Platelet Count Increments Research Articles

Platelet compatibility and platelet antibodies detection: A step towards resolving dilemma in management of platelet refractoriness in oncology patients

Background: Platelet refractoriness complicates the provision of platelet transfusions- a critical and essential part in management of thrombocytopenia in Oncology patients. Platelet refractoriness poses challenge due to alloimmunization to HLA (Class I) and human platelet antigens (HPAs) and is associated with adverse clinical outcomes and increases health care costs. Aim: A prospective, observational study was planned in medical oncology patients having thrombocytopenia to analyse result of platelet compatibility with post-transfusion platelet count increment and to ascertain presence of platelet antibodies as causative factor in platelet refractory patients. Methods: Eighty oncology patients having thrombocytopenia in a tertiary care centre; both solid organ and hematological malignancies, requiring platelet transfusion were included in this study. ABO-compatible, leucoreduced, random donor platelets with less than 72 hours storage and platelet cross matched were transfused. In case of platelet refractoriness and presence of platelet incompatibility, platelet antibody screening test was performed using SPRCA technique. A P-value

Laparoscopic splenectomy for immune thrombocytopenia (ITP): long-term outcomes of a modern cohort.

The advent of newer second-line medical therapies (SLMT) for immune thrombocytopenia (ITP) has contributed to decreased rates of splenectomy, following a trend to avoid or delay surgery. We aimed to characterize the long-term outcomes of laparoscopic splenectomy (LS) for ITP at our institution, examining differences in LS efficiency when performed before or after SLMTs. Adults with primary ITP who underwent LS between 2002 and 2016 were identified. Retrospective review of electronic medical records was supplemented with telephone interviews. Treatment response was defined according to current guidelines as complete responders (CR), responders (R), and non-responders (NR). Kaplan-Meier estimates assessed relapse-free rates, and predictors of long-term response were investigated using logistic regression. 109 patients met inclusion criteria, from which 42% were treated with an SLMT before referral to LS. LS was completed in all cases, with no conversions or intraoperative complications. The perioperative morbidity was 7.3%, including 3 deep vein and 2 portal vein thrombosis, one reoperation for bleeding, and no mortalities. Splenectomy was initially effective in 99 patients (CR + R = 90.8%), and 10 patients were NR. At a median 62-month follow-up, 25 patients relapsed, resulting in a 68% CR + R rate. Proportion of CR + R was similar in patients who previously received SLMT and those who did not (61 vs. 76.7%, p = 0.08). CR + R patients were younger (45 vs. 53, p = 0.03), had higher preoperative platelet counts (36 vs. 19, p = 0.01), and experienced a higher increment in platelet counts during hospital stay (117 vs. 38, p < 0.001) as well as 30-days postoperatively (329 vs. 124, p < 0.001). Only a robust response in platelet count at 30-days postoperatively was independently associated with long-term response (OR 1.005, p = 0.006). LS was curative in 68% of patients, with no statistically significant difference when performed before or after SLMTs. Outcomes remain challenging to predict preoperatively, with only a robust increase in platelet counts on short term being associated with long-term response.

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.

Interference of hepatitis B virus dual infection in platelet count recovery in chronic hepatitis C patients with curative antiviral therapy.

