Peri-operative desmopressin combined with pharmacokinetic-guided factor VIII concentrate in non-severe haemophilia A patients.

INTRODUCTION: Non-severe haemophilia A patient can be treated with desmopressin or factor VIII (FVIII) concentrate. Combining both may reduce factor consumption, but its feasibility and safety has never been investigated. AIM: We assessed the feasibility and safety of combination treatment in nonsevere haemophilia A patients. METHODS: Non-severe, desmopressin responsive, haemophilia A patients were included in one of two studies investigating peri-operative combination treatment. In the single-arm DAVID study intravenous desmopressin (0.3 µg/kg) once-a-day was, after sampling, immediately followed by PK-guided FVIII concentrate, for maximally three consecutive days. The Little DAVID study was a randomized trial in patients undergoing a minor medical procedure, whom received either PK-guided combination treatment (intervention arm) or PK-guided FVIII concentrate only (standard arm) up to 2 days. Dose predictions were considered accurate if the absolute difference between predicted and measured FVIII:C was ≤0.2 IU/mL. RESULTS: In total 32 patients (33 procedures) were included. In the DAVID study (n = 21), of the FVIII:C trough levels 73.7% (14/19) were predicted accurately on day 1 (D1), 76.5% (13/17) on D2. On D0, 61.9% (13/21) of peak FVIII:C levels predictions were accurate. In the Little DAVID study (n = 12), on D0 83.3% (5/6) FVIII:C peak levels for both study arms were predicted accurately. Combination treatment reduced preoperative FVIII concentrate use by 47% versus FVIII monotherapy. Desmopressin side effects were mild and transient. Two bleeds occurred, both despite FVIII:C > 1.00 IU/mL. CONCLUSION: Peri-operative combination treatment with desmopressin and PK-guided FVIII concentrate dosing in nonsevere haemophilia A is feasible, safe and reduces FVIII consumption.

Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database.

ABSTRACT: Congenital fibrinogen deficiency (CFD) is a rare bleeding disorder caused by mutations in FGA, FGB, and FGG. We sought to comprehensively characterize patients with CFD using PRO-RBDD (Prospective Rare Bleeding Disorders Database). Clinical phenotypes, laboratory, and genetic features were investigated using retrospective data from the PRO-RBDD. Patients were classified from asymptomatic to grade 3 based on their bleeding severity. In addition, FGA, FGB, and FGG were sequenced to find causative variants. A total of 166 CFD cases from 16 countries were included, of whom 123 (30 afibrinogenemia, 33 hypofibrinogenemia, 55 dysfibrinogenemia, and 5 hypodysfibrinogenemia) were well characterized. Considering the previously established factor activity and antigen level thresholds, bleeding severity was correctly identified in 58% of the cases. The rates of thrombotic events among afibrinogenemic and hypofibrinogenemic patients were relatively similar (11% and 10%, respectively) and surprisingly higher than in dysfibrinogenemic cases. The rate of spontaneous abortions among 68 pregnancies was 31%, including 86% in dysfibrinogenemic women and 14% with hypofibrinogenemia. Eighty-six patients received treatment (69 on-demand and/or 17 on prophylaxis), with fibrinogen concentrates being the most frequently used product. Genetic analysis was available for 91 cases and 41 distinct variants were identified. Hotspot variants (FGG, p.Arg301Cys/His and FGA, p.Arg35Cys/His) were present in 51% of dysfibrinogenemia. Obstetric complications were commonly observed in dysfibrinogenemia. This large multicenter study provided a comprehensive insight into the clinical, laboratory, and genetic history of patients with CFDs. We conclude that bleeding severity grades were in agreement with the established factor activity threshold in nearly half of the cases with quantitative defects.

Transition readiness among adolescents and young adults with haemophilia in the Netherlands: Nationwide questionnaire study.

