HLA-matched Platelets Research Articles

Practice Patterns and Clinical Outcomes of Platelet Alloimmunization in a Comprehensive Cancer Center

Introduction Platelet transfusion refractoriness (PTR) secondary to human leukocyte antigen (HLA) alloimmunization is a challenge in the treatment of hematology oncology patients and increases the risk of morbidity and mortality from bleeding events. Guidelines for treating PTR have not been clearly described in literature and the use of TPO mimetics or antifibrinolytics in routine clinical practice in the setting of PTR has not been well studied. Aim In this study, we aimed to describe the practice patterns for the management of PTR secondary to HLA alloimmunization, its supportive care interventions and to assess the mortality, thrombosis and bleeding related clinical outcomes at 30 days from the diagnosis of PTR and HLA alloimmunization. Methods A retrospective review was conducted of all PTR in adult hematology oncology patients at MD Anderson Cancer Center between May 2017 and April 2019. PTR was defined as post-transfusion platelet count increment < 10,000 per microliter in at least two consecutive occasions and within 24 hours after platelet transfusion. HLA typing, HLA antibody and platelet transfusion data were obtained from the Blood Bank Electronic records. Patient demographics and clinical data were obtained from the patients electronic medical records. The study was approved by the Institutional Review Board. Results A total of 51 cases of PTR secondary to HLA alloimmunization were analyzed. The majority of patients (98%) had a diagnosis of hematological malignancy of which 88.2% were undergoing active chemotherapy. Clinically relevant bleeding was observed in 33.3% while hemorrhagic shock was diagnosed in 7%. The rate of bleeding related-mortality was estimated at 7.8% (Table 1a). There was great heterogeneity in the management of bleeding risk and events. The use of antifibrinolytics and plasma products (including intravenous immunoglobulin) was more common in cases with major versus non-major bleeding (Table 1b). Grade A or B1U HLA matched products were available in less than half of cases. Conclusions Our study depicts several important observations related to clinical practice and supportive care during HLA platelet alloimmunization and PTR. 1. There is heterogeneity in the management of the bleeding risk and bleeding events during platelet refractoriness. 2. Antifibrinolytics are more commonly used in the patients who suffered severe bleeding. 3. Grade A and BU HLA-matched platelets are not always readily available. 4. The HLA typing and HLA antibody screen/identification testing are not always performed prior to PTR. 5. There is a significant morbidity impact on clinical outcomes due to PTR and its bleeding related complications. Limitations of our retrospective study include the underestimation of actual bleeding outcomes and clinical reasons for the selection of supportive measures (i.e. concern for thrombosis, renal failure). Prospective randomized control trials may be able to determine the safety and efficacy of antifibrinolytics and other supportive measures in the management of PTR. Disclosures No relevant conflicts of interest to declare.

HLA-matched platelet transfusions are effective only in refractory patients with positive HLA antibody screening.

Recipients of platelet transfusions with 1-hour corrected count increments (1hCCIs) of 7.5 or less on two subsequent platelet transfusions with random platelets may benefit from human leukocyte antigen (HLA)-matched platelet concentrates. We aimed to quantify the efficacy of HLA-matched platelets concentrates expressed in 1hCCIs. We performed a cohort study among consecutive refractory patients who received HLA-matched platelet concentrates in the Netherlands between 1994 and 2017. We performed mixed-model linear regression comparing 1hCCIs after HLA split-antigen-matched transfusions with 1hCCIs after HLA-mismatched transfusions, adjusted for within-patient correlations. A donor-to-patient match was categorized as a split-match if all donor HLA-A and -B antigens were present in the patient as well; that is, donor and patient were HLA identical or compatible. Subgroup analyses were performed for patients with positive or negative HLA antibody screens. Finally, the additional effect of ABO mismatches on 1hCCIs was investigated. The 1hCCI after an HLA-matched transfusion was 14.09 (95% reference interval, 1.13-29.89). This was 1.94 (95% confidence interval [CI], 0.74-3.15) higher than 1hCCI after HLA-mismatched transfusions. In patients with negative HLA antibody screening tests, HLA matching did not affect 1hCCIs. Conditional on HLA matching, 1hCCIs decreased by 3.70 (95% CI, -5.22 to -2.18) with major ABO mismatches. Matched platelet concentrates yielded maximal 1hCCIs, whereas mismatched transfusions still resulted in adequate increments. There is no indication for HLA-matched platelets in patients with negative antibody screens.

