Analysis of Platelet Count and New Cancer Diagnosis Over a 10-Year Period.

Importance: Individuals with cancer often have an elevated platelet count at the time of diagnosis. The extent to which an elevated platelet count is an indicator of cancer is unclear. Objective: To evaluate the association of an elevated platelet count with a cancer diagnosis. Design, Setting, and Participants: This nested case-control study included Ontario residents enrolled in the provincial health insurance plan who had 1 or more routine complete blood count (CBC) tests performed between January 1, 2007, and December 31, 2017, with follow-up through December 31, 2018. Case patients were individuals with a new cancer diagnosis during the observation period. Eligible control individuals were cancer free before the date of diagnosis for a case patient to whom they were matched. One case patient was matched to 3 controls based on sex, age, and health care use patterns. Data were analyzed from September 24, 2020, to July 13, 2021. Exposures: Case patients and controls were assigned to 1 of 5 exposure groups based on age- and sex-specific platelet count distributions in the control population: very low (≤10th percentile), low (>10th to 25th percentile), medium (>25th to <75th percentile), high (75th to <90th percentile), and very high (≥90th percentile). Main Outcomes and Measures: Odds ratios (ORs) were estimated for specific cancer sites for each category of platelet count at intervals up to 10 years after a blood test. Results: Of the 8 917 187 eligible Ontario residents with a routine CBC record available, 4 971 578 (55.8%) were women; the median age at the first CBC was 46.4 years (IQR, 32.5-59.5 years). Among individuals with a routine CBC record available, 495 341 (5.6%) received a diagnosis of first primary cancer during the 10-year observation period. The OR for a solid tumor diagnosis associated with a very high platelet count vs a medium platelet count in the 6-month period before the diagnosis was 2.32 (95% CI, 2.28-2.35). A very high platelet count was associated with colon (OR, 4.38; 95% CI, 4.22-4.54), lung (OR, 4.37; 95% CI, 4.22-4.53), ovarian (OR, 4.62; 95% CI, 4.19-5.09), and stomach (OR, 4.27; 95% CI, 3.91-4.66) cancers. Odds ratios attenuated with increasing time from CBC test to cancer diagnosis. Conclusions and Relevance: In this nested case-control study, an elevated platelet count was associated with increased risk of cancer at several sites. Our findings suggest that an elevated platelet count could potentially serve as a marker for the presence of some cancer types.

Combined immune score predicts the prognosis of newly diagnosed multiple myeloma patients in the bortezomib-based therapy era.

ABSTRACT: To investigate the effect of a combined immune score including the lymphocyte-to-monocyte ratio (LMR) and uninvolved immunoglobulin (u-Ig) levels on the prognosis of newly diagnosed multiple myeloma (NDMM) patients treated with bortezomib.Clinical data of 201 NDMM patients were retrospectively analyzed. Patients with LMR ≥ 3.6 and LMR < 3.6 were scored 0 and 1, respectively. Patients with preserved u-Ig levels, suppression of 1 u-Ig, and suppression of at least 2 u-Igs were scored 0, 1, and 2, respectively. The immune score, established from these individual scores, was used to separate patients into good (0-1 points), intermediate (2 points), and poor (3 points) risk groups. The baseline data, objective remission rate (ORR), whether receive maintenance treatment regularly and overall survival of patients before treatment were analyzed.The ORR of the good-risk group was significantly higher than that of the intermediate-risk group (75.6% vs 57.7%, P = .044) and the poor-risk group (75.6% vs 48.2%, P = .007). The multivariate analysis results showed that age ≥ 65 years, International Staging System stage III, platelet count ≤ 100 × 109/L, lactate dehydrogenase (LDH) > 250 U/L, serum calcium > 2.75 mmol/L, no receipt of regular maintenance treatment, LMR < 3.6, suppressed u-Igs = 1, suppressed u-Igs ≥ 2, intermediate-risk group and poor-risk group were independent predictors of poor overall survival.In the bortezomib era, the LMR, u-Ig levels, and the immune score play an important role in the prognosis of NDMM patients. Among them, the immune score showed the strongest prognostic value, and it could be a beneficial supplement for the early identification of high-risk patients.