Hepatitis C virus infection is associated with thrombocytopenia. Thrombocytopenia recovers after viral eradication. The current study explored the rate and factors associated with platelet (PLT) recovery, which may represent the degree of liver fibrosis regression. A total of 466 patients who achieved a sustained virological response were enrolled to compare the PLT change after a mean follow-up period of 85.5months (range 12-163months). Platelet counts increased significantly after achieving sustained virological response (from 166±55×103 to 201±61×103 u/L, P<0.001). The median PLT count increment was 5.03×103 u/L per year. Logistic regression analysis revealed that factors associated with slow PLT count recovery were high pretreatment PLT counts (odds ratio [OR]/ 95% confidence intervals [CI]: 0.992/0.989-0.996, P<0.001) and hepatitis B virus (HBV) co-infection (OR/CI: 0.416/0.220-0.785, P=0.007). High PLT counts were the only factor associated with slow PLT recovery in patients with mild liver disease (F0-2) (OR/CI: 0.992/0.987-0.996, P<0.001). On the other hand, HBV co-infection was the only factor associated with slow PLT recovery in patients with advanced fibrosis (OR/CI: 0.207/0.054-0.789, P=0.02). Linear regression analysis of factors correlated to the delta PLT count change per year in patients with F0-2 included pretreatment white blood cell (β: -0.001; CI: -0.002-0.000; P=0.01) and pretreatment PLT counts (β: -0.037; CI: -0.061 to -0.013; P=0.003). HBsAg seropositivity was the only factor correlated to the delta PLT count change per year (β: -10.193; CI: -16.752-3.635; P=0.003) among patients with F3-4. Platelet counts recovered after hepatitis C virus eradication. HBV dual infection disrupted PLT count recovery, especially in CHC patients with advanced liver disease.

Linear decline of corrected platelet count increment within 24hours after platelet transfusion in haematological patients: A prospective observational study.

The aim of this study was to prospectively explore the detailed longitudinal development of platelet increments in patients with chemotherapy-induced bone marrow aplasia during the first 24hours after platelet transfusion. Patients admitted to the Haematology department during 7months, and fulfilled inclusion criteria were divided into 4 groups: Group 1, patients with acute leukaemia; Group 2, patients after autologous stem cell transplantation (SCT); Group 3, patients after allogeneic SCT; and Group 4, patients given platelet transfusion prior to intervention. We used frequent blood sampling within 24hours after platelet transfusion to investigate the kinetics of platelet counts following transfusion. Fifty-four platelet transfusion occasions in patients with chemotherapy-induced bone marrow aplasia were included. The decrease in corrected count increment (CCI) 1-24hours after platelet transfusions in all groups could be described as linear functions. For patients in the aggregated Groups 1-3, the decline was 2.0%±0.6% (mean±standard deviation) per hour. For patients in Group 4, the decline of CCI was 2.8%±1.2% per hour. We found no differences between the groups, either in the rate of platelet elimination from the bloodstream or in the mean CCI, in the first 24hours post-transfusion.

Platelet transfusion refractoriness in patients with acute myeloid leukemia treated by intensive chemotherapy

Platelet transfusion refractoriness (PTR) is a major adverse event in the management of acute myeloid leukemia (AML). In a series of 897 adult patients with AML receiving intensive chemotherapy, we identified 41 patients (4.8%) with PTR. PTR was more frequently observed in parous women, patients with extra-medullary disease, a low white blood cell count, an infection, or hemophagocytic syndrome. Among the 31 patients with anti-human leucocyte antigen (HLA) antibodies, an HLA-matched donor was identified for 18 patients (58.1%). Median time between diagnosis of PTR and the first HLA-matched transfusion was 12.5days. HLA-matched transfusions induced a significant increment in platelet counts in 37% of cases. Thrombopoietin receptor agonists were given to 10 patients but did not shorten the duration of thrombocytopenia, reduce severe bleeding, or early death. Grade 3−4 bleeding events during induction, early death caused by bleeding, and death caused by bleeding at any time were significantly greater in patients that had platelet transfusion refractoriness (22% vs. 4.1%, P<0.0001; 12.2% vs. 1.4%, P=0.0006; and 24.4% vs. 5.3%, P<0.0001; respectively). PTR during chemotherapy for AML significantly increased the risk of early and late deaths caused by a severe bleeding event. Improved understanding of platelet destruction is needed to design mechanism-based therapeutic strategies.

