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- Heber, S, et al.
(författare)
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A Model Predicting Mortality of Hospitalized Covid-19 Patients Four Days After Admission: Development, Internal and Temporal-External Validation
- 2022
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Ingår i: Frontiers in cellular and infection microbiology. - : Frontiers Media SA. - 2235-2988. ; 11, s. 795026-
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Tidskriftsartikel (refereegranskat)abstract
- To develop and validate a prognostic model for in-hospital mortality after four days based on age, fever at admission and five haematological parameters routinely measured in hospitalized Covid-19 patients during the first four days after admission.MethodsHaematological parameters measured during the first 4 days after admission were subjected to a linear mixed model to obtain patient-specific intercepts and slopes for each parameter. A prediction model was built using logistic regression with variable selection and shrinkage factor estimation supported by bootstrapping. Model development was based on 481 survivors and 97 non-survivors, hospitalized before the occurrence of mutations. Internal validation was done by 10-fold cross-validation. The model was temporally-externally validated in 299 survivors and 42 non-survivors hospitalized when the Alpha variant (B.1.1.7) was prevalent.ResultsThe final model included age, fever on admission as well as the slope or intercept of lactate dehydrogenase, platelet count, C-reactive protein, and creatinine. Tenfold cross validation resulted in a mean area under the receiver operating characteristic curve (AUROC) of 0.92, a mean calibration slope of 1.0023 and a Brier score of 0.076. At temporal-external validation, application of the previously developed model showed an AUROC of 0.88, a calibration slope of 0.95 and a Brier score of 0.073. Regarding the relative importance of the variables, the (apparent) variation in mortality explained by the six variables deduced from the haematological parameters measured during the first four days is higher (explained variation 0.295) than that of age (0.210).ConclusionsThe presented model requires only variables routinely acquired in hospitals, which allows immediate and wide-spread use as a decision support for earlier discharge of low-risk patients to reduce the burden on the health care system.Clinical Trial RegistrationAustrian Coronavirus Adaptive Clinical Trial (ACOVACT); ClinicalTrials.gov, identifier NCT04351724.
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- Rosell, A, et al.
(författare)
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Prognostic value of circulating markers of neutrophil activation, neutrophil extracellular traps, coagulation and fibrinolysis in patients with terminal cancer
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 5074-
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Tidskriftsartikel (refereegranskat)abstract
- Predicting survival accurately in patients with advanced cancer is important in guiding interventions and planning future care. Objective tools are therefore needed. Blood biomarkers are appealing due to their rapid measurement and objective nature. Thrombosis is a common complication in cancer. Recent data indicate that tumor-induced neutrophil extracellular traps (NETs) are pro-thrombotic. We therefore performed a comprehensive investigation of circulating markers of neutrophil activation, NET formation, coagulation and fibrinolysis in 106 patients with terminal cancer. We found that neutrophil activation and NET markers were prognostic in terminal cancer patients. Interestingly, markers of coagulation and fibrinolysis did not have a prognostic value in this patient group, and there were weak or no correlations between these markers and markers of neutrophil activation and NETs. This suggest that NETs are linked to a poor prognosis through pathways independent of coagulation. Additional studies are needed to determine the utility of circulating neutrophil activation and NET markers, alone or in concert with established clinical parameters, as objective and reliable prognostic tools in advanced cancer.
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- He, S, et al.