INTRODUCTION: Care for adolescents with haemophilia is transferred from paediatric to adult care around the age of 18 years. Transition programs help to prepare adolescents for this transfer and prevent declining treatment adherence. Evaluating transition readiness may identify areas for improvement. OBJECTIVE: Assess transition readiness among Dutch adolescents and young adults with haemophilia, determine factors associated with transition readiness, and identify areas of improvement in transition programs. METHODS: All Dutch adolescents and young adults aged 12-25 years with haemophilia were invited to participate in a nationwide questionnaire study. Transition readiness was assessed using multiple-choice questions and was defined as being ready or almost ready for transition. Potential factors associated with transition readiness were investigated, including: socio-demographic and disease-related factors, treatment adherence, health-related quality of life, and self-efficacy. RESULTS: Data of 45 adolescents and 84 young adults with haemophilia (47% with severe haemophilia) were analyzed. Transition readiness increased with age, from 39% in 12-14 year-olds to 63% in 15-17 year-olds. Nearly all post-transition young adults (92%, 77/84) reported they were ready for transition. Transition readiness was associated with treatment adherence, as median VERITAS-Pro treatment adherence scores were worse in patients who were not ready (17, IQR 9-29), compared to those ready for transition (11, IQR 9-16). Potential improvements were identified: getting better acquainted with the adult treatment team prior to transition and information on managing healthcare costs. CONCLUSIONS: Nearly all post-transition young adults reported they were ready for transition. Improvements were identified regarding team acquaintance and preparation for managing healthcare costs.

Importance of Genotyping in von Willebrand Disease to Elucidate Pathogenic Mechanisms and Variability in Phenotype.

Genotyping is not routinely performed at diagnosis of von Willebrand disease (VWD). Therefore, the association between genetic variants and pathogenic mechanism or the clinical and laboratory phenotype is unknown in most patients, especially in type 1 VWD. To investigate whether genotyping adds to a better understanding of the pathogenic mechanisms and variability in phenotype, we analyzed the VWF gene in 390 well-defined VWD patients, included in the WiN study. A VWF gene variant was found in 155 patients (61.5%) with type 1, 122 patients (98.4%) with type 2, and 14 patients (100%) with type 3 VWD. Forty-eight variants were novel. For each VWF gene variant, the pathogenic mechanisms associated with reduced VWF levels was investigated using the FVIII:C/VWF:Ag and VWFpp/VWF:Ag ratios. In type 1 VWD, reduced synthesis or secretion of VWF was most frequently found in patients with nonsense variants, frameshift variants, and deletions, whereas rapid clearance of VWF was mainly found in patients with missense variants. Furthermore, type 1 VWD patients with and without a VWF gene variant were clearly distinct in their clinical features such as age of diagnosis, laboratory phenotype, and bleeding phenotype. In type 2 VWD, 81% of variants were associated with an increased clearance of VWF. To conclude, we identified the pathogenic mechanisms associated with various VWF gene variants in type 1, 2, and 3 VWD patients. Additionally, major differences in the phenotype of type 1 VWD patients with and without a variant were observed, which may be of importance for clinical management.

The bleeding phenotype in people with nonsevere hemophilia.

Detailed information on the onset, frequency, and severity of bleeding in nonsevere hemophilia is limited. We aimed to assess the bleeding phenotype of persons with nonsevere hemophilia and to analyze the association between baseline factor VIII/IX (FVIII/IX) levels and the joint bleeding rate. In the DYNAMO (Dynamic Interplay Between Bleeding Phenotype and Baseline Factor Level in Moderate and Mild Hemophilia A and B) study, an international multicenter cohort, we included males with nonsevere hemophilia (FVIII/IX, 0.02-0.35 IU/mL) aged 12 to 55 years. Information on age at first treated (joint) bleed, annual bleeding rates (ABRs), and annual joint bleeding rates (AJBRs) was collected from the medical files. The association between baseline FVIII/IX levels and the joint bleeding rate was assessed by using a frailty model for recurrent events. In total, 304 persons (70 with moderate hemophilia and 234 with mild hemophilia) were included. The median age was 38 years (interquartile range [IQR], 25-49 years), and the median baseline FVIII/IX level was 0.12 IU/mL (IQR, 0.05-0.21 IU/mL). In total, 245 (81%) persons had experienced at least 1 bleed, and 156 (51%) had experienced at least 1 joint bleed. The median age at first bleed and first joint bleed was 8 and 10 years, respectively. The median ABR and AJBR was 0.2 (IQR, 0.1-0.5) and 0.0 (IQR, 0.0-0.2). From baseline FVIII/IX levels 0.02 to 0.05 IU/mL to >0.25 IU/mL, the median ABR decreased from 0.6 (IQR, 0.2-1.4) to 0.1 (IQR, 0.0-0.2) and the AJBR from 0.2 (IQR, 0.0-0.4) to 0.0 (IQR, 0.0-0.0). Baseline FVIII/IX was inversely associated with the joint bleeding rate (P < .001). Low bleeding rates were observed in persons with nonsevere hemophilia. However, one-half of all adolescents and adults had experienced a joint bleed.