P096 Alloimmunized patients’ platelet count increment response to HLA-matched, antigen-negative or low-level antibody platelet unit transfusions

P096 Alloimmunized patients’ platelet count increment response to HLA-matched, antigen-negative or low-level antibody platelet unit transfusions

P019 HLA-Matched platelet transfusion rescued the life of a child with severe thrombocytopenia

A four-year-old female child who was initially diagnosed with myelodysplastic syndrome was admitted in the bone marrow work up. A fully matched HLA allogeneic bone marrow transplantation was performed. Post-transplant the patient received multiple platelets transfusions to manage extreme thrombocytopenia, but without any positive effects. The platelet count was zero/ μ l and the life of the patient was seriously in danger. At our center, we define the refractory for a patient as an increase of platelet count of less than 10 k after the transfusion of at least two fully functioned platelet units containing a sufficient number of platelets ( > 2 × 10 11 per unite). As a further therapeutic attempt, the young girl received Prednisolone 4 mg/kg/day for 4 days and IVI g 1 g/kg/day for 2 days. However, the medications did not render any response and the count of platelet was still zero and the life of this child was still threatened as she developed rapidly and increasingly petechial exanthema with a massive hemorrhagic in the skin. The HLA-workup showed that the patient developed multiple HLA antibodies against HLA class I antigens (B8. B55. B27. B18. B56. B7. B47. B13. A69. B54. B41. B37. B46. B35. B75. Cw10. B67. B76. Cw1. B53. B64. A68. Cw8. Cw9. B65. Cw14. A68. A34. Cw7. A66. A43). The screening for platelet specific antibodies against human platelet antigens (HPA) was negative. Using our in–house established platelet HLA-matched program, corresponding HLA-matched platelet units donated by 4 selected donors was given over several sessions. The child responded excellent to most of the given HLA-matched platelets. After the second transfusion, the platelets count raised to 51 × 10[c]/ μ l. Generally, we consider an increase in platelet count of more than 30 k per transfused unit as a sufficient transfusion. After the clinical symptoms and platelet count were stabilized the patient was discharged with a platelet count of 40 × 10[c]/ μ l. This case highlights the importance and the benefits of platelet matched HLA-program in rescuing the life, decreasing the mortality rate as well as the stay in the hospital and the treatment cost.

A subset of anti-HLA antibodies induces FcγRIIa-dependent platelet activation.

HLA antibodies are associated with refractoriness to platelet transfusion, leading to rapid platelet clearance, sometimes coinciding with clinical side effects such as fever and chills. The presence of HLA antibodies is not always manifested by clinical symptoms. It is currently unclear why refractoriness to platelet transfusion is only observed in a subset of patients. Here, we utilized the availability of a unique panel of human monoclonal antibodies to study whether these were capable of activating platelets. Three out of eight human HLA-specific monoclonal antibodies induced activation of HLA-matched platelets from healthy donors as evidenced by enhanced α-granule release, aggregation, and αIIbb3 activation. The propensity of HLA monoclonal antibodies to activate platelets was independent of the HLA subtype to which they were directed, but was dependent on the recognized epitope. Activation was fully inhibited either by blocking FcγRIIa, or by blocking FcγRIIa-dependent signaling with Syk inhibitor IV. Furthermore, activation required the presence of the IgG-Fc part, as F(ab’)2 fragments of HLA monoclonal antibodies were unable to induce platelet activation. Mixing experiments revealed that activation of platelets occurred in an intra-platelet dependent manner. Accordingly, a proportion of sera from refractory patients with HLA antibodies induced FcγRIIa-dependent platelet activation. Our data show that a subset of HLA antibodies is capable of crosslinking HLA and FcγRIIa thereby promoting platelet activation and enhancing these cells’ phagocytosis by macrophages. Based on these findings we suggest that FcγRIIa-dependent platelet activation may contribute to the decreased platelet survival in platelet-transfusion-dependent patients with HLA antibodies.

Antibodies to human platelet antigens form a significant proportion of platelet antibodies detected in Indian patients with refractoriness to platelet transfusions.

