Calibration of prothrombin time (PT) in terms of international normalized ratio (INR) has been outlined in “Guidelines for thromboplastins and plasmas used to control oral anticoagulant therapy” ... Show moreCalibration of prothrombin time (PT) in terms of international normalized ratio (INR) has been outlined in “Guidelines for thromboplastins and plasmas used to control oral anticoagulant therapy” (World Health Organization, 2013). The international standard ISO 17511:2020 presents requirements for manufacturers of in vitro diagnostic (IVD) medical devices (MDs) for documenting the calibration hierarchy for a measured quantity in human samples using a specified IVD MD. The objective of this article is to define an unequivocal, metrologically traceable calibration hierarchy for the INR measured in plasma as well as in whole blood samples. Calibration of PT and INR for IVD MDs according to World Health Organization guidelines is similar to that in cases where there is a reference measurement procedure that defines the measurand for value assignment as described in ISO 17511:2020. We conclude that, for PT/INR standardization, the optimal calibration hierarchy includes a primary process to prepare an international reference reagent and measurement procedure that defines the measurand by a value assignment protocol conforming to clause 5.3 of ISO 17511:2020. A panel of freshly prepared human plasma samples from healthy adult individuals and patients on vitamin K antagonists is used as a commutable secondary calibrator as described in ISO 17511:2020. A sustainable metrologically traceable calibration hierarchy for INR should be based on an international protocol for value assignment with a single primary reference thromboplastin and the harmonized manual tilt tube technique for clotting time determination. The primary international reference thromboplastin reagent should be used only for calibration of successive batches of the secondary reference thromboplastin reagent Show less
Nemeth, B.; Smeets, M.; Pedersen, A.B.; Kristiansen, E.B.; Nelissen, R.; Whyte, M.; ... ; Arya, R. 2024
Background: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. Objectives: To... Show moreBackground: The risk of venous thromboembolism (VTE) following total hip arthroplasty (THA) and total knee arthroplasty (TKA) is 1.0% to 1.5%, despite uniform thromboprophylaxis. Objectives: To develop and validate a prediction model for 90-day VTE risk. Methods: A multinational cohort study was performed. For model development, records were used from the Oxford Royal College of General Practitioners Research and Surveillance Centre linked to Hospital Episode Statistics and Office of National Statistics UK routine data. For external validation, data were used from the Danish Hip and Knee Arthroplasty Registry, the National Patient Registry, and the National Prescription Registry. Binary multivariable logistic regression techniques were used for development. Results: In the UK data set, 64 032 THA/TKA procedures were performed and 1.4% developed VTE. The prediction model consisted of age, body mass index, sex, cystitis within 1 year before surgery, history of phlebitis, history of VTE, presence of varicose veins, presence of asthma, history of transient ischemic attack, history of myocardial infarction, presence of hypertension and THA or TKA. The area under the curve of the model was 0.65 (95% CI, 0.63-0.67). Furthermore, 36 169 procedures were performed in the Danish cohort, of whom 1.0% developed VTE. Here, the area under the curve was 0.64 (95% CI, 0.61-0.67). The calibration slope was 0.92 in the validation study and 1.00 in the development study. Conclusion: This clinical prediction model for 90-day VTE risk following THA and TKA performed well in both development and validation data. This model can be used to estimate an individual’s risk for VTE following THA/TKA. Show less
Patient-reported outcome measures (PROMs) are patient-completed instruments that capture patient-perceived health status and well-being. PROMs measure disease impact and outcomes of care as... Show morePatient-reported outcome measures (PROMs) are patient-completed instruments that capture patient-perceived health status and well-being. PROMs measure disease impact and outcomes of care as reported by those who experience the disease. After pulmonary embolism or deep vein thrombosis, patients may face a broad spectrum of complications and long-term sequelae beyond the usual quality-of-care indicators of recurrent venous thromboembolism (VTE), bleeding complications, and survival. The full impact of VTE on individual patients can only be captured by assessing all relevant health outcomes from the patient’s perspective in addition to the traditionally recognized complications. Defining and measuring all important outcomes will help facilitate treatment tailored to the needs and preferences of patients and may improve health outcomes. The International Society on Thrombosis and Haemostasis Scientific and Standardization Committee Subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease endorsed the International Consortium for Health Outcomes Measurement (ICHOM) VTE project on development of a standardized set of patient-centered outcome measures for patients with VTE. In this communication, the course and result of the project are summarized, and based on these findings, we propose recommendations for the use of PROMs during clinical follow-up of patients with VTE. We describe challenges to implementation of PROMs and explore barriers and enablers. Show less