(författare)
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Fibrin Network Porosity and Endo-/Exogenous Thrombin Cross-talk
- 2021
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Ingår i: Seminars in thrombosis and hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 47:087, s. 775-786
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Tidskriftsartikel (refereegranskat)abstract
- The earliest assessment of fibrin network porosity used a liquid permeation system and confocal 3D microscopy, which was later replaced by scanning electron microscopy. Although the methods have extensively been applied in studies of health or disease, there remains debate on the choice of a proper clotting trigger. In this review, we assess published data and convey our opinions with regard to several issues. First, when the coagulation process is initiated by recombinant tissue factor (rTF) and phospholipids, the fibrin network porosity is regulated by the endogenous thrombin based on enzymatic activations of multiple coagulants. If purified thrombin (1.0 IU/mL) is employed as the clotting trigger, fibrin network porosity may be affected by exogenous thrombin, which directly polymerizes fibrinogen in plasma, and additionally by endogenous thrombin stemming from a “positive feedback loop” action of the added thrombin. Second, with use of either endogenous or exogenous thrombin, the concentration and clotting property of available fibrinogen both influence the fibrin network porosity. Third, in the assay systems in vitro, exogenous thrombin but not rTF-induced endogenous thrombin seems to be functional enough to activate factor XIII, which then contributes to a decrease in the fibrin network porosity. Fourth, fibrin network porosity determines the transport of fibrinolytic components into/through the clots and therefore serves as an indicator of the fibrinolysis potential in plasma.
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| 9. |
- He, S, et al.
(författare)
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The Clotting Trigger Is an Important Determinant for the Coagulation Pathway In Vivo or In Vitro-Inference from Data Review
- 2021
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Ingår i: Seminars in thrombosis and hemostasis. - : Georg Thieme Verlag KG. - 1098-9064 .- 0094-6176. ; 47:061, s. 63-73
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Tidskriftsartikel (refereegranskat)abstract
- Blood coagulation comprises a series of enzymatic reactions leading to thrombin generation and fibrin formation. This process is commonly illustrated in a waterfall-like manner, referred to as the coagulation cascade. In vivo, this “cascade” is initiated through the tissue factor (TF) pathway, once subendothelial TF is exposed and bound to coagulation factor VII (FVII) in blood. In vitro, a diminutive concentration of recombinant TF (rTF) is used as a clotting trigger in various global hemostasis assays such as the calibrated automated thrombogram, methods that assess fibrin turbidity and fibrin viscoelasticity tests such as rotational thromboelastometry. These assays aim to mimic in vivo global coagulation, and are useful in assessing hyper-/hypocoagulable disorders or monitoring therapies with hemostatic agents. An excess of rTF, a sufficient amount of negatively charged surfaces, various concentrations of exogenous thrombin, recombinant activated FVII, or recombinant activated FIXa are also used to initiate activation of specific sub-processes of the coagulation cascade in vitro. These approaches offer important information on certain specific coagulation pathways, while alterations in pro-/anticoagulants not participating in these pathways remain undetectable by these methods. Reviewing available data, we sought to enhance our knowledge of how choice of clotting trigger affects the outcome of hemostasis assays, and address the call for further investigations on this topic.
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- Hober, Sophia, Professor, 1965-, et al.
(författare)
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Systematic evaluation of SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay
- 2021
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Ingår i: Clinical & Translational Immunology. - : Wiley. - 2050-0068. ; 10:7
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Tidskriftsartikel (refereegranskat)abstract
- Objective. The COVID-19 pandemic poses an immense need for accurate, sensitive and high-throughput clinical tests, and serological assays are needed for both overarching epidemiological studies and evaluating vaccines. Here, we present the development and validation of a high-throughput multiplex bead-based serological assay. Methods. More than 100 representations of SARS-CoV-2 proteins were included for initial evaluation, including antigens produced in bacterial and mammalian hosts as well as synthetic peptides. The five best-performing antigens, three representing the spike glycoprotein and two representing the nucleocapsid protein, were further evaluated for detection of IgG antibodies in samples from 331 COVID-19 patients and convalescents, and in 2090 negative controls sampled before 2020. Results. Three antigens were finally selected, represented by a soluble trimeric form and the S1-domain of the spike glycoprotein as well as by the C-terminal domain of the nucleocapsid. The sensitivity for these three antigens individually was found to be 99.7%, 99.1% and 99.7%, and the specificity was found to be 98.1%, 98.7% and 95.7%. The best assay performance was although achieved when utilising two antigens in combination, enabling a sensitivity of up to 99.7% combined with a specificity of 100%. Requiring any two of the three antigens resulted in a sensitivity of 99.7% and a specificity of 99.4%. Conclusion. These observations demonstrate that a serological test based on a combination of several SARS-CoV-2 antigens enables a highly specific and sensitive multiplex serological COVID-19 assay.