Platelet-Derived PCSK9 Is Associated with LDL Metabolism and Modulates Atherothrombotic Mechanisms in Coronary Artery Disease.

Platelets play a significant role in atherothrombosis. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of LDL metabolism and interacts with platelet function. The effect of PCSK9 in platelet function is poorly understood. The authors of this article sought to characterize platelets as a major source of PCSK9 and PCSK9's role in atherothrombosis. In a large cohort of patients with coronary artery disease (CAD), platelet count, platelet reactivity, and platelet-derived PCSK9 release were analyzed. The role of platelet PCSK9 on platelet and monocyte function was investigated in vitro. Platelet count and hyper-reactivity correlated with plasma LDL in CAD. The circulating platelets express on their surface and release substantial amounts of PCSK9. Release of PCSK9 augmented platelet-dependent thrombosis, monocyte migration, and differentiation into macrophages/foam cells. Platelets and PCSK9 accumulated in tissue derived from atherosclerotic carotid arteries in areas of macrophages. PCSK9 inhibition reduced platelet activation and platelet-dependent thrombo-inflammation. The authors identified platelets as a source of PCSK9 in CAD, which may have an impact on LDL metabolism. Furthermore, platelet-derived PCSK9 contributes to atherothrombosis, and inhibition of PCSK9 attenuates thrombo-inflammation, which may contribute to the reported beneficial clinical effects.

Distribution and reference interval establishment of neutral-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) in Chinese healthy adults.

BACKGROUND: Neutral-to-lymphocyte ratio (NLR), lymphocyte-to-monocyte ratio (LMR), and platelet-to-lymphocyte ratio (PLR) are associated with coronavirus disease 2019 (COVID-19) and many diseases, but there are few data about the reference interval (RI) of NLR, LMR, and PLR. METHODS: The neutrophil count, lymphocyte count, monocyte count, and platelet count of 404,272 Chinese healthy adults (>18 years old) were measured by Sysmex XE-2100 automatic hematology analyzer, and NLR, LMR, and PLR were calculated. According to CLSI C28-A3, the nonparametric 95% percentile interval is defined as the reference interval. RESULTS: The results of Mann-Whitney U test showed that NLR (p < .001) in male was significantly higher than that in female; LMR (p < .001) and PLR (p < .001) in male were significantly lower than that in female. Kruskal-Wallis H test showed that there were significant differences in NLR, LMR, and PLR among different genders and age groups (p < .001). The linear graph showed that the reference upper limit of NLR and PLR increased with age and the reference upper limit of LMR decreases with age in male population. In female population, the reference upper limit of NLR in 50-59 group, LMR in >80 group, and PLR in 70-79 group appeared a trough; the reference upper limit of NLR in >80 group, LMR in 50-59 group, and PLR in 40-49 group appeared peak. CONCLUSION: The establishment of RI for NLR, LMR, and PLR in Chinese healthy adults according to gender and age will promote the standardization of clinical application.

Hematological parameters of type 2 diabetic adult patients at Debre Berhan Referral Hospital, Northeast Ethiopia: A comparative cross-sectional study.

