Need For Platelet Transfusions Research Articles

Detection of cellular traction forces via the force-triggered Cas12a-mediated catalytic cleavage of a fluorogenic reporter strand.

Molecular forces generated by cell receptors are infrequent and transient, and hence difficult to detect. Here we report an assay that leverages the CRISPR-associated protein 12a (Cas12a) to amplify the detection of cellular traction forces generated by as few as 50 adherent cells. The assay involves the immobilization of a DNA duplex modified with a ligand specific for a cell receptor. Traction forces of tens of piconewtons trigger the dehybridization of the duplex, exposing a cryptic Cas12-activating strand that sets off the indiscriminate Cas12-mediated cleavage of a fluorogenic reporter strand. We used the assay to perform hundreds of force measurements using human platelets from a single blood draw to extract individualized dose-response curves and half-maximal inhibitory concentrations for a panel of antiplatelet drugs. For seven patients who had undergone cardiopulmonary bypass, platelet dysfunction strongly correlated with the need for platelet transfusion to limit bleeding. The Cas12a-mediated detection of cellular traction forces may be used to assess cell state, and to screen for genes, cell-adhesion ligands, drugs or metabolites that modulate cell mechanics.

Using immature platelet fraction as a factor in deciding on the need for platelet transfusions

Our study aimed to assess the prognostic significance of immature platelet fraction (IPF) and its role in deciding whether to transfuse platelets. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. We monitored this hematologic parameter in 6 patients before and after hematopoietic stem cell transplantation (HSCT). For the study, we used whole blood collected in K EDTA tubes. IPF levels were measured by flow cytometry on the automated hematology analyzer SYSMEX XE-2100 (Sysmex, Kobe, Japan). The presence of platelet antibodies was detected using Capture-P Ready-Screen solid phase system for the detection of antibodies to platelets and the NEO Blood Bank Analyzer by Immucor, Inc. It was shown that the use of IPF enabled an early establishment of platelet engraftment and helped to make more a reasoned decision regarding the transfusion of platelets. It was established that if a rise in IPF > 6% was not accompanied by an increase in platelet count, serum platelet antibody testing was needed. IPF can help diagnose platelet engraftment failure following HSCT and thus eliminate the need for bone marrow aspiration. IPF is of great clinical importance; if adopted as a routine hematologic parameter, it can serve as an additional factor in deciding on the need for platelet transfusions and platelet antibody testing and subsequent personalized selection of platelets.

Thrombocytopenia requiring platelet transfusions is predictive of retinopathy of prematurity in preterm infants.

Recent studies suggest that some hematological parameters and ratios provided by blood count collected on the first day of life may be predictors for the development of retinopathy of prematurity (ROP). The aims of this study were to assess whether hematological parameters and ratios in blood count collected on the first day of life are associated with ROP. Retrospective data collection from electronic clinical files of inborn preterm infants with a gestational age of less than 30 weeks delivered from January 2008 to December 2022, in a level III Neonatal Intensive Care Unit (NICU). We collected detailed clinical and demographic data on the mother, pregnancy, mode of delivery, resuscitation, in-hospital neonatal morbidity, pathological examination of the placenta, and hematological parameters and ratios provided by blood count collected on the first day of life. We compared neonates with or without ROP and performed a subgroup analysis on patients with ROP≥2. We included 140 preterm infants with ophthalmic examination; 81(57.9%) developed ROP. The need for platelet transfusions (OR=5.28; 95% CI: 1.31-21.21; P=0.019) and bronchopulmonary dysplasia (BPD) (OR=5.12; 95% CI: 1.14-22.98; P=0.033) were independent risk factors for ROP. In the multivariate analysis, no associations were found between any of the hematological parameters or ratios studied and ROP. In our study, hematological parameters and ratios on the first day of life were not associated with the development of ROP. However, thrombocytopenia that required platelet transfusions was associated with ROP development and severity.

Successful administration of eltrombopag in preparation for peritoneal dialysis catheter placement in a girl with MYH9-related disease.

MYH9-related disease is an autosomal dominant disorder characterized by macrothrombocytopenia, nephropathy, inclusion bodies in leukocytes, sensorineural hearing loss, and cataract. Severe cases require kidney replacement therapy in the patient's second decade of life; thrombocytopenia constitutes a major risk factor for hemorrhagic complications during dialysis initiation or kidney transplantation. Prophylactic platelet transfusion prior to surgery is commonly administered to affected patients in these cases. However, transfusion in such patients has limitations other than the general risk of allergic reactions and blood-borne infections; it may also trigger alloimmunization, leading to platelet transfusion resistance or the development of anti-donor antibodies in potential kidney transplant recipients. Here, we describe prophylactic administration of eltrombopag, an oral thrombopoietin receptor agonist, prior to laparoscopic peritoneal dialysis catheter placement in a 15-year-old girl with MYH9-related disease. Her platelet count was approximately 30 × 103/μL at baseline; it increased to 61 × 103/μL on the day before surgery, thereby avoiding the need for platelet transfusions. There were no major bleeding or adverse events associated with eltrombopag administration. Thus, eltrombopag may be a safe and effective alternative to prophylactic platelet transfusions in patients with MYH9-related disease.

