Doctors Identify Hemorrhage Better during Chart Review when Assisted by Artificial Intelligence.

OBJECTIVES: This study evaluated if medical doctors could identify more hemorrhage events during chart review in a clinical setting when assisted by an artificial intelligence (AI) model and medical doctors' perception of using the AI model. METHODS: To develop the AI model, sentences from 900 electronic health records were labeled as positive or negative for hemorrhage and categorized into one of 12 anatomical locations. The AI model was evaluated on a test cohort consisting of 566 admissions. Using eye-tracking technology, we investigated medical doctors' reading workflow during manual chart review. Moreover, we performed a clinical use study where medical doctors read two admissions with and without AI assistance to evaluate performance when using and perception of using the AI model. RESULTS: The AI model had a sensitivity of 93.7% and a specificity of 98.1% on the test cohort. In the use studies, we found that medical doctors missed more than 33% of relevant sentences when doing chart review without AI assistance. Hemorrhage events described in paragraphs were more often overlooked compared with bullet-pointed hemorrhage mentions. With AI-assisted chart review, medical doctors identified 48 and 49 percentage points more hemorrhage events than without assistance in two admissions, and they were generally positive toward using the AI model as a supporting tool. CONCLUSION: Medical doctors identified more hemorrhage events with AI-assisted chart review and they were generally positive toward using the AI model.

Laboratory Tests and Outcome for Patients with Coronavirus Disease 2019: A Systematic Review and Meta-Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019 (COVID-19) and poses substantial challenges for healthcare systems. With a vastly expanding number of publications on COVID-19, clinicians need evidence synthesis to produce guidance for handling patients with COVID-19. In this systematic review and meta-analysis, we examine which routine laboratory tests are associated with severe COVID-19 disease. CONTENT: PubMed (Medline), Scopus, and Web of Science were searched until March 22, 2020, for studies on COVID-19. Eligible studies were original articles reporting on laboratory tests and outcome of patients with COVID-19. Data were synthesized, and we conducted random-effects meta-analysis, and determined mean difference (MD) and standard mean difference at the biomarker level for disease severity. Risk of bias and applicability concerns were evaluated using the Quality Assessment of Diagnostic Accuracy Studies-2. SUMMARY: 45 studies were included, of which 21 publications were used for the meta-analysis. Studies were heterogeneous but had low risk of bias and applicability concern in terms of patient selection and reference standard. Severe disease was associated with higher white blood cell count (MD, 1.28 ×109/L), neutrophil count (MD, 1.49 ×109/L), C-reactive protein (MD, 49.2 mg/L), lactate dehydrogenase (MD, 196 U/L), D-dimer (standardized MD, 0.58), and aspartate aminotransferase (MD, 8.5 U/L); all p < 0.001. Furthermore, low lymphocyte count (MD -0.32 × 109/L), platelet count (MD -22.4 × 109/L), and hemoglobin (MD, -4.1 g/L); all p < 0.001 were also associated with severe disease. In conclusion, several routine laboratory tests are associated with disease severity in COVID-19.

The effect of mycophenolate mofetil on platelet function.

: Mycophenolate mofetil (MMF) raises platelet counts in patients with primary immune thrombocytopenia. However, studies indicate that MMF inhibits collagen-induced platelet aggregation, potentially increasing bleeding risk following MMF therapy. The study evaluates the in-vitro effect of MMF on platelet function. Blood samples (n = 6) from healthy donors were incubated with vehicle, MMF or mycophenolic acid (MPA) at clinically relevant concentrations. Platelet aggregation was measured with flow cytometry and 96-well light transmission aggregometry (LTA). Using flow cytometry, we measured the expression of platelet CD49b, CD42b, CD42a, CD61 and CD41. Platelet activation was measured as the expression of P-selectin and the active form of the GPIIb/IIIa receptor following agonist stimulation. Agonists were: ADP, thrombin receptor-activating peptide, collagen, collagen-related peptide and U46619. The Platelet Function Analyzer-200 was used to measure global platelet function. MMF and MPA did not change platelet aggregation regardless of the agonist used. An exception was a significant, but minor decrease in collagen-induced platelet aggregation in samples with MMF (6 ±â€Š3%, P = 0.02) and MPA (8 ±â€Š4%, P = 0.01) compared with vehicle (22 ±â€Š11%). However, this was not observed using the lesser sensitive LTA method. Compared with vehicle, MPA led to a significantly lower relative disposition of the surface collagen-receptor GPVI (7.8 ±â€Š1.8 versus 8.8 ±â€Š2.1 mean fluorescence intensity, P < 0.001). In all other platelet-related tests, neither MMF nor MPA showed any effect. In conclusion, MMF and MPA only had a minor effect on collagen-induced platelet aggregation, with MPA reducing the relative disposition of surface GPVI receptors.

