Decline In Platelet Count Research Articles

Platelet decline rate as the indication of using recombinant human thrombopoietin to prevent chemotherapy induced thrombocytopenia: A prospective, randomized, controlled study.

e24171 Background: Doxorubicin combined with ifosfamide is the common regimen for patients with sarcoma, which will induce severe thrombocytopenia. Sarcoma patients especially those with rapid platelet count decline after receiving this regimen could not avoid severe thrombocytopenia, even Recombinant Human Thrombopoietin(rhTPO) was used when the platelet count decreased to 75,000/μL according to current guidelines. The present study aimed to test the efficiency and safety of using rhTPO to prevent severe thrombocytopenia when rapid platelet count decline occurred. Methods: Our previous data showed those patients with rapid platelet count decline more than 40% within 3 days after administration of doxorubicin combined with ifosfamide were more likely to develop severe thrombocytopenia. In this prospective study, 53 patients with this characteristic were randomly assigned to prevention group (starting rhTPO immediately after enrollment) or treatment group (starting rhTPO when platelet count was less than 75,000/μL after chemotherapy). rhTPO was administrated with 300IU/kg·d until the platelet count increased to 100,000/μL or by 50,000/μL. Incidence and duration of grade 3 to 4 thrombocytopenia, proportion of platelet transfusion and adverse reactions were collected and analyzed. Results: The incidence of grade 3 to 4 thrombocytopenia in the prevention group and the treatment group was 63% and 81% respectively (p = 0.224), however the incidence of grade 4 thrombocytopenia in the former was significantly lower than that in the latter(22% versus 50% , p = 0.047).The duration of grade 3 to 4 thrombocytopenia in the prevention group had a declining trend compared with the treatment group( 2.6±2.8d versus 3.7±3.3d, p = 0.198). There was no difference in the proportion of platelet transfusion between the two groups. No rhTPO related toxicities of grade 3 to 4 were observed in both groups. Conclusions: For sarcoma patients treated with doxorubicin combined with ifosfamide, rapid platelet count decline more than 40% within 3 days after chemotherapy can be used as an indicator for the prophylactic administration of rhTPO, which can significantly reduce the probability of grade 4 thrombocytopenia without increasing toxicity. Clinical trial information: ChiCTR1900022667 .

Thrombocytopenia in Malaria in Children

Introduction:Malaria is a cause of high mortality and morbidity. In 2022 during August-September, there was a sudden increment in malaria cases among children in our hospital. We evaluated the role of platelet count to diagnose malarial infection in children. Methodology: This study included paediatric patients seen in August-September of 2022 in BCM Hospital, Khairabad, Sitapur for fever who had thrombocytopenia in their first complete blood count report. This research comprised 230 children with fever and thrombocytopenia. Results:It was found that a moderate to severe platelet count decline was 86.21 per cent sensitive and 56.14 per cent specific for malaria with high negative and positive predictive values. Conclusion: In conclusion, moderate to severe thrombocytopenia is a key indicator of malaria, hence all children with fever and thrombocytopenia should be tested for malaria. If moderate to severe thrombocytopenia is seen, further specialised tests such as repeated peripheral blood smears, ELISA for parasite-specific antigens, etc. should be done.

Alantolactone induces platelet apoptosis by activating the Akt pathway

Alantolactone (ALT), a sesquiterpene lactone compound isolated from Inula helenium L., has recently attracted much attention for its anti-tumor properties. ALT reportedly functions by regulating the Akt pathway, which has been shown to be involved in programmed platelet death (apoptosis) and platelet activation. However, the precise effect of ALT on platelets remains unclear. In this study, washed platelets were treated with ALT in vitro, and apoptotic events and platelet activation were detected. In vivo, platelet transfusion experiments were employed to detect the effect of ALT on platelet clearance. Platelet counts were examined after intravenous injection of ALT. We found that ALT treatment induced Akt activation and Akt-mediated apoptosis in platelets. ALT-activated Akt elicited platelet apoptosis by activating phosphodiesterase (PDE3A) and PDE3A-mediated protein kinase A (PKA) inhibition. Pharmacological inhibition of the PI3K/Akt/PDE3A signaling pathway or PKA activation was found to protect platelets from apoptosis induced by ALT. Moreover, ALT-induced apoptotic platelets were removed faster in vivo, and ALT injection resulted in the platelet count decline. Either PI3K/Akt/PDE3A inhibitors or a PKA activator could protect platelets from clearance, ultimately ameliorating the ALT-induced decline in platelet count in the animal model. These results reveal the effects of ALT on platelets and their related mechanisms, suggesting potential therapeutic targets for the prevention and alleviation of possible side effects resulting from ALT treatments.

