Publications by authors named "Frank W G Leebeek"

194 Publications

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

Thromb Haemost 2021 Apr 14. Epub 2021 Apr 14.

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

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

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

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

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

Conclusion:  Bleeding complications are frequent in BUC patients, irrespective of pre- or perioperative hemostatic treatment. We recommend a low-threshold approach toward administration of hemostatic treatment in BUC patients, especially during delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-1726344DOI Listing
April 2021

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

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

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

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

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

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

Conclusions: We found that TG parameters are associated with a first IS in young patients. Further prospective studies are warranted to elucidate the role of TG in IS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.thromres.2021.03.028DOI Listing
March 2021

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

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

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

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

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

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

Conclusion: In this first GWAS and exome-sequencing analysis of NETs levels, we found several genes that were associated with NETs. The precise mechanism of how these genes may contribute to neutrophil function or the formation of NETs remains unclear and should be further investigated in experimental studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2021.615527DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944992PMC
February 2021

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

Blood Adv 2021 Mar;5(5):1513-1522

Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center (UMC), University of Amsterdam, Amsterdam, The Netherlands.

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).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948283PMC
March 2021

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1097/HS9.0000000000000542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7892298PMC
March 2021

ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease.

Blood Adv 2021 Jan;5(1):301-325

Outcomes and Implementation Research Unit, Division of Nephrology and Hypertension, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS.

Background: von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients.

Objective: These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD.

Methods: ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment.

Results: The panel agreed on 12 recommendations and outlined future research priorities.

Conclusions: These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003264DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805326PMC
January 2021

A systematic review of antithrombotic treatment of venous thromboembolism in patients with myeloproliferative neoplasms.

Blood Adv 2021 Jan;5(1):113-121

Department of Vascular Medicine and.

Patients with myeloproliferative neoplasms (MPNs), polycythemia vera, essential thrombocythemia, and primary myelofibrosis, have an increased risk of thrombosis. Risk of recurrent thrombosis can be reduced with antithrombotic therapy and/or cytoreduction, but the optimal long-term management in patients with MPN with a history of venous thromboembolism (VTE) is unknown, and clinical practice is heterogeneous. We performed a systematic review and meta-analysis of randomized trials and observational studies evaluating anticoagulant and/or antiplatelet therapy, with or without cytoreduction, in MPN patients with a history of VTE. A total of 5675 unique citations were screened for eligibility. No randomized trials were identified. Ten observational studies involving 1295 patients with MPN were included in the analysis. Overall, 23% had an arterial or recurrent venous thrombotic event on follow-up. The recurrence risk was lowest for patients on oral anticoagulation plus cytoreduction (16%); 55 of 313 (18%) with vitamin K antagonists (VKA) and 5 of 63 (8%) with direct oral anticoagulants (DOACs). In 746 analyzed patients, the risk of recurrent VTE ranged up to 33% (median 13%) and was low in 63 DOAC plus cytoreduction-treated patients (3.2%). All types of antithrombotic treatments were associated with a lower risk of recurrent VTE when combined with cytoreduction. Most studies had a high risk of bias, whereas clinical and statistical heterogeneity led to inconsistent and imprecise findings. In summary, evidence on the optimal antithrombotic treatment of VTE in patients with MPN is based on observational studies only with low certainty for all strategies. Our data suggest that a combination of anticoagulation and cytoreduction may provide the lowest recurrence risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/bloodadvances.2020003628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805324PMC
January 2021

Major differences in clinical presentation, diagnosis and management of men and women with autosomal inherited bleeding disorders.

EClinicalMedicine 2021 Feb 29;32:100726. Epub 2021 Jan 29.

Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, the Netherlands.

Background: In recent years, more awareness is raised about sex-specific dilemmas in inherited bleeding disorders. However, no large studies have been performed to assess differences in diagnosis, bleeding phenotype and management of men and women with bleeding disorders. Therefore, we investigated sex differences in a large cohort of well-defined patients with autosomal inherited bleeding disorders (von Willebrand disease (VWD), rare bleeding disorders (RBDs) and congenital platelet defects (CPDs)).

Methods: We included patients from three nationwide cross-sectional studies on VWD, RBDs and CPDs in the Netherlands, respectively the WiN, RBiN and TiN study. In all studies a bleeding score (BS) was obtained, and patients filled in an extensive questionnaire on the management and burden of their disorder.