Use of clinical data and acceleration profiles to validate pneumatic transportation systems.

Background Modern pneumatic transportation systems (PTSs) are widely used in hospitals for rapid blood sample transportation. The use of PTS may affect sample integrity. Impact on sample integrity in relation to hemolysis and platelet assays was investigated and also, we wish to outline a process-based and outcome-based validation model for this preanalytical component. Methods The effect of PTS was evaluated by drawing duplicate blood samples from healthy volunteers, one sent by PTS and the other transported manually to the core laboratory. Markers of hemolysis (potassium, lactate dehydrogenase [LD] and hemolysis index [HI]) and platelet function and activation were assessed. Historic laboratory test results of hemolysis markers measured before and after implementation of PTS were compared. Furthermore, acceleration profiles during PTS and manual transportation were obtained from a mini g logger in a sample tube. Results Hand-carried samples experienced a maximum peak acceleration of 5 g, while peaks at almost 15 g were observed for PTS. No differences were detected in results of potassium, LD, platelet function and activation between PTS and manual transport. Using past laboratory data, differences in potassium and LD significantly differed before and after PTS installation for all three lines evaluated. However, these estimated differences were not clinically significant. Conclusions In this study, we found no evidence of PTS-induced hemolysis or impact on platelet function or activation assays. Further, we did not find any clinically significant changes indicating an acceleration-dependent impact on blood sample quality. Quality assurance of PTS can be performed by surveilling outcome markers such as HI, potassium and LD.

Platelet aggregation is not altered among men with diabetes mellitus.

AIMS: Platelets are pivotal in arterial thrombosis, and platelet hyperresponsiveness may contribute to the increased incidence of cardiovascular events in diabetes mellitus. Consequently, we hypothesized that increased in vitro platelet aggregation responses exist in men with diabetes mellitus. METHODS: The Danish Cardiovascular Screening Trial (DANCAVAS) is a community-based cardiovascular screening trial including men aged 65-74 years. Platelet aggregation was tested using 96-well light transmission aggregometry with thrombin receptor-activating peptide (TRAP), adenosine diphosphate, collagen type 1, arachidonic acid and protease-activated receptor-4 in three concentrations. Further, cardiovascular risk factors and coronary artery calcification (CAC), estimated by CT scans and ankle-brachial index, were obtained. RESULTS: Included were 720 men aged 65-74 years, 110 with diabetes mellitus. Overall, there was no difference in platelet aggregation among men with versus without diabetes mellitus when adjusting for or excluding platelet inhibitor treatment and men with established cardiovascular disease (CVD). This was true for all agonists, e.g., 10 µM TRAP-induced platelet aggregation of median 69% (IQR 53-75) versus 70% (IQR 60-76) in men with versus without diabetes mellitus. Platelet aggregation did not correlate with HbA1c or CAC. Men with diabetes mellitus displayed higher CAC, median 257 Agatston units (IQR 74-1141) versus median 111 Agatston units (IQR 6-420) in the remaining individuals, p < 0.0001. CONCLUSIONS: Among outpatients with diabetes mellitus, but no CVD and no platelet inhibitor treatment, neither are platelets hyperresponsive in diabetes mellitus, nor is platelet aggregation associated with glycemic status or with the degree of coronary atherosclerosis. TRIAL REGISTRATION: ISRCTN12157806.

The role of platelets in bleeding in patients with thrombocytopenia and hematological disease.

This review evaluates the role of platelets in bleeding risk among patients with hematological disease and thrombocytopenia. Platelets are pivotal in primary hemostasis, and possess non-hemostatic properties involved in angiogenesis, tissue repair, inflammation and metastatis. Also, platelets safeguard vascular integrity in inflamed vessels. Overall, bleeding risk depends on the underlying disease, and patients with cancer and platelet count <6-10 × 109/L have a markedly increased bleeding risk, while the platelet count does not correlate with bleeding risk at higher platelet counts. Other factors might affect platelet properties and thus bleeding risk, for example, drugs, low hematocrit, coagulation system impairments or transfusion of dysfunctional donor platelets. For patients with leukemia and immune thrombocytopenia, reduced platelet activation, platelet aggregation, or thrombopoiesis, reflected by the reduced presence of reticulated platelets, are associated with bleeding phenotype. However, mechanistic insight into the cause of reduced platelet function in different thrombocytopenic conditions is sparse, except for some inherited platelet disorders. Promising tools for platelet function studies in thrombocytopenia are flow cytometry and biomarker studies on platelet constituents. An important message from this current paper is that bleeding risk assessment must be tailored to specific patient populations and cannot be applied broadly to all patients with thrombocytopenia.