The effect of variation in donor platelet function on transfusion outcome: a semirandomized controlled trial

AbstractThe effect of variation in platelet function in platelet donors on patient outcome following platelet transfusion is unknown. This trial assessed the hypothesis that platelets collected from donors with highly responsive platelets to agonists in vitro assessed by flow cytometry (high-responder donors) are cleared more quickly from the circulation than those from low-responder donors, resulting in lower platelet count increments following transfusion. This parallel group, semirandomized double-blinded trial was conducted in a single center in the United Kingdom. Eligible patients were those 16 or older with thrombocytopenia secondary to bone marrow failure, requiring prophylactic platelet transfusion. Patients were randomly assigned to receive a platelet donation from a high- or low-responder donor when both were available, or when only 1 type of platelet was available, patients received that. Participants, investigators, and those assessing outcomes were masked to group assignment. The primary end point was the platelet count increment 10 to 90 minutes following transfusion. Analysis was by intention to treat. Fifty-one patients were assigned to receive platelets from low-responder donors, and 49 from high-responder donors (47 of which were randomized and 53 nonrandomized). There was no significant difference in platelet count increment 10 to 90 minutes following transfusion in patients receiving platelets from high-responder (mean, 21.0 × 109/L; 95% confidence interval [CI], 4.9-37.2) or low-responder (mean, 23.3 × 109/L; 95% CI, 7.8-38.9) donors (mean difference, 2.3; 95% CI, −1.1 to 5.7; P = .18). These results support the current policy of not selecting platelet donors on the basis of platelet function for prophylactic platelet transfusion.

The association between platelet transfusions and bleeding in critically ill patients with thrombocytopenia

BackgroundPlatelet transfusions are commonly used to treat critically ill patients with thrombocytopenia. Whether platelet transfusions are associated with a reduction in the risk of major bleeding is unknown. Patients/MethodsObservational cohort study nested in a previous multicenter, randomized thromboprophylaxis trial in the intensive care unit (ICU). The objective was to evaluate the association between platelet transfusions and adjudicated major bleeding events. Platelet transfusion episodes were reviewed for timing of administration, product type, and dose. Major bleeding with and without platelet transfusions was adjusted for severity of thrombocytopenia, use of anti‐platelet agents, surgery and other covariates. Secondary outcomes were thrombosis, death in ICU and platelet count increment. ResultsAmong 2,256 patients, 71 (3.1%) received 190 platelet transfusions. Of those, 121 (63.7%) were administered to 54 non‐bleeding, thrombocytopenic patients. Adjusted rates of major bleeding were not statistically different with or without the administration of platelet transfusions (hazard ratio for transfused patients 0.85; 95% confidence interval, 0.42‐1.72). We did not find a significant association between platelet transfusion use and thrombosis or death in ICU in adjusted analyses. Thrombocytopenia, anemia, major or minor bleeding and use of anticoagulants were associated with platelet transfusion administration. The median post‐transfusion platelet count increment was 20×109/L at 3.5 hours post‐transfusion. ConclusionsRates of major bleeding were not different for patients who did and did not receive platelet transfusions. Inferences were limited by the small number of transfused patients. Clinical trials are needed to better investigate the potential hemostatic benefit and potential harms of platelet transfusions for this high‐risk population.

Dose- and time-related platelet response with apheresis platelet concentrates and pooled platelets

This study was carried out to compare the post-transfusion platelet increment between the apheresis platelet concentrate (n=74) and pooled platelets (n=54). Pre- and post-transfusion platelet count of the recipient were carried out by automated hematology analyzer. In apheresis platelet concentrate group, the mean 24 hours post-transfusion platelet increment was 47 x 109/L which was statistically significant (p&lt;0.001). On the other hand, in pooled platelets group, the mean 24 hours post–transfusions platelet count increment was 11.0 x 109/L which was also statistically significant (p&lt;0.001). This study concluded that the transfusion of apheresis platelet concentrate was more useful than the transfusion of pooled platelets in terms of platelet count increment and requirement of donor.

Clinical effectiveness of platelets in additive solution treated with two commercial pathogen-reduction technologies.

