Frequency of Thrombocytopenia in Neonates Following Phototherapy in Neonatology Unit of Tertiary Care Hospital

Aim: To determine the frequency of thrombocytopenia and its severity in relation to level of indirect hyperbilirubinemia in neonates following phototherapy at tertiary care hospital. Study Design: Descriptive study Place and duration: This study was conducted at Paediatric department (neonatal ward), Liaquat University Hospital, Hyderabad, from 1st August 2020 till 31st Jan 2021 Methodology: All neonates who fulfilled the inclusion criteria presented at pediatric department (neonatal ward), Liaquat University Hospital Hyderabad were included in the study. After written consent, brief history was taken from the mother or family member and complete blood count (CBC) was sent to check the baseline platelet count along with total serum bilirubin, it was repeated after 48 hours of phototherapy. Results: Out of 231 neonates 70 (30.3%) developed thrombocytopenia after phototherapy. In our study 117 neonates (50.6%) were males & 114 neonates (49.4%) were females with the mean age of 5.9307+1.6640 days. The thrombocytopenia was seen in 70 neonates (30.3%) and type of severity was mild, moderate & severe in 52(22.5%), 13(5.6%) & 5(2.2%) respectively. Conclusion: There was a decline in mean platelet count after phototherapy but it was not statistically significant. The treating doctor should also keep in mind, other causes of thrombocytopenia when the patient is receiving phototherapy.

442 Thrombocytopenia following transcatheter aortic valve implantation in portico and Evolute recipients

Aims Thrombocytopenia (TP) following transcatheter aortic valve implantation (TAVI) is a common phenomenon and is associated with mortality and complications. The underlying mechanisms are still unclear. Few data exist on differential risk of thrombocytopenia between different types of transcatheter valves. Methods and results This retrospective study aimed to evaluate the different behaviour of platelet count in Portico or Evolut recipients. Patients underwent TAVI between Feb 2017 to Aug 2021 at Gemelli Molise Hospital were enrolled and were divided in two groups: Portico (n = 90) and Evolut recipients (n = 64). Blood samples and platelets count were collected at admission (T1), implantation day (T2), second post TAVI day (T3), third post TAVI day (T4) and at discharge (T5). Drop platelets count (DPC) was calculated in this way: 100% × (baseline platelet count–nadir platelet count)/(baseline platelet count). CT and echo data were collected. The overall analysis consisted of a total of 154 patients who underwent TAVI. Among these patients, 90 patients (58%) were implanted with Portico valve, and 64 patients (42%) with an Evolut valve. We observed no differences among baseline characteristic between two groups. Interestingly, patients implanted with Portico valve, showed a high degree of thrombocytopenia at time T3, T4 and T5 (respectively, 122 ± 42 vs. 143 ± 43, P 0.004; 111 ± 39 vs. 137 ± 43, P 0.000; 136 ± 56 vs. 173 ± 69, P 0.001). DPC was greater in Portico valve (44 ± 16 vs. 31 ± 15, P = 0.000). No differences were found among inflammation variables (neutrophil lymphocyte ratio, CRP), implantation depth, degree of calcification evaluated with CT (FACTS score) and PVL. Balloon post dilatation (BPD) was performed in 33% of Portico recipients vs. 18% of Evolut recipients (P 0.044). No correlations were found between DPC and BPD in Portico patients (r = 0.035, P = 0.744) and Evolut recipients (r = 0.074, P = 0.569). Conclusions Our study suggests a more thrombocytopenia in Portico recipients, irrespective inflammation, valve calcification, perivalvular leak, implantation factors. Larger studies are needed to confirm these data.

Comparative Effectiveness of Fedratinib and Pacritinib for the Treatment of Myelofibrosis in Patients with Low Platelet Counts: A Simulated Treatment Comparison Study