Fibrinolytic assays in bleeding of unknown cause: Improvement in diagnostic yield.

Introduction: Analysis of fibrinolytic disorders is challenging and may potentially lead to underdiagnosis of patients with an increased bleeding tendency. Aim: To compare clinical characteristics, laboratory measurements, and treatment modalities in a monocenter cohort of patients in whom fibrinolytic studies were performed. Methods: Retrospective study of patients in whom fibrinolytic studies were performed between January 2016 and February 2020 in the Hemophilia Treatment Center, Nijmegen-Eindhoven-Maastricht, the Netherlands. Plasminogen activator inhibitor type 1 (PAI-1) antigen and activity level, α2-antiplasmin activity, tissue plasminogen activator, and euglobulin clot lysis time (ECLT) before and after venous compression were determined in all patients. Data of bleeding assessment tool (BAT) score, clinical characteristics, results of primary and secondary hemostasis assays, and general treatment plans were collected. Results: In total, 160 patients were included: 97 (61%) without and 63 (39%) with a laboratory-based fibrinolytic disorder. Mean BAT score did not differ between the groups (9.3 vs 9.8, respectively). The presumptive fibrinolytic disorders were distributed as follows: 34 patients had an increased ECLT ratio or low baseline ECLT, 25 patients had low PAI-1 antigen and activity level, and four patients had both. The majority of these patients were treated with tranexamic acid monotherapy (60%) with only 40% additional treatment options, whereas 80% of patients without a presumptive fibrinolytic disorder had multiple treatment modalities. Discussion: Analysis of fibrinolytic disorders in selected patients has a high diagnostic yield. General incorporation of fibrinolytic analysis in the diagnostic workup of patients with bleeding of unknown cause can improve diagnosis and management of their bleeding episodes.

Von Willebrand disease type 2M: Correlation between genotype and phenotype.

BACKGROUND: An appropriate clinical diagnosis of von Willebrand disease (VWD) can be challenging because of a variable bleeding pattern and laboratory phenotype. Genotyping is a powerful diagnostic tool and may have an essential role in the diagnostic field of VWD. OBJECTIVES: To unravel the clinical and laboratory heterogeneity of genetically confirmed VWD type 2M patients and to investigate their relationship. METHODS: Patients with a confirmed VWD type 2M genetic variant in the A1 or A3 domain of von Willebrand factor (VWF) and normal or only slightly aberrant VWF multimers were selected from all subjects genotyped at the Radboud university medical center because of a high suspicion of VWD. Bleeding scores and laboratory results were analyzed. RESULTS: Fifty patients had a clinically relevant genetic variant in the A1 domain. Median bleeding score was 5. Compared with the nationwide Willebrand in the Netherlands study type 2 cohort, bleeding after surgery or delivery was reported more frequently and mucocutaneous bleedings less frequently. Median VWF activity/VWF antigen (VWF:Act/VWF:Ag) ratio was 0.32, whereas VWF collagen binding activity/VWF antigen (VWF:CB/VWF:Ag) ratio was 0.80. Variants in the A3 domain were only found in two patients with low to normal VWF:Act/VWF:Ag ratios (0.45, 1.03) and low VWF:CB/VWF:Ag ratios (0.45, 0.63). CONCLUSION: Genetically confirmed VWD type 2M patients have a relatively mild clinical phenotype, except for bleeding after surgery and delivery. Laboratory phenotype is variable and depends on the underlying genetic variant. Addition of genotyping to the current phenotypic characterization may improve diagnosis and classification of VWD.