Risks and outcomes of hospitalizations in patients with chronic lymphocytic leukemia admitted with immune thrombocytopenia: an analysis of the National Inpatient Sample Database.

Immune thrombocytopenia (ITP) is a known autoimmune complication of chronic lymphocytic leukemia (CLL). Currently, there is limited data regarding the risk CLL confers on hospitalization outcomes in patients admitted with ITP.The National Inpatient Sample (NIS) database was queried using the International Classification of Diseases (ICD) codes to identify hospitalizations for ITP and then subclassified the data into hospitalizations with and without CLL. A multivariate logistic regression was designed to account for patient characteristics and comorbidities. The primary outcome was all-cause mortality. Secondary outcomes included major bleeding, gastrointestinal bleeding, intracranial bleeding, and the need for platelet transfusions, intravenous immunoglobulin, and splenectomy. Among 662,171 cases of ITP between 2005 and 2019, 15,672 had concurrent CLL. CLL patients were significantly older and had more comorbidities compared to patients without CLL. Multivariate analysis revealed CLL patients with ITP had a risk of all-cause mortality (odds ratio: 1.28, 95% CI: 1.19-1.37; p < 0.01). CLL patients also had a higher risk of complications, second-line ITP treatments, blood transfusions, and bleeding, with the exception of intracranial hemorrhage. Our study suggests CLL is an independent risk factor for increased morbidity and mortality among hospitalized patients with ITP. Prospective studies are needed to determine if refractoriness to conventional treatments for ITP can account these results.

Poor Mobilizers in Lymphoma but Not Myeloma Patients Had Significantly Poorer Progression-Free Survival after Autologous Stem Cell Transplantation: Results of a Large Retrospective, Single-Center Observational Study.

In our single-center study, 357 myeloma and lymphoma patients between 2009 and 2019 were mobilized with granulocyte colony-stimulating factor (G-CSF 7.5 µg/kg bid for four days) plus a fixed dose of 24 mg Plerixafor when indicated (Plerixafor Group, n = 187) or G-CSF alone (G-CSF Group, n = 170). The target CD34 cell yields were ≥2.0 × 106 CD34+ cells/kg in lymphoma and ≥4.0 × 106 CD34+ cells/kg in myeloma patients to enable putative second transplants in the latter. There were no significant differences in engraftment kinetics or transfusion requirements between the Plerixafor Group and the control group in the myeloma cohort, with lymphoma patients not requiring Plerixafor showing significantly faster neutrophil recovery, a trend to faster platelet recovery, and a significantly lower need for platelet transfusions, probably due to the significantly lower number of CD34-positive cells re-transfused. While in myeloma patients the outcome (overall survival, progression-free survival) following autologous stem cell transplantation (ASCT) was similar between the Plerixafor Group and the control group, hard to mobilize lymphoma patients had significantly poorer progression-free survival (47% vs. 74% at 36 months after ASCT, p = 0.003) with a trend also to poorer overall survival (71% vs. 84%). In conclusion, while there seem to be no differences in stemness capacity and long-term engraftment efficiency between the Plerixafor and the G-CSF Group in lymphoma as well as myeloma patients, poor mobilizing lymphoma patients per se constitute a high-risk population with a poorer outcome after ASCT. Whether disease characteristics and/or a more intense or stem cell-toxic pre-mobilization chemo-/radiotherapy burden in this cohort are responsible for this observation remains to be shown in future studies.

The impact of temporary mechanical circulatory support strategies on thrombocytopenia