Introduction: Myelofibrosis (MF) is a Philadelphia chromosome-negative myeloproliferative neoplasm with an estimated prevalence of 4-6/100,000 persons in the USA. Patients with MF experience aberrant hematopoiesis, bone marrow fibrosis, splenomegaly, and cytopenias, including thrombocytopenia, as well as diminished survival ranging from months to years, depending on risk status. Symptoms progressively worsen, underscoring the need for effective treatments across heterogeneous risk statuses and patient dispositions. Among intermediate- to high-risk patients, Janus kinase 2 (JAK2) inhibitors are the primary treatment for MF. Fedratinib was approved by the US Food and Drug Administration (FDA) based on the results of the JAKARTA trials (NCT01437787; NCT01523171), and a new drug application for pacritinib has been submitted to the FDA for the treatment of MF in patients with severe thrombocytopenia. A head-to-head trial of fedratinib and pacritinib for the treatment of MF has not been conducted. Moreover, there is a paucity of evidence evaluating these agents in patients with MF and thrombocytopenia (platelets < 100 × 10 9/L). Therefore, indirect treatment comparisons (ITCs) are required to assess the comparative efficacy of fedratinib and pacritinib in this population. Methods: A systematic literature review (SLR) was conducted to identify all clinical evidence in patients with MF and thrombocytopenia. Based on the SLR results, the JAKARTA, JAKARTA-2, and PERSIST-2 (NCT01773187) trials were identified as the studies to form the basis of the ITC. A pooled analysis data set was developed based on individual patient-level data from the fedratinib 400-mg arms of the JAKARTA and JAKARTA-2 trials including patients with platelets < 100 × 10 9/L. Published summary data from the pacritinib 200-mg arm of the PERSIST-2 trial served as the comparator. Simulated treatment comparisons (STCs) were used to compare spleen volume reduction (SVR) ≥ 35% while adjusting for mutually reported baseline patient characteristics such as age, sex, Dynamic International Prognostic Scoring System, Eastern Cooperative Oncology Group (ECOG) performance status (PS), JAK2 V617F mutation status, prior ruxolitinib exposure, and laboratory tests. Final adjustment models were selected based on fit statistics and the literature review. Indirect relative risk (RR) was estimated with 95% confidence intervals (CIs) using unanchored naive ITC (unadjusted) and STC (adjusted) methodologies. The PERSIST-2 trial included patients with baseline platelets < 50 × 10 9/L, but did not report median baseline counts. Therefore, a sensitivity analysis was conducted to evaluate the impact of differential median baseline platelet counts. In the sensitivity analysis, an outcome model was generated in the full pooled JAKARTA trial population irrespective of platelet count, and platelet count was forced into the multivariable adjustment model. Outcomes were simulated at 3 median baseline platelet counts (25, 50, and 75 × 10 9/L) and compared using similar methodology to the main analysis. Results: The main analysis suggests that fedratinib is associated with a greater proportion of SVR ≥ 35% than pacritinib (Table, A). According to the naive ITC, fedratinib was numerically favored over pacritinib in terms of SVR ≥ 35% (RR, 1.67 [95% CI, 0.94-2.97]). After adjustment for ECOG PS, JAK2 V6127F mutation status, and prior ruxolitinib exposure, fedratinib was statistically favored relative to pacritinib for SVR ≥ 35% (RR, 1.76 [95% CI, 1.00-3.10]). Results of the platelet-count-adjusted sensitivity analysis showed that a significant difference was observed in favor of fedratinib with respect to SVR ≥ 35% (Table, B). The resulting indirect RRs were similar regardless of simulated median baseline platelet count, which suggest that differential baseline platelet count has a minimal impact on the ITC results. Conclusion: This analysis used a population-adjusted ITC to assess the comparative efficacy of pacritinib and fedratinib in patients with MF and thrombocytopenia. Following population adjustment, fedratinib was associated with a greater proportion of patients achieving SVR ≥ 35% than pacritinib. In lieu of a head-to-head clinical trial, further real-world evidence studies should be conducted to assess the effectiveness of these treatments in the clinical setting. Figure 1 Figure 1. Disclosures Daniele: BMS/Celgene: Consultancy; Purple Squirrel Economics: Current Employment. Abraham: Bristol Myers Squibb: Current Employment. Kee: Bristol Myers Squibb: Current Employment. Tremblay: Cytel: Consultancy; Purple Squirrel Economics: Current Employment. Rose: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. McBride: BMS: Current Employment.

