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Contains fulltext : 193336.pdf (publisher's version ) (Open Access), Some comorbidities, such as hypertension, are associated with higher von Willebrand factor (VWF) levels in the general population. No studies have been conducted to assess this association in patients with von Willebrand disease (VWD). Therefore, we studied this association in patients with type 1 (n = 333) and type 2 (n = 203) VWD from the 'WiN" study. VWF antigen (VWF:Ag) was higher in type 1 VWD patients with hypertension [difference: 0.23 iu/ml, 95% confidence interval (CI): 0.11-0.35], diabetes mellitus (0.11 iu/ml, 95% CI: -0.02 to 0.23), cancer (0.14 iu/ml, 95% CI: 0.03-0.25) and thyroid dysfunction (0.14 iu/ml, 95% CI: 0.03-0.26) than in patients without these comorbidities (all corrected for age, sex and blood group). Similar results were observed for VWF collagen binding capacity (VWF:CB), VWF activity as measured by the VWF monoclonal antibody assay (VWF:Ab) and factor VIII (FVIII) coagulant activity (FVIII:C). In type 1 VWD, age was associated with higher VWF:Ag (0.03 iu/ml; 95% CI: 0.01-0.04), VWF:CB (0.02 iu/ml; 95% CI: 0.00-0.04), VWF:Ab (0.04 iu/ml; 95% CI: 0.02-0.06) and FVIII:C (0.03 iu/ml; 95% CI: 0.01-0.06) per decade increase. After adjustment for relevant comorbidities, these associations were no longer significant. Despite the higher VWF and FVIII levels, type 1 VWD patients with comorbidities had more bleeding episodes, particularly during surgery. There was no association between comorbidities and VWF/FVIII levels or bleeding phenotype in type 2 VWD patients. In conclusion, comorbidities are associated with higher VWF and FVIII levels in type 1 VWD and may explain the age-related increase of VWF and FVIII levels. more...

16 april 2018, Contains fulltext : 190533.pdf (Publisher’s version ) (Open Access), BACKGROUND: Red cell distribution width (RDW) is a standard component of the automated blood count, and is of prognostic value in heart failure and coronary heart disease. We investigated the association between RDW and cardiovascular events in patients with adult congenital heart disease (ACHD). METHODS AND RESULTS: In this prospective cohort study, 602 consecutive patients with ACHD who routinely visited the outpatient clinic were enrolled between 2011 and 2013. RDW was measured in fresh venous blood samples at inclusion in 592 patients (median age 33 [IQR 25-41] years, 58% male, 90% NYHA I) and at four annual follow-up visits. During 4.3 [IQR 3.8-4.7] years of follow-up, the primary endpoint (death, heart failure, hospitalization, arrhythmia, thromboembolic events, cardiac intervention) occurred in 196 patients (33%). Median RDW was 13.4 (12.8-14.1)% versus 12.9 (12.5-13.4)% in patients with and without the primary endpoint (P<0.001). RDW was significantly associated with the endpoint when adjusted for age, sex, clinical risk factors, CRP, and NT-proBNP (HR 1.20; 95% CI 1.06-1.35; P=0.003). The C-index of the model including RDW was slightly, but significantly (P=0.005) higher than the model without (0.74, 95% CI 0.70-0.78 versus 0.73, 95% CI 0.69-0.78). Analysis of repeated RDW measurements (n=2449) did not show an increase in RDW prior to the occurrence of the endpoint. CONCLUSIONS: RDW is associated with cardiovascular events in patients with ACHD, independently of age, sex, clinical risk factors, CRP, and NT-proBNP. This readily available biomarker could therefore be considered as an additive biomarker for risk stratification in these patients. more...