One common but not well-understood phenomenon of temporary mechanical circulatory support (MCS) use is thrombocytopenia. This clinical issue increases the risk of bleeding and the need for platelet transfusion. Additionally, heparin-induced thrombocytopenia must be considered as part of the differential diagnosis, which complicates patient management. In what follows, we analyze the degree and relative rate of platelet count drop with various temporary MCS strategies – Impella 5.5; Veno-venous Extracorporeal Membrane Oxygenation (VV ECMO); Veno-arterial ECMO (VA ECMO); Intra-aortic Balloon Pump (IABP) and Centrimag Biventricular Assist Device (BIVAD). A total of 337 cohort was investigated. 77 was included for analysis after strict exclusion criteria were utilized (platelet transfusions, bleeding complications, etc.). Repeated measure mixed effect and linear regression models were used to assess the percent platelet drop on implantation of MCS and recovery after explantation of MCS. A statistically significant mean percent drop occurred in MCS types – VA ECMO(−69.6%, p < 0.001), VV ECMO(−40.9%, p < 0.001), Impella 5.5(−20.9%, p = 0.01) and IABP(−28.3%, p = 0.01), except Centrimag BIVAD(−6.5%, p = 0.61). Platelet recovery to or above baseline occurred in VA ECMO(+107.0%, p = 0.42), Impella 5.5(+117.2%, p = 0.28), IABP(+108.3%, p = 0.37), VV-ECMO(163.3%, p = 0.01*) and Centrimag BIVAD(+100.1%, p = 0.99). These results show that the degree of thrombocytopenia depends on MCS device type and is reversible.

Safety and Efficacy of Continuous Use Avatrombopag in Chronic Liver Disease

Avatrombopag (AVA) is an oral thrombopoetin (TPO) agonist. In May of 2018 Avatrombopag was FDA approved for use in adults with chronic liver disease (CLD) undergoing a planned procedure. The ADAPT-1 and ADAPT-2 studies compared 40 mg Avatrombopag vs Placebo and 60 mg Avatrombopag vs Placebo. The use of Avatrombopag proved to statistically reduce the need for platelet transfusion, additional procedures to manage post-op bleeding and raised platelet counts to goal of ≥ 50 x 109/L compared to placebo. When using Avatrombopag for a planned procedure the dose is 40 mg for baseline platelet count 40K to 50K and 60 mg for baseline platelet count <40K. Avatrombopag is taken 10 to 13 days before the scheduled procedure which should occur 5-8 days after the last dose. It is not uncommon for CLD patients to need platelet support from either transfusion or a TPO agonist to achieve a platelet threshold >50K. At our large academic center there are CLD patients who require frequent procedures or need to safely remain on antiplatelet drugs or anticoagulation. This led to offering a role for continuous TPO agonist support with Avatrombopag in select cases. This is a single institute review on the use of Avatrombopag in chronic liver disease. We identified 8 patients with cirrhosis on continuous Avatrombopag between August 2020 and May 2022. The following parameters were gathered on chart review as seen in Table 1 and Table 2: Patient age and sex, dose and frequency of Avatrombopag, length of treatment, baseline platelet count, rise in platelet count, time to platelet response (>50K), maintenance of platelet goal, presence of cirrhosis, need for transfusion after starting Avatrombopag, bleeding events, thrombotic events and use of anti-platelet drug or anticoagulation. The dose of Avatrombopag needed to maintain a platelet goal >50K was 20 mg daily for 8 out of 10 patients. Two patients only required 20 mg every other day. The median length of treatment was 9 months (range 2-21 months). A median for 5.5 days were required to achieve the platelet goal >50K. All of the patients maintained the platelet goal while taking Avatrombopag. All patients had cirrhosis. Only one patient had AVA temporarily held due to critical illness with no home supply of drug available. During this time platelet count dropped below goal and at this time the patient developed a lower extremity DVT and required platelet support to remain safely on anticoagulation. There were no bleeding events. One patient was on anti-platelet only, two patients were on anticoagulation only and three patients were on both anti-platelet and anticoagulation. The concern for thrombosis with TPO agonists in cirrhosis has limited trials due to safety concerns. There are limited options for CLD patients requiring frequent procedures, anti-platelet drugs or anticoagulation. The continuous use of Avatrombopag to maintain a platelet goal >50K appears both safe and effective, but does require close monitoring. It is likely that a lower dose of Avatrombopag, 20 mg, can achieve prolonged platelet support. This lower dose could play a role in reducing potential thrombotic risk. In the future a multi-center trial should be pursued. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A single course of lusutrombopag for multiple invasive procedures in cirrhosis-associated thrombocytopenia: A case series.

Lusutrombopag is a thrombopoietin receptor agonist which reduces the need for platelet transfusions before planned invasive procedures. A post hoc analysis of data from the registration trials observed that lusutrombopag-treated patients who achieved a platelet count > 50 × 109/L (responder patients) did so in a median of 6 days and the effect on platelet count lasted for nearly 3 weeks in total. Since patients with cirrhosis often require repeat invasive procedures, this kind of response-time trend sheds light on the possibility of placing more than one invasive procedure within a single course of lusutrombopag treatment. Platelet transfusion represents the gold standard in this setting, but is limited by the risk of adverse events and limited availability. We describe our experience with lusutrombopag in three patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive procedures after a single course of treatment. The treatment schedule is lusutrombopag orally 3 mg/daily for 7 days and then a time window of 6 days (day 9-14) for the elective invasive procedure. All three patients achieved good response to lusutrombopag treatment and were able to undergone more invasive procedures in the same course of treatment without need of platelet transfusion. our preliminary experience supports the safety and the effectiveness of lusutrombopag in patients with severe cirrhosis-associated thrombocytopenia who underwent multiple invasive elective procedures after a single course.

