Publications by authors named "Moniek P M de Maat"

185 Publications

Does difference between label and actual potency of factor VIII concentrate affect pharmacokinetic-guided dosing of replacement therapy in haemophilia A?

Haemophilia 2022 May 8. Epub 2022 May 8.

Department of Pediatric Hematology and Oncology, Erasmus MC Sophia Children's Hospital, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: To account for interindividual variability in the pharmacokinetics (PK) of factor concentrates, PK-guided dosing is increasingly implemented in haemophilia patients. Calculations are based on provided label potency, but legislation allows a potency difference of ±20% between label and actual potency. It is unknown if these differences affect PK guidance.

Aim: Explore the effects of potency differences on individual factor VIII (FVIII) PK parameters and the prediction of FVIII trough levels of dosing regimens.

Methods: We analyzed individual preoperative PK profiling data from severe and moderate haemophilia A patients included in the OPTI-CLOT randomized controlled trial. Label and actual potency were compared, with data on potency provided by pharmaceutical companies. For both potencies, individual PK parameters were estimated and concentration-time curves were constructed by nonlinear mixed-effects modelling. Finally, we explored the effect of both the identified and the maximum legislated potency difference on predicted FVIII trough levels infused in a low and high dose regimen.

Results: In 45/50 included patients, actual potency was higher than its label potency. The median potency difference was 6.0% (range -9.2% to 18.4%) and resulted in varying individual PK parameter estimates but practically identical FVIII concentration-time curves. As expected, predicted FVIII trough levels were linearly correlated to the actual dose.

Conclusion: It is not necessary to take potency differences into account when applying PK guidance of FVIII concentrates in haemophilia A patients. However, when the patient is switched to another FVIII batch after PK-guided dosing, trough levels may deviate ±20% from calculations based on label dose.
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http://dx.doi.org/10.1111/hae.14575DOI Listing
May 2022

Reduced fibrin clot lysis in Klinefelter syndrome associated with hypogonadism.

Endocr Connect 2022 May 10;11(5). Epub 2022 May 10.

Unit for Thrombosis Research, Department of Regional Health Research, University of Southern Denmark, Odense, Denmark.

Objective: Klinefelter syndrome (KS) is associated with increased risk of thrombosis. Hypogonadism and accumulating body fat in KS have a potential impact on fibrinolysis. In this study, we assessed the fibrinolytic system and the association with testosterone levels in KS.

Design: This study is a cross-sectional comparison of men with KS and age-matched male controls.

Methods: Fibrin clot lysis was evaluated by turbidity measurements and by measuring levels of individual fibrinolytic proteins in plasma samples. Fibrin clot structure was evaluated by scanning electron microscopy. Total testosterone was measured by liquid chromatography-tandem mass spectrometry. Body fat was evaluated by dual-energy X-ray absorptiometry.

Results: In this study, 45 men with KS and 45 age- and education-matched controls were included. Men with KS had a 24% reduction in fibrin clot lysis compared with controls (46.2 ± 17.1 vs 60.6 ± 18.8 %/h, P = 0.0003) and higher levels of fibrinogen, factor XIII (P ≤ 0.01), and plasminogen activator inhibitor type 1 (P = 0.04). Men with KS had lower total testosterone (P = 0.008) and higher body fat (P = 0.001). In KS, reduced fibrin clot lysability was associated with higher fibrinogen and body fat related to decreasing total testosterone and hypogonadism among men with KS. Fibrin clot structure was not different compared to KS and controls.

Conclusions: Fibrin clot lysis in KS was markedly reduced, potentially contributing to a prothrombotic state and increasing thrombotic risk. Hypogonadism in KS was associated with increased fibrinogen and total body fat, predicting reduced fibrin clot lysis.
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http://dx.doi.org/10.1530/EC-21-0490DOI Listing
May 2022

Altered fibrin network structure and fibrinolysis in intensive care unit patients with COVID-19, not entirely explaining the increased risk of thrombosis.

J Thromb Haemost 2022 Mar 22. Epub 2022 Mar 22.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis.

Objectives: By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis.

Patients/methods: In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis.

Results: COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18).

Conclusions: Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk.
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http://dx.doi.org/10.1111/jth.15708DOI Listing
March 2022

Absence of COVID-19-associated changes in plasma coagulation proteins and pulmonary thrombosis in the ferret model.

Thromb Res 2022 02 21;210:6-11. Epub 2021 Dec 21.

Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands; Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands. Electronic address:

Background: Many patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection.

Objectives: This study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis.

Material And Methods: Histology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed.

Results: Lungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation.

Conclusions: We conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited.
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http://dx.doi.org/10.1016/j.thromres.2021.12.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8690567PMC
February 2022

Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice.

Rheumatol Adv Pract 2021 27;5(3):rkab093. Epub 2021 Nov 27.

Department of Hematology.

Objectives: Lupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice.

Methods: In this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018.

Results: During the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement ( < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-β2 glycoprotein I (β2GPI) IgG compared with patients with other indications.

Conclusion: The prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-β2GPI IgG and aCL IgG, which should be confirmed in future studies.
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http://dx.doi.org/10.1093/rap/rkab093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8669994PMC
November 2021

Impact of COVID-19 pandemic on the quality of test output in haemostasis laboratories.

Int J Lab Hematol 2022 Apr 22;44(2):407-413. Epub 2021 Nov 22.

ECAT Foundation (External quality Control for Assays and Tests), Voorschoten, Netherlands.

Introduction: The high incidence of thrombotic events in patients with COVID-19 affects health care worldwide and results in an increased workload in haemostasis laboratories due to more frequent testing of D-dimer, haemostatic parameters and anti-Xa tests. However, the impact of this increase in assay requests on the quality of performance in haemostasis laboratories remains unclear. In this study, the impact of the COVID-19 pandemic on the quality of performance and management of haemostasis laboratories was evaluated.

Methods: The impact on the quality of performance was studied using external quality assessment data from 2019 to 2020 derived from ECAT surveys. A questionnaire was sent to Dutch haemostasis laboratories to identify challenges and management strategies. Furthermore, the number of assays performed in 2019 and 2020 was supplied by four Dutch hospitals, located in regions with different disease incidence.