Findings: We included 1092 patients (834 VWD; 196 RBD; 62 CPD), of whom 665 (60.9%) were women. Women were more often referred because of a bleeding diathesis than men (47.9% vs 36.6%,  = 0.002). Age of first bleeding was similar between men and women, respectively 8.9 ± 13.6 (mean ±sd) years and 10.6 ± 11.3 years ( = 0.075). However, the diagnostic delay, which was defined as time from first bleeding to diagnosis, was longer in women (11.6 ± 16.4 years) than men (7.7 ± 16.6 years,  = 0.002). Similar results were found when patients referred for bleeding were analyzed separately. Of women aging 12 years or older, 469 (77.1%) had received treatment because of sex-specific bleeding.

Interpretation: Women with autosomal inherited bleeding disorders are more often referred for bleeding, have a longer diagnostic delay, and often require treatment because of sex-specific bleeding.

Funding: The WiN study was supported (in part) by research funding from the Dutch Hemophilia Foundation (Stichting Haemophilia), Shire (Takeda), and CSL Behring (unrestricted grant).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.eclinm.2021.100726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848767PMC
February 2021

Comparison of the Pharmacokinetic Properties of Extended Half-Life and Recombinant Factor VIII Concentrates by In Silico Simulations.

Thromb Haemost 2021 Jan 27. Epub 2021 Jan 27.

Hospital Pharmacy-Clinical Pharmacology, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Background:  The pharmacokinetic (PK) properties of extended half-life (EHL) factor VIII (FVIII) concentrates differ, leading to variation in the optimal dosing regimen for the individual patient. The aim of this study was to establish these PK differences for various EHL FVIII concentrates by in silico simulations.

Methods:  FVIII level over time profiles of rFVIII-SC, BAY 81-8973, rFVIII-Fc, BAX 855, BAY 94-9027, and standard half-life (SHL) rFVIII concentrates were simulated for 1,000 severe hemophilia A patients during steady-state dosing of 40 IU/kg every 72 hours or dosing as advised in the summary of product characteristics (SmPC).

Results:  Although the elimination half-life values were comparable for rFVIII-FC, BAX 855, and BAY 94-9027, a higher area under the curve (AUC; 2,779 IU/h/dL) for BAY 94-9027 was obtained. During steady-state dosing of 40 IU/kg every 72 hours, 58.5% (rFVIII-SC), 69.3% (BAY 81-8972), 89.0% (rFVIII-Fc), 83.9% (BAX 855), and 93.7% (BAY 94-9027) of the patients maintained a trough level of 1 IU/dL, compared with 56.0% for SHL rFVIII. Following dosing schemes described in the SmPC, between 51.0 and 65.4% or 23.2 and 31.1% of the patients maintained a target trough level of 1 IU/dL or 3 IU/dL, respectively.

Conclusion:  BAY 94-9027 showed the largest increase of AUC and best target attainment compared with SHL rFVIII, followed closely by BAX 855 and rFVIII-Fc. BAY 81-8973 and rFVIII-SC showed smaller PK improvements. Although our analyses increase insight into the PK of these FVIII concentrates, more studies evaluating the relation between factor levels and bleeding risk are needed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1721484DOI Listing
January 2021

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

Thromb Haemost 2021 Jan 14. Epub 2021 Jan 14.

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

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

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1722185DOI Listing
January 2021

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

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

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

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

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

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

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

Conclusions: The cutoff value of low VWF diagnosis should be set at 0.60 IU/ml. Furthermore, a risk score is developed to identify individuals with a high risk for bleeding after low VWF diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15227DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986755PMC
March 2021

The association between desmopressin exposure, FVIII response and side effects.

Haemophilia 2020 Dec 13. Epub 2020 Dec 13.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14227DOI Listing
December 2020

ADAMTS-13 and bleeding phenotype in von Willebrand disease.

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

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

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

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

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

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

Conclusion: ADAMTS-13 activity was highest in individuals with type 3 VWD, but it had only minor associations with VWF parameters. ADAMTS-13 activity does not influence the bleeding phenotype in individuals with VWD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/rth2.12442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695560PMC
November 2020

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

Br J Clin Pharmacol 2020 Nov 24. Epub 2020 Nov 24.

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

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 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 ), overweight (BMI 25-30 kg m ) and obese haemophilia A patients (BMI > 30 kg m ).