Maanen, R. van; Martens, E.S.L.; Takada, T.; Roy, P.M.; Wit, K. de; Parpia, S.; ... ; Luijken, K. 2023
BackgroundIn patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation (“gestalt”) of PE presence. Although shown to be predictive, gestalt is... Show moreBackgroundIn patients clinically suspected of having pulmonary embolism (PE), physicians often rely on intuitive estimation (“gestalt”) of PE presence. Although shown to be predictive, gestalt is criticized for its assumed variation across physicians and lack of standardization.ObjectivesTo assess the diagnostic accuracy of gestalt in the diagnosis of PE and gain insight into its possible variation.MethodsWe performed an individual patient data meta-analysis including patients suspected of having PE. The primary outcome was diagnostic accuracy of gestalt for the diagnosis of PE, quantified as risk ratio (RR) between gestalt and PE based on 2-stage random-effect log-binomial meta-analysis regression as well as gestalts’ sensitivity and specificity. The variability of these measures was explored across different health care settings, publication period, PE prevalence, patient subgroups (sex, heart failure, chronic lung disease, and items of the Wells score other than gestalt), and age.ResultsWe analyzed 20 770 patients suspected of having PE from 16 original studies. The prevalence of PE in patients with and without a positive gestalt was 28.8% vs 9.1%, respectively. The overall RR was 3.02 (95% CI, 2.35-3.87), and the overall sensitivity and specificity were 74% (95% CI, 68%-79%) and 61% (95% CI, 53%-68%), respectively. Although variation was observed across individual studies (I2, 90.63%), the diagnostic accuracy was consistent across all subgroups and health care settings.ConclusionA positive gestalt was associated with a 3-fold increased risk of PE in suspected patients. Although variation was observed across studies, the RR of gestalt was similar across prespecified subgroups and health care settings, exemplifying its diagnostic value for all patients suspected of having PE. Show less
BackgroundHeavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs),... Show moreBackgroundHeavy menstrual bleeding (HMB) is associated with a reduced quality of life and limitations in social and physical functioning. Data on HMB in women with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, are scarce.ObjectivesTo analyze the prevalence, severity, and treatment of HMB in Dutch women with an RBD.MethodsThe Rare Bleeding Disorders in the Netherlands (RBiN) study included 263 patients with an RBD from all 6 hemophilia treatment centers (October 2017-November 2019). In this analysis, data of 111 women aged ≥16 years were studied. According to the International Society on Thrombosis and Haemostasis bleeding assessment tool, HMB symptoms were scored from 0 (no/trivial) to 4 (severe symptoms requiring medical intervention). HMB was defined as a score ≥1. Age at RBD diagnosis was extracted from patient files.ResultsHMB was reported by 80% of women (89/111) and was more prevalent in women with a fibrinolytic disorder (33/35; 94%) than in women with a coagulation factor deficiency (56/76; 74%) (P = .011). Of the 89 women with HMB, 82% (n = 73) ever required treatment. Multiple treatment modalities were frequently used, both in severe and mild deficiencies. Hormonal treatment was mostly used (n = 64; 88%), while antifibrinolytics were prescribed less frequently (n = 18; 25%). In women with HMB since menarche (n = 61; 69%), median age at RBD diagnosis was 28 years (IQR, 14-41).ConclusionHMB is common in women with RBDs. Women with mild deficiencies also frequently reported HMB. Only a minority of women were treated with hemostatic agents. A significant diagnostic delay was observed after the onset of HMB symptoms. Show less
Yuan, L.S.; Han, J.H.; Velden, A.I.M.V.; Vink, H.; Mutsert, R. de; Rosendaal, F.R.; ... ; Berg, B.M. van den 2023