The effects of storage on platelet function in different blood products.

OBJECTIVES: Reduced platelet (PLT) function during storage has been shown for buffy-coat-derived platelet concentrates (BCP) and apheresis platelet units (AP), while for whole blood (WB) it has not been well studied. The aim of this study was to investigate PLT function in these blood products throughout storage using a novel flow cytometric assay. METHODS: Flow cytometric measurement of agonist-induced platelet aggregation, CD62P expression and PAC-1 binding during storage in BCP, AP (1-9 days at 20°C) and WB (1-21 days at 2-6°C). RESULTS: PLT-aggregation capacity decreased from day 1 to day 7 for almost all product-agonist combinations (P = .004 to P = .029) with aggregation capacity of WB being similar to that of AP and BCP. WB aggregation capacity remained relatively unchanged from day 7 to day 21. For all blood products, the fraction of agonist-induced CD62P-expression remained high and the fraction of PAC-1 binding decreased during storage. WB PLTs underwent only small changes in CD62P expression and PAC-1 binding from day 7 to day 21. CONCLUSION: This study found PLT aggregation in WB stored at 4°C to be as least as good as for BCP and AP stored at 20°C. WB retained significant PLT-aggregation capacity to day 21.

The effect of centrifugation speed and time on pre-analytical platelet activation.

BACKGROUND: The results of laboratory analyses are affected by pre-analytical variables, and in particular can platelets be activated by shear handling stress and secrete granular substances. We therefore evaluated the effect of centrifugation speed and time on pre-analytical platelet activation. METHODS: Citrate- and EDTA-anticoagulated blood from healthy volunteers were centrifuged at 80-10,000 g for 5-15 min to prepare plasma and platelet-rich plasma. Pre-analytical platelet activation was assessed by flow cytometric measurement of platelet P-selectin (CD62p) expression. Blood cell counts, mean platelet volume (MPV), immature platelet fraction (IPF), and platelet distribution width (PDW) were measured. Platelet aggregation in platelet-rich plasma induced by arachidonic acid (AA), ADP or thrombin receptor activator peptide-6 (TRAP) was tested by 96-well aggregometry. RESULTS: The median percentage of platelets expressing P-selectin in citrate- and EDTA-plasma centrifuged at 2000 g for 10 min were 43% [interquartile range (IQR), 38%-53%] and 56% (IQR, 31%-78%), respectively (p=0.82). Platelet-rich plasma prepared at 100-250 g for 10 min had significantly lower platelet P-selectin expression (11%-15%), p<0.001. Platelet count in plasma samples decreased with increasing speed but platelets were only completely removed if plasma was re-centrifuged. In platelet-rich plasma, increasing centrifugation speed significantly increased platelet yield but decreased contamination from other blood cells, platelet composition was altered as platelet parameters (MPV, IPF, and PDW) was lowered. Platelet aggregation was not affected by the centrifugation speed platelet-rich plasma was prepared. CONCLUSIONS: Proportional to centrifugation speed, platelets in plasma and platelet-rich plasma were activated with centrifugation speed, cell content and composition changed while platelet aggregation was unaltered.

Prediction of bleeding and prophylactic platelet transfusions in cancer patients with thrombocytopenia.