Caplacizumab as rescue therapy in refractory TTP involving neurologic features

BackgroundThe role of caplacizumab in the routine treatment of immune thrombotic thrombocytopenic purpura (iTTP) remains to be established. Case summaryA 56-year-old woman was transferred to our center with iTTP and neurologic features. At the outside hospital, she was initially diagnosed and managed as Immune Thrombocytopenia (ITP). Upon transfer to our center, daily plasma exchange, steroids, and rituximab were initiated. After an initial improvement, refractoriness became evident with a decline in platelet count and continued neurologic abnormalities. Initiation of caplacizumab resulted in rapid hematologic and clinical responses. ConclusionCaplacizumab is a valuable treatment modality in iTTP, particularly in cases associated with refractoriness or neurologic features.

Severe thrombocytopenia in a patient with diffuse toxic goitre

Abstract Introduction Diffuse toxic goitre is an autoimmune disorder with a marked prevalence in women. Thrombocytopenia may coexist with diffuse toxic goitre. Nevertheless, the mechanisms of decline in platelet count alongside with autoimmune thyroid disease have not been extensively investigated. Clinical Case A case of diffuse toxic goitre is reported in a 55-year-old man who has been receiving continuous treatment with methimazole for 7 years. The physical examination revealed an asthenic man, with an enlarged thyroid gland, inactive bilateral orbitopathy and multiple ecchymosis, but no lymphadenopathy or hepatosplenomegaly. Laboratory analysis revealed suppressed thyroid stimulating hormone (TSH) 0.01 mlU/ml, normal free T4 level 21.60 pmol/l, increased free T3 6.99 pmol/l and thyroid stimulating immunoglobulin (TSI) level of 23.60 IU/L. Complete blood count revealed severely decreased platelets 3×10^9 / l, decreased hemoglobin 110.00 g/l and hematocrit 21.90%, normal leucocytes 9.58×10^9/l, low prothrombin Index 11% and International normalized ratio (INR) 7.00. Additional serological investigations excluded HIV infection and C viral hepatitis. The bone marrow aspiration disclosed a rich cellular and polymorph marrow, an increased number of megakaryocytes suggesting that the thrombocytopenia is due to platelet destruction. The patient has recovered from viral pneumonia caused by SARS-COV-2, 1 month prior to the medical consultation. He received platelet transfusion and was started on 1 mg/kg oral prednisolone followed by a gradual taper and improvement of platelet count. Thrombocytopenia observed in diffuse toxic goitre may be mediated by both metabolic and immunological phenomena. In our case, the following causes may be considered: (1) an overlapping autoimmune process; (2) methimazole creating destructive antibodies; (3) COVID-19 disease. An autoimmune process is capable of triggering both conditions by activation of the reticuloendothelial system by thyroid hormones along with a cross-reaction between thyroid antibodies and platelet epitopes. Methimazole generates a drug-dependent immune response against platelets, involving platelet endothelial cell adhesion molecules and thus provoking thrombocytopenia. SARS-CoV-2 can induce thrombocytopenia by increasing the number of autoantibodies and immune complexes that destroy platelets. Lung damage by decreasing pulmonary capillary bed and platelet aggregation in the lungs indirectly leads to a reduced number of circulatory platelets. Conclusion Severe thrombocytopenia was detected in a patient with Grave's disease, in whom the number of platelets was 50 times below the lower limit of the reference range. Coexistence of thrombocytopenia may be explained by (1) an overlapping autoimmune process; (2) the effect of methimazole; (3) its occurrence or aggravation secondary to COVID-19.

Predialysis trajectories of estimated GFR and concurrent trends of Chronic Kidney Disease-relevant biomarkers.

The glomerular filtration rate (GFR) decline varies in patients with advanced chronic kidney disease (CKD), and the concurrent changes in CKD-related biomarkers are unclear. This study aimed to examine the changes in CKD-related biomarkers along with the kidney function decline in various GFR trajectory groups. This study was a longitudinal cohort study originated from the pre-end-stage renal disease (pre-ESRD) care program in a single tertiary center between 2006 and 2019. We adopted a group-based trajectory model to categorize CKD patients into three trajectories according to estimated glomerular filtration rate (eGFR) changes. A repeated-measures linear mixed model was used to estimate the concurrent biomarker trends in a 2-year period before dialysis and to examine the differences among trajectory groups. A total of 15 biomarkers were analyzed, including urine protein, serum uric acid, albumin, lipid, electrolytes, and hematologic markers. Using longitudinal data from 2 years before dialysis initiation, 1758 CKD patients were included. We identified three distinct eGFR trajectories: persistently low eGFR levels, progressive loss of eGFR, and accelerated loss of eGFR. Eight of the 15 biomarkers showed distinct patterns among the trajectory groups. Compared with the group with persistently low eGFR values, the other two groups were associated with a more rapid increase in the blood urea nitrogen (BUN) level and urine protein-creatinine ratio (UPCR), especially in the year before dialysis initiation, and a more rapid decline in hemoglobin and platelet counts. A rapid eGFR decline was associated with lower levels of albumin and potassium, and higher levels of mean corpuscular hemoglobin concentration (MCHC) and white blood cell (WBC). The albumin level in the group with an accelerated loss of eGFR was below the normal range. Using longitudinal data, we delineated the changes in CKD biomarkers with disease progression. The results provide information to clinicians and clues to elucidate the mechanism of CKD progression.