BACKGROUND: Diabetes is a global public health problem and associated with metabolic, cellular, and blood disturbances. Hematological changes have been reported in diabetes and play a major role in diabetes-associated complications. However, reports are contradicting and data on hematological parameters of type 2 diabetic patients in the study area are scarce. Therefore, the aim of this study was to assess the hematological parameters of type 2 diabetic adult patients at Debre Berhan Referral Hospital, Northeast Ethiopia from May 01 to June 30, 2020. METHODS: A comparative cross-sectional study was conducted on 268 (134 type 2 diabetic patients and 134 controls) study participants selected by systematic random sampling technique. Socio-demographic, behavioral, and clinical data were collected using a structured questionnaire and checklist. Ethical approval was obtained from Jimma University. All phase of quality assurance was maintained. Hematological parameters and blood glucose levels were determined using UniCel DxH 800 (Beckman Coulter, USA) and Biosystems A25 (Costa Brava, Spain) analyzers, respectively. Independent t-test, Mann-Whitney U-test, correlation, and logistic regression were used during data analysis. P-value <0.05 was considered as statistically significant. RESULTS: The current study found that total white blood cell count, absolute counts of neutrophil, lymphocyte, eosinophil, and basophil, red blood cell distribution width, platelet count, and mean platelet volume were significantly higher in type 2 diabetic patients as compared to the control group (P<0.05). On the other hand, the mean hemoglobin was significantly lower in type 2 diabetic patients than the control group (P = 0.007). Anemia was found in 17.9% of type 2 diabetic patients. Longer duration of diabetes (AOR = 3.05, 95% CI = 1.12-8.34) and milk consumption (AOR = 4.60, 95% CI = 1.50-14.00) were significantly associated with anemia. CONCLUSION: This study showed a statistically significant variation in some hematological parameters of type 2 diabetic patients compared to control group. Anemia among type 2 diabetic patients was found to be a mild public health problem. Therefore, routine screening of hematological parameters should be considered for proper management of type 2 diabetic patients. Close attention should also be given to the duration of diabetes and dietary practice.

Combine effect of exposure to petrol, kerosene and diesel fumes: On hepatic oxidative stress and haematological function in rats.

Petroleum product fumes (PPFs) containing toxic organic components are pervasive in the environment, emanating from anthropogenic activities, including petroleum exploration and utilization by end-user activities from petrol-gasoline stations. Petrol station attendants are exposed to PPF through inhalation and dermal contact with consequent toxicological implications. We investigated the effects of chronic exposure (60 and 90 days) to petrol (P), kerosene (K) and diesel (D) alone and combined exposure to petrol, kerosene and diesel (PKD) fumes on hepatotoxicity, haematological function and oxidative stress in rats. Following sacrifice, we evaluated hepatic damage biomarkers, blood glucose, oxidative stress and haematological function. Chronic exposure to PPF significantly increased organo-somatic indices, blood glucose, biomarkers of hepatic toxicity and oxidative stress in an exposure duration-dependent manner. There was a simultaneous decrease in the protective capacity of antioxidants. Furthermore, exposure to PPF increased pro-inflammatory biomarkers in rats (90 > 60 days). Regardless of exposure duration, plateletcrit, mean platelet volume, platelet distribution width and red cell distribution width in the coefficient of variation increased, whereas red blood cell count, haemoglobin, packed cell volume, mean corpuscular volume, mean corpuscular haemoglobin, mean corpuscular haemoglobin concentration, white blood cell, lymphocyte, monocyte-basophil-eosinophil mixed counts and platelet count decreased after 60 and 90 days exposure. Microscopic examination of the liver demonstrated hepatic pathological changes paralleling the duration of exposure to PKD fumes. However, the injury observed was lesser to that of rats treated with the diethylnitrosamine - positive control. Our results expanded previous findings and further demonstrated the probable adverse effect on populations' health occasioned by persistent exposure to PPF. Individuals chronically exposed by occupation to PPF may be at greater risk of developing disorders promoted by continuous oxido-inflammatory perturbation and suboptimal haematological-immunologic function - thereby enabling a permissive environment for pathogenesis notwithstanding the limitation of quantifying PPF absolute values in our model system.

Combined use of peripheral blood blast count and platelet count during and after induction therapy to predict prognosis in children with acute lymphoblastic leukemia.