Results: No differences in response rate nor the quality of the measurements were observed between the EQA surveys in 2019 and 2020. The questionnaire results showed a large increase of >25% in the number of test requests for anti-Xa, D-dimer and fibrinogen assays in 2020 compared to 2019. Extreme peaks in test requests were also observed in the four evaluated hospitals. Additionally, 84% of the respondents indicated that they had experienced increased work pressure, and increased sick leave was observed in 71% of the participating laboratories.

Conclusions: The enormous increase in test requests, especially for D-dimer assays and anti-Xa activity, did not affect the quality of performance within haemostatic laboratories during the COVID-19 pandemic.
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http://dx.doi.org/10.1111/ijlh.13760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9011814PMC
April 2022

Detectable A Disintegrin and Metalloproteinase With Thrombospondin Motifs-1 in Serum Is Associated With Adverse Outcome in Pediatric Sepsis.

Crit Care Explor 2021 Nov 8;3(11):e0569. Epub 2021 Nov 8.

Laboratory Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Importance: A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 is hypothesized to play a role in the pathogenesis of invasive infection, but studies in sepsis are lacking.

Objectives: To study A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 protein level in pediatric sepsis and to study the association with outcome.

Design: Data from two prospective cohort studies.

Setting And Participants: Cohort 1 is from a single-center study involving children admitted to PICU with meningococcal sepsis (samples obtained at three time points). Cohort 2 includes patients from a multicenter study involving children admitted to the hospital with invasive bacterial infections of differing etiologies (samples obtained within 48 hr after hospital admission).

Main Outcomes And Measures: Primary outcome measure was mortality. Secondary outcome measures were PICU-free days at day 28 and hospital length of stay.

Results: In cohort 1 ( = 59), nonsurvivors more frequently had A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels above the detection limit than survivors at admission to PICU (8/11 [73%] and 6/23 [26%], respectively; = 0.02) and at t = 24 hours (2/3 [67%] and 3/37 [8%], respectively; = 0.04). In cohort 2 ( = 240), A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels in patients within 48 hours after hospital admission were more frequently above the detection limit than in healthy controls (110/240 [46%] and 14/64 [22%], respectively; = 0.001). Nonsurvivors more often had detectable A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 levels than survivors (16/21 [76%] and 94/219 [43%], respectively; = 0.003), which was mostly attributable to patients with .

Conclusions And Relevance: In children with bacterial infection, detection of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 within 48 hours after hospital admission is associated with death, particularly in meningococcal sepsis. Future studies should confirm the prognostic value of A Disintegrin and Metalloproteinase with Thrombospondin Motifs-1 and should study pathophysiologic mechanisms.
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http://dx.doi.org/10.1097/CCE.0000000000000569DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8577672PMC
November 2021

Clinical value of early assessment of hyperfibrinolysis by rotational thromboelastometry during postpartum hemorrhage for the prediction of severity of bleeding: A multicenter prospective cohort study in the Netherlands.

Acta Obstet Gynecol Scand 2022 Jan 3;101(1):145-152. Epub 2021 Nov 3.

Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands.

Introduction: Coagulopathy may be the result of hyperfibrinolysis and could exacerbate bleeding following childbirth. Timely recognition of hyperfibrinolysis during the earliest stages of postpartum hemorrhage could identify women at risk of more severe blood loss who may benefit from targeted anti-fibrinolytic therapy. Rotational thromboelastometry (ROTEM ) is a point-of-care test that could detect hyperfibrinolysis. The aim of this study was to evaluate whether early assessment of hyperfibrinolysis by ROTEM during postpartum hemorrhage could predict progression to severe postpartum hemorrhage.

Material And Methods: During a prospective cohort study in the Netherlands among women with postpartum hemorrhage (total blood loss at least 1000 ml within 24 h after childbirth) ROTEM measurements were performed following 800-1500 ml of blood loss. Hyperfibrinolysis was defined as an enzymatic fibrinolysis index (ROTEM EXTEM maximum clot lysis [ML] minus the ROTEM APTEM ML) above 15%. Severe postpartum hemorrhage was defined as a composite end point of total blood loss greater than 2000 ml, transfusion of four or more units of packed cells, and/or need for an invasive intervention. The predictive value of hyperfibrinolysis for progression to severe postpartum hemorrhage was assessed by area under the receiver operating curve (AUC) and positive and negative predictive values.

Trial Registration: ClinicalTrials.gov (NCT02149472).

Results: Of 390 women included, 82 (21%) had severe postpartum hemorrhage. Four (1%) women had thromboelastometric evidence of hyperfibrinolysis, of whom two developed severe postpartum hemorrhage. The AUC for enzymatic fibrinolysis index more than 15% for progression to severe postpartum hemorrhage was 0.47 (95% CI 0.40-0.54). Positive and negative predictive values for this index were 50.0% (95% CI 6.8-93.2) and 79.3% (95% CI 74.9-83.2), respectively.

Conclusions: Thromboelastometric evidence of hyperfibrinolysis was rare in women with postpartum hemorrhage when assessed between 800 and 1500 ml of blood loss. The clinical predictive value of viscoelastometric point-of-care testing for hyperfibrinolysis for progression to severe postpartum hemorrhage during early postpartum hemorrhage is limited.
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http://dx.doi.org/10.1111/aogs.14279DOI Listing
January 2022

Automated Fiber Diameter and Porosity Measurements of Plasma Clots in Scanning Electron Microscopy Images.

Biomolecules 2021 10 18;11(10). Epub 2021 Oct 18.

Department of Physics, Wake Forest University, Winston-Salem, NC 27109, USA.