Background: Microvascular dysfunction is a growing determinant of sex differences in coronary heart disease (CHD). Dysregulation of the coagulation system is involved in CHD pathogenesis and can be... Show moreBackground: Microvascular dysfunction is a growing determinant of sex differences in coronary heart disease (CHD). Dysregulation of the coagulation system is involved in CHD pathogenesis and can be induced by endothelial glycocalyx (EG) perturbation. However, little is known about the link between EG function and coagulation parameters in population-based studies on sex specificity.Objectives: We sought to examine the sex differences in the relationship between EG function and coagulation parameters in a middle-aged Dutch population.Methods: Using baseline measurements of 771 participants from the Netherlands Epidemiology of Obesity study (age, 56 years [IQR, 51-61 years]; 53% women; body mass index, 27.9 kg/m2 [IQR, 25.1-30.9 kg/m2 ]), associations between glycocalyxrelated perfused boundary region (PBR) derived using sidestream dark-field imaging and coagulation parameters (factor [F]VIII/IX/XI; thrombin generation parameters; and fibrinogen) were investigated using linear regression analyses, adjusting for possible confounders (including C-reactive protein, leptin, and glycoprotein acetyls), followed by sex-stratified analyses.Results: There was a sex difference in the associations between PBR and coagulation parameters. Particularly in women, 1-SD PBR (both total and feed vessel, indicating poorer glycocalyx status) was associated with higher FIX activity ([1.8%; 95% CI, 0.3%- 3.3%] and [2.0%; 95% CI, 0.5%-3.4%], respectively) and plasma fibrinogen levels ([5.1 mg/dL; 95% CI, 0.4-9.9 mg/dL] and [5.8 mg/dL; 95% CI, 1.1-10.6 mg/dL], respectively). Furthermore, 1-SD PBRcapillary was associated with higher FVIII activity (3.5%; 95% CI, 0.4%-6.5%) and plasma fibrinogen levels (5.3 mg/dL; 95% CI, 0.6-10.0 mg/dL).Conclusion: We revealed a sex-specific association between microcirculatory health and procoagulant status, which suggests that microvascular health be considered during early development of CHD in women. Show less
BackgroundRecombinant factor (F)IX-FIAV has previously been shown to function independently of activated FVIII (FVIIIa) and ameliorate the hemophilia A (HA) phenotype in vitro and in vivo.Objective... Show moreBackgroundRecombinant factor (F)IX-FIAV has previously been shown to function independently of activated FVIII (FVIIIa) and ameliorate the hemophilia A (HA) phenotype in vitro and in vivo.ObjectivesThe aim of this study was to assess the efficacy of FIX-FIAV in plasma from HA patients using thrombin generation (TG) and intrinsic clotting activity (activated partial thromboplastin time [APTT]) analyses.MethodsPlasma obtained from 21 patients with HA (>18 years; 7 mild, 7 moderate, and 7 severe patients) was spiked with FIX-FIAV. The FXIa-triggered TG lag time and APTT were quantified in terms of FVIII-equivalent activity using FVIII calibration for each patient plasma.ResultsThe linear, dose-dependent improvement in the TG lag time and APTT reached its maximum with approximately 400% to 600% FIX-FIAV in severe HA plasma and with approximately 200% to 250% FIX-FIAV in nonsevere HA plasma. The cofactor-independent contribution of FIX-FIAV was therefore suggested and confirmed by the addition of inhibitory anti-FVIII antibodies to nonsevere HA plasma, resulting in a FIX-FIAV response similar to severe HA plasma. Addition of 100% (5 μg/mL) FIX-FIAV mitigated the HA phenotype from severe to moderate (from <0.01% to 2.9% [IQR 2.3%-3.9%] FVIII-equivalent activity), from moderate to mild (3.9% [IQR 3.3%-4.9%] to 16.1% [IQR 13.7%-18.1%] FVIII-equivalent activity), and from mild to normal (19.8% [IQR 9.2%-24.0%] to 48.0% [IQR 34.0%-67.5%] FVIII-equivalent activity). No substantial effects were observed when combining FIX-FIAV with current HA therapies.ConclusionFIX-FIAV is capable of increasing the FVIII-equivalent activity and coagulation activity in plasma from HA patients, thereby mitigating the HA phenotype. Hence, FIX-FIAV could serve as a potential treatment for HA patients with or without inhibitors. Show less
BackgroundRecombinant factor (F)IX-FIAV has previously been shown to function independently of activated FVIII (FVIIIa) and ameliorate the hemophilia A (HA) phenotype in vitro and in vivo.Objective... Show moreBackgroundRecombinant factor (F)IX-FIAV has previously been shown to function independently of activated FVIII (FVIIIa) and ameliorate the hemophilia A (HA) phenotype in vitro and in vivo.ObjectivesThe aim of this study was to assess the efficacy of FIX-FIAV in plasma from HA patients using thrombin generation (TG) and intrinsic clotting activity (activated partial thromboplastin time [APTT]) analyses.MethodsPlasma obtained from 21 patients with HA (>18 years; 7 mild, 7 moderate, and 7 severe patients) was spiked with FIX-FIAV. The FXIa-triggered TG lag time and APTT were quantified in terms of FVIII-equivalent activity using FVIII calibration for each patient plasma.ResultsThe linear, dose-dependent improvement in the TG lag time and APTT reached its maximum with approximately 400% to 600% FIX-FIAV in