The transfusion of platelets is an important therapeutic strategy in bleeding patients with thrombocytopenia. However, some chronically transfused patients fail to achieve the appropriate platelet count increment following transfusion due to the presence of platelet alloantibodies. The aims of this research were to study the prevalence of platelet alloimmunisation and to characterise the platelet-reactive (PR) antibodies in haematology patients refractory to platelet transfusions in an Indian setting. A total of 80 patients with a prior history of multiple transfusions (minimum of five cellular transfusions) were included in the study if they did not achieve an adequate corrected count increment within 24 h of the platelet transfusion. Patients with non-immunological causes of platelet refractoriness were excluded from the study. The test was performed on a blood sample of 4mL of Ethylenediaminetetraacetic acid (EDTA) blood sample in which plasma was separated and stored at -80 °C and underwent batch testing in PAK-2LE. The overall prevalence of platelet alloimmunisation in our study was 60%. Of the 48 patients who were detected to have platelet antibodies, the combination of anti-human leucocyte antigen (HLA) and platelet-specific (PS) antibodies together constituted the majority of 54·2%. The overall prevalence of anti-HLA antibodies was 51·25% and of PS antibodies was 41·25% in the total study population of 80. The overall prevalence of PS antibodies in our study was greater than that reported by other groups in India and other countries. This needs to be considered, particularly in the management of patients refractory to platelet transfusions, where HLA-matched platelets constitute current best practice.

Platelets from donors with consistently low HLA-B8, -B12, or -B35 expression do not undergo antibody-mediated internalization

AbstractPatients refractory to platelet transfusions because of alloimmunization require HLA-matched platelets, which is only possible if a large HLA-typed donor pool is available. However, even then, patients with broad immunization or rare haplotypes may not have suitable donors. In these patients, transfusions with platelets showing low HLA class I expression may be an alternative to fully HLA-matched transfusions. In this study, we quantified the proportion of donors with consistently low HLA-B8, -B12, and -B35 expression on platelets using human monoclonal antibodies specific for these antigens. Furthermore, as model for in vivo clearance, antibody-mediated internalization of these platelets by macrophages was investigated. The expression of HLA-B8, -B12, or -B35 on platelets was extremely variable between individuals (coefficients of variation, 41.4% to 73.6%). For HLA-B8, but not for HLA-B12 or -B35, this variation was in part explained by zygosity. The variation was most pronounced in, but not exclusive to, platelets. Expression within one donor was consistent over time. Remarkably, 32% of 113 HLA-B8, 34% of 98 HLA-B12, and 9% of 66 HLA-B35 donors showed platelet antigen expression that was not or only minimally above background. Antibody-mediated internalization of platelets by macrophages correlated with antibody opsonization and antigen expression and was absent in platelets with low or minimal HLA expression. In conclusion, our findings indicate that a substantial proportion of donors have platelets with consistently low expression of specific HLA class I antigens. These platelets may be used to treat refractory patients with antibodies directed against these particular antigens, despite HLA mismatches.

P213 Creation of a platelet transfusion refractoriness web app for use at the point-of-care

Aim Platelet transfusions are a cornerstone of therapy for patients who develop thrombocytopenia while undergoing hematopoietic stem cell transplantation (HSCT). Many of these patients demonstrate anti-HLA alloantibody mediated platelet transfusion refractoriness (PTR) and require HLA-matched platelets. The calculated panel reactive antibody (cPRA) is a useful tool for identifying patients at risk for PTR, but it requires manual intervention to calculate and so it is only calculated when requested. However, routine use of cPRA before every HSCT, using the existing pre-HSCT alloantibody results, could identify PTR earlier and more efficiently manage its complex transfusion needs for improved patient care. To accomplish this goal, we created an electronic medical record (EMR) web app for use by clinicians, blood bank/donor center, and tissue typing lab to better identify and manage PTR patients. Methods An online cPRA web-service was created to electronically receive alloantibody data and return cPRA values for several different ethnicities. Additionally, to increase flexibility, the cPRA web-service calculation can be customized with user defined antigen frequencies and epitopes. To utilize the cPRA web-service, a PTR web app was created with connections to several clinical data sources including: Tissue Typing Lab, Blood Bank, Donor Center, and EMR. The PTR web app was embedded into the EMR so that it could be easily viewed while caring for patients undergoing HSCT. Platelet utilization and transfusion effectiveness were compared before and after implementation. Results The cPRA web-service allows for automated computer generated cPRAs, making it feasible to calculate up-to-date cPRAs for every HSCT patient. The web app displays platelet counts along with platelet transfusion events, platelet units in inventory, and has a section for the clinical care teams and lab staff to communicate. We plan on making the cPRA web-service publicly available for others to use and customize. Conclusions We built a customizable cPRA web-service and platelet transfusion visualization web app to provide better point-of-care access to real time cPRA values to enable PTR risk stratification of HSCT patients. The web app also summarizes all of the key clinical data to efficiently manage PRT and improve platelet usage.