All-Trans Retinoic Acid Plus Low-Dose Rituximab Vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

Introduction Approximately one-third of immune thrombocytopenia (ITP) patients fail to achieve a response with first-line treatments, and most patients who respond to first-line treatment relapse and require further second-line therapies. Rituximab (RTX) has been frequently used in ITP treatment, and proposed schedules include the standard dose (SD) and low dose (LD). Previous studies on LD-RTX in ITP revealed a comparable overall response (OR) and reduced incidences of short- and long-term complications (e.g., infections) compared with SD-RTX (Blood, 2012; Platelets, 2019). However, LD-RTX does not achieve a rapid and long-lasting response in the treatment of ITP. Our preliminary studies demonstrated the efficacy of all-trans retinoic acid (ATRA) in the ITP model due to its effects on inducing megakaryocyte maturation and its immunomodulatory effects (Stem Cells Dev, 2017; J Thromb Haemost, 2017; Br J Haematol, 2018; Haematologica, 2019). Since RTX and ATRA share disparate mechanisms in treating ITP, a combination of RTX and ATRA may work synergistically based on a "double-hit" mechanism targeting both platelet production and destruction, which may overcome the long TTR and improve the SR rate of LD-RTX. Therefore, our study aimed to determine the efficacy and safety of ATRA plus LD-RTX compared to LD-RTX monotherapy in patients with corticosteroid-resistant or relapsed ITP (NCT03304288). Methods Eligible corticosteroid-resistant or relapsed ITP patients with a platelet count < 30 × 10 9/L or bleeding symptoms at enrolment were randomly allocated in a 2:1 ratio to receive 100 mg of RTX weekly for 6 weeks plus ATRA orally at 20 mg/m 2 daily for 12 weeks or 100 mg of RTX weekly for 6 weeks. Stable doses of concomitant corticosteroids, danazol, and cyclosporin were permitted. Treatment was discontinued if platelet counts in two consecutive tests at least 2 weeks apart were more than 300 × 10 9/L and resumed when the platelet count fell to less than 150 × 10 9/L. Assessments were performed at baseline, weekly during the first 4 weeks, every 2 weeks until week 24, and every 4 weeks thereafter. The primary outcome was OR, defined as a platelet count ≥ 30 × 10 9/L, a doubling of the baseline platelet count and the absence of bleeding. Secondary endpoints included sustained response (SR), initial response, complete response, time to response, duration of response and adverse events. SR was defined as maintenance of a platelet count > 30 × 10 9/L, the absence of bleeding, and no requirement for other ITP-specific treatment for 6 consecutive months. Results One hundred sixty-eight patients from 7 tertiary medical centres in China were included between 2017 and 2020, 112 patients received combination treatment of LD-RTX and ATRA, and 56 patients received LD-RTX monotherapy. All the baseline characteristics were comparable between the two groups. The median ages of patients in the LD-RTX plus ATRA group and LD-RTX monotherapy group were 46.0 years and 44.5 years, respectively. For patients in the combination and monotherapy groups, the median number of previous therapies was 2.0. The median baseline platelet count was 17.0 × 10 9/L in the combination group and 19.0 × 10 9/L in the monotherapy group. All the patients were followed up for more than 11 months. OR was observed in 90 (80.4%) patients in the combination group and 33 (58.9%) in the LD-RTX monotherapy group (between-group difference, 0.22; 95% CI, 0.07 to 0.36), indicating that the combination treatment increased the response rate. SR was achieved by 68 (60.7%) patients in the combination group and 23 (41.1%) patients in the monotherapy group at the 6-month follow-up (between-group difference, 0.20; 95% CI, 0.04 to 0.35). Additionally, 56 (50%) subjects in the combination group and 19 (34%) in the monotherapy group were still in sustained remission at 12 months (between-group difference: 0.16; 95% CI, -0.01 to 0.33). No significant difference was found between the 2 treatment groups in terms of the time to a response. The severity of AEs was primarily of grade 1-2. The 2 most common AEs for the combination group were dry skin and headache or dizziness, with incidences of 40.2% (45/112) and 18.8% (21/112), respectively. Conclusions In conclusion, ATRA plus LD-RTX significantly increased the overall and sustained response, indicating a novel promising treatment option for corticosteroid-resistant or relapsed adult ITP patients. Disclosures No relevant conflicts of interest to declare.

Linezolid Induced Thrombocytopenia: A Case Report

Linezolid (LZD) is an antimicrobial agent with a broad spectrum of activity against virtually all clinically important Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCoNS) and vancomycin-resistant enterococci (VRE). Thrombocytopenia (TP) is a common adverse effect of Linezolid (LZD). Prolonged treatment duration, renal insufficiency, chronic liver disease, malignancy, previous vancomycin use, baseline platelet count, and lower body weight have been reported as possible risk factors for LZD-associated TP. Here, we illustrate a case of a 51-year-old male patient diagnosed with pancreatitis and urinary tract infection and was prescribed several antibiotics including Linezolid. In this case, platelets count which were initially normal started declining from day 7 of initiating Linezolid. Linezolid was withdrawn from treatment from day 9. Platelet count gradually came back to normal on day 16. This suggests reversible type of thrombocytopenia by Linezolid. This case illustrates need for careful observation of platelet count during the treatment with Linezolid. Keywords: Linezolid, Thrombocytopenia, Dechallenge