Results: In total, 57 haemophilia A patients (FVIII≤0.05 IU mL ) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bcp.14670DOI Listing
November 2020

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

J Thromb Haemost 2021 03 18;19(3):645-653. Epub 2020 Dec 18.

Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands.

Objective: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward.

Patients/methods: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018.

Results: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time.

Conclusions: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.15182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986360PMC
March 2021

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

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

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

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

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21197107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582521PMC
September 2020

Treatment of acquired hemophilia A, a balancing act: results from a 27-year Dutch cohort study.

Am J Hematol 2021 01 10;96(1):51-59. Epub 2020 Oct 10.

Van Creveldkliniek, University Medical Center Utrecht, University Utrecht, Utrecht, The Netherlands.

Acquired hemophilia A (AHA) is a severe auto-immune bleeding disorder. Treatment of AHA is burdensome and optimal management is still unresolved. Therefore a retrospective nationwide multi-center cohort study (1992-2018) was performed to evaluate clinical presentation and treatment efficacy and safety of AHA in the Netherlands. Multivariate logistic and Cox regression analysis was used to study independent associations between patient characteristics and clinical outcomes. A total of 143 patients (median age 73 years; 52.4% male) were included with a median follow-up of 16.8 months (IQR 3.6-41.5 months). First-line immunosuppressive treatment was mostly steroid monotherapy (67.6%), steroids/cyclophosphamide (11.9%) and steroids/rituximab (11.9%), with success rates of 35.2%, 80.0% and 66.7% respectively, P < .05. Eventually 75% of patients achieved complete remission (CR). A high anti-FVIII antibody titer, severe bleeding and steroid monotherapy were associated with lower CR rates. Infections, the most important adverse event, occurred significantly more often with steroid combination therapy compared to steroids alone (38.7% vs 10.6%; P = .001). Overall mortality was 38.2%, mostly due to infections (19.2%) compared to 7.7% fatal bleeds. Advanced age, underlying malignancy and ICU admission were predictors for mortality. This study showed that AHA is characterized by significant disease-related and treatment-related morbidity and mortality. A high anti-FVIII titer, severe bleeding and steroid monotherapy were associated with a lower CR rate. The efficacy of steroid combination therapies however, was overshadowed by higher infection rates and infections represented the most important cause of death. The challenging and delicate balance between treatment effectivity and safety requires ongoing monitoring of AHA and further identification of prognostic markers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajh.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756759PMC
January 2021

Population Pharmacokinetics of Clotting Factor Concentrates and Desmopressin in Hemophilia.

Clin Pharmacokinet 2021 Jan;60(1):1-16

Hospital Pharmacy-Clinical Pharmacology, Academic University Medical Centers, Location AMC, Amsterdam, The Netherlands.

Hemophilia A and B are bleeding disorders caused by a deficiency of clotting factor VIII and IX, respectively. Patients with severe hemophilia (< 0.01 IU mL) and some patients with moderate hemophilia (0.01-0.05 IU mL) administer clotting factor concentrates prophylactically. Desmopressin (D-amino D-arginine vasopressin) can be applied in patients with non-severe hemophilia A. The aim of administration of factor concentrates or desmopressin is the prevention or cessation of bleeding. Despite weight-based dosing, it has been demonstrated that factor concentrates still exhibit considerable pharmacokinetic variability. Population pharmacokinetic analyses, in which this variability is quantified and explained, are increasingly performed in hemophilia research. These analyses can assist in the identification of important patient characteristics and can be applied to perform patient-tailored dosing. This review aims to present and discuss the population pharmacokinetic analyses that have been conducted to develop population pharmacokinetic models describing factor levels after administration of factor VIII or factor IX concentrates or D-amino D-arginine vasopressin. In total, 33 publications were retrieved from the literature. Two approaches were applied to perform population pharmacokinetic analyses, the standard two-stage approach and non-linear mixed-effect modeling. Using the standard two-stage approach, four population pharmacokinetic models were established describing factor VIII levels. In the remaining 29 analyses, the non-linear mixed-effect modeling approach was applied. NONMEM was the preferred software to establish population pharmacokinetic models. In total, 18 population pharmacokinetic analyses were conducted on the basis of data from a single product. From all available population pharmacokinetic analyses, 27 studies also included data from pediatric patients. In the majority of the population pharmacokinetic models, the population pharmacokinetic parameters were allometrically scaled using actual body weight. In this review, the available methods used for constructing the models, key features of these models, patient population characteristics, and established covariate relationships are described in detail.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s40262-020-00936-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7808974PMC
January 2021

Ex vivo Improvement of a von Willebrand Disease Type 2A Phenotype Using an Allele-Specific Small-Interfering RNA.