severe HA plasma and with approximately 200% to 250% FIX-FIAV in nonsevere HA plasma. The cofactor-independent contribution of FIX-FIAV was therefore suggested and confirmed by the addition of inhibitory anti-FVIII antibodies to nonsevere HA plasma, resulting in a FIX-FIAV response similar to severe HA plasma. Addition of 100% (5 μg/mL) FIX-FIAV mitigated the HA phenotype from severe to moderate (from <0.01% to 2.9% [IQR 2.3%-3.9%] FVIII-equivalent activity), from moderate to mild (3.9% [IQR 3.3%-4.9%] to 16.1% [IQR 13.7%-18.1%] FVIII-equivalent activity), and from mild to normal (19.8% [IQR 9.2%-24.0%] to 48.0% [IQR 34.0%-67.5%] FVIII-equivalent activity). No substantial effects were observed when combining FIX-FIAV with current HA therapies.ConclusionFIX-FIAV is capable of increasing the FVIII-equivalent activity and coagulation activity in plasma from HA patients, thereby mitigating the HA phenotype. Hence, FIX-FIAV could serve as a potential treatment for HA patients with or without inhibitors. Show less
BackgroundThe population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces... Show moreBackgroundThe population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT.ObjectivesThe objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia.MethodsWe performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands.ResultsIn total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02).ConclusionThis study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population. Show less
Mulder, F.I.; Kraaijpoel, N.; Carrier, M.; Guman, N.A.; Jara-Palomares, L.; Nisio, M. di; ... ; Es, N. van 2023
BackgroundPlatelet RNA sequencing has been shown to accurately detect cancer in previous studies.ObjectivesTo compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited .Show moreBackgroundPlatelet RNA sequencing has been shown to accurately detect cancer in previous studies.ObjectivesTo compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screeningin patients with unprovoked venous thromboembolism (VTE).MethodsPatients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity.ResultsA total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47).ConclusionPlatelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm. Show less
Zwagemaker, A.F.; Kloosterman, F.R.; Gouw, S.C.; Boyce, S.; Brons, P.; Cnossen, M.H.; ... ; DYNAMO Study Grp 2023
BackgroundType 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived... Show moreBackgroundType 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions.ObjectiveThe objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS.MethodsAn indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay.ResultsIn total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14).ConclusionsAnti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used. Show less
BackgroundWomen with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, may have a higher risk of postpartum hemorrhage (PPH). Information on this... Show moreBackgroundWomen with rare bleeding disorders (RBDs), including coagulation factor deficiencies and fibrinolytic disorders, may have a higher risk of postpartum hemorrhage (PPH). Information on this patient category is lacking in the existing PPH guidelines because data on PPH in patients with RBDs are scarce.ObjectiveTo describe the prevalence of PPH in women with an RBD and evaluate the use of peripartum hemostatic prophylaxis.MethodsIn the Rare Bleeding Disorders in the Netherlands (RBiN) study, patients with RBDs (n = 263) were included from all 6 Dutch hemophilia treatment centers. Patient–reported information on delivery, peripartum hemostatic prophylaxis, and occurrence of PPH was collected retrospectively. If available, information about the precise volume of postpartum blood loss was extracted from electronic patient files. PPH was defined as blood loss ≥500 mL (World Health Organization guideline).ResultsA total of 244 pregnancies, including 193 livebirths, were reported by 85 women. A considerable proportion of these women experienced PPH, ranging from 30% in factor V deficiency to 100% in hyperfibrinolysis. Overall, PPH was reported in 44% of deliveries performed with and 53% of deliveries performed without administration of peripartum hemostatic prophylaxis. Blood loss was significantly higher in deliveries without administration of hemostatic prophylaxis (median 1000 mL) compared to deliveries with administration of prophylaxis (median 400 mL) (p = 0.011). Patients with relatively mild deficiencies also frequently experienced PPH when peripartum hemostatic prophylaxis was omitted.ConclusionPPH is common in rare coagulation factor deficiencies, both severe and mild, and fibrinolytic disorders, especially when peripartum prophylactic hemostatic treatment was not administered. The use of prophylactic hemostatic treatment was associated with less postpartum blood loss. Show less