Contains fulltext : 175124.pdf (publisher's version ) (Closed access), Essentials Data on bleeding-related causes of death in non-severe hemophilia A (HA) patients are scarce. Such data may provide new insights into areas of care that can be improved. Non-severe HA patients have an increased risk of dying from intracranial bleeding. This demonstrates the need for specialized care for non-severe HA patients. SUMMARY: Background Non-severe hemophilia (factor VIII concentration [FVIII:C] of 2-40 IU dL-1 ) is characterized by a milder bleeding phenotype than severe hemophilia A. However, some patients with non-severe hemophilia A suffer from severe bleeding complications that may result in death. Data on bleeding-related causes of death, such as fatal intracranial bleeding, in non-severe patients are scarce. Such data may provide new insights into areas of care that can be improved. Aims To describe mortality rates, risk factors and comorbidities associated with fatal intracranial bleeding in non-severe hemophilia A patients. Methods We analyzed data from the INSIGHT study, an international cohort study of all non-severe hemophilia A patients treated with FVIII concentrates during the observation period between 1980 and 2010 in 34 participating centers across Europe and Australia. Clinical data and vital status were collected from 2709 patients. We report the standardized mortality rate for patients who suffered from fatal intracranial bleeding, using a general European male population as a control population. Results Twelve per cent of the 148 deceased patients in our cohort of 2709 patients died from intracranial bleeding. The mortality rate between 1996 and 2010 for all ages was 3.5-fold higher than that in the general population (95% confidence interval [CI] 2.0-5.8). Patients who died from intracranial bleeding mostly presented with mild hemophilia without clear comorbidities. Conclusion Non-severe hemophilia A patients have an increased risk of dying from intracranial bleeding in comparison with the general population. This demonstra more...

Item does not contain fulltext, Assessment of clinical outcome after joint bleeding is essential to identify joint damage and optimise treatment, to prevent disability. However, disease-specific tools to assess the musculoskeletal status in patients with von Willebrand disease (VWD) are lacking. We aimed to determine validity and reliability of the Haemophilia Joint Health Score (HJHS) and Haemophilia Activities List (HAL) in patients with Von Willebrand disease (VWD). Ninety-six patients with VWD were included (mean age 46 years) of whom 27 had more than five documented joint bleeds. The HJHS was performed in all patients and all patients completed the HAL and Impact on Participation and Autonomy (IPA) questionnaires. Health-related quality of life (SF36) results were obtained from the prior 'Willebrand in the Netherlands' study. Joint X-rays of knees, elbows and ankles were scored according to Pettersson (PS). Internal consistency of the HJHS (Cronbach's alpha (alpha)=0.75) and HAL (alpha=0.89) were good. Inter-observer agreement of the HJHS was good (ICC 0.84; Limits of Agreement +/- 10.3). The HJHS showed acceptable correlation with the X-ray PS (Spearman's r (rs)>0.60 all joints) and HAL (rs=0.71). The HAL also showed acceptable correlation with the SF36 physical functioning (rs=0.65) and IPA (rs=0.69). Hypothesis testing showed adequate discriminative power of both instruments: in patients with a history of >5 versus more...

Contains fulltext : 177213.pdf (publisher's version ) (Open Access), Patients with severe von Willebrand disease (VWD) may develop arthropathy after joint bleeds. Information on its prevalence and severity is limited. We aimed to assess the occurrence and severity of arthropathy in VWD and its impact on daily life. VWD patients with and without verified joint bleeds were matched for age, sex and Factor VIII level or von Willebrand Factor activity in a nested case-control study within the Willebrand in the Netherlands study. Assessments included the Hemophilia Joint Health Score (0-124), Pettersson score (0-13 per joint X-ray), Hemophilia Activity List score (0-100), joint pain (Visual Analog Scale 0-10), and the Impact on Participation and Autonomy questionnaire (0-20). Arthropathy was defined as a Hemophilia Joint Health Score of 10 or higher, or a Pettersson score over 3 of at least one joint. We included 48 patients with verified joint bleeds (cases) and 48 controls: 60% males, mean age 46 years (range 18-80), median von Willebrand Factor activity 5 versus 8 IU/dL and Factor VIII 24 versus 36 IU/dL. Arthropathy occurred in 40% of the cases versus 10% of the controls (P<0.01). The cases reported more functional limitations compared to the controls (median Hemophilia Activity List score: 88 vs. 100, P<0.01). Arthropathy was related to joint pain and less social participation (Visual Analog Scale>3: 13 of 19 vs. 3 of 28, P<0.01, and median score on the participation questionnaire 6.1 vs. 0.9, P<0.01). In conclusion, arthropathy occurs in 40% of VWD patients after joint bleeds and is associated with pain, radiological abnormalities, functional limitations, and less social participation (Dutch trial register: NTR4548). more...