Renal Klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl‐xL ubiquitination and degradation

BackgroundThrombosis and hemorrhage as two opposite pathologies are prevalent within the chronic kidney disease (CKD) population. Platelet homeostasis, which positions centrally in their pathogenesis, varies among the CKD population, while the underlying mechanism is poorly understood. ObjectiveTo investigate the change character and mechanism of platelet homeostasis in CKD and its association with renal Klotho deficiency. MethodsThe change character of platelet homeostasis and its association with renal Klotho deficiency were determined based on a cohort study as well as CKD mice and Klotho‐deficient mice with CKD. The effects on thrombopoiesis and platelet lifespan were examined by flow cytometry and platelet transfer. The underlying mechanism was explored by proteomics, flow cytometry, western blot, and immunoprecipitation. ResultsWe show that platelet count declines both in patient and mouse models with advanced CKD (Adv‐CKD) and is positively associated with circulating Klotho levels. Mechanistically, we identify that ubiquitin ligase UBE2O governs Bcl‐xL ubiquitination and degradation in platelets, whereas Adv‐CKD–induced oxidative stress in platelets stimulates p38MAPK to promote Bcl‐xL phosphorylation, which facilitates UBE2O binding to Bcl‐xL and subsequent Bcl‐xL degradation. Consequently, platelet lifespan is shortened in Adv‐CKD, culminating in platelet count decline. However, kidney‐secreted soluble Klotho protein restricts oxidative stress in platelets, thereby preserving Bcl‐xL expression and platelet lifespan. ConclusionsOur findings uncover the mechanism of platelet count decline in Adv‐CKD and identify renal Klotho as a long‐range regulator of platelet lifespan, which not only provide a molecular mechanism underlying CKD‐associated thrombocytopenia and hemorrhage but also offer a promising therapy choice.

Sars-Cov-2 Vaccination in Pre-Existing and De Novo ITP: A Single Center Experience with Long-Term Follow-up

Introduction: SARS-CoV-2 vaccines can induce de novo immune thrombocytopenia (ITP) and worsen pre-existing ITP. Almost all cases of vaccine-induced or -exacerbated ITP respond to ITP therapies. We investigated longer-term outcomes of patients with ITP de novo or relapsed post-SARS-CoV-2 vaccination requiring treatment. We included outcomes following SARS-CoV-2 booster vaccines and considered that some post-vaccination relapses may NOT be related to vaccination. Methods: This is a single-center retrospective study of patients ≥18 years old with pre-existing ITP or de novo ITP following SARS-CoV-2 vaccination seen at The Center for Blood Disorders at New York-Presbyterian/Weill Cornell Medicine from January 2021 to May 2022. We included consecutive ITP patients with at least one platelet count following initial SARS-CoV-2 vaccinations or boosters. The study was approved by the NYP-WCM Institutional Review Board. An "ITP exacerbation” was defined as: a) ≥50% decline in platelet count from pre-vaccination baseline; b) >20% decline from pre-vaccination baseline to a platelet nadir <30x109/L; and/or c) receiving rescue therapy for ITP. Results: Among 95 patients with pre-existing ITP, sixteen (17%) experienced at least one ITP exacerbation after one (or several) SARS-CoV-2 vaccinations. Ten of 84 (12%) had an ITP exacerbation after dose#1. Among these, 7 experienced another exacerbation: 6 after dose#2 (with 3 receiving boosters, all without exacerbation) and 1 only after a booster. Of the remaining 3 who had had an ITP exacerbation after dose#1, 2 tolerated dose#2, and 1 was not re-challenged. Seventy-four received dose#2 of a SARS-CoV-2 vaccine. Nine (12%) experienced ITP exacerbations, including 6 who also had exacerbations following dose#1. Three tolerated dose#1 and an ITP exacerbation following dose#2. Two of these patients received booster vaccines, with 1 experiencing another ITP exacerbation. Of 24 patients who received at least one booster, 5 (21%) had ITP exacerbations after their boosters. While 3 of the 5 patients had tolerated previous vaccinations well, 1 had had an exacerbation following dose#1 and 1 following dose#2. Eleven of 16 patients experiencing ITP exacerbation(s) following SARS-CoV-2 vaccine(s) received rescue treatment, of whom seven (64%) had difficult-to-control ITP on chronic treatment, including intravenous immune globulin (IVIG) every 2 to 8 weeks. All responded to rescue treatment; the frequency of intermittent IVIG infusions did not increase following SARS-CoV-2 vaccination. Excluding these 7 whose ITP exacerbations were possibly not related to vaccination, 5/77 (6.5%) patients had exacerbations after dose #1, 4/68 (5.9%) after dose #2, and 4/20 (20%) after a booster. Four patients had exacerbations after more than 1 vaccination. Six patients had presumed de novo ITP post-SARS-CoV-2 vaccine: 2 females, 4 males, median age 35 years (range 30-72), and median follow-up 11 months (range 3-15) post ITP diagnosis. All presented with mucocutaneous bleeding and a median platelet count of 4 x109/L (1-29x109/L) at a median of 12 days post-vaccination (range 1-21). De novo ITP developed following dose#1 in 4 patients (mRNA-1273 = 2, BNT162b2 mRNA COVID-19 = 1, Ad26COV2 =1) and a first booster vaccine in 2 (BNT162b2 mRNA COVID-19). All 6 responded to IVIG and corticosteroids; 3 did not require further treatment remaining in complete response (CR) at 7-15 months post-vaccination. One completed a steroid taper and remains in CR 1 month off steroids; the other 2 patients remain on TPO-RA in on-treatment CR - at 3 and 12 months, 1 being tapered. Two received additional doses of the same vaccine and did well, both in CR off treatment up to 15 months since the initial diagnosis of ITP. Conclusions: ITP exacerbations and de novo ITP can occur with subsequent vaccination doses (including boosters) of the SARS-CoV-2 vaccine despite tolerance to previous doses. Conversely, many tolerate subsequent doses well, implying that the mechanism is unlikely to involve the generation of anti-platelet antibodies. Furthermore, in certain patients, ITP "exacerbations” may not be due to the vaccination but part of the course of their ITP. ITP exacerbation post-SARS-CoV-2 vaccination does not seem to cause lasting change in the state of the ITP on follow-up. Cases of de novo ITP generally responded well to standard treatments for ITP and, in our small cohort, had favorable longer-term outcomes.