Two noninferiority, randomized, controlled trials were conducted in parallel comparing the safety and efficacy of platelets treated with Intercept or Mirasol pathogen-reduction technologies versus standard platelets. The primary endpoint was the percentage of hematology patients who developed World Health Organization Grade 2 or greater bleeding. A noninferiority margin of 11% was chosen based on expected Grade 2 or greater bleeding in 20% of controls. The study was closed for financial restrictions before reaching the planned sample size of 828 patients, and an intention-to-treat analysis was conducted on 424 evaluable patients. In the Intercept trial (113 treated vs. 115 control patients), the absolute risk difference in Grade 2 or greater bleeding was 6.1%, with an upper one-sided 97.5% confidence limit of 19.2%. The absolute risk difference in the Mirasol trial (99 treated vs. 97 control patients) was 4.1%, and the upper one-sided 97.5% confidence limit was 18.4%. Neither absolute risk difference was statistically significant. In both trials, posttransfusion platelet count increments were significantly lower in treated versus control patients. Mean blood component use in treated patients versus controls was 54% higher (95% confidence interval, 36%-74%; Intercept) and 34% higher (95% confidence interval, 16%-54%; Mirasol) for platelets and 23% higher (95% confidence interval, 8%-39%; Intercept) and 32% higher (95% confidence interval, 10%-57%; Mirasol) for red blood cells. Unexpected reactions and adverse events were not reported. Mortality did not differ significantly between treated and control patients. Although conclusions on noninferiority could not be drawn due to low statistical power, the study provides additional information on the safety and efficacy of pathogen-reduced platelets treated with two commercial pathogen-reduction technologies.

Various aspects of plateletpheresis: Its impact on donor and patients

Background and Aim: Platelet transfusion plays an important role in the treatment of hematological, oncological, surgical, and transplant patients. Aphaeresis technology is widely available in the world and some part of India, but it is new for our region. The present study aims at various aspects of plateletpheresis including donor safety, donor hematological changes following single donor platelet (SDP) donation, quality of product, and impact on patient following SDP transfusion. Materials and Methods: Preprocedural hematological count such as total platelet count (TPC), hemoglobin, red blood cells, and white blood cells count was recorded. All donors were observed for adverse donor reactions. Postdonation (after 30 min) sample was drawn to see the hematological parameters and compared to that of pre donation hematological parameters. Quality control of all SDP products was done. All recipients were observed for any transfusion reactions. Post 24 h transfusion sample was obtained from the SDP recipient and compared to that of pretransfusion sample to see the platelet increment. Results: A total of 135 plateletpheresis procedures were performed on cell separator. SDP was collected from the donors as per standard operating procedure. All donors were observed for adverse donor reaction. We found an adverse event with one donor. There was decrease in mean value of all hematological parameters in the postdonation sample. There was no thrombocytopenia either clinically or from laboratory value. Similar trend was seen with double yield collection. Mean acid citrate dextrose (ACD) used was 328, mean blood volume processed 3385 ml, mean product volume was 249 ml, mean time was 76.8 min during the procedure. Quality control of all SDP products was done. Mean yield was found to be 4.18 ± 0.95 × 1011 per unit. A positive correlation was seen between pre TPC of donor and product yield. Post 24 h transfusion sample was obtained from the SDP recipient and compared to that of pretransfusion sample to see the platelet increment. We observed mean increment of platelet count to be 76.15 × 109/L. Overall therapeutic benefit was observed in all cases. Conclusion: The study found that plateletpheresis procedure is very safe from donor point of view and SDP product is effective from recipient's point of view.

Thrombopoietin-Receptor Agonist in Systemic Lupus Erythematosus Associated Immune Thrombocytopenia: Results of the 16 Patients from the French Cohort