A Multicentre Randomised Trial of First Line Treatment Pathways for Newly Diagnosed Immune Thrombocytopenia: Standard Steroid Treatment Versus Combined Steroid and Mycophenolate. the Flight Trial

BACKGROUND Immune thrombocytopenia (ITP) is a rare autoimmune condition associated with bleeding risk and fatigue. Current first line ITP treatment is with high dose corticosteroids but frequent side effects, heterogeneous responses and high relapse rates are significant problems, with only 20% remaining in sustained long-term remission. In the UK, mycophenolate (MMF) is frequently used as second line treatment, with retrospective data in ITP suggesting efficacy in 50-80% of patients with good tolerability, although responses are often delayed. The FLIGHT trial aimed to test the hypothesis that MMF combined with corticosteroid is a more effective first line ITP treatment than current standard of care, corticosteroid alone. METHODS In this multicentre, UK based, open label, randomised controlled trial, we randomly assigned 120 patients with ITP requiring first line treatment, to corticosteroid alone (standard care) versus combined corticosteroid and MMF (1:1 ratio). Patients >16 years old, with baseline platelet count <30 x109/L requiring first line treatment were eligible. Exclusions included HIV, Common Variable Immunodeficiency (CVID), pregnancy, breast feeding or an unwillingness to follow contraception advice if assigned to MMF. Dosing of corticosteroid followed international consensus guidance (either dexamethasone pulses or prednisolone initial daily dose of 1mg/kg then taper) and dosing of MMF included a strategy to taper and stop 6 months after starting treatment. The primary efficacy outcome was time from randomisation to treatment failure, defined as platelets <30x109/L and a clinical need for second line treatment (included refractory and relapsed ITP). Secondary outcomes included side effects, bleeding events, and patient reported outcomes (PROM) measured at baseline, 2, 4, 6 and 12 months, by validated questionnaires (SF36v2 (Your health & wellbeing): Quality of life (QoL), FACIT-Fatigue (v4): Fatigue, FACT-Th6 (v4): Bleeding and ICECAP-A v2: QoL) RESULTS Of the 120 ITP patients consented, recruited and randomised (52.4% male, mean age 54 years, range 17-87), mean baseline platelet count was 7 x109/L and mean follow up was for 18 months (maximum follow up 24 months, minimum follow up of 12 months). Patient demographics and baseline values are shown in table 1. Significantly fewer treatment failures occurred in patients randomised to MMF as shown in figure 1 (22% [n=13 of 59] vs 44% [n=27 of 61], aHR=0.41 [0.21, 0.80], p=0.0064, and when secondary ITP patients were excluded, aHR 0.37 [0.19, 0.71] p=0.0029). There were similar rates between the groups of significant adverse events, bleeding events, rescue treatments, hospital admissions and treatment side effects including infection (n=14 in each group), neutropenia (4 patients in corticosteroid group), and gastrointestinal side effects (table 2). However, some aspects of quality of life (QoL) were worse in those patients assigned to the MMF group including physical role, physical function and fatigue. CONCLUSIONS This is the first randomised trial using MMF to treat ITP, demonstrating good efficacy and tolerability, even with the inclusion of elderly patients (27.5% were >70 years, 15.8% >75 years). Therefore, MMF may be considered an effective, well tolerated first line treatment option, alongside a short course of steroids, for some patients with ITP, approximately halving the risk of refractory or relapsed ITP. At final follow up, 56% of patients treated with corticosteroid alone had not required 2nd line treatment, which is higher than previous reports. It is unclear why some aspects of QoL were worse in the MMF group. This is an important reminder that disease response and patient experience may not correlate and emphasises the importance of including PROM outcomes within trials. For ITP, to date, PROMs have only been systematically evaluated in the TPO-RA randomised controlled trials. The FLIGHT trial received ethical approval from NRES Committee South West and is registered, (EudraCT Number: 2017-001171-23. ClinicalTrials.gov number: NCT03156452). This abstract presents independent research funded by the National Institute for Health Research (NIHR) under its Research for Patient Benefit (RfPB) Programme (Grant Reference Number PB-PG-0815-20016). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Mycophenolate is unlicensed for ITP treatment