Causes of platelet loss during extracorporeal life support.

Most pediatric patients show a decline in platelet counts while on extracorporeal life support (ECLS) and require multiple platelet transfusions. To better understand platelet loss during ECLS, this study estimated platelet loss rates due to diagnostic phlebotomy, platelet activation, bleeding and other causes. We collected data on 91 patients (1d-20y, 50 M, 41F). Platelet losses were estimated based on changes in platelet count, patient+circuit blood volume, and transfused platelet volumes. Platelet extracellular vesicles were measured by flow cytometry. Median platelet loss was 2.8 × 109 /L/hr, more than twice the normal rate of platelet removal and equivalent to a 67 000/μl decrease in platelet count per day. While platelet loss was correlated with platelet transfusion (r2 =0.51), transfusion underestimated platelet loss in patients with large decreases in platelet count and over-estimated platelet loss in neonates where the circuit volume > patient blood volume. Patients with disseminated intravascular coagulation before or significant bleeding during ECLS have double the rate of platelet loss. Platelet activation accounted for ~32% of total platelet loss, bleeding ~36% and phlebotomy 4%, with the remaining one-third due to other causes. Annexin-negative platelet extracellular vesicle release, a measure of platelet damage, was increased 9-fold during ECLS. Our study is the first to quantitate total, phlebotomy and activation related platelet loss during ECLS. Platelet activation accounts for ~32% of total platelet loss, while bleeding doubles the platelet loss rate. The etiology of the remaining platelet loss is unknown.

Effect of Jungga Orange Peel Essential Oil (Citrus Jambhiri) on Platelet Function in Male Rats Given High Intensity Physical Activity

Physical activity is one of the stress factors that can provide physiological changes to the function of the hematological system such as changes in platelet count. Physical activity can produce free radicals that can result in cell damage including platelets. Platelets play a role in the hemostasis process, If the platelet count is too low, it can cause excessive bleeding. However, if there is an increase in platelet count too high, it can cause thrombosis that can inhibit blood vessels. Antioxidants have a protective effect on cells and eliminate free radicals. The objective of this research was to ascertain the reaction of platelets to the injection of jungga orange peel essential oil (citrus jambhiri) in male rats that were subjected to strenuous exercise. Twenty male rats (3-4 months old, 180-200 grams) of the Wistar strain of the white rat (Rattus norvegicus) were used in the experiment. Using a random number generator, 20 white rats were split into two groups. In group P1, the rats swam for 50 minutes, three times a week, for four weeks. In group P2, the rats swam for 50 minutes, three times a week, for four weeks, and were also given 0.05 milliliters of jungga orange peel essential oil every hour prior to swimming. Based on these findings, it appears that there is a statistically significant difference between the P1 and P2 groups in terms of the average platelet count, with the P2 group exhibiting a decline in platelet count. Antioxidant substances contained in the essential oil of jungga orang have the ability to inhibit the decline in platelet function after high-intensity physical activity.