Combining factor VIII levels and thrombin/plasmin generation: A population pharmacokinetic-pharmacodynamic model for patients with haemophilia A.

AIMS: Prophylactic treatment of haemophilia A patients with factor VIII (FVIII) concentrate focuses on maintaining a minimal trough FVIII activity level to prevent bleeding. However, due to differences in bleeding tendency, the pharmacokinetic (PK)-guided dosing approach may be suboptimal. An alternative approach could be the addition of haemostatic pharmacodynamic (PD) parameters, reflecting a patient's unique haemostatic balance. Our aim was to develop a population PK/PD model, based on FVIII activity levels and Nijmegen Haemostasis Assay (NHA) patterns, a global haemostatic assay that measures thrombin/plasmin generation simultaneously. METHODS: PK/PD measurements were collected from 30 patients treated with standard half-life FVIII concentrate. The relationship between FVIII activity levels and the thrombin/plasmin generation parameters (thrombin potential, thrombin peak height and plasmin peak height), were described by sigmoidal Emax functions. RESULTS: The obtained EC50 value was smallest for the normalized thrombin potential (11.6 IU/dL), followed by normalized thrombin peak height (56.6 IU/dL) and normalized plasmin peak height (593 IU/dL), demonstrating that normalized thrombin potential showed 50% of the maximal effect at lower FVIII activity levels. Substantial inter-individual variability in the PD parameters, such as EC50 of thrombin potential (86.9%) was observed, indicating that, despite similar FVIII activity levels, haemostatic capacity varies significantly between patients. CONCLUSION: These data suggest that dosing based on patients' individual PK/PD parameters may be beneficial over dosing solely on individual PK parameters. This model could be used as proof-of-principle to examine the application of PK/PD-guided dosing. However, the relation between the PD parameters and bleeding has to be better defined.

Perioperative pharmacokinetic-guided factor VIII concentrate dosing in haemophilia (OPTI-CLOT trial): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Dosing of replacement therapy with factor VIII concentrate in patients with haemophilia A in the perioperative setting is challenging. Underdosing and overdosing of factor VIII concentrate should be avoided to minimise risk of perioperative bleeding and treatment costs. We hypothesised that dosing of factor VIII concentrate on the basis of a patient's pharmacokinetic profile instead of bodyweight, which is standard treatment, would reduce factor VIII consumption and improve the accuracy of attained factor VIII levels. METHODS: In this open-label, multicentre, randomised, controlled trial (OPTI-CLOT), patients were recruited from nine centres in Rotterdam, Groningen, Utrecht, Nijmegen, The Hague, Leiden, Amsterdam, Eindhoven, and Maastricht in The Netherlands. Eligible patients were aged 12 years or older with severe or moderate haemophilia A (severe haemophilia was defined as factor VIII concentrations of <0·01 IU/mL, and moderate haemophilia as 0·01-0·05 IU/mL), without factor VIII inhibitors, and planned for elective low or medium risk surgery as defined by surgical risk score. Patients were randomly assigned (1:1) using a web-based randomisation system and treatment minimisation, stratified by method of administration of factor VIII concentrate (continuous infusion vs bolus administration) and risk level of surgery (low and medium risk surgery), to the pharmacokinetic-guided or standard treatment group. The primary endpoint was total amount of infused factor VIII concentrate (IU per kg bodyweight) during perioperative period (from day of surgery up to 14 days after surgery). Analysis was by intention to treat and the safety analysis population comprised all participants who underwent surgery with factor VIII concentrate. This study is registered with the Netherlands Trial Registry, NL3955, and is now closed to accrual. FINDINGS: Between May 1, 2014, and March 1, 2020, 98 patients were assessed for eligibility and 66 were enrolled in the trial and randomly assigned to the pharmacokinetic-guided treatment group (34 [52%]) or the standard treatment group (32 [48%]). Median age was 49·1 years (IQR 35·0 to 62·1) and all participants were male. No difference was seen in consumption of factor VIII concentrate during the perioperative period between groups (mean consumption of 365 IU/kg [SD 202] in pharmacokinetic-guided treatment group vs 379 IU/kg [202] in standard treatment group; adjusted difference -6 IU/kg [95% CI -88 to 100]). Postoperative bleeding occurred in six (18%) of 34 patients in the pharmacokinetic-guided treatment group and three (9%) of 32 in the standard treatment group. One grade 4 postoperative bleeding event occurred, which was in one (3%) patient in the standard treatment group. No treatment-related deaths occurred. INTERPRETATION: Although perioperative pharmacokinetic-guided dosing is safe, it leads to similar perioperative factor VIII consumption when compared with standard treatment. However, pharmacokinetic-guided dosing showed an improvement in obtaining factor VIII concentrations within the desired perioperative factor VIII range. These findings provide support to further investigation of pharmacokinetic-guided dosing in perioperative haemophilia care. FUNDING: Dutch Research Council (NWO)-ZonMw and Takeda.