Item does not contain fulltext, INTRODUCTION: von Willebrand disease (VWD) is the most common inherited bleeding disorder. In VWD patients, large variations in bleeding tendency are observed, which cannot be completely explained by the variation in von Willebrand factor levels or activities. Thus, there must be additional factors, for instance, changes in fibrinolysis that have an effect on the variation in bleeding tendency in VWD patients. AIM: To investigate whether plasminogen activator inhibitor-1 (PAI-1) level influences the variation in bleeding tendency in VWD patients. METHODS: PAI-1 antigen levels were measured in the plasma of 633 patients with moderate or severe VWD who participated in the 'Willebrand in the Netherlands' (WiN) study, a nationwide multicentre cross-sectional study. Bleeding severity was assessed using the Tosetto bleeding score. RESULTS: PAI-1 levels increased with age (Spearman's rho: 0.225, P < 0.001) and were higher in men (23 [IQR 12-60] vs. 20 [IQR 10-44] ng mL-1 in women, P = 0.039), whereas the bleeding score was higher in women (11 [IQR 7-17] vs. 9 [IQR 5-14] ng mL-1 in men, P = 0.002). After adjustment for age and sex by stratification, PAI-1 level and bleeding score were negatively correlated (Spearman's rho: -0.170, P = 0.017) in the group of 196 young (age more...

Contains fulltext : 171161.pdf (publisher's version ) (Closed access), Essentials Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory. SUMMARY: Background Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs. Objectives This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1) ). Patients and Methods One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus >/= 0.20 IU mL(-1) . Results Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio [OR] 6.3, 95% confidence interval [CI] 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treat more...

Item does not contain fulltext, Haemophilia A is an X-linked inherited, rare bleeding disorder, caused by a deficiency of coagulation factor VIII (FVIII). Previous studies in prophylactic dosing have demonstrated that FVIII consumption can be significantly reduced by individualising dosing based on combined analysis of individual pharmacokinetic (PK) profiling and population PK data (Bayesian analysis). So far, no studies have been performed that address perioperative concentrate consumption using iterative PK-guided dosing based on a PK population model. The "OPTI-CLOT" trial is an open-label, prospective, multicentre randomised controlled superiority trial (RCT), aiming to detect a 25 % difference in perioperative FVIII concentrate consumption with iterative Bayesian PK-guided dosing in comparison to the standard dosing procedure. Sixty haemophilia A patients >/= 12 years of age, with FVIII plasma levels more...

Item does not contain fulltext, BACKGROUND: Joint bleeds (JB) are reported in a minority of patients with von Willebrand disease (VWD) but may lead to structural joint damage. Prevalence, severity and impact of JB in VWD are largely unknown. OBJECTIVES: The aim of this study was to assess JB prevalence, onset, treatment and impact on health-related quality of life (HR-QoL) and joint integrity in moderate and severe VWD. METHODS: In the Willebrand in the Netherlands study 804 moderate and severe VWD patients [von Willebrand factor (VWF) activity more...

Item does not contain fulltext, The ratios between von Willebrand factor propeptide (VWFpp) or factor VIII activity ( FVIII: C) and VWF antigen (VWF:Ag) reflect synthesis, secretion, and clearance of VWF. We aimed to define the pathophysiology of 658 patients with type 1, 2, or 3 von Willebrand disease (VWD) with VWF levels more...

Item does not contain fulltext, BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to -0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD. more...