Kreft, I.C.; Huisman, E.J.; Cnossen, M.H.; Alphen, F.P.J. van; Zwaan, C. van der; Leeuwen, K. van; ... ; Hoogendijk, A.J. 2023
BackgroundInherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet... Show moreBackgroundInherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited.ObjectivesThe objective of this study was to profile the platelet proteomics signatures of IPDs.MethodsWe performed unbiased label-free quantitative mass spectrometry (MS)–based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development.ResultsIn line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins.ConclusionsWith this study, we demonstrate a MS–based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function. Show less
Background: Patients with lower-leg injuries and those undergoing knee arthroscopy are at increased risk of developing venous thromboembolism. The mechanism is un-known, including the influence of... Show moreBackground: Patients with lower-leg injuries and those undergoing knee arthroscopy are at increased risk of developing venous thromboembolism. The mechanism is un-known, including the influence of lower-leg injury and knee arthroscopy on natural anticoagulant factors and fibrinolysis.Objectives: To study the effect of lower-leg injury and knee arthroscopy on plasma levels of anticoagulant and fibrinolytic factors.Methods: We applied the following 2 designs to investigate this effect: a cross-sectional study for lower-leg trauma and a before-and-after study for knee arthroscopy. Plasma samples of POT-CAST- and POT-KAST-randomized clinical trial participants (collected shortly after lower-leg trauma or before or after arthroscopy) were analyzed for clot lysis time and levels of antithrombin, tissue factor pathway inhibitor, protein C, free protein S, plasminogen, tissue plasminogen activator, plasminogen activator inhibitor 1, antiplasmin, thrombin activatable fibrinolysis inhibitor, plasmin-antiplasmin, and D-dimer. For the effect of lower-leg injury, samples of 289 patients were compared with preoperative samples of 293 arthroscopy patients, acting as controls using linear regression and adjusting for age, sex, body mass index, comorbidities, and diurnal variation. For the effect of knee arthroscopy, mean changes were calculated for 277 patients using linear mixed models adjusted for diurnal variation. Parameters other than CLT and D-dimer were measured in smaller subsets.Results: In lower-leg injury patients, most parameters were stable, whereas D-dimer increased. After arthroscopy, most parameters decreased (especially clot lysis time, D-dimer, plasminogen, and anticoagulant factors), whereas tissue plasminogen activator and thrombin activatable fibrinolysis inhibitor slightly increased.Conclusion: In contrast to lower-leg injury, knee arthroscopy was associated with decreased natural anticoagulant factor levels. Neither lower-leg injury nor knee arthroscopy affected in vivo fibrinolysis. Show less
Background The formation of alloantibodies directed against class I human leukocyte antigens (HLA) continues to be a clinically challenging complication after platelet transfusions, which can lead... Show moreBackground The formation of alloantibodies directed against class I human leukocyte antigens (HLA) continues to be a clinically challenging complication after platelet transfusions, which can lead to platelet refractoriness (PR) and occurs in approximately 5%-15% of patients with chronic platelet support. Interestingly, anti-HLA IgG levels in alloimmunized patients do not seem to predict PR, suggesting functional or qualitative differences among anti-HLA IgG. The binding of these alloantibodies to donor platelets can result in rapid clearance after transfusion, presumably via Fc gamma R-mediated phagocytosis and/or complement activation, which both are affected by the IgG-Fc glycosylation. Objectives To characterize the Fc glycosylation profile of anti-HLA class I antibodies formed after platelet transfusion and to investigate its effect on clinical outcome. Patients/Methods We screened and captured anti-HLA class I antibodies (anti-HLA A2, anti-HLA A24, and anti-HLA B7) developed after platelet transfusions in hemato-oncology patients, who were included in the PREPAReS Trial. Using liquid chromatography-mass spectrometry, we analyzed the glycosylation profiles of total and anti-HLA IgG1 developed over time. Subsequently, the glycosylation data was linked to the patients' clinical information and posttransfusion increments. Results The glycosylation profile of anti-HLA antibodies was highly variable between patients. In general, Fc galactosylation and sialylation levels were elevated compared to total plasma IgG, which correlated negatively with the platelet count increment. Furthermore, high levels of afucosylation were observed for two patients. Conclusions These differences in composition of anti-HLA Fc-glycosylation profiles could potentially explain the variation in clinical severity between patients. Show less