IntroductionSystemic Lupus Erythematosus (SLE) is associated with thrombocytopenia in approximately 20 % of cases. Management of such cases has been similar to that of Immune ThrombocytoPenia (ITP) as an immune-mediated mechanism is inferred in the pathogenesis of SLE-associated thrombocytopenia. First line treatment is similar to primary ITP (corticosteroids, intravenous immunoglobulin), with the use of hydroxychloroquin in addition. Immunosuppressive agents, rituximab or splenectomy can be used as second line treatment. However, a significant number of patients will not respond to these treatments and will relapse afterward. More recently, Romiplostim and Eltrombopag, 2 agonists of thrombopoietin receptor (TPO-RA) have been approved for ITP as second line therapy resulting in sustained increment in platelet count in about 70-80 % of cases with reduction in bleeding. However, the experience with this class of agents in SLE is only anecdotal. Their effectiveness and side effects in SLE related ITP is unknown.Patients and MethodThis was a multicenter retrospective cohort study of patients with SLE related ITP diagnosed from 1998 to 2015 and treated with TPO-RA. All participating centers (n=13) were secondary or tertiary care hospitals belonging to the French national network for adult ITP. Clinical data were retrospectively collected from medical charts for each patient and completed by telephone interviews with patients and physicians by using a standardized questionnaire. ITP was defined according to the international working group definitions. SLE was defined according to the international guidelines (American College of Rheumatology for systemic lupus erythematosus, revised Sapporo criteria for antiphospholipid syndrome). Response (R) and complete response (CR) were defined according to standardized international criteria: platelet count > 30 × 109/L with at least a doubling of the baseline value or >100 × 109/L.2 Non-response (NR) was defined as the absence of platelet count increase >30 × 109/L with at least a doubling of the baseline count or the need for rescue therapy (IVIg and/or corticosteroids).Patient’s characteristics (table 1&2) PSPitiŽ Salptrire, F: female, M: male, HCQ: hydroxychloroquin, MMF: Mycophenolate mofetil, CTC: corticosteroid, RTX : rituximab, CYC: cyclophosphamide, IVIG : intravenous immunoglobulin, AZA: azathioprine, spm: splenectomy, Toci: tocilizumab, Aba: abatacept, Csa: ciclosporine, TPO-RA : thrombopoietin-receptor agonist, Elt : eltrombopag, Romipl : romiplostim, NS :non specified, CR: complete remission, R :responder, NR :non responder APLSantiphospholipid syndrome, APL : antiphospholipid (presence of antibody without clinical symptoms)Results and DiscussionA total of 16 patients (12 F/ 4M) received TPO-RA (Romiplostim 36%, eltrombopag 28 %, both 36%). Patients had received a median of 5.5 treatment lines for ITP. All but one patient responded at least to one of TPO-RA (93%). No SLE flare has been observed with these treatments. Unexpectedly, 3 patients (18,5%) developed thrombotic events as a side effect. Two arterial thrombosis occurred in patients receiving eltrombopag (both of them with a previous history of APL or APLS), and two venous thrombosis in the same patient (without antiphospholipid) treated with romiplostim. The same strategy was used in the 3 patients: TPO-RA was stopped but rechallenged promptly to increase platelet level, given that they were receiving anticoagulant or anti-aggregant therapy. No reoccurrence has been observed. The other side effects were similar to that observed with primary ITP.This study has some limitations due to its retrospective design, including some potential selection bias but the rapid and sustained response observed raises the possibility that in certain refractory cases of thrombocytopenia associated with SLE, TPO-RA might be a second line therapy to be considered in this patient population. Given the high rate of thrombotic events, we suggest that TPO-RA should be used with caution in patient with APL. Prospective systematic studies would help define the role of this class of agents in SLE and other rheumatic disease that progress with immune mediated thrombocytopenia. [Display omitted] [Display omitted] DisclosuresTerriou:amgen: Consultancy; Novartis: Consultancy. Bussel:Prophylix Pharma: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Protalex: Membership on an entity’s Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; BiologicTx: Research Funding; GSK: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Symphogen: Membership on an entity’s Board of Directors or advisory committees; Genzyme: Research Funding; Sysmex: Research Funding; Shionogi: Membership on an entity’s Board of Directors or advisory committees; Momenta Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Cangene: Research Funding.