Neonatal alloimmune thrombocytopaenia associated with maternal HLA antibodies

Neonatal alloimmune thrombocytopaenia (NAIT) generally results from platelet opsonisation by maternal antibodies against fetal platelet antigens inherited from the infant’s father. Newborn monochorionic twins presented with petechial haemorrhages at 10...

HLAMatchmaker is effective for selecting appropriate platelet units for alloimmunised thrombocytopaenic patients who are refractory to random donor platelets.

HLAMatchmaker has been used in the Irish Blood Transfusion Service (IBTS) to select platelets for HLA-alloimmunised, platelet refractory thrombocytopaenic patients since 2006. Although available since 2002, only three studies have been published supporting the programme's effectiveness for this indication. We sought to examine increments to HLA-matched platelets (HMPs) at various matchmaker scores and to examine the impact of transfusing older platelets and ABO-mismatched platelets to this patient group. A total of 20 consecutive HLA-alloimmunised thrombocytopaenic patients were retrospectively studied. Data collected included: pre- and post-transfusion platelet count, indication for transfusion, HLAMatchmaker score, age of unit and degree of ABO mismatch. Data were also collected on the last 3 U of (RDPs). The Mann-Whitney U-test was used to compare increments between transfusion episodes of random donor platelets (RDPs) vs HMPs with matchmaker scores <3, 4-7 or >8. Increments at <2 h were available for 63 transfusion episodes. Increments at 2-24 h were available for 93 transfusion episodes. Increments were higher when transfusing HMPs than when transfusing RDPs. Increments for HMPs that were ABO mismatched were no different than for ABO-identical units, with the exception of late increments post-transfusing HMPs with a major ABO mismatch. Age of platelets did not influence increments. The use of HLAMatchmaker to select platelet units for thrombocytopaenic HLA-alloimmunised patients produced satisfactory platelet increments. When providing HLAMatchmaker-selected HMPs, ABO mismatch and the use of platelet units that are up to 7 days old should be permissible.

A FHIR Human Leukocyte Antigen (HLA) Interface for Platelet Transfusion Support.

Platelet transfusions are a cornerstone of therapy for patients who develop thrombocytopenia while undergoing Hematopoietic Stem Cell Transplantation (HSCT). Many patients who develop Platelet Transfusion Refractoriness (PTR) require HLA-matched platelets. Identifying these patients early could lead to better utilization of platelets as well as increased platelet counts. We built a SMART on FHIR visualization tool to aid the oncology, blood bank, and blood donor center teams in identifying these patients by showing trends in thrombocytopenia along with a computer generated calculated Panel Reactive Antibody (cPRA) level. To do this, we required a FHIR interface to our HLA database. We describe our methods and outcome for constructing this FHIR interface, as well as the architecture and data flow of HLA data from its proprietary database to the SMART on FHIR environment and application database along with RESTful cPRA web service calculator. Future work will evaluate the clinical impact of this platelet visualization tool and overall success of our FHIR implementation.

Complement Inhibition Using Eculizumab Overcomes Platelet Transfusion Refractoriness in Allo-Immunized Patients Receiving HLA Mismatched Platelets