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study.

BACKGROUND: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). OBJECTIVES: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. PATIENTS/METHODS: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. RESULTS: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. CONCLUSIONS: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

The SLIM study-Shared medical appointments to change lifestyles of overweight people with haemophilia: A randomized multiple baseline (n-of-1) design.

INTRODUCTION: People with haemophilia suffer from haemophilic joint disease that may result in physical inactivity and overweight. Shared medical appointments (SMAs) might help limit the consequences of haemophilic arthropathy. SMAs are group meetings supervised by one or more healthcare professionals that can be utilized to improve lifestyle. AIM: To evaluate the feasibility and efficacy of SMAs in people with haemophilia to improve physical activity and eating habits. METHODS: A multiple baseline single-case design was used. Overweight people with haemophilia were eligible to participate. Seven weekly SMAs were conducted using multiple behavioural change techniques to improve physical activity and eating habits. Feasibility of SMAs was evaluated using (a) dropout rate, (b) occurrence of adverse events (AEs), (c) adherence rate and (d) patient satisfaction. During 13 weeks, physical activity was measured daily and eating habits were measured three times per week. The efficacy of SMAs was determined using randomization tests and visual data inspection. RESULTS: Out of the six men participating in the study, one participant dropped out. No study-related AEs occurred. The adherence rate of SMAs was 80%, and participants reported to be 'very satisfied' with the SMAs. Randomization tests and visual analyses demonstrated (statistical) improvements in physical activity (p = .03). No effect was found in self-reported eating habits (p = .55). CONCLUSION: Shared medical appointments are feasible in people with haemophilia and appear to improve physical activity. The effect on improving eating habits could not be established. Scientific replication of our approach is warranted to confirm or refute the merit of SMAs in people with haemophilia.

Validation of a perioperative population factor VIII pharmacokinetic model with a large cohort of pediatric hemophilia a patients.

AIMS: Population pharmacokinetic (PK) models are increasingly applied to perform individualized dosing of factor VIII (FVIII) concentrates in haemophilia A patients. To guarantee accurate performance of a population PK model in dose individualization, validation studies are of importance. However, external validation of population PK models requires independent data sets and is, therefore, seldomly performed. Therefore, this study aimed to validate a previously published population PK model for FVIII concentrates administrated perioperatively. METHODS: A previously published population PK model for FVIII concentrate during surgery was validated using independent data from 87 children with severe haemophilia A with a median (range) age of 2.6 years (0.03-15.2) and body weight of 14 kg (4-57). First, the predictive performance of the previous model was evaluated with MAP Bayesian analysis using NONMEM v7.4. Subsequently, the model parameters were (re)estimated using a combined dataset consisting of the previous modelling data and the data available for the external validation. RESULTS: The previous model underpredicted the measured FVIII levels with a median of 0.17 IU mL-1 . Combining the new, independent and original data, a dataset comprising 206 patients with a mean age of 7.8 years (0.03-77.6) and body weight of 30 kg (4-111) was obtained. Population PK modelling provided estimates for CL, V1, V2, and Q: 171 mL h-1  68 kg-1 , 2930 mL 68 kg-1 , 1810 mL 68 kg-1 , and 172 mL h-1  68 kg-1 , respectively. This model adequately described all collected FVIII levels, with a slight median overprediction of 0.02 IU mL-1 . CONCLUSIONS: This study emphasizes the importance of external validation of population PK models using real-life data.