HMGB1-activatied NLRP3 inflammasome induces thrombocytopenia in heatstroke rat.

BackgroundThrombocytopenia, an early common complication in heatstroke (HS), has been widely considered as a mortality predictor of HS. The mechanism underlying thrombocytopenia in HS remains unknown. It is not known whether NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is activated in HS platelet, which, in turn, induces platelet activation and thrombocytopenia. This study tried to clarify the activation of the NOD-like receptor signaling pathway under HS conditions and investigate its roles in mediating HS-induced thrombocytopenia.MethodsRat HS models were established in a certain ambient temperature and humidity. Platelets, isolated from blood, were counted and CD62P, an index of platelet activation, was measured by flow cytometry in all rats. The colocalization of NLRP3 inflammasome in platelet was detected by confocal fluorescence microscopy. Mitochondrial-derived reactive oxygen species (ROS) was detected using the molecular probes. Plasma HMGB1 and IL-1β levels were measured by ELISA.ResultsPlatelet activation, showed by upregulated CD62P, and thrombocytopenia were observed in HS rats. HS activated the NLRP3 inflammasome, which was induced by elevated levels of ROS, while the upregulated CD62P and thrombocytopenia triggered by NLRP3 inflammasome were attributed to the high mobility group box protein 1 (HMGB1) inplasma. Moreover, inhibition of the NOD-like receptor signaling pathway in rats with HS suppressed platelet activation and the decline of platelet count. Similar results were obtained when the receptor toll-like receptor 4 (TLR4)/advanced glycation end product (RAGE) was blocked.ConclusionsThe NOD-like receptor signaling pathway induces platelet activation and thrombocytopenia in HS rats. These findings suggested that the NLRP3 inflammasome might be the potential target for HS treatment.

Early recognition and treatment of pre-VITT syndrome after adenoviral vector-based SARS-CoV-2 vaccination may prevent from thrombotic complications: review of published cases and clinical pathway.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare but highly morbid complication after adenoviral vector-based SARS-CoV-2 vaccination. The pre-VITT syndrome is defined as vaccine-induced immune thrombocytopenia without thrombosis typically presenting with new-onset headache. This review aims to identify at-risk patients before complications such as cerebral venous sinus thrombosis occur. We review previously published reports of 19 patients (median age 35 years, range 23–74; 16 females) who met the diagnostic criteria for a pre-VITT syndrome. Seven patients progressed to VITT, 12 patients did not. Patients who experienced VITT received delayed treatment. The median interval between the onset of headache and VITT-treatment (i.e. anticoagulation, immune globulins, or corticosteroids) was 5 days (range 1–8 days) compared with 2 days (0–5 days) in those without subsequent VITT (P = 0.033). The interval from onset of headache to anticoagulation was longer in patients with VITT (median 7 vs. 2 days; range 3–9 vs. 0–7 days; P = 0.01). Anticoagulation was safe in all patients with a pre-VITT syndrome as no haemorrhagic complications occurred after anticoagulation was started despite low platelets. The transient decline of platelet count after admission was significantly more pronounced in patients who progressed to VITT (median 67 vs. 0 × 103/µL; range 0–77 × 103/µL vs. 0–10 × 103/µL; P = 0.005). d-dimers did not differ between groups. Pre-VITT syndrome is a ‘red flag’ and allows to identify and preemptively treat patients at-risk of further progression to VITT. However, it must be distinguished from post-vaccination immune thrombocytopenia.

Characterization of coagulopathy and outcomes in cancer patients with severe COVID ‐19 illness: Longitudinal changes in hospitalized cancer patients

There is a lack of data focused on the specific coagulopathic derangements in COVID‐19 versus non‐COVID‐19 acutely ill cancer patients. Our objective was to characterize features of coagulopathy in cancer patients with active COVID‐19 illness who required hospitalization at MD Anderson in the Texas Medical Center and to correlate those features with thrombotic complications, critical illness, and mortality within the first 30 days after hospital admission for COVID‐19 illness. COVID‐19 and non‐COVID‐19 hospitalized cancer patients, with at least five consecutive measures of PT, PTT, d‐dimer, and CBC during the same period, were matched 1:1 to perform a retrospective analysis. We reviewed complete blood cell counts with differential, PT, PTT, fibrinogen, D‐Dimer, serum ferritin, IL‐6, CRP, and peripheral blood smears. Clinical outcomes were thrombosis, mechanical ventilation, critical illness, and death. Compared with matched hospitalized cancer patients without COVID‐19, we found elevated neutrophil and lower lymphocyte counts in those with critical illness ( p = 0.00) or death ( p = 0.00); only neutrophils correlated with thrombosis. COVID‐19 cancer patients with a platelet count decline during the hospital stay had more frequent critical illness ( p = 0.00) and fatal outcomes ( p = 0.00). Of the inflammatory markers, interleukin‐6 showed consistently higher levels in the COVID‐19 patients with poor outcomes. The findings of unique platelet changes and coagulopathy during severe COVID‐19 illness in the cancer population are of interest to explore disease mechanisms and future risk stratification strategies to help with the management of cancer patients with COVID‐19.