ABSTRACT: Several studies have reported an association between the rapidity of reduction in peripheral blood blast count or recovery of normal hematopoiesis and treatment outcome during therapy in children with acute lymphoblastic leukemia (ALL). However, little is known about the impact of both of these aspects on prognosis in pediatric ALL. Accordingly, the purpose of this study was to evaluate whether the combined use of blood blast count and platelet count could predict event-free survival (EFS) and overall survival (OS) when minimal residual disease (MRD) detection was not available.A total of 419 patients aged 0 to 14 years diagnosed and treated for ALL between 2011 and 2015 were enrolled.Patients with a blast count ≥0.1 × 109/L on day 8 exhibited significantly lower survival rates than that in those with blast counts <0.1 × 109/L. The EFS and OS in patients with platelet count ≥100 × 109/L on day 33 were significantly higher than those with platelet counts <100 × 109/L. In univariate and multivariate analyses, patients with low blast count on day 8 and high platelet count on day 33 were significantly associated with better EFS and OS. The combination of blast cell count on day 8 and platelet count on day 33 demonstrated a strong association with MRD-based risk stratification.Complete blood count is an inexpensive, easy to perform, and reliable measurement in children with ALL. The combination of blast count and platelet count during and after induction chemotherapy was a significant and independent prognostic factor for treatment outcome in pediatric ALL.

Dexamethasone plus oseltamivir versus dexamethasone in treatment-naive primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

BACKGROUND: Primary immune thrombocytopenia is an autoimmune bleeding disorder. Preclinical reports suggest that the sialidase inhibitor oseltamivir induces a platelet response in the treatment of immune thrombocytopenia. This study investigated the activity and safety of dexamethasone plus oseltamivir versus dexamethasone alone as initial treatment in adult patients with primary immune thrombocytopenia. METHODS: This multicentre, randomised, open-label, parallel group, phase 2 trial was done in five tertiary medical hospitals in China. Eligible patients were aged 18 years or older with newly diagnosed, treatment-naive primary immune thrombocytopenia. Participants were randomly assigned (1:1), using block randomisation, to receive either dexamethasone (orally at 40 mg per day for 4 days) plus oseltamivir (orally at 75 mg twice a day for 10 days) or dexamethasone monotherapy (orally at 40 mg a day for 4 days). Patients who did not respond to treatment (platelet counts remained <30 × 109 cells per L or showed bleeding symptoms by day 10) were given an additional cycle of dexamethasone for 4 days in each group. Patients in the dexamethasone plus oseltamivir group who relapsed (platelet counts reduced again to <30 × 109 cells per L) after an initial response were allowed a supplemental course of oseltamivir (75 mg twice a day for 10 days). The coprimary endpoints were 14-day initial overall response and 6-month overall response. Complete response was defined as a platelet count at or above 100 × 109 cells per L and an absence of bleeding. Partial response was defined as a platelet count at or above 30 × 109 cells per L but less than 100 × 109 cells per L and at least a doubling of the baseline platelet count and an absence of bleeding. A response lasting for at least 6 months without any additional primary immune thrombocytopenia-specific intervention was defined as sustained response. All patients who were randomly assigned and received the allocated intervention were included in the modified intention-to-treat population analysis. This study has been completed and is registered with ClinicalTrials.gov, number NCT01965626. FINDINGS: From Feb 1, 2016, to May 1, 2019, 120 patients were screened for eligibility, of whom 24 were ineligible and excluded, 96 were enrolled and randomly assigned to receive dexamethasone plus oseltamivir (n=47) or dexamethasone (n=49), and 90 were included in the modified intention-to-treat analysis. Six patients did not receive the allocated intervention. Patients in the dexamethasone plus oseltamivir group had a significantly higher initial response rate (37 [86%] of 43 patients) than did those in the dexamethasone group (31 [66%] of 47 patients; odds ratio [OR] 3·18; 95 CI% 1·13-9·23; p=0·030) at day 14. The 6-month sustained response rate in the dexamethasone plus oseltamivir group was also significantly higher than that in the dexamethasone group (23 [53%] vs 14 [30%]; OR 2·17; 95 CI% 1·16-6·13; p=0·032). During the median follow-up of 8 months (IQR 5-14), two of 90 patients discontinued treatment due to serious adverse events (grade 3); one (2%) patient with general oedema in the dexamethasone plus oseltamivir group and one (2%) patient with fever in the dexamethasone group. The most frequently observed adverse events of any grade were fatigue (five [12%] of 43 in the dexamethasone plus oseltamivir group vs eight [17%] of 47 in the dexamethasone group), gastrointestinal reactions (eight [19%] vs three [6%]), insomnia (seven [16%] vs four [9%]), and anxiety (five [12%] vs three [6%]). There were no grade 4 or 5 adverse events and no treatment-related deaths. INTERPRETATION: Dexamethasone plus oseltamivir offers a readily available combination therapy in the management of newly diagnosed primary immune thrombocytopenia. The preliminary activity of this combination warrants further investigation. Multiple cycles of oseltamivir, as a modification of current first-line treatment, might be more effective in maintaining the platelet response. FUNDING: National Natural Science Foundation of China.