▪Background: 30-50% of heavily platelet transfused patients will ultimately develop HLA allo-immunization. Although HLA-matched platelets can be lifesaving for these patients, a substantial proportion of patients receiving partially HLA-matched platelet products develop platelet transfusion refractoriness, putting them at risk for serious bleeding complications. Recent data suggest compliment activation leading to the destruction of platelets bound by HLA allo-antibodies may play a pathophysiologic role in platelet refractoriness. Eculizumab is a monoclonal antibody that binds and inhibits C5 compliment, blocking both the classic and alternative pathways of compliment. Here we investigated whether eculizumab treatment could be used to overcome platelet transfusion refractoriness in HLA allo-immunized patients.Methods: We conducted a one armed; phase II pilot trial (NCT02298933) in which HLA allo-immunized patients with platelet transfusion refractoriness received a single infusion of eculizumab at a dose of 1200mg. Eligible patients included adults age 18-75 with severe thrombocytopenia who had detectable HLA class I antibodies associated with platelet transfusion refractoriness (defined as a post-transfusion corrected count increment (CCI) of <7500/ul and <5000/ul at 10-60 mins and 18-24 hrs respectively that occurred following at least 2 consecutive platelet transfusions). Patients were defined to respond to therapy if one of the first 2 platelet transfusions following eculizumab infusion resulted in a CCI>7500/uL at 10-60 mins and CCI>5000/uL at 18-24 hrs post transfusion. Subjects were taken off study 14 days following eculizumab treatment. Responding patients who developed recurrent platelet refractoriness after planned study withdrawal were eligible to re-enroll on study. All patients were required meningococcal vaccination before eculizumab infusion +/- antibiotic prophylaxis to cover N. meningitidis.Results: As of 8/2016, 8 Eculizumab infusions were administered to 7 HLA allo-immunized subjects (median age 40 yrs, range 24-71) with severe thrombocytopenia associated with platelet transfusion refractoriness. Patients had an underlying diagnosis of SAA (n=3), refractory/relapsed AML (n=2; 1 patient had just finished conditioning for a haplo-identical transplant), relapsed ALL (n=1; post MUD transplant) and high risk MDS (n=1).Compliment, total (CH50) was the most reliable and consistent measure for complement inhibition. After Eculizumab infusion, CH50 decreased to <20U/ml in all treated patients. 3 of 8 (43%) patients had a response to therapy with platelet refractoriness resolving following 4/8 (50%) eculizumab administrations (Figures 1-3). Subject 1 received an additional 2nd treatment with eculizumab 2 months after her 1st response and again had resolution of platelet refractoriness (Figure 1A&1B).In 3 out of 4 cases where platelet refractoriness was overcome, the administered platelet product given immediately after eculizumab treatment expressed an HLA allele for which an HLA antibody had been detected in the patient's serum. Resolution of platelet refractoriness resulted in a clinically meaningful reduction in the requirement for platelet transfusions: the median number of platelet transfusion given 2 weeks before and 2 weeks after the eculizumab infusion in responding patients was 8.5 (range 3-10) and 4.5 (range 3-5) transfusions respectively. For the non-responders, the median number of platelet transfusions given 2 weeks before and 2 weeks after the eculizumab infusion was 8 (range 7-10 ) and 9.5 (range 6-15) transfusions respectively.Conclusions: The preliminary data from this ongoing trial suggest eculizumab may have efficacy in overcoming HLA antibody-associated platelet transfusion refractoriness. Remarkably, we observed eculizumab overcame platelet refractoriness in a subset of HLA allo-immunized patients receiving HLA mismatched platelet products that expressed an HLA allele for which an HLA antibody was detectable in the patient's serum. These data raise the possibility that eculizumab administration could be of therapeutic benefit in patients with platelet refractoriness as a consequence of newly discovered HLA antibodies, buying time for transfusion medicine departments to acquire HLA matched platelets or until platelet recovery occurs following chemotherapy or stem cell transplant. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Utility of Fluorescence Cytometric Cross-Matched Platelets in Severely Alloimmunized Patients