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Background:Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.Methods:Adults with non–high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non–HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.Results:Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58–69) years, 44% were female, the median non–HDL-C was 132.4 (interquartile range, 118.0–154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4–270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non–HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%–16.0% and 6.0%–15.1%, respectively) and without a clear dose-response relationship‚ and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).Conclusions:Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non–HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction.Registration:URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

COVID-19 vaccination in patients with immune thrombocytopenia

AbstractImmune thrombocytopenia (ITP) is an acquired autoimmune disorder that is characterized by low platelet count and increased bleeding risk. COVID-19 vaccination has been described as a risk factor for de novo ITP, but the effects of COVID-19 vaccination in patients with ITP are unknown. We aimed to investigate the effects of COVID-19 vaccination in patients with ITP on platelet count, bleeding complications, and ITP exacerbation (≥50% decline in platelet count, or nadir platelet count < 30 × 109/L with a >20% decrease from baseline, or use of rescue therapy). Platelet counts in patients with ITP and healthy controls were collected immediately before and 1 and 4 weeks after the first and second vaccinations. Linear mixed-effects modeling was applied to analyze platelet counts over time. We included 218 patients with ITP (50.9% female; mean age, 55 years; and median platelet count, 106 × 109/L) and 200 healthy controls (60.0% female; mean age, 58 years; median platelet count, 256 × 109/L). Platelet counts decreased by 6.3% after vaccination. We did not observe any difference in decrease between the groups. Thirty patients with ITP (13.8%; 95% confidence interval [CI], 9.5-19.1) had an exacerbation and 5 (2.2%; 95% CI, 0.7-5.3) suffered from a bleeding event. Risk factors for ITP exacerbation were platelet count < 50 × 109/L (odds ratio [OR], 5.3; 95% CI, 2.1-13.7), ITP treatment at time of vaccination (OR, 3.4; 95% CI, 1.5-8.0), and age (OR, 0.96 per year; 95% CI, 0.94-0.99). Our study highlights the safety of COVID-19 vaccination in patients with ITP and the importance of the close monitoring of platelet counts in a subgroup of patients with ITP. Patients with ITP with exacerbation responded well on therapy.

Changes in Platelet Counts and Thrombocytopenia Risk in Patients with Chronic Liver Disease with Different Etiologies Using Real-World Japanese Data.

IntroductionThrombocytopenia, a common complication of chronic liver disease (CLD), adversely affects the treatment in patients requiring invasive procedures. Multiple pathophysiological mechanisms contribute to the development of thrombocytopenia; thus, its incidence could differ among CLD etiologies. We investigated the risk of decline in platelet counts and developing thrombocytopenia across different CLDs in a real-world Japanese setting.MethodsA Japanese claims database including 25 million patients (April 2008–August 2018) was used. Patients with at least one CLD diagnosis were classified into nine mutually exclusive categories: hepatitis B, hepatitis C, hepatitis B and C, unspecified viral hepatitis, autoimmune hepatitis, toxin/drug-induced hepatitis, alcoholic hepatitis, nonalcoholic steatohepatitis, and others. A random effects model was used to estimate the changes in platelet counts; proportional hazard analyses were used to examine factors associated with the incidence of thrombocytopenia based on the diagnosis. Patients with laboratory test data as variables were included in each analysis.ResultsThe simulation included 68,536 patients. The mean values representing changes in the platelet count were significantly negative in the hepatitis C patients and negative, though non-significant, in the hepatitis B, toxin/drug-induced hepatitis, alcoholic hepatitis, and nonalcoholic steatohepatitis patients. In the proportional hazard analysis, 708 of 22,728 patients had thrombocytopenia. The hazard ratio (HR) was significantly high for patients with hepatitis B (HR, 2.879; p < 0.001), hepatitis C (HR, 1.876; p < 0.001), and hepatitis B and C (HR, 2.992; p < 0.001).ConclusionA decreasing tendency in platelet counts was observed in most CLD etiologies, with hepatitis C showing a significant decrease. The incidence of thrombocytopenia was mostly associated with hepatitis B and/or C. Further research is warranted to elucidate the discrepancy between the decline in platelet counts and thrombocytopenia diagnosis, considering the factors relevant to the diagnosis, such as the frequency of outpatient visits and CLD treatment.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12325-021-02008-x.