Scanning Electron Microscopy (SEM) is a powerful, high-resolution imaging technique widely used to analyze the structure of fibrin networks. Currently, structural features, such as fiber diameter, length, density, and porosity, are mostly analyzed manually, which is tedious and may introduce user bias. A reliable, automated structural image analysis method would mitigate these drawbacks. We evaluated the performance of DiameterJ (an ImageJ plug-in) for analyzing fibrin fiber diameter by comparing automated DiameterJ outputs with manual diameter measurements in four SEM data sets with different imaging parameters. We also investigated correlations between biophysical fibrin clot properties and diameter, and between clot permeability and DiameterJ-determined clot porosity. Several of the 24 DiameterJ algorithms returned diameter values that highly correlated with and closely matched the values of the manual measurements. However, optimal performance was dependent on the pixel size of the images-best results were obtained for images with a pixel size of 8-10 nm (13-16 pixels/fiber). Larger or smaller pixels resulted in an over- or underestimation of diameter values, respectively. The correlation between clot permeability and DiameterJ-determined clot porosity was modest, likely because it is difficult to establish the correct image depth of field in this analysis. In conclusion, several DiameterJ algorithms (M6, M5, T3) perform well for diameter determination from SEM images, given the appropriate imaging conditions (13-16 pixels/fiber). Determining fibrin clot porosity via DiameterJ is challenging.
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http://dx.doi.org/10.3390/biom11101536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533744PMC
October 2021

Platelet-dependent signaling and Low Molecular Weight Protein Tyrosine Phosphatase expression promote aggressive phenotypic changes in gastrointestinal cancer cells.

Biochim Biophys Acta Mol Basis Dis 2022 01 2;1868(1):166280. Epub 2021 Oct 2.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, the Netherlands. Electronic address:

Over the last decades, some members of the protein tyrosine phosphatase family have emerged as cancer promoters. Among them, the Low Molecular Weight Protein Tyrosine Phosphatase (LMWPTP) has been described to be associated with colorectal cancer liver metastasis and poor prostate cancer prognosis. Of importance in the process of cancer progression and metastasis is the interaction between tumor cells and platelets, as the latter are thought to promote several tumor hallmarks. Here, we examine to what extent LMWPTP expression in tumor cells affects their interaction with platelets. We demonstrate that the gene encoding LMWPTP is overexpressed in upper gastrointestinal (GI) cancer cell as well as colorectal cancer, and subsequently employ cell line models to show that the level of this phosphatase may be further augmented in the presence of platelets. We demonstrate that tumor-platelet interaction promotes GI tumor cell proliferation. Additionally, using know-down/-out models we show that LMWPTP expression in cancer cells contributes to a more efficient interaction with platelets and drives platelet-induced proliferation. These data are the first to demonstrate that phosphatases play a positive role in the tumor-promoting activities of platelets, with LMWPTP emerging as a key player promoting oncogenic phenotypic changes in tumor cells.
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http://dx.doi.org/10.1016/j.bbadis.2021.166280DOI Listing
January 2022

Immunothrombosis and new-onset atrial fibrillation in the general population: the Rotterdam Study.

Clin Res Cardiol 2022 Jan 24;111(1):96-104. Epub 2021 Sep 24.

Department of Epidemiology, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Atrial fibrillation (AF) is the most common age-related cardiac arrhythmia. The etiology underlying AF is still largely unknown. At the intersection of the innate immune system and hemostasis, immunothrombosis may be a possible cause of atrial remodeling, and therefore be an underlying cause of AF.

Methods: From 1990 to 2014, we followed participants aged 55 and over, free from AF at inclusion. Immunothrombosis factors fibrinogen, von Willebrand factor, ADAMTS13, and neutrophil extracellular traps (NETs) levels were measured at baseline. Participants were followed until either onset of AF, loss-to-follow-up, or reaching the end-date of 01-01-2014. Cox proportional hazard modelling was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted for cardiovascular risk factors.

Results: We followed 6174 participants (mean age 69.1 years, 57% women) for a median follow-up time of 12.8 years. 364 men (13.7%, incidence rate 13.0/1000 person-years) and 365 women (10.4%, incidence rate 8.9/1000 person-years) developed AF. We found no significant association between markers of immunothrombosis and new-onset AF after adjusting for cardiovascular risk factors [HR 1.00 (95% CI 0.93-1.08) for fibrinogen, 1.04 (0.97-1.12) for von Willebrand factor, 1.00 (1.00-1.01) for ADAMTS13, and 1.01 (0.94-1.09) for NETs]. In addition, we found no differences in associations between men and women.

Conclusion: We found no associations between markers of immunothrombosis and new-onset AF in the general population. Inflammation and immunothrombosis may be associated with AF through other cardiovascular risk factors or predisposing conditions of AF. Our findings challenge the added value of biomarkers in AF risk prediction.
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http://dx.doi.org/10.1007/s00392-021-01938-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8766396PMC
January 2022

Circulating Myeloperoxidase (MPO)-DNA complexes as marker for Neutrophil Extracellular Traps (NETs) levels and the association with cardiovascular risk factors in the general population.

PLoS One 2021 11;16(8):e0253698. Epub 2021 Aug 11.

Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.

Introduction: Neutrophil extracellular traps (NETs) are DNA scaffolds enriched with antimicrobial proteins. NETs have been implicated in the development of various diseases, such as cardiovascular disease. Here, we investigate the association of demographic and cardiovascular (CVD) risk factors with NETs in the general population.

Material And Methods: Citrated plasma was collected from 6449 participants, aged ≥55 years, as part of the prospective population-based Rotterdam Study. NETs were quantified by measuring MPO-DNA complex using an ELISA. We used linear regression to determine the associations between MPO-DNA complex and age, sex, cardio-metabolic risk factors, and plasma markers of inflammation and coagulation.

Results: MPO-DNA complex levels were weakly associated with age (log difference per 10 year increase: -0.04 mAU/mL, 95% confidence interval [CI] -0.06;-0.02), a history of coronary heart disease (yes versus no: -0.10 mAU/mL, 95% CI -0.17;-0.03), the use of lipid-lowering drugs (yes versus no: -0.06 mAU/mL, 95% CI -0.12;-0.01), and HDL-cholesterol (per mmol/l increase: -0.07 mAU/mL/, 95% CI -0.12;-0.03).