Background Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and... Show moreBackground Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI ( increment t(inhi-ITI)) is debatable. Objective The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. Methods Severe (factor VIII activity level <1%) PwHA-HRi on ITI (n = 142) were enrolled in 15 hemophilia treatment centers. PwHA-HRi were treated according to the Brazilian ITI Protocol. ITI outcomes were defined as success (i.e., recovered responsiveness to exogenous FVIII) and failure (i.e., no responsiveness to exogenous FVIII and requirement of bypassing agents to control bleeding). Results Median ages at inhibitor detection and at ITI start were 3.2 years (interquartile range [IQR], 1.6-8.1) and 6.9 years [IQR, 2.6-20.1), respectively. PwHA-HRi were stratified according to increment t(inhi-ITI) quartiles: first (0.0-0.6 year), second (>0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. Conclusion In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start. Show less
Background Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an... Show moreBackground Treatment choices for individual patients with an inborn bleeding disorder are increasingly challenging due to increasing options and rising costs for society. We have initiated an integrated interdisciplinary national research program. Objectives The SYMPHONY consortium strives to orchestrate personalized treatment in patients with an inborn bleeding disorder, by unraveling the mechanisms behind interindividual variations of bleeding phenotype. Patients The SYMPHONY consortium will investigate patients with an inborn bleeding disorder, both diagnosed and not yet diagnosed. Results Research questions are categorized under the themes: (1) diagnosis, (2) treatment, and (3) fundamental research, and consist of work packages addressing specific domains. Importantly, collaborations between patients and talented researchers from different areas of expertise promise to augment the impact of the SYMPHONY consortium, leading to unique interactions and intellectual property. Conclusions SYMPHONY will perform research on all aspects of care, treatment individualization in patients with inborn bleeding disorders, as well as diagnostic innovations and results of molecular genetics and cellular model technology with regard to the hemostatic process. We believe that these research investments will lead to health-care innovations with long-term clinical and societal impact. This consortium has been made possible by a governmental, competitive grant from the Netherlands Organization for Scientific Research (NWO) within the framework of the NWA-ORC Call grant agreement NWA.1160.18.038. Show less
Patients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of... Show morePatients with acute venous thromboembolism (VTE) require anticoagulant therapy to prevent recurrent VTE and death, which exposes them to an inherent increased risk of bleeding. Identification of patients at high risk of bleeding, and mitigating this risk, is an essential component of the immediate and long-term therapeutic management of VTE. The bleeding risk can be estimated by either implicit judgment, weighing individual predictors (clinical variables or biomarkers), or by risk prediction tools developed for this purpose. Management of bleeding risk in clinical practice is, however, far from standardized. International guidelines are contradictory and lack clear and consistent guidance on the optimal management of bleeding risk. This report of the ISTH subcommittee on Predictive and Diagnostic Variables in Thrombotic Disease summarizes the evidence on the prediction of bleeding in VTE patients. We systematically searched the literature and identified 34 original studies evaluating either predictors or risk prediction models for prediction of bleeding risk on anticoagulation in VTE patients. Based on this evidence, we provide recommendations for the standardized management of bleeding risk in VTE patients. Show less
Background Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of... Show moreBackground Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. Methods Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004-2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. Results A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow-up of 15 months (interquartile range 9.0-22). The adjusted 1-year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9-9.3), of ATE 4.1% (95% CI 3.0-5.6), and of MB 12% (95% CI 9.6-14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow-up was associated with MB (adjusted HR 4.7, 95% CI 2.5-9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3-2.1 and 1.3, 95% CI 1.0-1.7, respectively). Conclusion We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients. Show less