▪Introduction:Platelet refractoriness due to alloimmunization (AI) is associated with increased bleeding, longer hospitalization, higher costs, and delay of therapy in oncologic patients. Platelet refractoriness in AI patients is traditionally managed by using commercially-available cross-match compatible and/or HLA-matched platelets. Our HLA laboratory has developed a fluorescence cytometric-based XM (FCXM) for patients with severe AI and platelet refractoriness for whom HLA compatible platelets were not available. We present a retrospective analysis of the utility of FCXM in oncologic patients who are refractory to random single donor apheresis platelet transfusions.Methods:Patients with platelet refractoriness during 2015 to 2016, as determined by platelet increments <10,000, and having HLA Class I antibodies with a Calculated Panel Reactive Antibody (cPRA) >90%, were selected for study. Data collected include gender, age, diagnosis, ongoing treatment and underlying medical illness during hospitalization, complications, time of release of unit from the Blood Bank, and time of platelet count post-transfusion. Platelet counts increments within 0-1 hour and 1-2 hours after transfusion were recorded. Platelet increments from random-donor platelet units served as controls for FCXM platelet unit increments for the same patient. Statistical analysis was performed using an unpaired t test.Results:We identified 36 patients with platelet refractoriness, of whom 5 met our study criteria (cPRA >90%): 4 female, 1 male. Median age was 67 years (range 48 to 78), with 4 Caucasians and 1 African American. Underlying diagnoses were multiple myeloma (2), colon cancer (1), acute myelocytic leukemia (1), and myelodysplastic syndrome (1). Two out of 5 patients had significant bleeding, 4 out of 5 had sepsis and mucositis (Table 1). All units were leukocyte-reduced, single donor apheresis platelets. The mean number of FCXM testing performed was 3 (8 units each, 24 total) with 13 and 9 units that were compatible and less compatible identified, respectively. The mean platelet increment within 0-1 and 1-2 hour of transfusion for FCXM vs non-FCXM were 9.5 and 7.2 (p= 0.78), and 8.4 vs 5.8 (p= 0.7), respectively. While a trend existed, the small numbers in the study were insufficient to demonstrate statistical significance (Table 2). One patient died during hospital admission due to diffuse pulmonary hemorrhage post induction chemotherapy. Although 1 other patient had significant bleeding, the remaining four patients were able to complete their planned chemotherapy.Conclusion:An overall increase in platelet counts occurs with FCXM identified compatible platelet units in severely AI patients who were refractory to random single donor apheresis platelet units. Although the mean increment using FCXM platelets was < 10,000 and did not differ statistically from the non-FCXM group, we were able to identify units to transfuse patients during chemotherapy and help prevent/treat major bleeding complication and death in 4/5 patients. FCXM testing may be a viable option for identifying compatible platelet units in severely AI patients. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Platelet Transfusion Refractoriness Following Induction Chemotherapy in Acute Myeloid Leukemia

▪Platelet transfusion refractoriness (PTR) is defined by the repeated failure to appropriately increment platelet count after platelet transfusion. PTR represents a real concern in the management of patients (pts) who require iterative platelet transfusions, in particular those undergoing intensive treatment (Stanworth, Br J Haematol 2015). PTR can be secondary to non-immune and immune causes and is associated with adverse events including longer hospital stays, severe hemorrhages and increased risk of early deaths. After induction chemotherapy for acute myeloid leukemia (AML), intensive transfusion support is required during the 4-6 weeks of treatment-induced aplasia. There is few data regarding management and outcome of AML pts with PTR in this setting.This study included all consecutive pts treated by intensive chemotherapy for non-promyelocytic AML in Toulouse University Hospital between January 2001 and December 2014 who developed PTR during the induction phase. Platelet count is measured daily and transfusion of ABO-identical platelets is performed when <10.109/L according to standard guidelines. We pragmatically used a clinical definition of PTR, ie. persistent thrombocytopenia <10.109/L despite at least two successive daily platelet transfusions. Control patients were those treated by intensive chemotherapy without PTR. Intensive chemotherapy consisted in daunorubicin (60-90 mg/m² d1-3) or idarubicin (8 mg/m² d1-5) with cytarabine (100-200 mg/m² d1-7); lomustin being added in pts > 60y.We identified 41 cases of PTR among 897 pts in our database (4.8%; 2.9 patients/y). PTR patients were mostly women (78.1% vs 42.4% in non-PTR pts, p<0.0001), with a median age at diagnosis of 57y vs. 59y in non-PTR (table). PTR pts had more often splenomegaly which is a classical factor associated with PTR (22% vs 8.5%, p<0.009). PTR-AML were de novo in 73.2% of cases (only 10 pts had received platelet transfusions prior to initiation of the induction therapy [24.4%]), with cytogenetics and molecular abnormalities not significantly different to non-PTR AML (favorable/intermediate/adverse karyotype: 14.6/61/22% vs 9.1/68/20.4%,; NPM1 mutations: 33.3% vs 33%; FLT3-ITD mutations: 9.7% vs 22.8%). Anti-HLA antibodies were identified in 34/40 PTR pts (82.9%). The median time from chemotherapy initiation to PTR diagnosis was 10.5 days (IQR, 6-16.5). The median duration of thrombocytopenia (from PTR diagnosis to the first platelets count > 50.109/L) was 19 days (IQR 15 - 25.5).Management of PTR-pts was as follows: a twice-daily prophylactic transfusion strategy in 30 pts (73.2%) regardless of bleeding events, one or more HLA-matched platelet transfusion in 15 pts (83.3% of 18 patients with matched donors), corticosteroids (n=15, 36.6%), intravenous immunoglobulins (n=14, 34.2%), TPO agonists (n=10, 24.4%) or rituximab (n=1). Median time between PTR diagnosis and first HLA-matched platelet transfusion was 12.5 days (IQR, 6.5-15).There were 7 early deaths in the PTR group (17.1%) compared to 80 (9.3%) in the non-PTR group (p=0.1). Grade 3-4 bleeding events during induction, early death rate (before end of aplasia) by grade 3-4 bleeding and death rate by bleeding regardless of the phase of treatment (induction+consolidation) were significantly higher in the PTR group (respectively 22% vs 4.1%, p<0.0001, 12.2% vs 1.4%, p<0.0006 and 24.4% vs 5.3%, p<0.0001). However, there was no significant difference in 5-year overall survival between both groups (25.9% vs 33.7%, p= 0.35).HLA-matched transfusions have induced an increment in platelet count >10.109/L in 37% of cases.TPO agonists did neither shorten PTR duration (11.5 days with TPO agonists [IQR, 5.5-15] vs. 10.5 days [IQR, 6-16.5]), nor reduce severe bleeding or early death rate (40% and 20% with TPO agonists vs. 21.9% and 17.1% without).PTR during induction therapy for AML pts significantly increases the risk of early and late deaths by severe bleeding. While TPO agonists did not appear as a relevant strategy for PTR pts, the efficacy of both massive prophylactic and HLA-matched transfusion could have reduced the risk of severe bleeding but remains to be clearly established. Since steroids, immunoglobulins or even rituximab did not prove efficacy in this setting, a better understanding of platelet destruction is needed to design mechanism-based therapeutic strategies for this very high risk condition. [Display omitted] DisclosuresTavitian:Novartis: Membership on an entity’s Board of Directors or advisory committees. Huguet:Pfizer, Novartis, BMS, Ariad, Jazz, Amgen: Membership on an entity’s Board of Directors or advisory committees. Récher:Celgene, Sunesis, Amgen, Novartis, Chugai: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