Platelet storage: Progress so far.

There is a crucial need for platelet transfusion during an emergency-surgery and treatment of platelet disorders. The unavailability of donors has furthermore increased the demand for platelet storage. Platelets have limited shelf life due to bacterial contamination and storage lesions. Temperature, materials, oxygen availability, media, platelet processing and manufacturing methods influence the platelet quality and viability during storage. The conception of various platelet additive solutions along with the advent of plastic storage during the 1980s led to enormous developments in platelet storage strategies. Cold storage of platelets gained attention despite its inability to contribute to platelet survival post-transfusion as it offers faster haemostasis. Several developments in platelet storage strategies over the years have improved the quality and shelf-life of stored platelets. Despite the progress, the efficacy of platelets during storage beyond a week has not been achieved. Antioxidants as additives have been explored in platelet storage and have proven to enhance the efficacy of platelets during prolonged storage. However, the molecular interactions of antioxidants in platelets can provide a better understanding of their mechanism of action. Optimization of dosage concentrations of antioxidants is also a critical parameter to be considered as they tend to exhibit toxicity at certain levels. This review provides comprehensive insights into the critical factors affecting platelet storage and the evolution of platelet storage. It also emphasizes the role of antioxidants as additives in platelet storage solutions and their future prospects towards better platelet banking.

Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

IntroductionLusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag’s efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures.MethodsAn electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 109/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration’s tool assessing risk of bias.ResultsThe meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 109/L and increase of at least 20 × 109/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74).ConclusionThis meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-022-02235-w.

Treatment of chemotherapy-induced thrombocytopenia in patients with non-hematologic malignancies.

Chemotherapy-induced thrombocytopenia (CIT) is a common complication of the treatment of non-hematologic malignancies. Many patient-related variables (e.g., age, tumor type, number of prior chemotherapy cycles, amount of bone marrow tumor involvement) determine the extent of CIT. CIT is related to the type and dose of chemotherapy, with regimens containing gemcitabine, platinum, or temozolomide producing it most commonly. Bleeding and the need for platelet transfusions in CIT are rather uncommon except in patients with platelet counts below 25x109/L in whom bleeding rates increase significantly and platelet transfusions are the only treatment. Nonetheless, platelet counts below 70x109/L present a challenge. In patients with such counts, it is important to exclude other causes of thrombocytopenia (medications, infection, thrombotic microangiopathy, post-transfusion purpura, coagulopathy and immune thrombocytopenia). If these are not present, the common approach is to reduce chemotherapy dose intensity or switch to other agents. Unfortunately decreasing relative dose intensity is associated with reduced tumor response and remission rates. Thrombopoietic growth factors (recombinant human thrombopoietin, pegylated human megakaryocyte growth and development factor, romiplostim, eltrombopag, avatrombopag and hetrombopag) improve pretreatment and nadir platelet counts, reduce the need for platelet transfusions, and enable chemotherapy dose intensity to be maintained. National Comprehensive Cancer Network guidelines permit their use but their widespread adoption awaits adequate phase III randomized, placebo-controlled studies demonstrating maintenance of relative dose intensity, reduction of platelet transfusions and bleeding, and possibly improved survival. Their potential appropriate use also depends on consensus by the oncology community as to what constitutes an appropriate pretreatment platelet count as well as identification of patient-related and treatment variables that might predict bleeding.

Prediction of platelet counts with ROTEM-sigma in cardiac surgery.

Excessive bleeding is common after cardiac surgery. According to transfusion algorithms based on ROTEM results (TEM International Inc., Munich, Germany), platelet transfusion is recommended when FIBTEM amplitude is normal and EXTEM amplitude is reduced. The aim of this study was to evaluate whether ROTEM (TEM International Inc.) parameters may predict accurately platelet counts in cardiac surgery patients, and to determine which of these parameters is the most useful for predicting platelet counts. In this retrospective single center study data from 83 patients who underwent cardiac surgery were reviewed. We analyzed the results of patients for whom ROTEM (TEM International Inc.) and conventional laboratory tests were performed simultaneously. The derived ROTEM (TEM International Inc.) parameter PLTEM was used to estimate platelet count; PLTEM is calculated by subtracting FIBTEM from EXTEM. Correlation between ROTEM (TEM International Inc.) variables and platelet counts were determined. Logistic regression analyses were performed to predict platelet counts. ROTEM A5 values show a high linear correlation with MCF values. PLTEM has a strong linear correlation with platelet counts. According to our results for PLTEM A5<32 mm the probability of platelet count <150×109/L is 100%, for PLTEM A5<27 mm the probability of platelet count <100×109/L is nearly 80%, and for PLTEM A5<22 the probability of platelet count <75×109/L is 70%. This study demonstrates the reliability of considering early ROTEM (TEM International Inc.) results and the feasibility of using PLTEM A5 to predict platelet counts and so, improve our ability to decide the need of platelet transfusion in cardiac surgery patients.