Treatment and outcomes of heparin-induced thrombocytopenia (HIT) in patients with neoplasm, a case series.

Heparin-induced thrombocytopenia (HIT) is a highly thrombogenic condition. Cancer patients are already at high risk of thrombosis. The treatment and outcomes of HIT in cancer patients are not well established. We retrospectively identified patients with active cancer who were diagnosed with HIT at our institution. Only patients with a positive HIT assay and intermediate to high 4Ts score were included. We assessed patients for baseline characteristics, HIT characteristics, non-heparin agent usage, and outcomes (recurrent thrombosis, bleeding, and death) up to 180 days after diagnosis of HIT. Between November 1, 2006 and December 31, 2016, 39 patients with active cancer received a diagnosis of HIT. Of these, 35.9% had thrombotic complications at diagnosis. Gastrointestinal cancer was the most common solid organ malignancy while myeloproliferative neoplasm (MPN) was the most common hematological malignancy. Fondaparinux was the most often used parenteral agent at any point of follow-up (87.2%), followed by argatroban (41.0%). Less than half the patients transitioned to an oral agent. The recurrent thrombosis rate was 17.9%, the bleeding rate was 20.5%, the major bleeding rate was 10.3%, and the mortality rate was 15.4% in the entire cohort. HIT in cancer patients is associated with poor outcomes.

Comprehensive analysis and insights gained from long-term experience of the Spanish DILI Registry.

BACKGROUND & AIMS: Prospective drug-induced liver injury (DILI) registries are important sources of information on idiosyncratic DILI. We aimed to present a comprehensive analysis of 843 patients with DILI enrolled into the Spanish DILI Registry over a 20-year time period. METHODS: Cases were identified, diagnosed and followed prospectively. Clinical features, drug information and outcome data were collected. RESULTS: A total of 843 patients, with a mean age of 54 years (48% females), were enrolled up to 2018. Hepatocellular injury was associated with younger age (adjusted odds ratio [aOR] per year 0.983; 95% CI 0.974-0.991) and lower platelet count (aOR per unit 0.996; 95% CI 0.994-0.998). Anti-infectives were the most common causative drug class (40%). Liver-related mortality was more frequent in patients with hepatocellular damage aged ≥65 years (p = 0.0083) and in patients with underlying liver disease (p = 0.0221). Independent predictors of liver-related death/transplantation included nR-based hepatocellular injury, female sex, higher onset aspartate aminotransferase (AST) and bilirubin values. nR-based hepatocellular injury was not associated with 6-month overall mortality, for which comorbidity burden played a more important role. The prognostic capacity of Hy's law varied between causative agents. Empirical therapy (corticosteroids, ursodeoxycholic acid and MARS) was prescribed to 20% of patients. Drug-induced autoimmune hepatitis patients (26 cases) were mainly females (62%) with hepatocellular damage (92%), who more frequently received immunosuppressive therapy (58%). CONCLUSIONS: AST elevation at onset is a strong predictor of poor outcome and should be routinely assessed in DILI evaluation. Mortality is higher in older patients with hepatocellular damage and patients with underlying hepatic conditions. The Spanish DILI Registry is a valuable tool in the identification of causative drugs, clinical signatures and prognostic risk factors in DILI and can aid physicians in DILI characterisation and management. LAY SUMMARY: Clinical information on drug-induced liver injury (DILI) collected from enrolled patients in the Spanish DILI Registry can guide physicians in the decision-making process. We have found that older patients with hepatocellular type liver injury and patients with additional liver conditions are at a higher risk of mortality. The type of liver injury, patient sex and analytical values of aspartate aminotransferase and total bilirubin can also help predict clinical outcomes.