Transfusion of ABO-Incompatible HLA-Matched Platelets as Support for Patients with Acute Myeloid Leukaemia Undergoing Chemotherapy

Background: ABO-incompatible human leukocyte antigen (HLA)-matched platelets are used to manage thrombocytopenic patients with anti-HLA-A and/or anti-HLA-B (HLA-A/B) antibodies when ABO-identical donors are not available. This study assessed the effectiveness of ABO-incompatible HLA-matched platelets in an unselected group of patients with acute myeloid leukaemia (AML) undergoing cytotoxic chemotherapy. Material and Methods: The study cohort consisted of 12 AML patients undergoing cytotoxic chemotherapy and administered HLA-matched single donor platelet transfusions. Patients positive for anti-HLA-A/B antibodies were defined as candidates for HLA-matched platelet transfusion. The effectiveness of platelet transfusions was determined by measuring corrected count increments (CCIs). Results: The 12 patients received a total of 128 HLA-matched platelet transfusions. The median CCIs 1 hour after ABO-minor and -major incompatible HLA-matched transfusions were 11.4 (range: 3.2-24.9) and 12.4 (range: 3-37), respectively. There were no significant differences in 1- and 24-hour CCIs among ABO-identical and ABOminor and major incompatible transfusions. Discussion: ABO-incompatible HLA-matched platelets are effective in supporting thrombocytopenic AML patient’s positive for anti-HLA-A/B antibodies and undergoing cytotoxic chemotherapy.

Korean Red Cross HLA-Matched Platelet Donor Registry

Korean Red Cross HLA-Matched Platelet Donor Registry

Guidelines for the diagnosis and management of adult aplastic anaemia.

Sally B. Killick (Writing Group Chair), Nick Bown, Jamie Cavenagh, Inderjeet Dokal, Theodora Foukaneli, Peter Hillmen, Robin Ireland, Austin Kulasekararaj, Ghulam Mufti, John A Snowden, Sujith Samarasinghe, Anna Wood (BCSH Task Force Member), Judith C.W. Marsh on behalf of the British Society for Standards in Haematology. The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, Northern Genetics Service, Newcastle upon Tyne, St Bartholomew’s Hospital, Barts Health NHS Trust, London, Barts and The London School of Medicine and Dentistry, Queen Mary University of London and Barts Health NHS Trust, London, Addenbrooks Hospital, University of Cambridge, Cambridge, Leeds Teaching Hospitals, Leeds, Kings College Hospital NHS Foundation Trust, London, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield Great Ormond Street Hospital for Children NHS Foundation Trust, London, West Hertfordshire NHS Trust, Watford.