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.&#x0D; Study Design: Descriptive study&#x0D; Place and duration: This study was conducted at Paediatric department (neonatal ward), Liaquat University Hospital, Hyderabad, from 1st August 2020 till 31st Jan 2021&#x0D; 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.&#x0D; Results: Out of 231 neonates 70 (30.3%) developed thrombocytopenia after phototherapy. In our study 117 neonates (50.6%) were males &amp; 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 &amp; severe in 52(22.5%), 13(5.6%) &amp; 5(2.2%) respectively.&#x0D; 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.

Study of Platelet Count as a Prognostic Factor in Burns Patients

Aim: To study the platelet count as a prognostic indicator in burns patients&#x0D; Objective: To evaluate the platelet count in patients with burns and its significance in early detection of post burn septicemia.&#x0D; Methodology: A study was carried out in the department of surgery in Saveetha medical college from January to June 2021.&#x0D; 50 burns patients were included in the study and their platelet count was monitored on day 1 and assessed on day 7, 14 and 21 using standard methods. Based on the outcome the patients were grouped as survivors and non survivors.&#x0D; Results: Out of the 50 patients 32 patients survived, 18 patients died. In both the groups the platelet count decreased initially. In the survivors group the platelet count increased gradually whereas in the non-survivors it was found to be decrease and continued till death.&#x0D; Conclusion: A decline in platelet count is a poor prognostic factor. The outcome of burns patients can be improved by giving appropriate and timely treatment.

A Road Paved with Good Intentions: A Platelet Count-Based Alert to Facilitate Diagnosis of Heparin-Induced Thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) is a rare disorder with potential to cause significant morbidity and mortality. Early identification and initiation of non-heparin anticoagulation can prevent devastating thrombotic events. However, over-testing is common and can lead to result misinterpretation, unnecessary heparin avoidance, and increased cost. When there is concern for HIT, guidelines from the American Society of Hematology recommend calculation of the 4Ts score to determine the need for laboratory testing. The Choosing Wisely® initiative recommends against laboratory testing in patients with a low probability score of ≤3. In patients with an intermediate or high probability score (≥4), screening with enzyme-linked immunosorbent assay (ELISA) is performed first. If positive, the diagnosis of HIT is confirmed with a functional assay, commonly the serotonin release assay (SRA).Methods: In an effort to increase recognition of HIT, providers at a large academic medical center received a non-interruptive alert in the electronic medical record (EMR) on all patients in whom the platelet count declined by ≥50% starting in Aug 2017. We performed a retrospective evaluation of 1) the number of alerts and 2) all ELISA results obtained with or without an alert, over a 90-day period (Dec 2019 to March 2020). A 4Ts score was calculated by chart review by the first author in real-time as the alert was sent (blinded to ELISA and SRA results). Among those patients with multiple alerts or test orders, the first instance was used for analysis. Demographic and clinical characteristics were reported using frequencies and percentages, means (standard deviation, SD), and medians (interquartile range, IQR). Patients with alerts and ELISA testing ordered were compared with 2 groups: 1) patients with alerts but no ELISA ordered; 2) patients with no alerts but ELISA ordered. Comparisons were performed using chi squared tests, Fisher's exact tests, t-tests and Wilcoxon rank-sum tests as appropriate.Results: In the 90-day observation period, 302 alerts were fired in 270 patients (Figure 1). Thirty alerts (28 patients, 10%) were generated for patients admitted for organ donation or post-stem cell transplantation, for whom platelet count decline was expected. Excluding these patients, there were 272 alerts in 242 patients (approximately 3 alerts per day in a 1,157-bed hospital). Of patients with alerts, 22 (8%) had a platelet count inaccuracy (i.e. platelets clump or another reason) and 18 (7%) did not receive heparin prior to platelet decline, for a cumulative total of 40 (15%) inappropriate alerts.In patients with an alert, the ELISA was ordered more frequently for those with a lower platelet nadir (77x10 9/L vs. 115x10 9/L, p<0.0001) or in those with a thrombotic event (11 patients (17%) vs. 6 patients (4%), p=0.0021) (Table 1). Those without an ELISA ordered were more likely to have a low 4Ts score (23 patients (36%) vs. 81 patients (58%), p<0.0001).In addition to 71 patients with an alert, an ELISA was also ordered for 67 patients without an alert (n=138) (Figure 1). Close to half of ELISA-tested patients had a low 4Ts score (n=51, 46%) (Figure 2). In patients with an alert and ELISA not ordered, 18 (27%) had an intermediate or high 4Ts score.Seven patients were diagnosed with HIT based on a positive SRA, 6 with an alert and 1 without. The alert demonstrated a sensitivity of 86% (95% CI, 59.8-100%) and specificity of 50% (95% CI, 41.8-58.9%) with a positive predictive value of 0.0845 (95% CI, 0.0198-0.1492) and negative predictive value of 0.9851 (95% CI, 0.9560-1.0000).Conclusion: An EMR alert based on platelet count decline had multiple shortcomings including frequent inappropriate firings and a lack of guidance on appropriate indications for testing. This evaluation of institutional testing practices indicates frequent use and misinterpretation of ELISA discordant with evidence-based guidelines. Although prompt diagnosis of HIT is important, alternative strategies for identification of at-risk patients and communication of recommended actions to providers should be considered. Because the 4Ts score includes variables difficult to automate in the EMR, our institution is exploring electronic consultation and real-time expert provider access to overcome these limitations. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Longitudinal Evaluation of Cytopenia Severity in Patients with Clonal Cytopenia of Undetermined Significance (CCUS) and Correlation with the Presence of Sub-Clinical Dysplasia

