet transfusions to reduce unnecessary transfusions, thereby avoiding transfusion-related risks to the patients and the costs of platelet therapy. Platelet products available for transfusion are whole blood derived platelet concentrates and apheresis platelets. Leukoreduced platelets can be used to reduce platelet alloimmunization, cytomegalovirus transmission, and febrile transfusion reactions, while gamma irradiation prevents transfusion-associated graftversus-host disease. Other topics discussed are the expected response to transfused platelets and reasons for poor responses related to alloimmunization, underlying disease state, clinical conditions, and drugs. Appropriate transfusion guidelines based on pretransfusion platelet count, platelet dose, and whether the transfusion is prophylactic or therapeutic are outlined. Identification, prevention, and management of adverse consequences of platelet transfusions and platelet refractoriness are discussed.