Haemostasis in Immune Trombocytopenia Patients Responders to Agonists of Thrombopoietin Receptor

Introduction: The goal of treatment of patients with immune thrombocytopaenia (ITP) is to raise platelet count to a level that will minimize or stop bleeding. One of the therapeutic strategies employed is to augment platelet production with agonists of the thrombopoietin receptor (TPOR-A). Clinical trials for TPOR-A comparing their effects with placebo showed a reduction in proportion of patients reporting bleeding (Tarantino et al, Blood Coag Fibrinolysis, 2013, 24:284-296). This effect might rely on the increase in platelet count, but other factors known to compensate bleeding risk in thrombocytopenic ITP patients might be regulated by TPOR-A.Objective: We aimed to compare haemostasis in ITP patients untreated with any pharmacologic agent (UT-ITPp) and treated with TPOR-A (TPOA-Rp) using the coagulation global assays thromboelastrometry (ROTEM®) and Calibrated Automated Thrombogram (CAT).Methods: Thirty chronic UT-ITPp [platelet count: (86±60)x109 platelets/L], twenty six responders to TPOR-A [16 with Romiplostim® and 10 with Revolade®, platelet count: (132±46)x109 platelets/L] and fifty healthy controls were included. Citrated blood was centrifuged at 152 g 10 min at 23°C for obtaining platelet rich plasma (PRP) and at 1,500 g for 15 min at 23°C for platelet-poor plasma (PPP). Aliquots were stored at -80ºC until analysis.Non-activated ROTEM was performed on PRP adjusted to a platelet count of 25 x 109/L. Clotting time (CT, time from start of measurement until initiation of clotting [in seconds], alpha angle, which reflects the rate of fibrin polymerisation (tangent to the curve at 2-mm amplitude [in degrees]), maximum clot firmness, which reflects the maximum tensile strength of the thrombus (MCF, [in mm]) and LI60, which describes the percentage of maximum clot strength present at 60 min (in %), were recorded.Plasma thrombin generation was measured in PPP using the CAT test at a final concentration of 1 pM tissue factor and 4 microM phospholipids. We evaluated the endogenous thrombin potential (ETP, the total amount of thrombin generated over time); the lag time (the time to the beginning of the explosive burst of thrombin generation); the peak height of the curve (the maximum thrombin concentration produced); and the time to the peak.Platelet activation was determined by flow cytometry through PAC1-FITC binding after stimulation with 100 micromol/L thrombin receptor-activating peptide 6 (TRAP). Fibrinolytic proteins were tested in PPP using commercialized kits.Comparisons of quantitative variables were made with SPSS.22 software. Values of p≤0.05 were considered statistically significant.Results: Platelets from all patients with ITP had a defect in their ability to be activated, as shown by the lower PAC1 binding (p<0.001).No differences were observed among groups for thrombin generation except for an increase in ETP in both groups of ITP patients [control: 1240±320 nMxmin, UT-ITPp: 1464±443 nMxmin (p<0.05), TPOA-Rp: 1533±390 nMxmin (p<0.05)].In ROTEM experiments, PRP from UT-ITPp and TPOA-Rp showed a prolonged CT [control: 550± 95 sec, UT-ITPp: 1090±75 sec (p<0.05), TPOA-Rp: 859±209 sec (p<0.05)]. Only UT-ITPp presented a diminished alpha angle [control: 60.3±7.5, UT-ITPp: 49.3±7.3 (p<0.05), TPOA-Rp: 55.8±5.58]. On the other hand, TPOA-Rp had an increased MCF (control: 46.5±2.1 mm, UT-ITPp: 50.2±5.6 mm, TPOA-Rp: 57.9±4.4 mm, p<0.05) and LI60 (control: 91.8±3.1 %, UT-ITPp: 94.1±3.1 %, TPOA-Rp: 97.6±1.1 %, p<0.05).To evaluate whether increased LI60 values were due to an imbalance in fibrinolysis related proteins, tPA, uPA, TAFI and PAI-1 plasma levels were measured. No differences were observed among the two groups of patients and healthy controls except for PAI-1 which level was increased in TPOA-Rp (control: 12.9±12.3 ng/ml, UT-ITPp: 17.3±12.5 ng/ml, TPOA-Rp: 46.8±20.8, ng/ml p<0.05).Conclusions: As we previously described, TPOR-A treatment increased platelet count but did not ameliorate their function (Álvarez Román et al, Thromb Haemost. 2014, 112:65-72). Nevertheless, ITP patients responders to TPOR-A showed a haemostasis unbalanced on a hypercoagulable profile due, at least in part, to a hipofibrinolytic pattern mainly caused by an increase in PAI-1 plasma level. This fact, together with the increment in platelet count caused by TPOR-A, might help to protect these patients from bleeding.This work was supported by a grant from the FIS-FEDER PI15/01457 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.