Population pharmacokinetics of the von Willebrand factor-factor VIII interaction in patients with von Willebrand disease.

Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may improve dosing and quality of care. In total, 695 VWF:Act and 894 FVIII level measurements from 118 patients (174 surgeries) who were treated perioperatively with the VWF/FVIII concentrate were used to develop this population PK model using nonlinear mixed-effects modeling. VWF:Act and FVIII levels were analyzed simultaneously using a turnover model. The protective effect of VWF:Act on FVIII clearance was described with an inhibitory maximum effect function. An average perioperative VWF:Act level of 1.23 IU/mL decreased FVIII clearance from 460 mL/h to 264 mL/h, and increased FVIII half-life from 6.6 to 11.4 hours. Clearly, in the presence of VWF, FVIII clearance decreased with a concomitant increase of FVIII half-life, clarifying the higher FVIII levels observed after repetitive dosing with this concentrate. VWF:Act and FVIII levels during perioperative treatment were described adequately by this newly developed integrated population PK model. Clinical application of this model may facilitate more accurate targeting of VWF:Act and FVIII levels during perioperative treatment with this specific VWF/FVIII concentrate (Humate P/Haemate P).

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

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], P < 0.001), normal multimers from absence of HMW multimers (AUC 1.00 [1.00-1.00], P < 0.001), and type 2A and 2B from type 2M and 2N (AUC: 0.96 [0.94-0.99], P < 0.001). Additionally, higher medium-large VWF multimer index was associated with lower BS in type 1 VWD: ß = -7.6 (-13.0 to -2.1), P = 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.

Dosing of factor VIII concentrate by ideal body weight is more accurate in overweight and obese haemophilia A patients.

AIMS: Under- and, especially, overdosing of replacement therapy in haemophilia A patients may be prevented by application of other morphometric variables than body weight (BW) to dose factor VIII (FVIII) concentrates. Therefore, we aimed to investigate which morphometric variables best describe interindividual variability (IIV) of FVIII concentrate pharmacokinetic (PK) parameters. METHODS: PK profiling was performed by measuring 3 FVIII levels after a standardized dose of 50 IU kg-1 FVIII concentrate. A population PK model was constructed, in which IIV for clearance (CL) and central volume of distribution (V1) was quantified. Relationships between CL, V1 and 5 morphometric variables (BW, ideal BW [IBW], lean BW, adjusted BW, and body mass index [BMI]) were evaluated in normal weight (BMI < 25 kg m-2 ), overweight (BMI 25-30 kg m-2 ) and obese haemophilia A patients (BMI > 30 kg m-2 ). RESULTS: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL-1 ) were included with median BW of 83 kg (range: 53-133) and median age of 48 years (range: 18-77). IBW best explained observed variability between patients, as IIV for CL and V1 was reduced from 45.1 to 37.6 and 26.% to 14.1%, respectively. CL, V1 and half-life were similar for all BMI categories. The national recommended dosing schedule did not result in adequate trough levels, both in case of dosing based on BW and IBW. However, dosing based on IBW prevented unnecessary high FVIII peaks. CONCLUSION: IBW is the most suitable morphometric variable to explain interindividual FVIII PK variability and is more appropriate to dose overweight and obese patients.

ADAMTS-13 and bleeding phenotype in von Willebrand disease.

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.

Pharmacodynamic monitoring of factor VIII replacement therapy in hemophilia A: Combining thrombin and plasmin generation.