Phase 2 study of avatrombopag in Japanese patients with chronic liver disease and thrombocytopenia.

Avatrombopag, a thrombopoietin receptor agonist, can reduce the need for platelet transfusions or rescue interventions for bleeding in patients with chronic liver disease (CLD) and thrombocytopenia undergoing scheduled procedures. A model analysis indicated that the effect of avatrombopag on platelet production was reduced in East Asian versus non-East Asian patients; however, the difference was deemed not clinically significant. Furthermore, a subgroup analysis of pooled Phase 3 trials showed similar avatrombopag efficacy across racial subgroups. The aim of this Phase 2 study was to corroborate the efficacy and safety of avatrombopag in Japanese patients with thrombocytopenia due to CLD. Japanese patients with CLD and thrombocytopenia were randomized to receive placebo or avatrombopag 20, 40, or 60mg daily for 5days. The primary endpoint was responder rate in platelet counts at Visit 4 (10-13days after treatment initiation), defined as the proportion of patients with platelet count ≥50×109 /L and ≥20×109 /L increase from baseline. Thirty-nine patients were randomized and completed the study (placebo, n=11; avatrombopag 20mg, n=7; 40mg, n=11; 60mg, n=10). Avatrombopag treatment was associated with significant increases in responder rate at Visit 4 in the 40mg (63.6%; p=0.004) and 60mg (40%; p=0.024) groups versus placebo (9.1%). Avatrombopag was well tolerated and no new safety signals were detected. Efficacy and safety results from this study were consistent with previous studies in patients with CLD and thrombocytopenia undergoing elective procedures, supporting treatment with avatrombopag in the Japanese population. gov identifier: NCT02227693.

A Comparative Study of Multiple Electrode Aggregometry Technologies in Cardiac Surgery: Different Values, Same Clinical Relevance

The assessment of platelet function in cardiac surgery patients who recently received dual-antiplatelet therapy is considered in the existing guidelines. Among available devices, Multiplate (MP) and ROTEM Platelet (RP) are both based on electrical impedance. This study aimed to determine the agreement between MP and RP in cardiac surgery patients under dual-antiplatelet therapy discontinued before surgery. Secondarily, it compared the ability of the MP and RP in predicting postoperative bleeding and the need for platelet transfusion. A prospective cohort study. A hospital in Milan, Italy. Fifty adult patients preoperatively and postoperatively tested. None. Patients were studied with adenosine diphosphate (ADP) and thrombin receptor-activating peptide (TRAP) testing on both of the devices. The mean preoperative ADP tests were below the respective lower limit of the reference value, thus reflecting a good ability of these tests to detect the residual or ongoing effects of antiplatelet drugs acting on the P2Y12 receptor. The agreement between the 2 methodologies was very poor for both the ADP and TRAP tests, with a percentage error of 80%. The preoperative ADP tests were predictive for the need of platelet concentrate transfusion, with cut-off values at 35 U for the ADP-MP and 60 Ω/min for the ADP-RP. No correlation was found for postoperative bleeding. Both technologies seemed to offer potential benefits in the surgical approach to patients who preoperatively received antiplatelet drugs. However, the results of these tests are not interchangeable, and different cut-off values should be applied.

Avatrombopag: A Review in Thrombocytopenia.

Avatrombopag (Doptelet®) is an orally administered second generation thrombopoietin receptor agonist (TPO-RA) approved for the treatment of primary chronic immune thrombocytopenia (ITP) in adult patients who are refractory or have an unsatisfactory response to other treatments, as well as for the treatment of thrombocytopenia in adult patients with chronic liver disease (CLD) scheduled to undergo an invasive procedure. In phase III studies, avatrombopag was associated with a significantly greater platelet response than placebo in patients with chronic ITP, and was superior to placebo in reducing the requirement for platelet transfusion or rescue procedures for bleeding caused by surgery in patients with CLD with a platelet count < 50 × 109/L at baseline. Longer term data indicate that avatrombopag is associated with high durable response rates in ITP and may have corticosteroid-sparing effects. The drug was generally well tolerated in both indications. Avatrombopag thus represents a convenient and effective second-line treatment for patients with chronic ITP and can prevent bleeding events in patients with CLD scheduled to undergo a procedure, offering a useful alternative to other available treatments in both indications.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40265-021-01613-y.