Safety and efficacy of cryopreserved autologous platelet concentrates in HLA-alloimmunized patients with hematologic malignancies.

Curative chemotherapy approaches in patients with malignancies and platelet (PLT) transfusion refractoriness due to alloimmunization may be hampered by the lack of suitable PLT donors. For these patients, transfusion of cryopreserved autologous PLTs is an option, but is time- and resource-consuming. We aimed at further simplifying this process. A retrospective single-center analysis was conducted on the transfusion of cryopreserved autologous PLTs in nine female alloimmunized, PLT transfusion-refractory patients treated for acute leukemia (n=8) and non-Hodgkin's lymphoma (n=1). No additional processing was used before transfusion, and most notably, washing and centrifugation steps were omitted. Clinical efficacy and safety, as well as a flow cytometric assessment of structural and functional PLT changes, were analyzed. A total of 40 autologous PLT concentrates were thawed at bedside and transfused a median of 32 (range, 9 to 994) days after cryopreservation. No major bleeds and no severe dimethyl sulfoxide toxicity were observed. The median PLT count increments did not differ 1 and 18 to 24 hours after transfusion and reached 6×109 /L (interquartile range [IQR], 3×109 -7.5×109 /L) and 6×109 /L (IQR, 2.5×109 -9.5×109 /L), respectively. Cryopreservation resulted in partial activation of one-third of the PLTs. In vitro stimulation with strong agonists induced additional full activation of cryopreserved PLTs: median, 55% (IQR, 42%-60%) after thrombin and 39% (IQR, 36%-39%) after convulxin. The transfusion of cryopreserved autologous PLTs is feasible and safe. Despite the cryopreservation process, PLT functionality is partially maintained.

Clinical and laboratory correlates of platelet alloimmunization and refractoriness in the PLADO trial.

Platelet alloimmunization and refractoriness to platelet transfusion are complications of platelet transfusion therapy. The platelet dose (PLADO) trial, as the largest prospective randomized trial of prophylactic platelet therapy to date, afforded an opportunity to analyse these two issues. PLADO patient records were examined for evidence of platelet alloimmunization, defined as an increase in HLA Class I panel-reactive antibodies (PRA) to ≥20%, and clinical refractoriness, defined as two consecutive ≤4 h posttransfusion corrected platelet count increments (CCI) of <5000. Multivariate logistic regression, restricted to platelet-transfused subjects who received exclusively either in-process leucoreduction apheresis or whole blood-derived (WBD) leucocyte-reduced platelets, compared the frequency of these outcomes by platelet unit and patient characteristics. Forty of 816 evaluable platelet-transfused patients (5%) became alloimmunized during the trial. Prior pregnancy, chemotherapy only compared to progenitor cell transplant, and low platelet dose - all were associated with significantly higher rates of alloimmunization. Among 35 alloimmunized patients evaluated for refractoriness, 8 (23%) had two consecutive CCI < 5000/μl. Regardless of alloimmunization status, CCIs < 5000/μl were observed following 17% of platelet transfusions. Among 734 patients receiving at least two platelet transfusions, two consecutive CCIs of ≤5000 occurred in 102 (14%). The incidence of new platelet alloimmunization was low in the PLADO study, but follow-up was at most 30 days. Alloimmunization was present in only 8 of 102 (8%) of observed cases of refractoriness, suggesting that other causes of poor posttransfusion increments are frequent.