Studies on markers for bleeding risk among thrombocytopenic cancer patients are lacking. This prospective observational cohort study investigated whether platelet parameters and a standardised bleeding questionnaire predicted bleeding or prophylactic platelet transfusions in patients with cancer and thrombocytopenia. Admitted adult patients with cancer and platelet count <80 × 10(9)/L were enrolled, but excluded if they experienced surgery or trauma within 7 days or platelet transfusion within 14 days. Patients were interviewed, blood samples collected and, subsequently, spontaneous bleeding and prophylactic platelet transfusion within 30 days were registered. Of 197 patients enrolled, 56 (28%) experienced bleeding. In multivariate analyses, predictors of bleeding were infection (adjusted odds ratio (OR) = 2.65 and 95% confidence interval (95% CI) 1.04-6.74); treatment with platelet inhibitors, heparin or warfarin OR = 2.34, 95% CI 1.23-4.48; urea nitrogen OR = 1.15, 95% CI 1.07-1.25; creatinine OR = 1.01, 95% CI 1.01-1.01; and haemoglobin OR = 0.62, 95% CI 0.41-0.93. Specific information regarding previous gastrointestinal bleeding OR = 3.33, 95% CI 1.19-9.34 and haematuria OR = 3.00, 95% CI 1.20-7.52 predicted bleeding whereas the standardised bleeding questionnaire did not. Prophylactic platelet transfusions were administered to 97 patients. Predictors of prophylactic platelet transfusions were: platelet count OR = 0.96, 95% CI 0.94-0.97; fibrinogen OR = 0.88, 95% CI 0.83-0.95; mean platelet volume OR = 0.69, 95% CI 0.49-0.97; platelet aggregometry with OR = 2.48, 95% CI 1.09-5.64 for collagen-induced platelet aggregation within the lowest quartile; and albumin OR = 1.07, 95% CI 1.01-1.15. In conclusion, except for immature platelet fraction (IPF), platelet parameters predicted prophylactic platelet transfusion but not bleeding. Bleeding risk factors were previous haematuria or gastrointestinal bleeding, infection, antiplatelet or anticoagulant treatment, high urea nitrogen, low haemoglobin or high creatinine.

Mortality and prognostic factors of patients who have blood cultures performed in the emergency department: a cohort study.

BACKGROUND: Early identification and treatment of patients with severe infection improve their prognosis. The aims of this study were to describe the 30-day mortality and to identify prognostic factors among blood-cultured patients in a medical emergency department (MED). PATIENTS AND METHODS: This was a hospital-based cohort study including all adult (≥15 years old) blood-cultured patients at the MED at Odense University Hospital between 1 August 2009 and 31 August 2011. RESULTS: During the study period, 5499/11 988 (45.9%) patients had blood cultures performed within 72 h of arrival and were included in the study. Of those included, 2631 (47.8%) were men, median age 69 years (range 15-103), and 418 (7.6%) were diagnosed with bacteraemia. The overall 30-day mortality among blood-cultured patients was 11.0% (10.2-11.9). In a multivariate Cox regression model, age of more than 80 years [hazard ratio (HR) 4.6 (95% CI 3.6-6.0)], at least two organ failure [HR 3.6 (2.9-4.5)], bacteraemia [HR 1.4 (1.1-1.8)], Charlson Comorbidity Index of at least 2 h [HR 1.7 (1.3-2.0)], SIRS [HR 1.5 (1.2-1.7)], a history of alcohol dependency [HR 1.7 (1.3-2.3)] and late drawing of blood cultures 24-48 h after arrival [HR 1.7 (1.3-2.2)] were found to be prognostic factors of mortality among blood-cultured patients in the MED. CONCLUSION: Among blood-cultured patients in the MED, we found an 11.0% overall 30-day mortality. Factors associated with 30-day mortality were age more than 80 years, at least two organ failure, bacteraemia, Charlson Comorbidity Index of at least 2, SIRS, a history of alcohol dependency and late drawing of blood cultures.

Interference from lupus anticoagulant on von Willebrand factor measurement in splenic marginal zone lymphoma: a case report.

We present a case concerning a patient with splenic marginal zone lymphoma (SMZL) and isolated prolonged activated partial thromboplastin time (aPTT) caused by lupus anticoagulant. Von Willebrand factor (VWF) activity and antigen were immeasurable by latex particle immunoturbidimetric assays, and several coagulation factor levels were decreased. However, VWF activity and antigen were normal when analyzed by other methods. Also, coagulation factor levels were normal if an aPTT reagent with low lupus anticoagulant sensitivity or a chromogenic method was applied. Altogether, the initial findings were because of lupus anticoagulant interference and in fact, the patient had normal VWF activity and coagulation status. Interference of lupus anticoagulant in clot-based assays is well known but has not previously been described in VWF assays. This is furthermore the first report in which lupus anticoagulant activity in SMZL cannot be ascribed to a monoclonal immunoglobulin. In our study, aPTT normalized after treatment, suggesting resolution of lupus anticoagulant. APTT could thus be a marker of treatment response in SMZL. Whether treatment decreases the thrombosis risk due to lupus anticoagulant remains unknown.

An overview of platelet indices and methods for evaluating platelet function in thrombocytopenic patients.