Utility of the 4Ts score in excluding heparin-induced thrombocytopenia in lung transplant recipients.

Heparin-induced thrombocytopenia (HIT) is a prothrombotic complication following heparin exposure. Data is limited on the incidence of HIT and validity of 4Ts score in the solid organ transplant population. This retrospective observational cohort included patients who underwent lung transplant between August 2015 and June 2018 and had a clinical suspicion of HIT with heparin-PF4 testing. The 4Ts score was correlated with the heparin-PF4 antibody and serotonin release assay (SRA) results, with positive SRA considered confirmed HIT. Of 146 patients evaluated, the overall incidence of HIT was low (2(1%)). Fifty-one patients had heparin-PF4 testing and were included in the cohort; 5 (10%) had positive heparin-PF4 and 1 (2%) had confirmed HIT. The median 4Ts score was 3 (3-4). Thirty (59%), 17 (33%), and 4 (8%) patients had low, intermediate, and high risk, respectively. The intermediate/high risk group compared to the low risk group had a higher use of alternative non-heparin anticoagulation [13 (62%) vs 7 (23%); p = 0.0086)] and a higher incidence of thrombosis [13 (62%) vs 1 (3%); p < 0.0001]. No patient with a low 4Ts score had confirmed HIT, supporting the utility of low 4Ts score to exclude HIT diagnosis in lung transplant recipients.

Platelet count trends and response to fondaparinux in a cohort of heparin-induced thrombocytopenia suspected patients after pulmonary endarterectomy.

A definitive diagnosis of heparin-induced thrombocytopenia (HIT) is difficult to make, especially in patients undergoing cardiac surgery. In this retrospective cohort study, we assessed the platelet count trends and the response to fondaparinux in a population of patients of suspected HIT after pulmonary endarterectomy (PEA). Patients enrolled in this study were over the age of 18 years, and survived longer than 7 days after PEA between January 1, 2011 and December 31, 2015. HIT likelihood was assessed by the 4 T's score and interpreted by our institutional algorithm. 54 patients were operated, and 49 patients met the inclusion criteria. Six patients met the criteria for suspected HIT and were treated with fondaparinux until the platelet recovered. No significant difference was observed of clinical characteristics between intermediate to high HIT likelihood patients (HIT SUSPECTED) and low HIT likelihood patients (NO HIT SUSPECTED). HIT SUSPECTED patients reached platelet count lowest later (about 5.5 days after PEA), while NO HIT SUSPECTED patients is about 4.0 days after PEA. Percentage of platelet counts decrease (> 50%) was larger than NO HIT SUSPECTED patients (< 50%). There was no difference in mortality or residual pulmonary hypertension between HIT SUSPECTED and NO HIT SUSPECTED patients. Two HIT SUSPECTED patients who used heparin after PEA died, the other four survived by replacing heparin or low molecular weight heparin with fondaparinux. Suspected HIT patients should be surveilled carefully. Platelet counts trends may have some hints in the prevention of HIT. Fondaparinux may be effective for patients with suspected HIT.

A pilot study of procoagulant platelet extracellular vesicles and P-selectin increase during induction treatment in acute lymphoblastic leukaemia paediatric patients: two new biomarkers of thrombogenic risk?