IntroductionClonal cytopenia of undetermined significance (CCUS) represents a clonal group of cells with the presence of a hematologic malignancy-associated somatic mutation without meeting the morphologic criteria for MDS. CCUS patients have a variable risk of progression to MDS. The WHO requires at least 10% of a cell lineage have dysplastic morphology for the diagnosis of MDS, but CCUS patients have been described with no evidence of dysplasia (CCUS-ND) or with low level dysplasia (CCUS-D). We previously identified CCUS-D as biologically distinct with higher risk MDS mutations. We hypothesized that CCUS-D would be independently associated with the risk of progressive cytopenia over time and thus may have clinical relevance in the setting of CCUS.MethodsCases of CCUS were identified on review of bone marrow biopsies completed for the diagnosis of cytopenia from 8/2016 to 9/2018 with results of a custom 31-gene NGS hotspot panel to detect mutations in the following genes: ASXL1, BRAF, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MPL, MYD88, NPM1, NRAS, PHF6, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, and ZRSR2. The classification of CCUS-D or CCUS-ND required two or more board-certified hematopathologists to score the degree of morphologic dysplasia on bone marrow aspirates with at least one of the following morphologic criteria: >2%-<10% erythroid precursors with nuclear irregularities, >50% erythroid cells with megaloblastoid changes and/or basophilic stippling, >5%-<10% hypogranular and/or hypolobated granulocytes, or ≥10% megakaryocytes that were small and hypolobated or showed other nuclear abnormalities such as grape-like nuclei. We recorded baseline characteristics including cytogenetics, results of next-generation sequencing, and lab findings and then followed patients with annual blood counts.Statistical differences of baseline characteristics were evaluated by T-test for continuous variables, and Chi-square / Fisher's exact test were used for association between categorical variables. The repeated measures over time for various outcomes (WBC, ANC, hemoglobin, platelet) were visualized using scatter plot supervised with lowess smoother. The effects of dysplasia on various longitudinal outcomes were estimated using linear mixed-effect models.ResultsWe identified 54 CCUS patients on review of 200 marrows completed for undiagnosed cytopenia. Twenty-six patients were identified with CCUS-D, and 28 patients with CCUS-ND. Baseline clinical characteristics including age, gender, race, smoking status, or presence of infection at time of initial diagnosis were similar. Hematology laboratory parameters including White Blood Cell Count (WBC), Absolute Neutrophil Count (ANC), Hemoglobin (Hgb), and Platelet Count (Plts) did not differ. (Table 1). Patients with CCUS-D had an average of 1.62 mutated genes detected per patient with the most common being TET2 (26.19%), SRSF2 (14.29%), and DNMT3A (14.29%). Patients with CCUS-ND had an average of 1.41 mutations per patient with the most common being TET2 (31.57%) and DNMT3A (31.57%).Patients were followed for a median of 32.2 months and a range from 1.0 to 48.8 months. On long term follow up, WBC, ANC, Hgb and plts trended lower in patients with CCUS-D compared to CCUS-ND, but the difference was marginally statistically significant (p = 0.09, 0.16, 0.13, 0.64 respectively). We also evaluated the rate of change in hematology parameters and found no significant difference in change rate of WBC, ANC, and hgb (p = 0.25, 0.13, and 0.28, respectively). There was a significant difference in the change rate of platelet counts between the two groups (p = 0.026). In particular, patients with CCUS-D had decreasing platelet counts at a rate of -0.04119 10E9/L/day and patients with CCUS-ND had increasing platelet counts at a rate of 0.01075 10E9/L/day.Two patients in the CCUS-D cohort progressed to MDS at an average of 938.5 days. One patient with CCUS-ND progressed to Large Granular Lymphocytic Leukemia at 805 days.ConclusionsLow level (< 10%) dysplasia in cell lineages in CCUS is associated with a higher rate of decline in platelet counts but was not independently associated with increased risk of progressive neutropenia, leukopenia, or anemia. Longer follow up may be required to further understand the clinical significance of low level dysplasia in CCUS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.