Platelets made HLA deficient by acid treatment aggregate normally and escape destruction by complement and phagocytes in the presence of HLA antibodies.

The presence of antibodies against HLA Class I can lead to platelet (PLT) transfusion refractoriness, that is, the repeated failure to achieve adequate posttransfusion PLT count increments. PLT refractoriness can be overcome by transfusion of HLA-matched donor PLTs. A different approach is to remove HLA from the PLT surface using low pH. Previous case studies using HLA-stripped PLTs showed encouraging but inconsistent results and lacked information on the biologic effects of acid treatment on PLT function as well as sensitivity to PLT destruction in the presence of HLA antibodies. PLTs prepared from buffy coats were stripped from HLA Class I using a brief incubation at pH 2.9. Kinetics of acid stripping, viability, phenotypic alterations, and sensitivity to complement-mediated lysis and phagocytosis were determined by flow cytometry. Functional potential was evaluated using a multiplate analyzer. Acid-treated PLTs were viable, upregulated activation markers normally and aggregated to a similar extent as untreated PLTs in response to stimulation with three natural agonists. Acid treatment removed 70% to 90% of HLA Class I complexes from the PLT surface, which led to complete protection from HLA antibody-mediated complement lysis and reduced monocyte-mediated phagocytosis in the presence of anti-HLA in vitro. Our study fills an important knowledge gap in how acid treatment affects PLT function and interactions with immune cells, paving the way for controlled clinical trials to evaluate acid-treated PLTs as an alternative to HLA-matched donors in PLT refractoriness.

Successful Kidney Transplantation in Epstein Syndrome With Antiplatelet Antibodies and Donor-specific Antibodies: A Case Report

An autosomal dominant hereditary disease, Epstein syndrome (ES) is characterized by sensorineural hearing impairment, macrothrombocytopenia, and hereditary nephritis, and can progress to end-stage kidney disease after puberty. Generally, kidney transplantation is difficult to perform in Epstein syndrome owing to the high risk of perioperative bleeding. Additionally, due to previous platelet transfusions, ES patients sometimes have antihuman leukocyte antigen (HLA) antibodies, including antiplatelet antibodies and donor-specific anti-HLA antibodies (DSA), which may result in refractoriness to platelet transfusion and antibody-mediated rejection (AMR). We report a case of successful kidney transplantation in a patient with ES who had DSA and antiplatelet antibodies. To prevent AMR, we used a desensitization protocol (a combination of plasmapheresis, rituximab, and basiliximab induction). Surveillance biopsy performed at 4 months and 1 year after transplantation showed no pathological findings suggesting AMR. To prevent perioperative bleeding complications, we infused the patient with HLA-matched platelets, thereby maintaining the platelet count at >10.0 × 104/μL, and no postoperative episodes of bleeding occurred.

Current trends in platelet transfusions practice: The role of ABO-RhD and human leukocyte antigen incompatibility.

Platelet transfusions have contributed to the revolutionary modern treatment of hypoproliferative thrombocytopenia. Despite the long-term application of platelet transfusion in therapeutics, all aspects of their optimal use (i.e., in cases of ABO and/or Rh (D incompatibility) have not been definitively determined yet. We reviewed the available data on transfusion practices and outcome in ABO and RhD incompatibility and platelet refractoriness due to anti-human leukocyte antigen (HLA) antibodies. Transfusion of platelets with major ABO-incompatibility is related to reduced posttransfusion platelet (PLT) count increments, compared to ABO-identical and minor, but still are equally effective in preventing clinical bleeding. ABO-minor incompatible transfusions pose the risk of an acute hemolytic reaction of the recipient that is not always related to high anti-A, B donor titers. ABO-identical PLT transfusion seems to be the most effective and safest therapeutic strategy. Exclusive ABO-identical platelet transfusion policy could be feasible, but alternative approaches could facilitate platelet inventory management. Transfusion of platelets from RhD positive donors to RhD negative patients is considered to be effective and safe though is associated with low rate of anti-D alloimmunization due to contaminating red blood cells. The prevention of D alloimmunization is recommended only for women of childbearing age. HLA alloimmunization is a major cause of platelet refractoriness. Managing patients with refractoriness with cross-matched or HLA-matched platelets is the current practice although data are still lacking for the efficacy of this practice in terms of clinical outcome. Leukoreduction contributes to the reduction of both HLA and anti-D alloimmunization.