Item does not contain fulltext, BACKGROUND AND STUDY AIMS: Hemospray (Cook Medical Inc., Winston-Salem, North Carolina, USA) is a novel, hemostatic, powder spray that has been developed for gastrointestinal use. The powder is thought to achieve hemostasis by concentrating clotting factors and forming a mechanical plug on the injured blood vessel. However, no detailed studies on the hemostatic mode of action have been performed. The aim of this study was to examine the effects of Hemospray on coagulation and clot formation both in vitro and in vivo. MATERIALS AND METHODS: Recalcification time, thromboelastometry using EXTEM and INTEM assays, and plasma coagulation tests (activated partial thromboplastin time and prothrombin time) were carried out on blood samples mixed with Hemospray, and compared with talcum powder (negative control) and kaolin (positive control) at 1 mg/mL and 10 mg/mL. Scanning electron microscopy (SEM) and light microscopy were performed on in vitro thrombi and on gastric thrombi from an animal model of gastrointestinal hemorrhage treated with Hemospray. RESULTS: The median recalcification time of whole blood was 187.5 seconds. The addition of 1 mg/mL and 10 mg/mL Hemospray significantly shortened this time (median 60 and 45 seconds, respectively; P < 0.05). The median clotting time of whole blood, measured using the INTEM assay, was 160 seconds (interquartile range [IQR] 159 - 176.5) and this was also significantly reduced by the addition of Hemospray (91 seconds [IQR 84 - 102]; P = 0.005). The plasma prothrombin time of 11.6 seconds was significantly reduced by Hemospray (9.5 seconds; P = 0.011). SEM of in vivo clots demonstrated that Hemospray rapidly interacted with whole blood, forming one confluent mass over the bleeding site. In sufficient amounts, Hemospray was able to deform and pack erythrocytes. CONCLUSIONS: Hemospray covered the bleeding site and enhanced clot formation in vivo, and shortened coagulation time in vitro. Elaboration of these unique properties in clini more...

Contains fulltext : 153620.pdf (Publisher’s version ) (Open Access), Patients on rivaroxaban requiring percutaneous coronary intervention (PCI) represent a clinical conundrum. We aimed to investigate whether rivaroxaban, with or without an additional bolus of unfractionated heparin (UFH), effectively inhibits coagulation activation during PCI. Stable patients (n=108) undergoing elective PCI and on stable dual antiplatelet therapy were randomised (2:2:2:1) to a short treatment course of rivaroxaban 10 mg (n=30), rivaroxaban 20 mg (n=32), rivaroxaban 10 mg plus UFH (n=30) or standard peri-procedural UFH (n=16). Blood samples for markers of thrombin generation and coagulation activation were drawn prior to and at 0, 0.5, 2, 6-8 and 48 hours (h) after start of PCI. In patients treated with rivaroxaban (10 or 20 mg) and patients treated with rivaroxaban plus heparin, the levels of prothrombin fragment 1 + 2 at 2 h post-PCI were 0.16 [0.1] nmol/l (median) [interquartile range, IQR] and 0.17 [0.2] nmol/l, respectively. Thrombin-antithrombin complex values at 2 h post-PCI were 3.90 [6.8]microg/l and 3.90 [10.1] microg/l, respectively, remaining below the upper reference limit (URL) after PCI and stenting. This was comparable to the control group of UFH treatment alone. However, median values for thrombin-antithrombin complex passed above the URL with increasing tendency, starting at 2 h post-PCI in the UFH-alone arm but not in rivaroxaban-treated patients. In this exploratory trial, rivaroxaban effectively suppressed coagulation activation after elective PCI and stenting. more...

Item does not contain fulltext, BACKGROUND: Because the number of elderly von Willebrand disease (VWD) patients is increasing, the pathophysiology of aging in VWD has become increasingly relevant. OBJECTIVES: To assess age-related changes in von Willebrand factor (VWF) and factor VIII (FVIII) levels and to compare age-related differences in bleeding phenotype between elderly VWD patients and those < 65 years. We also studied co-morbidity in elderly patients. PATIENTS/METHODS: We included VWD patients with VWF levels more...

1 mei 2013, Item does not contain fulltext, BACKGROUND: High von Willebrand factor (VWF) levels are an established risk factor for arterial thrombosis, including coronary heart disease and ischemic stroke. It has been hypothesized that von Willebrand disease (VWD) patients are protected against arterial thrombosis; however, this has never been confirmed in clinical studies. OBJECTIVES: To investigate the prevalence of arterial thrombosis in VWD patients relative to the general population. PATIENTS/METHODS: We included 635 adult patients with VWF levels more...