Conclusions: Older age, a history of coronary heart disease, the use of lipid-lowering drugs and higher HDL-cholesterol are weakly correlated with lower plasma levels of NETs. These findings show that the effect of CVD risk factors on NETs levels in a general population is only small and may not be of clinical relevance. This supports that NETs may play a more important role in an acute phase of disease than in a steady state situation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253698PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357174PMC
November 2021

Use of rotational thromboelastometry to predict hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation: A retrospective cohort study.

Res Pract Thromb Haemost 2021 Jul 14;5(5):e12553. Epub 2021 Jul 14.

Department of Pediatric Hematology Erasmus Medical Center - Sophia Children's Hospital Rotterdam The Netherlands.

Background: The incidence of hemostatic complications in pediatric patients undergoing extracorporeal membrane oxygenation (ECMO) is high. The optimal anticoagulation strategy in children undergoing ECMO is unknown.

Objectives: To study the association between hemostatic complications, coagulation tests, and clinical parameters in pediatric patients undergoing ECMO and their effect on survival.

Methods: We performed a retrospective cohort study of pediatric patients undergoing centrifugal pump ECMO. Collected data included patient characteristics, risk factors, and coagulation test results. Statistical analysis was done using logistic regression analysis for repeated measurements. Dependent variables were thrombosis and bleeding, independent variables were rotational thromboelastometry (ROTEM), activated partial thromboplastin time (aPTT) and antifactor-Xa assay (aXa) results, ECMO duration, age <29 days, sepsis and surgery.

Results: Seventy-three patients with 623 ECMO days were included. Cumulative incidences of thrombosis and bleeding were 43.5% (95% confidence interval [CI], 26.0%-59.8%) and 25.4% (95% CI, 13.4%-39.3%), respectively. A lower maximum clot firmness of intrinsic ROTEM (INTEM; odds ratio [OR], 0.946; 95% CI, 0.920-0.969), extrinsic ROTEM (OR, 0.945; 95% CI, 0.912-0.973), and INTEM with heparinase (OR, 0.936; 95% CI, 0.896-0.968); higher activated partial thromboplastin time aPTT; OR, 1.020; 95% CI, 1.006-1.024) and age <29 days (OR, 2.900; 95% CI, 1.282-6.694); surgery (OR, 4.426; 95% CI, 1.543-12.694); and longer ECMO duration (OR, 1.149; 95% CI, 1.022-1.292) significantly increased thrombotic risk. Surgery (OR, 2.698; 95% CI, 1.543-12.694) and age <29 days (OR 2.242, 95% CI 1.282-6.694) were significantly associated with major bleeding. Patients with hemostatic complications had significantly decreased survival to hospital discharge ( = .009).

Conclusion: The results of this study help elucidate the role of ROTEM, aPTT, anti-factor Xa, and clinical risk factors in predicting hemostatic complications in pediatric patients undergoing ECMO.
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http://dx.doi.org/10.1002/rth2.12553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8279126PMC
July 2021

Clinical value of early viscoelastometric point-of-care testing during postpartum hemorrhage for the prediction of severity of bleeding: A multicenter prospective cohort study in the Netherlands.

Acta Obstet Gynecol Scand 2021 Sep 19;100(9):1656-1664. Epub 2021 Jun 19.

Center for Clinical Transfusion Research, Sanquin Research, Leiden, the Netherlands.

Introduction: To evaluate rotational fibrin-based thromboelastometry (ROTEM FIBTEM) with amplitude of clot firmness at 5 min (A5) as an early point-of-care parameter for predicting progression to severe postpartum hemorrhage, and compare its predictive value with that of fibrinogen.

Material And Methods: Prospective cohort study in the Netherlands including women with 800-1500 ml of blood loss within 24 h following birth. Blood loss was quantitatively measured by weighing blood-soaked items and using a fluid collector bag in the operating room. Both FIBTEM A5 values and fibrinogen concentrations (Clauss method) were measured between 800 and 1500  ml of blood loss. Predictive accuracy of both biomarkers for the progression to severe postpartum hemorrhage was measured by area under the receiver operating curves (AUC). Severe postpartum hemorrhage was defined as a composite endpoint of (1) total blood loss >2000 ml, (2) transfusion of ≥4 packed cells, and/or (3) need for an invasive intervention to cease bleeding.

Results: Of the 391 women included, 72 (18%) developed severe postpartum hemorrhage. Median (IQR) volume of blood loss at blood sampling was 1100 ml (1000-1300) with a median (interquartile range [IQR]) fibrinogen concentration of 3.9 g/L (3.4-4.6) and FIBTEM A5 value of 17 mm (13-20). The AUC for progression to severe postpartum hemorrhage was 0.53 (95% confidence interval [CI] 0.46-0.61) for FIBTEM A5 and 0.58 (95% CI 0.50-0.65) for fibrinogen. Positive predictive values for progression to severe postpartum hemorrhage for FIBTEM A5 ≤12 mm was 22.5% (95% CI 14-33) and 50% (95% CI 25-75) for fibrinogen ≤2 g/L.

Conclusions: The predictive value of FIBTEM A5 compared to fibrinogen concentrations measured between 800 and 1500 ml of blood loss following childbirth was poor to discriminate between women with and without progression towards severe postpartum hemorrhage.
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http://dx.doi.org/10.1111/aogs.14172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8453832PMC
September 2021

International Council for Standardization in Haematology (ICSH) laboratory guidance for the verification of haemostasis analyser-reagent test systems. Part 2: Specialist tests and calibrated assays.

Int J Lab Hematol 2021 Oct 20;43(5):907-916. Epub 2021 Apr 20.

Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, U.K.

Before a new method is used for clinical testing, it is essential that it is evaluated for suitability for its intended purpose. This document gives guidance for the performance, verification and implementation processes required by regulatory and accreditation bodies. It covers the planning and verification of specialist haemostatic tests, including factor assays, D-dimers, direct anticoagulants and thrombophilia testing.
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http://dx.doi.org/10.1111/ijlh.13550DOI Listing
October 2021

Outcome of Surgical Interventions and Deliveries in Patients with Bleeding of Unknown Cause: An Observational Study.

Thromb Haemost 2021 Nov 14;121(11):1409-1416. Epub 2021 Apr 14.

Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Background:  The most optimal management for patients with bleeding of unknown cause (BUC) is unknown, as limited data are available.

Objective:  Evaluate management and outcome of surgical procedures and deliveries in patients with BUC.

Materials And Methods:  All patients ≥12 years of age, referred to a tertiary center for a bleeding tendency, were included. Bleeding phenotype was assessed and hemostatic laboratory work-up was performed. Patients were diagnosed with BUC or an established bleeding disorder (BD). Data on bleeding and treatment during surgical procedures and delivery following diagnosis were collected.

Results:  Of 380 included patients, 228 (60%) were diagnosed with BUC and 152 (40%) with an established BD. In 14/72 (19%) surgical procedures major bleeding occurred and 14/41 (34%) deliveries were complicated by major postpartum hemorrhage (PPH). More specifically, 29/53 (55%) of the BUC patients who underwent surgery received prophylactic treatment to support hemostasis. Despite these precautions, 4/29 (14%) experienced major bleeding. Of BUC patients not treated prophylactically, bleeding occurred in 6/24 (25%). Of pregnant women with BUC, 2/26 (8%) received prophylactic treatment during delivery, one women with and 11 (46%) women without treatment developed major PPH.

Conclusion:  Bleeding complications are frequent in BUC patients, irrespective of pre- or perioperative hemostatic treatment. We recommend a low-threshold approach toward administration of hemostatic treatment in BUC patients, especially during delivery.
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http://dx.doi.org/10.1055/s-0041-1726344DOI Listing
November 2021

Thrombin generation is associated with ischemic stroke at a young age.

Thromb Res 2021 06 29;202:139-144. Epub 2021 Mar 29.

Erasmus MC, University Medical Center Rotterdam, Department of Hematology, the Netherlands. Electronic address:

Introduction: Understanding the underlying mechanisms in ischemic stroke (IS) in young adults remains challenging. Thrombin activates processes that contribute to the development and progression of arterial diseases. We investigated the association between thrombin generation (TG) and a first IS or transient ischemic attack (TIA) in young adults.

Methods: In this case-control study, we included consecutive patients (≤45 years in men, ≤55 years in women) with a first IS or TIA (n = 160) and healthy controls (n = 160). TG was determined with the calibrated automated thrombogram (CAT) assay. Logistic regression was used to analyze the association between TG and IS. Men and women were analyzed separately.

Results: TG started earlier, reached its peak earlier and was also terminated earlier in patients than in healthy controls. Peak height (PH) was higher in patients than in controls, 227 nM (25th-75th percentile 145-326) versus 179 nM (110-294), p = 0.02. The endogenous thrombin potential (ETP) was not different in patients and controls, 1530 nM·min (1089-2045) versus 1454 nM·min (1011-2139), p = 0.52. Lag time (LT) (Odds Ratio (OR) 0.91 (95% confidence interval (CI) 0.83-0.99)), time to peak (TTP) (OR 0.91, 95% CI 0.84-0.97) and time to tail (TTT) (OR 0.92, 95% CI 0.88-0.97) were associated with a first IS and TIA. In men LT, TTP and TTT were associated with IS, but not in women.

Conclusions: We found that TG parameters are associated with a first IS in young patients. Further prospective studies are warranted to elucidate the role of TG in IS.
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http://dx.doi.org/10.1016/j.thromres.2021.03.028DOI Listing
June 2021

Common and Rare Variants Genetic Association Analysis of Circulating Neutrophil Extracellular Traps.

Front Immunol 2021 24;12:615527. Epub 2021 Feb 24.

Department of Epidemiology, Erasmus University Medical Center, Rotterdam, Netherlands.

Introduction: Neutrophils contribute to host defense through different mechanisms, including the formation of neutrophil extracellular traps (NETs). The genetic background and underlying mechanisms contributing to NET formation remain unclear.

Materials And Methods: We performed a genome-wide association study (GWAS) and exome-sequencing analysis to identify common and rare genetic variants associated with plasma myeloperoxidase (MPO)-DNA complex levels, a biomarker for NETs, in the population-based Rotterdam Study cohort. GWAS was performed using haplotype reference consortium(HRC)-imputed genotypes of common variants in 3,514 individuals from the first and 2,076 individuals from the second cohort of the Rotterdam Study. We additionally performed exome-sequencing analysis in 960 individuals to investigate rare variants in candidate genes.

Results: The GWAS yielded suggestive associations (p-value < 5.0 × 10) of SNPs annotated to four genes. In the exome-sequencing analysis, a variant in gene was significantly associated with MPO-DNA complex levels (p-value < 3.06×10). Moreover, gene-based analysis showed ten genes () to be associated with MPO-DNA complex levels (p-value between 4.48 × 10 and 1.05 × 10). Pathway analysis of the identified genes showed their involvement in cellular development, molecular transport, RNA trafficking, cell-to-cell signaling and interaction, cellular growth and proliferation. Cancer was the top disease linked to the NET-associated genes.

Conclusion: In this first GWAS and exome-sequencing analysis of NETs levels, we found several genes that were associated with NETs. The precise mechanism of how these genes may contribute to neutrophil function or the formation of NETs remains unclear and should be further investigated in experimental studies.
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http://dx.doi.org/10.3389/fimmu.2021.615527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944992PMC
July 2021

Von Willebrand Factor Multimer Densitometric Analysis: Validation of the Clinical Accuracy and Clinical Implications in Von Willebrand Disease.

Hemasphere 2021 Mar 17;5(3):e542. Epub 2021 Feb 17.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, The Netherlands.