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- Thalin, C, et al.
(författare)
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Trousseau's Syndrome, a Previously Unrecognized Condition in Acute Ischemic Stroke Associated With Myocardial Injury
- 2014
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Ingår i: Journal of investigative medicine high impact case reports. - : SAGE Publications. - 2324-7096. ; 2:2, s. 2324709614539283-
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Tidskriftsartikel (refereegranskat)abstract
- Trousseau’s syndrome is a well-known malignancy associated hypercoagulative state leading to venous or arterial thrombosis. The pathophysiology is however poorly understood, although multiple mechanisms are believed to be involved. We report a case of Trousseau’s syndrome resulting in concomitant cerebral and myocardial microthrombosis, presenting with acute ischemic stroke and markedly elevated plasma troponin T levels suggesting myocardial injury. Without any previous medical history, the patient developed multiple cerebral infarctions and died within 11 days of admission. The patient was postmortem diagnosed with an advanced metastatic adenocarcinoma of the prostate with disseminated cerebral, pulmonary, and myocardial microthrombosis. Further analyses revealed, to the best of our knowledge for the first time in stroke patients, circulating microvesicles positive for the epithelial tumor marker CK18 and citrullinated histone H3 in thrombi, markers of the recently described cancer-associated procoagulant DNA-based neutrophil extracellular traps. We also found tissue factor, the main in vivo initiator of coagulation, both in thrombi and in metastases. Troponin elevation in acute ischemic stroke is common and has repeatedly been associated with an increased risk of mortality. The underlying pathophysiology is however not fully clarified, although a number of possible explanations have been proposed. We now suggest that unexplainable high levels of troponin in acute ischemic stroke deserve special attention in terms of possible occult malignancy.
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- Zenlander, R, et al.
(författare)
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Neutrophil extracellular traps in patients with liver cirrhosis and hepatocellular carcinoma
- 2021
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Ingår i: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 18025-
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophil extracellular traps (NETs) are web-like structures consisting of DNA, histones and granule proteins, released from neutrophils in thrombus formation, inflammation, and cancer. We asked if plasma levels of the NET markers myeloperoxidase (MPO)-DNA and citrullinated histone H3 (H3Cit)-DNA, are elevated in liver cirrhosis and hepatocellular carcinoma (HCC) and if the levels correlate with clinical parameters. MPO-DNA, H3Cit-DNA, and thrombin–antithrombin (TAT) complex, as a marker of coagulation activity, were measured using ELISA in plasma from 82 patients with HCC, 95 patients with cirrhosis and 50 healthy controls. Correlations were made to clinical parameters and laboratory data and patients were followed for a median of 22.5 months regarding thrombosis development. H3Cit-DNA was significantly (p < 0.01) elevated in plasma from cirrhosis (66.4 ng/mL) and HCC (63.8 ng/mL) patients compared to healthy controls (31.8 ng/mL). TAT levels showed similar pattern (3.1, 3.7, and 0.0 µg/mL respectively, p < 0.01). MPO-DNA was significantly (p < 0.01) elevated in cirrhosis patients (0.53 O.D.) as compared to controls (0.33 O.D.). Levels of MPO-DNA and H3Cit-DNA correlated positively with Child–Pugh and MELD score. TAT was increased in all Child–Pugh and MELD groups. In multivariable logistic regression, Child B and C liver cirrhosis were independent predictors of elevated H3Cit-DNA in plasma. Levels of MPO-DNA and H3Cit-DNA were similar in patients with or without history of thrombosis, or thrombus formation during follow-up. In conclusion, plasma markers of NET formation are elevated in liver cirrhosis and correlate to the degree of liver dysfunction in patients with liver cirrhosis and/or HCC. The presence of HCC did not further increase the plasma levels of NET markers as compared to patients with cirrhosis only.
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