Item does not contain fulltext, AIMS: Patients receiving long-term anticoagulant treatment with dabigatran may need to undergo a percutaneous coronary intervention (PCI). We studied markers of coagulation activation during elective PCI in patients using dabigatran in order to investigate whether coagulation activation upon balloon inflation and stenting is suppressed by dabigatran without additional heparin treatment. METHODS AND RESULTS: This phase IIa, exploratory, multicentre, randomised, open-label study included 50 stable patients having an elective PCI. Patients on standard dual antiplatelet therapy (DAPT) were randomised (2:2:1) to either pre-procedural dabigatran 110 mg BID (n=19) or 150 mg BID (n=21), as compared to standard intraprocedural unfractionated heparin (UFH) (n=10). Following PCI, a significant increase in the levels of prothrombin fragment 1+2 (F1+2) in the combined dabigatran group was observed compared to the level just before the start of PCI (159.1 [1.4] pmol/l; geometric mean [gSD]). Levels at 0.5, 1.0, 1.5 and 2 hrs after the start of PCI ranged from 193.5 (1.4) to 270.6 pmol/l (1.7); (p-value for paired analysis=0.015, 0.022, 0.2342, 0.0379, respectively). Also, thrombin-antithrombin (TAT) complexes were increased significantly in the combined dabigatran group compared to pre-PCI levels (4.2 [2.2] ug/l). Levels ranged from 5.2 (2.5) to 8.5 (2.3) (p=0.0497, 0.0343, 0.005 and 0.1628, respectively). In contrast, in the control group of patients treated with UFH, no increase was observed in F1+2 and TAT complexes during PCI. Five out of 40 (12.5%) patients required bail-out anticoagulation in the dabigatran group, of whom four experienced a procedural myocardial infarction (MI), versus one out of 10 in the UFH group, who had a stent thrombosis without MI prior to the study-PCI. One minor access-site bleeding occurred in the dabigatran group. CONCLUSIONS: Dabigatran treatment (110 mg or 150 mg BID) may not provide sufficient anticoagulation during PCI. EudraCT. No: 2007-0075 more...

Item does not contain fulltext, Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A. more...

1 oktober 2012, Item does not contain fulltext, We performed a nation-wide cross-sectional study to evaluate determinants of bleeding symptoms in a large unselected cohort of adults with von Willebrand disease (VWD). VWD patients were included (n=664), based on lowest historically measured VWF:Ag and VWF:Act levels 30 IU/dl. In type 3 patients 1 IU/dl FVIII:C decrease was associated with 0.6 point (95% CI 0.1-1.1) BS increase (p=0.021). In conclusion, in VWD patients the bleeding phenotype is strongly associated with type of VWD and VWF and FVIII levels. more...

Item does not contain fulltext, BACKGROUND: Whether newer risk markers for coronary heart disease (CHD) improve CHD risk prediction remains unclear. OBJECTIVE: To assess whether newer risk markers for CHD risk prediction and stratification improve Framingham risk score (FRS) predictions. DESIGN: Prospective population-based study. SETTING: The Rotterdam Study, Rotterdam, the Netherlands. PARTICIPANTS: 5933 asymptomatic, community-dwelling participants (mean age, 69.1 years [SD, 8.5]). MEASUREMENTS: Traditional CHD risk factors used in the FRS (age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and newer CHD risk factors (N-terminal fragment of prohormone B-type natriuretic peptide levels, von Willebrand factor antigen levels, fibrinogen levels, chronic kidney disease, leukocyte count, C-reactive protein levels, homocysteine levels, uric acid levels, coronary artery calcium [CAC] scores, carotid intima-media thickness, peripheral arterial disease, and pulse wave velocity). RESULTS: Adding CAC scores to the FRS improved the accuracy of risk predictions (c-statistic increase, 0.05 [95% CI, 0.02 to 0.06]; net reclassification index, 19.3% overall [39.3% in those at intermediate risk, by FRS]). Levels of N-terminal fragment of prohormone B-type natriuretic peptide also improved risk predictions but to a lesser extent (c-statistic increase, 0.02 [CI, 0.01 to 0.04]; net reclassification index, 7.6% overall [33.0% in those at intermediate risk, by FRS]). Improvements in predictions with other newer markers were marginal. LIMITATION: The findings may not be generalizable to younger or nonwhite populations. CONCLUSION: Among 12 CHD risk markers, improvements in FRS predictions were most statistically and clinically significant with the addition of CAC scores. Further investigation is needed to assess whether risk refinements using CAC scores lead to a meaningful change in clinical outcome. Whether to use CAC score scree more...

1 april 2012, Item does not contain fulltext, CONTEXT: Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE: The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING: During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS: Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES: We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS: Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and alpha2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS: The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have impl more...