АНТИАГРЕГАНТНАЯ ТЕРАПИЯ И ВТОРИЧНАЯ ПРОФИЛАКТИКА ПОСЛЕ КОРОНАРНОГО ШУНТИРОВАНИЯ ПРИ ОСТРЫМ КОРОНАРНЫМ СИНДРОМЕ

Antiplatelet therapy with aspirin and clopidogrel has clear advantages in reducing serious adverse cardiovascular events and mortality following acute coronary syndrome. Although these drugs may pose an additional risk of bleeding in the small percentage of acute coronary syndrome patients who will undergo coronary artery bypass grafting, the benefits are vastly superior, and most bleeding can be reduced, if possible, by delaying coronary artery bypass grafting. Short-acting anticoagulants can be administered flexibly, allowing platelet function to be restored after clopidogrel is discontinued. The postoperative bleeding time may clarify the need for platelet transfusion in case of bleeding. Coronary artery bypass grafting without the use of a heart-lung machine may offer some benefits by avoiding heparinization and the inflammatory response associated with bypass surgery. Secondary prophylaxis with antiplatelet therapy, beta-blockers, lipid-lowering therapy, and ACE inhibitors or angiotensin-converting enzyme inhibitors is critical to the long-term success of revascularization. In this regard, it should be borne in mind that regardless of the method of revascularization, patients with acute coronary syndrome are characterized by the clinical benefit of taking antiplatelet agents such as aspirin and clopidogrel, since these drugs reduce the risk of serious adverse events. On the other hand, antiplatelet agents also increase the risk of bleeding in patients who will eventually undergo coronary artery bypass grafting. However, scientists indicate that in most cases, the benefits of early initiation of antiplatelet therapy outweigh the potential risks [1]. In addition, the beneficial effects of aspirin and clopidogrel in acute coronary syndrome are additive. In the study of clopidogrel, indicated for the prevention of recurrence of unstable angina and non-ST-segment elevation myocardial infarction, patients taking both clopidogrel and aspirin were less likely to die of cardiac death, non-fatal myocardial infarction, or stroke at 30 days and 1 year compared with patients who took only aspirin [22]. All these studies confirm that antiplatelet therapy with aspirin and clopidogrel should be carried out in the early stages of acute coronary syndrome. In patients with ST-segment elevation myocardial infarction, clopidogrel improves outcomes in addition to aspirin. In a trial of clopidogrel and metoprolol for myocardial infarction, clopidogrel, in addition to aspirin, was associated with a significant reduction in death, re-heart attack, or stroke compared with aspirin alone [14].

Implementing pre-procedural thrombopoietin receptor agonists in cirrhotic patients with severe thrombocytopenia: Indiscriminate, selective or unneeded?