In paediatric acute lymphoblastic leukaemia (ALL), focus has shifted towards preventing treatment-related complications, including venous thromboembolism, the cause of significant mortality and morbidity. To better understand thrombogenic mechanisms during induction treatment, we studied the number, origin and procoagulant activity of extracellular vesicles (EVs) and P-selectin level throughout the induction course in 24 paediatric patients. EVs were mainly of platelet origin. We observed a significant increase in EV number, in platelet EV number and P-selectin level throughout the induction course. There was a correlation between higher EV and platelet EV number, P-selectin level, higher platelet count and leucocyte count. We also observed a correlation between higher EV procoagulant activity and higher platelet count and leucocyte count and higher P-selectin level. Older age and T phenotype were associated with a higher EV procoagulant activity. Platelet EV generation may play a role in thrombogenic complications in ALL patients and could serve as a biomarker to identify patients with a high risk of thrombosis. As a marker of platelet activation, P-selectin may be another relevant marker with the advantage of being easier to analyse in clinical practice.

Plasma Insulin-like Growth Factor Binding Protein 7 Contributes Causally to ARDS 28-Day Mortality: Evidence From Multistage Mendelian Randomization.

BACKGROUND: ARDS is a devastating syndrome with heterogeneous subtypes, but few causal biomarkers have been identified. RESEARCH QUESTION: Would multistage Mendelian randomization identify new causal protein biomarkers for ARDS 28-day mortality? STUDY DESIGN AND METHODS: Three hundred moderate to severe ARDS patients were selected randomly from the Molecular Epidemiology of ARDS cohort for proteomics analysis. Orthogonal projections to latent structures discriminant analysis was applied to detect the association between proteins and ARDS 28-day mortality. Candidate proteins were analyzed using generalized summary data-based Mendelian randomization (GSMR). Protein quantitative trait summary statistics were retrieved from the Efficiency and safety of varying the frequency of whole blood donation (INTERVAL) study (n = 2,504), and a genome-wide association study for ARDS was conducted from the Identification of SNPs Predisposing to Altered Acute Lung Injury Risk (iSPAAR) consortium study (n = 534). Causal mediation analysis detected the role of platelet count in mediating the effect of protein on ARDS prognosis. RESULTS: Plasma insulin-like growth factor binding protein 7 (IGFBP7) moderately increased ARDS 28-day mortality (OR, 1.11; 95% CI, 1.04-1.19; P = .002) per log2 increase. GSMR analysis coupled with four other Mendelian randomization methods revealed IGFBP7 as a causal biomarker for ARDS 28-day mortality (OR, 2.61; 95% CI, 1.33-5.13; P = .005). Causal mediation analysis indicated that the association between IGFBP7 and ARDS 28-day mortality is mediated by platelet count (OR, 1.03; 95% CI, 1.02-1.04; P = .01). INTERPRETATION: We identified plasma IGFBP7 as a novel causal protein involved in the pathogenesis of ARDS 28-day mortality and platelet function in ARDS, a topic for further experimental and clinical investigation.

Reduced sensitivity of PLASMIC and French scores for the diagnosis of thrombotic thrombocytopenic purpura in older individuals.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disorder characterized by thrombocytopenia, microangiopathic hemolysis, and ischemic organ failure. The PLASMIC and French TTP scores can help guide clinical decisions when ADAMTS13 testing is not immediately available. Older individuals often present atypically, but the impact of age on these tools is not known. STUDY DESIGN AND METHODS: We calculated the sensitivity and specificity of the PLASMIC and French TTP scores in patients enrolled in the Johns Hopkins thrombotic microangiopathy (TMA) registry. RESULTS: Of 257 patients with TMA enrolled in the registry, we excluded patients less than 18 years of age (n = 19), with prior TMA (n = 81) or who initially presented at another hospital (n = 25). The remaining 132 patients (75 with TTP and 57 with other TMA) were analyzed. Sensitivity of a French score of 2 decreased with age and was 72.2%, 61.5%, and 46.2% for ages 18 to 39, 40 to 59, and ≥ 60 years old, respectively. A PLASMIC score ≥ 5 had higher sensitivity than the French score but this also decreased with age; sensitivity was 91.4% (95% confidence interval [CI], 76.9-98.2), 78.3% (95% CI, 56.3-92.5), and 76.9% (95% CI, 46.2-95.0) for patients 18 to 39, 40 to 59, and ≥ 60 years old, respectively. Older patients had higher platelet counts and serum creatinine than the youngest group, contributing to the loss in sensitivity. CONCLUSION: The PLASMIC and French TTP scores have reduced sensitivity at age ≥ 60 years and are less reliable in identifying TTP in older patients. A high index of suspicion and availability of rapid ADAMTS13 assays is required to correctly diagnose all patients with TTP.