01 maart 2012, Item does not contain fulltext, OBJECTIVE: Ischemic heart disease mortality is lower in hemophilia patients than in the general male population. As coagulation plays a role in the inflammatory pathways involved in atherogenesis, we investigated whether the clotting factor deficiency protects hemophilia patients from developing atherosclerosis. METHODS AND RESULTS: Coronary artery calcification, measured with multidetector-row computed tomography, was compared between 42 men, >/=59 years, with severe or moderate hemophilia A, and 613 nonhemophilic men from the Rotterdam Study, a prospective population-based study. None of the study subjects were HIV infected or had a history of cardiovascular disease. Coronary artery calcification was quantified by calculating the Agatston score and calcification mass. Data were analyzed using linear regression. Mean difference (beta) of the natural log-transformed Agatston score between men with and without hemophilia was 0.141 (95% CI -0.602 to 0.885, P=0.709). Results did not change after adjustment for age, body mass index, hypercholesterolemia, hypertension, and use of antidiabetic medication (beta=0.525, 95% CI -0.202 to 1.252, P=0.157). Comparable results were found for calcification mass. CONCLUSION: The extent of coronary artery atherosclerosis is comparable between elderly men with and without hemophilia. Results from this study underline the importance of screening and treating atherosclerosis risk factors in hemophilia patients. more...

Item does not contain fulltext, BACKGROUND: Von Willebrand disease (VWD) is the most frequent inherited bleeding disorder. Whether VWD is associated with health-related quality of life (HR-QoL) in children is unknown. OBJECTIVES: This nationwide cross-sectional study measured HR-QoL in children with moderate or severe VWD. Our primary aim was to compare HR-QoL of VWD patients with that of reference populations. Additionally, we studied the impact of bleeding phenotype and VWD type on HR-QoL. METHODS: HR-QoL was assessed with the Infant/Toddler QoL Questionnaire (0-5 years) and Child Health Questionnaire (6-15 years), and compared with reference population scores. Multivariate analysis was used to evaluate the influence of type of VWD and bleeding phenotype on HR-QoL scores. RESULTS: Preschool children (0-5 years, n = 46) with VWD had lower HR-QoL scores for general health perceptions and parental time than reference populations. School children (6-15 years, n = 87) with VWD had lower scores for physical functioning, role functioning - emotional/behavioral, general health perceptions, and physical summary. Type of VWD was associated with HR-QoL in school children for bodily pain, general health perceptions, parental emotion, family activities, and physical summary. Scores of children with type 3 VWD were, on average, 15 points lower than those of the reference population on the above-mentioned scales. A more severe bleeding phenotype was associated with a lower score on 11/15 physical, emotional and social scales. CONCLUSION: HR-QoL is lower in VWD children than in reference populations, in particular in school children. The negative impact of VWD is sensitive to type of VWD and bleeding phenotype; as well as physical scales, emotional and social scales are affected. more...

Contains fulltext : 95943.pdf (Publisher’s version ) (Closed access), A nation-wide cross-sectional study was initiated to assess gynaecological and obstetrical symptoms in an unselected cohort of women with moderate and severe von Willebrand disease (VWD) in the Netherlands. A total of 423 women aged >/=16 years were included. Bleeding severity was measured using the Tosetto Bleeding Score (BS). Menorrhagia, defined as occurrence of >/=2 menorrhagia symptoms, was reported by 81%. Of all VWD women, 78% received any kind of treatment for menorrhagia and 20% underwent a hysterectomy predominantly because of severe menstrual bleeding. Over half of the women reported more blood loss than can be expected with a normal delivery. In 52% of reported pregnancy losses curettage was needed because of bleeding. Mean number of live births was 1.9, which is comparable with the general Dutch population. In conclusion, women with moderate or severe VWD frequently have menorrhagia in need of treatment, and 20% of the VWD women underwent a hysterectomy. Bleeding complications occurred in over 50% of the women after childbirth or pregnancy loss. Progeny seems not to be affected in women with moderate or severe VWD. more...