Von Willebrand factor (VWF) multimer analysis is important in the classification of von Willebrand disease (VWD). Current visual VWF multimer analysis is time consuming and inaccurate in detecting subtle changes in multimer patterns. Although VWF multimer densitometric analysis may be useful, the accuracy needs further investigation before it can be widely applied. In this study we aimed to validate VWF multimer densitometric analysis in a large cohort of VWD patients and to identify patient characteristics associated with densitometric outcomes. Patients were included from the Willebrand in the Netherlands (WiN) study, in which a bleeding score (BS) was obtained, and blood was drawn. For multimer analysis, citrated blood was separated on an agarose gel and visualized by Western blotting. IMAGEJ was used to generate densitometric images and medium-large VWF multimer index was calculated. We included 560 VWD patients: 328 type 1, 211 type 2, and 21 type 3 patients. Medium-large VWF multimer index performed excellent in distinguishing visually classified normal VWF multimers from reduced high-molecular-weight (HMW) multimers (area under the curve [AUC]: 0.96 [0.94-0.98], < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: β = -7.6 (-13.0 to -2.1), = 0.007, adjusted for confounders. Densitometric analysis of VWF multimers had an excellent accuracy compared with visual multimer analysis and may contribute to a better understanding of the clinical features such as the bleeding phenotype of VWD patients.
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http://dx.doi.org/10.1097/HS9.0000000000000542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892298PMC
March 2021

Endothelial Dysfunction, Atherosclerosis, and Increase of von Willebrand Factor and Factor VIII: A Randomized Controlled Trial in Swine.

Thromb Haemost 2021 May 14;121(5):676-686. Epub 2021 Jan 14.

Department of Hematology, Erasmus Medical Center, University Medical Center Rotterdam, Rotterdam, The Netherlands.

It is well known that high von Willebrand factor (VWF) and factor VIII (FVIII) levels are associated with an increased risk of cardiovascular disease. It is still debated whether VWF and FVIII are biomarkers of endothelial dysfunction and atherosclerosis or whether they have a direct causative role. Therefore, we aimed to unravel the pathophysiological pathways of increased VWF and FVIII levels associated with cardiovascular risk factors. First, we performed a randomized controlled trial in 34 Göttingen miniswine. Diabetes mellitus (DM) was induced with streptozotocin and hypercholesterolemia (HC) via a high-fat diet in 18 swine (DM + HC), while 16 healthy swine served as controls. After 5 months of follow-up, FVIII activity (FVIII:C) was significantly higher in DM + HC swine (5.85 IU/mL [5.00-6.81]) compared with controls (4.57 [3.76-5.40],  = 0.010), whereas VWF antigen (VWF:Ag) was similar (respectively 0.34 IU/mL [0.28-0.39] vs. 0.34 [0.31-0.38],  = 0.644). DM + HC swine had no endothelial dysfunction or atherosclerosis during this short-term follow-up. Subsequently, we performed a long-term (15 months) longitudinal cohort study in 10 Landrace-Yorkshire swine, in five of which HC and in five combined DM + HC were induced. VWF:Ag was higher at 15 months compared with 9 months in HC (0.37 [0.32-0.42] vs. 0.27 [0.23-0.40],  = 0.042) and DM + HC (0.33 [0.32-0.37] vs. 0.25 [0.24-0.33],  = 0.042). Both long-term groups had endothelial dysfunction compared with controls and atherosclerosis after 15 months. In conclusion, short-term hyperglycemia and dyslipidemia increase FVIII, independent of VWF. Long-term DM and HC increase VWF via endothelial dysfunction and atherosclerosis. Therefore, VWF seems to be a biomarker for advanced cardiovascular disease.
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http://dx.doi.org/10.1055/s-0040-1722185DOI Listing
May 2021

Criteria for low von Willebrand factor diagnosis and risk score to predict future bleeding.

J Thromb Haemost 2021 03 24;19(3):719-731. Epub 2021 Jan 24.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Background: Important diagnostic and clinical aspects of moderately reduced von Willebrand factor (VWF) levels are still unknown. There is no clear evidence which cutoff value (0.50 vs 0.60 IU/ml) should be used to diagnose "low VWF." Also, the incidence of bleeding after the diagnosis has been made, and risk factors for bleeding are unknown yet.

Objectives: To investigate the incidence of postsurgical bleeding, postpartum hemorrhage (PPH), and traumatic and spontaneous bleeding after low VWF diagnosis, and to develop a risk score to predict future bleeding.

Methods: We performed a cohort study in patients with historically lowest VWF levels of 0.31 to 0.60 IU/ml. Clinical data of patients were retrospectively collected.

Results: We included 439 patients with low VWF. During a follow-up of 6.3 ± 3.7 years, 259 surgical procedures, 81 deliveries, and 109 spontaneous and traumatic bleeding episodes were reported. The incidence of postsurgical bleeding was 2.7%, whereas 10% of deliveries was complicated by PPH. Overall, 65 patients (14.8%) had bleeding requiring treatment, which was not different between patients with historically lowest VWF levels of 0.31-0.50 and 0.51-0.60 IU/ml (p = .154). Age <18 years, abnormal bleeding score at diagnosis, and being referred for bleeding symptoms at the time of diagnosis were independent risk factors for bleeding during follow-up, and therefore included in the risk score.

Conclusions: The cutoff value of low VWF diagnosis should be set at 0.60 IU/ml. Furthermore, a risk score is developed to identify individuals with a high risk for bleeding after low VWF diagnosis.
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http://dx.doi.org/10.1111/jth.15227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986755PMC
March 2021

A Mendelian randomization of γ' and total fibrinogen levels in relation to venous thromboembolism and ischemic stroke.

Blood 2020 12;136(26):3062-3069

Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.

Fibrinogen is a key component of the coagulation cascade, and variation in its circulating levels may contribute to thrombotic diseases, such as venous thromboembolism (VTE) and ischemic stroke. Gamma prime (γ') fibrinogen is an isoform of fibrinogen that has anticoagulant properties. We applied 2-sample Mendelian randomization (MR) to estimate the causal effect of total circulating fibrinogen and its isoform, γ' fibrinogen, on risk of VTE and ischemic stroke subtypes using summary statistics from genome-wide association studies. Genetic instruments for γ' fibrinogen and total fibrinogen were selected, and the inverse-variance weighted MR approach was used to estimate causal effects in the main analysis, complemented by sensitivity analyses that are more robust to the inclusion of pleiotropic variants, including MR-Egger, weighted median MR, and weighted mode MR. The main inverse-variance weighted MR estimates based on a combination of 16 genetic instruments for γ' fibrinogen and 75 genetic instruments for total fibrinogen indicated a protective effect of higher γ' fibrinogen and higher total fibrinogen on VTE risk. There was also a protective effect of higher γ' fibrinogen levels on cardioembolic and large artery stroke risk. Effect estimates were consistent across sensitivity analyses. Our results provide evidence to support effects of genetically determined γ' fibrinogen on VTE and ischemic stroke risk. Further research is needed to explore mechanisms underlying these effects and their clinical applications.
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http://dx.doi.org/10.1182/blood.2019004781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770565PMC
December 2020

Biomarker association with cardiovascular disease and mortality - The role of fibrinogen. A report from the NHANES study.