Recent studies promote thrombopoietin-receptor agonists (TRAs), instead of platelet transfusions, before elective invasive procedures in patients with cirrhosis and platelet count below 50 × 109/L [ 1 Afdhal N.H. Giannini E.G. Tayyab G. et al. Eltrombopag before procedures in patients with cirrhosis and thrombocytopenia. N Engl J Med. 2012; 367: 716-724 Crossref PubMed Scopus (214) Google Scholar , 2 Hidaka H. Kurosaki M. Tanaka H. et al. Lusutrombopag reduces need for platelet transfusion in patients with thrombocytopenia undergoing invasive procedures. Clin Gastroenterol Hepatol. 2019; 17: 1192-1200 Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar , 3 Tateishi R. Seike M. Kudo M. et al. A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation. Jpn J Gastroenterol. 2019; 54: 171-181 Crossref Scopus (53) Google Scholar , 4 Peck-Radosavljevic M. Simon K. Iacobellis A. et al. Lusutrombopag for the treatment of thrombocytopenia in patients with chronic liver disease undergoing invasive procedures (L-PLUS 2). Hepatology. 2019; 70: 1336-1348 Crossref PubMed Scopus (75) Google Scholar , 5 Terrault N. Chen Y.C. Izumi N. et al. Avatrombopag before procedures reduces need for platelet transfusion in patients with chronic liver disease and thrombocytopenia. Gastroenterology. 2018; 155: 705-718 Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar – [6] Terrault N.A. Hassanein T. Howell C.D. et al. Phase II study of avatrombopag in thrombocytopenic patients with cirrhosis undergoing an elective procedure. J Hepatol. 2014; 61: 1253-1259 Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar to prevent procedure-related bleeding. In the current issue of Digestive and Liver Disease the systematic review and meta-analysis by Rose and colleagues [ [7] Rose P.D. Au M. Woodman R.J. et al. Pre-procedural use of thrombopoietin-receptor agonists in cirrhosis and severe thrombocytopenia: a systematic review and meta-analysis. Dig Liver Dis. 2021; 53: 1396-1403 Abstract Full Text Full Text PDF Scopus (2) Google Scholar ] confirms that TRAs significantly decrease the amount of the supposed required platelet transfusions. At variance with platelet transfusions, which have a slight and short-term effect on the platelet count, second generation TRAs more often achieve a predictable and persistent increase of the platelet count above the conventional threshold of 50 × 109/L, thus allegedly providing higher protection against peri‑procedural and delayed bleeding. This benefit appears to occur without increasing the thrombotic risk as compared to placebo, and the risks related to platelet transfusion, as plasma volume expansion, transfusion reactions, infection, alloimmunization and refractoriness after repeated transfusions, are avoided. Pre-procedural use of thrombopoietin-receptor agonists in cirrhosis and severe thrombocytopenia: A systematic review and meta-analysisDigestive and Liver DiseaseVol. 53Issue 11PreviewSevere thrombocytopenia in cirrhosis can preclude invasive procedures. Platelet transfusion is recommended if platelet count pre-procedure is potential alternative to platelet transfusion is thrombopoietin-receptor (TPO) agonists. Full-Text PDF

Superiority of Avatrombopag to Placebo in Increasing Platelet Counts in Patients with Chronic Liver Disease-Associated Thrombocytopenia Undergoing Scheduled Procedures: Results from 2, Phase 3 Randomized Studies

Background: Thrombocytopenia (TCP) is common in patients with chronic liver disease (CLD). These patients may require platelet transfusions before routine procedures associated with a bleeding risk, thereby exposing them to the risks of transfusion reactions, infections and platelet alloimmunization, while complicating the performance of the procedure and impacting platelet supplies. Avatrombopag (AVA) is an oral, 2ndgeneration, small molecule thrombopoietin receptor agonist being developed to provide a measured increase in platelet counts (PC) as an alternative to platelet transfusions. Two randomized, double-blind, placebo (PBO)-controlled Phase 3 trials evaluated the potential for AVA to increase PC and reduce the need for platelet transfusions in patients with CLD undergoing scheduled procedures.Methods: ADAPT1 (NCT01972529) and ADAPT2 (NCT01976104) enrolled adults with CLD and TCP (mean Baseline PC <50x109/L), scheduled to undergo a procedure. Cohorts were based on Baseline PC (Cohort 1 - <40x109/L, or Cohort 2 - 40 to <50x109/L), and patients randomized 2:1 to receive once-daily oral AVA (Cohort 1- 60 mg; Cohort 2 - 40 mg) or PBO for 5 days with the procedure scheduled 5 to 8 days after the last dose (Day 10 to 13).The primary efficacy endpoint was the proportion of patients not requiring platelet transfusion or any bleeding rescue procedure up to 7 days post-procedure. Secondary endpoints assessed the proportion of patients achieving the target PC of ≥50x109/L by Procedure Day, change in PC from Baseline to Procedure Day, and safety.Results: Together, these studies randomized 435 patients. ADAPT1included 231 patients (median age 57 y; 68% male; Baseline median PC 38x109/L; CLD etiology: alcohol 14%, viral hepatitis 62%, other 23%). In Cohort 1, 90 patients were randomized to AVA and 48 to PBO and in Cohort 2, 59 were randomized to AVA and 34 to PBO. ADAPT2randomized 204 patients (median age 59 y; 62% male; Baseline median PC 39x109/L; CLD etiology: alcohol 15%, viral hepatitis 53%, other 33%). In Cohort 1, there were 70 patients who received AVA and 43 PBO, and in Cohort 2, 58 were randomized to AVA and 33 to PBO.Both studies met their primary efficacy endpoint, demonstrating the superiority of AVA to PBO in increasing the proportion of patients not requiring a platelet transfusion or rescue procedure for bleeding with treatment differences of ADAPT1: Cohort 1 - 42.6% (P<0.001), Cohort 2 - 49.9%, (P<0.0001); ADAPT2: Cohort 1-33.7% (P=0.0006), Cohort 2 - 54.6% (P <0.0001). In addition, a significantly higher proportion of AVA-treated patients successfully achieved the target PC of ≥50x109/L by Procedure Day compared with PBO in both cohorts in ADAPT1 and ADAPT2 (Table). Further, the magnitude of the change in mean PC from Baseline to Procedure Day was significantly larger in AVA-treated compared with PBO-treated patients in both ADAPT1 and ADAPT2in both cohorts (Table). Only 3 AVA-treated subjects achieved PC ≥200x109/L; all were asymptomatic.In both Phase 3 studies, the mean PC in AVA-treated patients started increasing on Day 4 and peaked at ~2 times Baseline PC on Procedure Day (Day 10 to 13); by 7 days post-procedure, mean PC had decreased in both AVA groups, returning to Baseline by Day 35.The most common treatment-emergent adverse events (TEAE) were pyrexia, abdominal pain, nausea, and headache. TEAEs were similar for AVA and PBO arms in both studies. Most TEAEs were mild to moderate in severity; one thrombotic TEAE (partial right portal vein thrombosis) occurred with 40 mg AVA in Cohort 2 in ADAPT2 on Day 7 post-procedure, 14 days after the last AVA dose.Conclusions: Both Phase 3 studies demonstrated the superiority of AVA to PBO in increasing the proportion of patients not requiring a platelet transfusion or any rescue procedure for bleeding. AVA given orally over 5 days resulted in a significant increase in patients achieving the target PC of ≥50x109/L by Procedure Day compared to PBO. The mean change in PC from Baseline to Procedure Day was significantly greater for AVA-treated patients than those who received PBO. In both studies, AVA-treated patients' PC peaked at ~2 times Baseline on Procedure Day, and returned to Baseline by Day 35. AVA was well tolerated, with a safety profile similar to PBO. An agent that provides a measured increase in PC and reduces the need for platelet transfusions may be advantageous for patients with CLD and TCP undergoing invasive procedures to importantly reduce their risks. [Display omitted] DisclosuresTerrault:Merck: Research Funding; AbbVie: Research Funding; Gilead: Research Funding; BMS: Research Funding; Allergan: Research Funding; Eisai: Research Funding. Kuter:Pfizer: Consultancy; Genzyme: Consultancy; Merck: Consultancy; Shire: Consultancy, Research Funding; Protalex: Consultancy, Research Funding; 3SBIO: Consultancy; ONO: Consultancy; BMS: Consultancy, Research Funding; Rigel: Consultancy, Research Funding; Alexion: Consultancy, Research Funding; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy; Incyte: Consultancy, Research Funding; Fujifilm: Consultancy; Zafgen: Consultancy; Amgen: Consultancy; Syntimmune: Consultancy, Research Funding; Novartis: Consultancy. Bibbiani:Eisai, Inc.: Employment.