Predictors of short-term thrombocytopenia after transcatheter aortic valve implantation: a retrospective study at a single Japanese center

Objective Thrombocytopenia is common after transcatheter aortic valve implantation (TAVI) and is associated with mortality and major complications, although the underlying mechanisms are unclear. This retrospective single-center study aimed to identify factors associated with the decrease in platelet count (DPC) after TAVI in Japanese patients. Patients with severe aortic valve stenosis who underwent transfemoral TAVI between March 2014 and August 2019 were grouped according to DPC values of < 50% or ≥ 50% (DPC = 100% × [baseline platelet count–nadir platelet count]/[baseline platelet count]). Multivariable logistic regression analysis was performed to identify factors associated with a DPC of ≥ 50%. Results Among the 131 patients who underwent transfemoral TAVI, 74 patients (56%) had a DPC of ≥ 50%, and 57 patients (44%) had a DPC of < 50%. Significant risk factors for a DPC of ≥ 50% were older age, lower body mass index (BMI), and use of balloon-expandable valves (BEV). The multivariable analysis revealed that a DPC of ≥ 50% was independently predicted by low BMI (adjusted odds ratio: 0.884, 95% confidence interval: 0.785–0.997; P = 0.039) and BEV use (adjusted odds ratio: 3.014, 95% confidence interval: 1.003–9.056; P = 0.045). Platelet count monitoring after TAVI, especially when using BEV devices, is essential for Japanese patients with low BMI.

Predictors of Thrombocytopenia After Transcatheter Aortic Valve Implantation: A Retrospective Study at a Single Japanese Center

Objective: Thrombocytopenia is common after transcatheter aortic valve implantation (TAVI) and is associated with mortality and major complications, although the underlying mechanisms are unclear. This retrospective single-center study aimed to identify factors associated with the decrease in platelet count (DPC) after TAVI in Japanese patients. Patients with severe aortic valve stenosis who underwent transfemoral TAVI between March 2014 and August 2019 were grouped according to DPC values of <50% or ≥50% (DPC = 100%×[baseline platelet count–nadir platelet count]/[baseline platelet count]). Multivariable logistic regression analysis was performed to identify factors associated with a DPC of ≥50%.Results: Among the 131 patients who underwent transfemoral TAVI, 74 patients (56%) had a DPC of ≥50% and 57 patients (44%) had a DPC of <50%. Significant risk factors for a DPC of ≥50% were older age, lower body mass index (BMI), and use of balloon-expandable valves (BEV). The multivariable analysis revealed that a DPC of ≥50% was independently predicted by low BMI (adjusted odds ratio: 0.884, 95% confidence interval: 0.785–0.997; P=0.039) and BEV use (adjusted odds ratio: 3.014, 95% confidence interval: 1.003–9.056; P=0.045). Platelet count monitoring after TAVI, especially when using BEV devices, is essential for Japanese patients with low BMI.

Association of baseline platelet count with all-cause mortality after acute myocardial infarction

Background We sought to evaluate baseline platelet count as a prognostic indicator in patients with acute myocardial infarction (AMI). Methods Data of 13,085 patients with AMI were retrieved from a prospective nationwide AMI registry from November 2011 to December 2015. Using Cox hazards models, cumulative risks for adverse outcomes were compared among patients with baseline platelet count of less than 150 K/µL (lowest quartile), 150 to 249 K/µL, 250 to 349 K/µL (reference) and equal to or greater than 350 K/µL (higher quartile). The primary outcome of interest was all-cause mortality. Secondary outcomes included myocardial infarction, re-hospitalisation for heart failure, and stroke. Results During a median follow-up of 2.1 years, a steep U-shaped association was observed for the occurrence of all-cause mortality ( p for non-linearity <0.001). For stroke, a similar U-shaped curve was also seen ( p for non-linearity = 0.095). After multiple adjustments, the lowest and higher quartiles of baseline platelet count were positively associated with all-cause mortality (adjusted hazard ratio: 2.120; 95% confidence interval: 1.345–3.341; p = 0.001, and adjusted hazard ratio: 1.642; 95% confidence interval: 0.957–2.817; p = 0.072, respectively). Similar results were observed in sensitivity analyses even after excluding patients with age ≥75 years or patients with heart failure. Conclusions In patients with AMI, baseline platelet count demonstrated a U-shaped association with an increased risk of all-cause mortality at two years. If validated, these findings suggest that baseline platelet count could serve as a preferred prognostic marker in AMI due to its low cost and universal availability.