Thrombocytopenia is associated with bleeding risk. However, in thrombocytopenic patients, platelet count does not correlate with bleeding risk and other factors are thus likely to contribute to this risk. This review presents currently available platelet-related markers available on automated haematology analysers and commonly used methods for testing platelet function. The test principles, advantages and disadvantages of each test are described. We also evaluate the current literature regarding the clinical utility of the test for prediction of bleeding in thrombocytopenia in haematological and oncological diseases. We find that several platelet-related markers are available, but information about the clinical utility in thrombocytopenia is limited. Studies support that mean platelet volume (MPV) can aid diagnosing the cause of thrombocytopenia and low MPV may be associated with bleeding in thrombocytopenia. Flow cytometry, platelet aggregometry and platelet secretion tests are used to diagnose specific platelet function defects. The flow cytometric activation marker P-selectin and surface coverage by the Cone-and-Plate[let] analyser predict bleeding in selected thrombocytopenic populations. To fully uncover the clinical utility of platelet-related tests, information about the prevalence of platelet function defects in thrombocytopenic conditions is required. Finally, knowledge of the performance in thrombocytopenic samples from patients is essential.

An ELISA for the quantitation of von Willebrand factor: osteoprotegerin complexes in plasma.

BACKGROUND: Von Willebrand factor (VWF) is pivotal in arterial thrombosis, and osteoprotegerin (OPG) is besides being a bone protein also related to cardiovascular diseases. OPG can bind VWF, but the significance of this interaction is not known. OBJECTIVES: The aim was to develop an assay for measurement of von Willebrand factor-osteoprotegerin complex (VWF:OPG) in human plasma. Furthermore, the significance of VWF:OPG complex as a marker of cardiovascular disease (CVD) was evaluated. PATIENTS/METHODS: A sandwich ELISA for quantification of VWF:OPG was developed using a polyclonal rabbit anti-human VWF capturing antibody and a monoclonal anti-human OPG detecting antibody. Samples were quantified relative to a standard curve obtained from dilutions of a plasma pool from healthy individuals. The assay was evaluated in two groups of patients with CVD and two groups of asymptomatic individuals with and without documented coronary calcification (total n=118). RESULTS AND CONCLUSIONS: The assay detected VWF:OPG complexes in human plasma, while no significant signal was observed when testing solutions containing VWF or recombinant OPG alone. Importantly, the ELISA assay was able to detect in vitro formed complexes between human VWF and recombinant OPG in a dose-dependent manner. There was a large inter-individual variation in plasma VWF:OPG levels, but we found no significant differences in the level of VWF:OPG complexes between the four groups. Thus, we conclude that increasing OPG plasma levels in atherosclerotic CVD are not derived from increased levels of complexed form of VWF and OPG, but are more likely due to increased amounts of OPG secreted into the circulation.

Does C-reactive protein independently predict mortality in adult community-acquired bacteremia patients with known sepsis severity?

We evaluated whether sepsis severity and C-reactive protein (CRP) level on admission prognostically corroborated or annulled each other in adult patients with incident community-acquired bacteremia (Funen, Denmark, 2000-2008). We used logistic regression and area under the receiver operating characteristic curve (AUC) to evaluate 30-day mortality in four models: (i) age, gender, comorbidity, bacteria, and ward. (ii) Model 1 and sepsis severity. (iii) Model 1 and CRP. (iv) Model 1, sepsis severity, and CRP. Altogether, 416 of 1999 patients died within 30 days. CRP independently predicted 30-day mortality [Model 4, odds ratio (95% CIs) for 100 mg/L: 1.16 (1.06-1.27)], but it did not contribute to the AUC (Model 2 vs Model 4: p = 0.31). In the 963 non-severe sepsis patients, CRP independently predicted 30-day mortality [Model 4: 1.42 (1.20-1.69)] and it increased the AUC (Model 2 vs Model 4: p = 0.06), thus CRP contributed as much as sepsis severity to prognosis.

Ulcerating and stenosing enteropathy treated with misoprostol: a case report with analysis of prostaglandin metabolism.

A case of a 40-year-old man with chronic anaemia because of nonspecific ulcerating and stenosing enteropathy is presented. The diagnosis was made on the basis of capsule endoscopy, histology of resected ileum and no use of NSAIDs. He showed a clinical response to treatment with misoprostol, and therefore, he was investigated for a possible impairment in eicosanoid biosynthesis compared with healthy controls. No deficient synthesis of prostacyclin, prostaglandin E2 and thromboxane was found on examination of metabolites in blood and urine. This suggests a normal release of arachidonic acid from phospholipids. Ex-vivo cyclooxygenase (COX) assays showed normal COX-1 and COX-2 activities. The clinical response to treatment with the prostaglandin E1 analogue misoprostol suggests a defective prostaglandin E synthesis in the intestinal mucosa.