1 juli 2010, Contains fulltext : 88411.pdf (publisher's version ) (Closed access), SUMMARY BACKGROUND: von Willebrand Disease (VWD) is the most frequent inherited bleeding disorder. It is unknown how this disorder affects quality of life. OBJECTIVES: This nationwide multicenter cross-sectional study determined health-related quality of life (HR-QoL) in adult patients with moderate or severe VWD, and assessed whether bleeding severity and type of VWD are associated with HR-QoL. METHODS: HR-QoL was assessed using the Short Form (SF)-36, and bleeding severity was measured using the Bleeding Score (BS). RESULTS: Five hundred and nine patients participated; 192 males and 317 females, median age and range 45 (16-87) and 47 (16-84) years, respectively. Compared with the general population, HR-QoL in VWD patients was lower in the vitality domain (61 vs. 66 P < 0.001 for females, 67 vs. 72 P < 0.001 for males). Patients with the most severe bleeding phenotype (highest quartile BS, BS > 17) had a lower HR-QoL in eight domains than patients with a less severe bleeding type (lowest quartile BS, BS < 7) in the univariate analysis. After adjustment for age, gender, co-morbidity and employment/educational status, a more severe bleeding phenotype was associated with lower scores on the domains of physical functioning, role limitations due to physical functioning, bodily pain, general health, social functioning and physical component summary. CONCLUSIONS: HR-QoL is lower in VWD patients compared with the general population. HR-QoL is strongly associated with bleeding phenotype. more...

Contains fulltext : 70040.pdf (publisher's version ) (Closed access), High D-dimer levels are predictors of death in patients with pulmonary embolism (PE), as are more proximally located, larger emboli. The direct link between these three has not yet been described. A cohort of 674 consecutive patients with confirmed PE was studied. Patients were followed up for 3 months. D-dimer levels were measured only in patients with an unlikely clinical probability (n = 262). The odds ratio (OR) for death of all variables was calculated. Multivariate analysis was performed to identify independent risk factors for mortality. The best predictive D-dimer cut-off point for mortality was a concentration >3000 ng/ml FEU (OR 7.29). High D-dimer levels were correlated with active malignancy and age over 65 years, both being indicators of 3-month mortality. High D-dimer levels were also correlated with centrally located pulmonary emboli and 15-d mortality. The combination of high D-dimer levels and central emboli increased early mortality risk by 2.2. High D-dimer levels in patients with an unlikely clinical probability were associated with fatal outcome after PE. Centrally located pulmonary emboli were associated with higher D-dimer levels and worse 15-d mortality. Active malignancy, being an inpatient at time of diagnosis and age over 65 years were associated with higher D-dimer levels and worse 3-month survival. more...

Item does not contain fulltext, BACKGROUND: Pulmonary embolism (PE) is a potentially fatal disease with risks of recurrent venous thrombotic events (venous thromboembolism [VTE]) and major bleeding from anticoagulant therapy. Identifying risk factors for recurrent VTE, bleeding, and mortality may guide clinical decision making. OBJECTIVE: To evaluate the incidence of recurrent VTE, hemorrhagic complications, and mortality in patients with PE, and to identify risk factors and the time course of these events. DESIGN: We evaluated consecutive patients with PE derived from a prospective management study, who were followed for 3 months, treated with anticoagulants, and underwent objective diagnostic testing for suspected recurrent VTE or bleeding. RESULTS: Of 673 patients with complete follow-up, 20 patients (3.0%; 95% confidence interval [CI], 1.8 to 4.6%) had recurrent VTE. Eleven of 14 patients with recurrent PE had a fatal PE (79%; 95% CI, 49 to 95%), occurring mostly in the first week after diagnosis of initial PE. In 23 patients (3.4%; 95% CI, 2.2 to 5.1%), a hemorrhagic complication occurred, 10 of which were major bleeds (1.5%; 95% CI, 0.7 to 2.7%), and 2 were fatal (0.3%; 95% CI, 0.04 to 1.1%). During the 3-month follow-up, 55 patients died (8.2%; 95% CI, 6.2 to 10.5%). Risk factors for recurrent VTE were immobilization for > 3 days and being an inpatient; having COPD or malignancies were risk factors for bleeding. Higher age, immobilization, malignancy, and being an inpatient were risk factors for mortality. CONCLUSIONS: Recurrent VTE occurred in a small percentage of patients treated for an acute PE, and the majority of recurrent PEs were fatal. Immobilization, hospitalization, age, COPD, and malignancies were risk factors for recurrent VTE, bleeding, and mortality. Close monitoring may be indicated in these patients, precluding them from out-of-hospital start of treatment. more...

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Item does not contain fulltext, AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe. more...