Platelet Transfusion Practices in the ICU: Data From a Large Transfusion Registry

Platelet transfusions are commonly used in critically ill patients, but transfusion thresholds, count increments, and predictors of ineffectual transfusions remain unclear. This retrospective study included consecutive adult nononcology patients who received platelet transfusions in ICUs at three Canadian academic hospitals between 2006 and 2015. Data were collected from a validated transfusion database. We determined independent predictors of ineffectual platelet transfusions, defined as transfusions that raised platelet counts by< 5× 10(9)/L. Reasons for transfusion were adjudicated in a subgroup of patients who underwent transfusion despite normal platelet counts. We identified 7,320 ICU admissions (n= 7,073 patients) during which 15,879 platelet transfusions were administered. Most admissions (78.7%) were for cardiac surgery. Based on 5,700 analyzable transfusions, the median pretransfusion platelet count was 87×10(9)/L (interquartile range [IQR], 57-130). The pretransfusion platelet count was≥ 50× 10(9)/L and≥ 150× 10(9)/L for 79.6% and 17.8% of transfusions, respectively. Reasons for transfusion despite a normal platelet count were active bleeding or surgery in patients receiving antiplatelet agents or anticoagulants. The median platelet count increment was 23× 10(9)/L (IQR, 7-44), and 21.8%of transfusions were ineffectual. ABO incompatibility, sepsis, liver disease, and red cell and cryoprecipitate transfusions were associated with a poor platelet count increment. Platelet transfusions were commonly used in the ICU when platelet counts were≥ 50× 10(9)/L. One platelet transfusion increased platelet count by 23× 10(9)/L. One in five transfusions was ineffectual, and ABO incompatibility was identified as a modifiable risk factor. These data can help direct efforts to reduce platelet overuse and improve transfusion quality.

Regulation of platelet count by erythropoiesis-stimulating agents - iron axis in hemodialysis patients.

Higher doses of erythropoiesis-stimulating agents (ESAs) contribute to atherothrombotic cardiovascular disease in hemodialysis (HD) patients. Thrombocytosis is associated with increased mortality in ESA-treated HD patients. We investigated variables affecting platelet count and its variability (platelet count increment [Δplatelet count]) in HD patients. This retrospective longitudinal and observational study of HD outpatients was carried out over 3 years. The outcome was independent determinants of platelet count and Δplatelet count, which were associated with iron indices, ESA dose, and C-reactive protein. In univariate regression analysis, V-shaped relationship was observed between platelet count and transferrin saturation (TSAT), ferritin, serum iron, and hemoglobin (Hb) with the bottom of 0.21, 330 ng/mL, 49 µg/dL, and 10.3 g/dL, respectively. Mixed-effect multivariate regression analysis revealed that TSAT (inversely), Hb ≤10.3 g/dL (inversely), C-reactive protein, and ESA dose were independently associated with platelet count. Δplatelet count was independently and inversely correlated with ΔTSAT and directly correlated with Δferritin. TSAT was independently and inversely associated with ESA dose. ESA dose was directly correlated with iron dose and inversely correlated with TSAT, ferritin ≤330 ng/mL, and Hb ≤10.3 g/dL. ESA dose and TSAT were correlated in determining platelet count and Δplatelet count. Targets of iron indices that reflect iron supply sufficient to avoid platelet count increment and variability may be >21% of TSAT and 300 ng/mL of serum ferritin for appropriate ESA therapy in HD patients.

The increment of platelet count is risk factor of pulmonary thromboembolism in patients with pancreatic cancer treated with gemcitabine

Methods: A retrospective 1:2 matched cohort study was performed to evaluate the risk of PTE in patient with gemcitabinebased chemotherapy for pancreatic cancer. Clinical parameter including rate of increment of platelet count (Inc-Plt) was checked in PTE group and non-PTE group. Inc-Plt was defined as the difference of platelet count from new cycle day 1 to last cycle day 15. The rate of Inc-Plt was defined as the rate of increased platelet count at new cycle day 1 compared with previous cycle day 15. Each patient in PTE group was matched with two patients in the non-PTE group.

The increment of platelet count is a risk factor of pulmonary thromboembolism in patients with pancreatic cancer treated with gemcitabine

The increment of platelet count is a risk factor of pulmonary thromboembolism in patients with pancreatic cancer treated with gemcitabine