Thromb Res 2021 02 16;198:182-189. Epub 2020 Dec 16.

Centre of Excellence for Nutrition, North-West University, Potchefstroom, South Africa; Pediatric Epidemiology, Department of Pediatrics, University Medicine Leipzig, Leipzig, Germany.

Background: While fibrinogen is a known cardiovascular disease (CVD) risk marker, its quantitative input to mortality risk is a topic of debate.

Methods: We investigated the contribution of fibrinogen, among that of other biomarkers, to prevalent CVD and incident CVD mortality in 4487 participants of the US National Health and Nutrition Examination Survey (NHANES). Participants were observed for a median period of 14 years, resulting in more than 58,000 person-years.

Results: At baseline 551 participants had CVD and during follow up, 1339 all-cause deaths occurred, 321 (24%) of which were due to CVD. Hierarchical cluster analysis and principal component analysis (PCA) were performed to derive clusters of association between biomarkers. Next, structural equation modelling was performed to investigate the association of these clusters with baseline CVD and all-cause and CVD mortality during follow-up. Mediation analysis was used to determine which biomarkers played a mediatory role between prevalent CVD and future mortality. Fibrinogen clustered with C-reactive protein only and was associated with CVD at baseline (p < 0.0001) and with all-cause (p < 0.001) and CVD (p < 0.001) mortality at follow-up. Only fibrinogen (4.7%), followed by gamma-glutamyl transferase (GGT) (3.5%) and uric acid (2.3%) were identified as possible mediators between CVD status and all-cause mortality, with fibrinogen (3.2%) and GGT (3.1%) the only mediators between CVD status and CVD mortality.

Conclusion: This data shows that fibrinogen is not only cross-sectionally associated with CVD, but also contributes to all-cause and CVD mortality at follow-up. It furthermore appears to mediate the association between prevalent CVD and both all-cause and CVD mortality.
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http://dx.doi.org/10.1016/j.thromres.2020.12.009DOI Listing
February 2021

ADAMTS-13 and bleeding phenotype in von Willebrand disease.

Res Pract Thromb Haemost 2020 Nov 31;4(8):1331-1339. Epub 2020 Oct 31.

Department of Hematology Erasmus MC, University Medical Center Rotterdam Rotterdam The Netherlands.

Background: The bleeding phenotype of von Willebrand disease (VWD) varies highly between patients and can only partly be explained by von Willebrand factor (VWF) parameters. By cleaving large VWF multimers into smaller, less active multimers, ADAMTS-13 is an important regulator of VWF activity. However, it is unknown what the role of ADAMTS-13 is in individuals with VWD.

Objectives: We therefore studied how ADAMTS-13 activity is associated with the laboratory and bleeding phenotype in individuals with VWD.

Methods: We measured ADAMTS-13 activity using the fluorescence resonance energy transfer substrate VWF 73 assay in 638 individuals with VWD in the nationwide cross-sectional Willebrand in the Netherlands study and in 36 healthy controls. The bleeding phenotype was assessed using the Tosetto bleeding score.

Results: ADAMTS-13 activity was similar in individuals with VWD (109% ± 20.6%) and controls (110% ± 19.7%). ADAMTS-13 activity was higher in individuals with VWD with type 3 than those with type 1 (mean difference, 11.8%; 95% confidence interval [CI], 2.9%-20.8%) or type 2 (mean difference, 16.1%; 95% CI, 7.1%-25.1%). ADAMTS-13 activity was not associated with the Tosetto bleeding score (0.1 Tosetto bleeding score increase per 10% ADAMTS-13 increase, 95% CI, -0.2 to 0.3). Furthermore, ADAMTS-13 activity did not differ between individuals with and without a bleeding event during the year preceding blood sampling (mean difference, 1.4%; 95% CI, -2.1% to 4.9%).

Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD.
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http://dx.doi.org/10.1002/rth2.12442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695560PMC
November 2020

International Council for Standardization in Haematology (ICSH) laboratory guidance for the evaluation of haemostasis analyser-reagent test systems. Part 1: Instrument-specific issues and commonly used coagulation screening tests.

Int J Lab Hematol 2021 Apr 29;43(2):169-183. Epub 2020 Nov 29.

Sheffield Haemophilia and Thrombosis Centre, Royal Hallamshire Hospital, Sheffield, UK.

Before a new method is used for clinical testing, it is essential that it is evaluated for suitability for its intended purpose. This document gives guidance for the performance of verification, validation and implementation processes required by regulatory and accreditation bodies. It covers the planning and execution of an evaluation of the commonly performed screening tests (prothrombin time, activated partial thromboplastin time, thrombin time and fibrinogen assay), and instrument-specific issues. Advice on selecting an appropriate haemostasis analyser, planning the evaluation, and assessing the reference, interval, precision, accuracy, and comparability of a haemostasis test system are also given. A second companion document will cover specialist haemostasis testing.
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http://dx.doi.org/10.1111/ijlh.13411DOI Listing
April 2021

Effects of Diabetes Mellitus on Fibrin Clot Structure and Mechanics in a Model of Acute Neutrophil Extracellular Traps (NETs) Formation.

Int J Mol Sci 2020 Sep 26;21(19). Epub 2020 Sep 26.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.
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http://dx.doi.org/10.3390/ijms21197107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582521PMC
September 2020

FIBTEM clot firmness parameters correlate well with the fibrinogen concentration measured by the Clauss assay in patients and healthy subjects.

Scand J Clin Lab Invest 2020 Nov 14;80(7):600-605. Epub 2020 Sep 14.