BACKGROUND: Clinical severity of hemophilia A (HA) varies, possibly due to interplay of many factors in the hemostatic pathway. Pharmacokinetic monitoring of factor VIII (FVIII) replacement therapy in HA patients consists of measuring FVIII activity levels and subsequent dose adjustment. The Nijmegen Hemostasis Assay (NHA) measures thrombin generation (TG) and plasmin generation (PG). OBJECTIVE: To determine differences in TG and PG between HA patients before and during a pharmacokinetic study and identify best parameters to develop a pharmacodynamic model. METHODS: Twenty-five HA patients (baseline FVIII < 1-9 IU/dL) underwent a pharmacokinetic study with a single dose of 25-50 IU/kg standard half-life FVIII concentrate. At baseline and after administration of FVIII TG and PG parameters were measured with the NHA. RESULTS: FVIII activity level increased from median 1.0 IU/dL (interquartile range < 1.0-6.0) to 71 IU/dL (62-82) 15 minutes after administration and decreased to 15 IU/dL (10-26) at 24 hours. TG was enhanced simultaneously, with thrombin peak height (TPH) increasing from 22nM (15-35) to 222nM (159-255), and thrombin potential (TP) from 404nM/min (undetectable-876) to 1834nM/min (1546-2353). Twenty-four hours after infusion, TG parameters remained high (TPH 73nM [58.5-126.3]; TP 1394nM/min [1066-1677]) compared to FVIII activity level. PG showed hyperfibrinolysis in severe HA patients compared to mild patients and controls, which normalized after FVIII supplementation. CONCLUSION: HA patients showed clear differences in baseline TG and PG despite having comparable FVIII activity levels. These results reveal a discrepancy between FVIII activity level and TG, in which the latter may be a better parameter to monitor individualized treatment in HA patients.

von Willebrand Factor and Factor VIII Clearance in Perioperative Hemophilia A Patients.

BACKGROUND: von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting. AIM: To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial. METHODS: Linear mixed effects modeling was applied to analyze VWF kinetics. One-way and two-way analyses of variance were used to investigate perioperative VWFpp/VWF:Ag ratios and associations with surgical bleeding. RESULTS: Fifty-nine patients with median age of 48.8 years (interquartile range: 34.8-60.0) were included. VWF:Ag and VWF:GPIbM increased significantly postoperatively. Blood type non-O or medium risk surgery were associated with higher VWF:Ag and VWF:GPIbM levels compared with blood type O and low risk surgery. VWFpp/VWF:Ag was significantly higher immediately after surgery than 32 to 57 hours after surgery (p < 0.001). Lowest VWF:Ag quartile (0.43-0.92 IU/mL) was associated with an increase of FVIII concentrate clearance of 26 mL/h (95% confidence interval: 2-50 mL/h) compared with highest VWF antigen quartile (1.70-3.84 IU/mL). VWF levels were not associated with perioperative bleeding F(4,227) = 0.54, p = 0.710. CONCLUSION: VWF:Ag and VWF:GPIbM levels increase postoperatively, most significantly in patients with blood type non-O or medium risk surgery. Lower VWF antigen levels did not lead to clinically relevant higher FVIII clearance. VWF:Ag or VWF:GPIbM levels were not associated with perioperative hemorrhage.

Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series.

Congenital afibrinogenemia is a rare autosomal recessive disorder associated with an increased risk of hemorrhage, thrombosis, and obstetric complications. This case series of 4 pregnancies in 2 related patients seeks to address the key clinical question of the necessary doses of fibrinogen concentrate during pregnancy and puerperium. One pregnancy without the prophylactic use of fibrinogen concentrate resulted in spontaneous abortion. The second pregnancy was complicated by a subchorionic hematoma despite the prophylactic administration of fibrinogen concentrate to maintain the plasma trough levels at ≥0.6 g/L. Labor was complicated by postpartum hemorrhage with a blood loss volume of 1480 cc. Two weeks later, the patient presented with postpartum thrombosis. The other 2 pregnancies were uncomplicated with fibrinogen trough levels ≥1.0 g/L during pregnancy and ≥1.5 g/L during labor. These cases illustrate that during pregnancy, patients may benefit from fibrinogen trough levels ≥1.0 g/L. In addition, the increased risk of postpartum thrombosis with prolonged fibrinogen supplementation warrants personalized postpartum advice that is guided by postpartum blood loss.