Correlation of c-MPL Expression and Platelet Count in Thrombocytopenia Due to Chemotherapy Patients

Background: Thrombocytopenia is a commonly occurring side effect of chemotherapy and being the most common reason for clinicians in platelet transfusion. Many problems arise due to platelet transfusion, such as the availability, high cost, refractoriness and disease transmission. Therefore, it takes an alternative strategy to reduce the need for platelet transfusion. Thrombopoietin and its receptor c-MPL is a major regulator of platelet production that works by increasing proliferation and decreasing apoptosis of cells in the megakaryocytopoiesis system. Chemotherapy causes thrombocytopenia by myelosuppression process to megakaryocytopoiesis in which c-MPL expression is found. In thrombocytopenia due to chemotherapy there is an increase in thrombopoietin as a mechanism against the decrease of megakaryocytopoiesis, but unable to increase platelet production because of decreased expression of c-MPL due to suppression of megakaryocytopoiesis.Aim: To know the correlation of c-MPL expression and platelet count in thrombocytopenia due to chemotherapy patientsMethods : An analytic observational study with a cross-sectional approach in October 2015-March 2016 in hematology and medical oncology clinic and inpatient of DR.M.Djamil Padang and private hospitals in Padang City. Subjects were chosen on a consecutive basis (n = 30).Results : In this study obtained that thrombocytopenia due to chemotherapy was common in female sex and the most cases were rectal carcinoma. The mean expression of c-MPL was 11.18 ± 7.59 copies lower than the mean expression of c-MPL in healthy individuals was 797.18 ± 297.27 copies with p <0.05. Mean platelet count was 58,150 ± 39,474,81/mm3. There was a positive correlation between decreased expression of c-MPL and decreased platelet count in thrombocytopenia due to chemotherapy patients (r = 0.798; P <0.05).Conclusion: There was a strong positive correlation between c-MPL expression and platelet count of thrombocytopenia due to chemotherapy patients, in other words a decrease in the level of c-MPL is in line with the decrease in platelet count. DisclosuresNo relevant conflicts of interest to declare.