Department of Hematology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

The Clauss assay is the assay most often used for measuring plasma fibrinogen levels. However, the FIBTEM-assay, determined using thromboelastometry (ROTEM) can also be used to estimate fibrinogen levels. A major advantage of the FIBTEM is that it can provide information about fibrinogen levels within minutes, while the Clauss assay needs 30-60 min before the result is available. The aim of this study was to investigate the correlation between fibrinogen levels measured by the Clauss assay and results from the FIBTEM-assay. We included 111 patients ≥18 years for whom both ROTEM analyses and a fibrinogen measurement using the Clauss assay were available. In addition, ROTEM and Clauss measurements from 75 healthy subjects were included. Spearman correlation was used to determine the association between the results of both assays. The patients included were mostly patients with major trauma or undergoing large surgery (e.g. cardiac surgery or liver transplantation). Strong correlations were found between FIBTEM clot firmness parameters and fibrinogen levels measured by the Clauss assay in patients (Spearman's correlation coefficients (r) above 0.80 ( < .001) for all subgroups) and healthy subjects (r = 0.66,  < .001). The correlation between early FIBTEM parameters (clot firmness at 5 or 10 min) and the maximum clot firmness was almost perfect (r above 0.96). Also, the correlation between the α-angle and FIBTEM parameters was strong (r above 0.7). In conclusion, strong correlations were found between early FIBTEM parameters and fibrinogen levels.
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http://dx.doi.org/10.1080/00365513.2020.1818283DOI Listing
November 2020

Reductions in plasmin inhibitor and fibrinogen predict the improved fibrin clot lysis 6 months after obesity surgery.

Clin Obes 2020 Dec 22;10(6):e12397. Epub 2020 Aug 22.

Department of Clinical Biochemistry, Unit for Thrombosis Research, University Hospital of Southern Denmark, Esbjerg, Denmark.

Prothrombotic and metabolic variables are decreased after obesity surgery, and fibrin clot lysis is increased. It is unknown how fibrinolytic variables are affected, and whether fibrinolytic and metabolic changes predict the enhanced clot lysis. Study aims were to determine fibrinolytic biomarkers before and 6 months after Roux-en-Y gastric bypass (RYGB) and to identify predictors of the RYGB-induced increase in clot lysis. Women (n = 42) and men (n = 18) with obesity underwent RYGB, and factor XIII (FXIII), thrombin activatable fibrinolysis inhibitor (TAFI), plasminogen and plasmin inhibitor (PI) were measured before and 6 months after surgery. Regression analyses identified determinants of the RYGB-induced increase in clot lysis among changes in fibrinogen and in fibrinolytic and metabolic variables. Results showed that after RYGB, FXIII, TAFI, plasminogen and PI were reduced (P < .0005). Reductions in PI (β = -0.59) and fibrinogen (β = -0.35), together with age (β = -0.22) and male sex (β = 0.22), predicted the enhanced clot lysis with the model explaining 56% (P < .0005). Predictors of the reduction in PI were reductions in cholesterol (β = 0.37) and glucose (β = 0.29), together with male sex (β = -0.28), whereas reductions in fibrinogen were predicted by lowering of interleukin-6 (IL-6) (β = 0.32). In conclusion, fibrinolytic variables were reduced 6 months after RYGB. Targeting PI and fibrinogen, by reducing metabolic variables such as glucose, cholesterol and IL-6, has a profibrinolytic effect in obesity.
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http://dx.doi.org/10.1111/cob.12397DOI Listing
December 2020

Correction: Faria, A.V.S. et al., Targeting Tyrosine Phosphatases by 3-Bromopyruvate Overcomes Hyperactivation of Platelets from Gastrointestinal Cancer Patients. 2019, , 936.

J Clin Med 2020 Aug 13;9(8). Epub 2020 Aug 13.

Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, NL-3000 CA Rotterdam, The Netherlands.

The authors wish to make the following correction to their paper [...].
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http://dx.doi.org/10.3390/jcm9082625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465274PMC
August 2020

The one-stage assay or chromogenic assay to monitor baseline factor VIII levels and desmopressin effect in non-severe haemophilia A: Superiority or non-inferiority?

Haemophilia 2020 Sep 26;26(5):916-922. Epub 2020 Jul 26.

Department of Haematology, Erasmus University Medical Centre, Rotterdam, The Netherlands.

Introduction: Diagnosis, treatment monitoring and assessment of desmopressin effect in haemophilia A patients are performed by measurement of factor VIII activity (FVIII). The two assays commonly applied are the one-stage assay and the chromogenic assay. Especially in non-severe haemophilia A, discrepancies between these assays are common. It is still unestablished which assay corresponds best with bleeding phenotype and desmopressin effect.

Aim: To correlate FVIII levels measured by the one-stage assay and by the chromogenic assay with bleeding phenotype and, additionally, to compare FVIII assay discrepancies before and after desmopressin administration.

Method: Factor VIII was measured in 130 non-severe haemophilia A patients during routine visits to the outpatient clinic and/or during desmopressin testing. FVIII was measured by both the one-stage assay and the chromogenic assay. Discrepancies between assays were defined as at least a twofold difference of FVIII or an absolute FVIII difference between measurements of ≥0.10 IU/mL. Bleeding phenotype was defined as annual number of treated bleedings (adjusted ABR).

Results: Hundred and thirty non-severe haemophilia A patients were included. In 31/130 patients, assay results were discrepant. However, FVIII measurements with both assays correlated adequately with adjusted ABR. In addition, in 27/130 patients FVIII measurements at baseline and after desmopressin administration were analysed. In 13/27 patients, all measurements were either equivalent or discrepant when results were compared. In 14/27 patients, this was not the case as both equivalent measurements and discrepant measurements at different time points within one patient were observed.

Conclusion: Neither the one-stage assay nor the chromogenic assay is superior in predicting bleeding phenotype. In addition, equivalent or discrepant FVIII results measured before desmopressin do not always predict FVIII assay results after desmopressin administration.
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http://dx.doi.org/10.1111/hae.14106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590113PMC
September 2020
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