Relationship of mortality with neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume in patients undergoing acute abdominal surgery.

BACKGROUND: Acute abdominal surgery has a high rate of mortality and morbidity, and intensive care is often needed in the postoperative period. In intensive care units, various scoring systems are used to determine prognosis and mortality but are not sufficient to predict mortality and prognosis. For this purpose, easily applicable, effective methods are being investigated. In this study, we aimed to investigate the relationship between mortality and blood parameters, such as neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and mean platelet volume (MPV), in patients undergoing acute abdominal surgery. METHODS: This study included a total of 249 patients who underwent acute abdominal surgery. The patients were divided into two groups as survivors (n=126) and non-survivors (n=123). The patient data were retrospectively analysed. The NLR, PLR, and MPV values were compared between the groups. Data including age, sex, Acute Physiology and Chronic Health Evaluation II-IV scores (APACHEII-IV), Sequential Organ Failure Assessment scores (SOFA), Glasgow Coma Scale were assessed. RESULTS: The mortality rate was 49.4% in our study. There was no statistically significant difference in the NLR and PLR values between the groups. However, MPV was significantly higher in the non-survivors group (p<0.004). CONCLUSION: Our study results showed that MPV values were significantly higher in the non-survivors following acute abdominal surgery, and NLR and PLR were not associated with mortality.

First Human Use of RUC-4: A Nonactivating Second-Generation Small-Molecule Platelet Glycoprotein IIb/IIIa (Integrin αIIbß3) Inhibitor Designed for Subcutaneous Point-of-Care Treatment of ST-Segment-Elevation Myocardial Infarction.

Background Despite reductions in door-to-balloon times for primary coronary intervention, mortality from ST-segment-elevation myocardial infarction has plateaued. Early pre-primary coronary intervention treatment of ST-segment-elevation myocardial infarction with glycoprotein IIb/IIIa inhibitors improves pre-primary coronary intervention coronary flow, limits infarct size, and improves survival. We report the first human use of a novel glycoprotein IIb/IIIa inhibitor designed for subcutaneous first point-of-care ST-segment-elevation myocardial infarction treatment. Methods and Results Healthy volunteers and patients with stable coronary artery disease receiving aspirin received escalating doses of RUC-4 or placebo in a sentinel-dose, randomized, blinded fashion. Inhibition of platelet aggregation (IPA) to ADP (20 µmol/L), RUC-4 blood levels, laboratory evaluations, and clinical assessments were made through 24 hours and at 7 days. Doses were increased until reaching the biologically effective dose (the dose producing ≥80% IPA within 15 minutes, with return toward baseline within 4 hours). In healthy volunteers, 15 minutes after subcutaneous injection, mean±SD IPA was 6.9%+7.1% after placebo and 71.8%±15.0% at 0.05 mg/kg (n=6) and 84.7%±16.7% at 0.075 mg/kg (n=6) after RUC-4. IPA diminished over 90 to 120 minutes. In patients with coronary artery disease, 15 minutes after subcutaneous injection of placebo or 0.04 mg/kg (n=2), 0.05 mg/kg (n=6), and 0.075 mg/kg (n=18) of RUC-4, IPA was 14.6%±11.7%, 53.6%±17.0%, 76.9%±10.6%, and 88.9%±12.7%, respectively. RUC-4 blood levels correlated with IPA. Aspirin did not affect IPA or RUC-4 blood levels. Platelet counts were stable and no serious adverse events, bleeding, or injection site reactions were observed. Conclusions RUC-4 provides rapid, high-grade, limited-duration platelet inhibition following subcutaneous administration that appears to be safe and well tolerated. Registration URL: https://www.clini​caltr​ials.gov; Unique identifier: NTC03844191.