Thromb Haemost 2020 Nov 15;120(11):1569-1579. Epub 2020 Aug 15.

Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, the Netherlands.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is mainly caused by dominant-negative mutations in the multimeric protein von Willebrand factor (VWF). These mutations may either result in quantitative or qualitative defects in VWF. VWF is an endothelial protein that is secreted to the circulation upon endothelial activation. Once secreted, VWF multimers bind platelets and chaperone coagulation factor VIII in the circulation. Treatment of VWD focuses on increasing VWF plasma levels, but production and secretion of mutant VWF remain uninterrupted. Presence of circulating mutant VWF might, however, still affect normal hemostasis or functionalities of VWF beyond hemostasis. We hypothesized that inhibition of the production of mutant VWF improves the function of VWF overall and ameliorates VWD phenotypes. We previously proposed the use of allele-specific small-interfering RNAs (siRNAs) that target frequent single nucleotide polymorphisms to inhibit mutant . The aim of this study is to prove the functionality of these allele-specific siRNAs in endothelial colony-forming cells (ECFCs). We isolated ECFCs from a VWD type 2A patient with an intracellular multimerization defect, reduced VWF collagen binding, and a defective processing of proVWF to VWF. After transfection of an allele-specific siRNA that specifically inhibited expression of mutant VWF, we showed amelioration of the laboratory phenotype, with normalization of the VWF collagen binding, improvement in VWF multimers, and enhanced VWF processing. Altogether, we prove that allele-specific inhibition of the production of mutant VWF by siRNAs is a promising therapeutic strategy to improve VWD phenotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1715442DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649061PMC
November 2020

How I manage pregnancy in carriers of hemophilia and patients with von Willebrand disease.

Blood 2020 11;136(19):2143-2150

Department of Hematology and.

Women with inherited bleeding disorders, including carriers of hemophilia A and B, or with von Willebrand disease, have an increased risk of bleeding during pregnancy and delivery. The unborn child may also be affected by the bleeding disorder for which specific measures have to be considered. This requires a multidisciplinary approach, with a team that includes a hematologist, a pediatric hematologist, a clinical geneticist, an obstetrician-perinatologist, and an anesthesiologist. An optimal approach includes prepregnancy genetic counseling, prenatal diagnostic procedures, and a treatment plan for delivery for both the mother and child. Recent retrospective studies show that even if strict guidelines are followed, these women are still at risk of postpartum bleeding. This occurs even if coagulation factor levels are normalized, either due to the pregnancy-induced rise of factor levels or by infusion of coagulation factor concentrates at the time of delivery. In this article, we describe our current diagnostic and clinical management of pregnancy and delivery in women with inherited bleeding disorders. We also briefly discuss possible interventions to improve the outcome of current strategies by increasing target factor levels during and after delivery.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood.2019000964DOI Listing
November 2020

Population Pharmacokinetic Modeling of von Willebrand Factor Activity in von Willebrand Disease Patients after Desmopressin Administration.

Thromb Haemost 2020 Oct 3;120(10):1407-1416. Epub 2020 Aug 3.

Hospital Pharmacy-Clinical Pharmacology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Objective:  Most von Willebrand disease (VWD) patients can be treated with desmopressin during bleeding or surgery. Large interpatient variability is observed in von Willebrand factor (VWF) activity levels after desmopressin administration. The aim of this study was to develop a pharmacokinetic (PK) model to describe, quantify, and explain this variability.

Methods:  Patients with either VWD or low VWF, receiving an intravenous desmopressin test dose of 0.3 µg kg, were included. A PK model was derived on the basis of the individual time profiles of VWF activity. Since no VWF was administered, the VWF dose was arbitrarily set to unity. Interpatient variability in bioavailability (), volume of distribution (), and clearance (Cl) was estimated.

Results:  The PK model was developed using 951 VWF activity level measurements from 207 patients diagnosed with a VWD type. Median age was 28 years (range: 5-76), median predose VWF activity was 0.37 IU/mL (range: 0.06-1.13), and median VWF activity response at peak level was 0.64 IU/mL (range: 0.04-4.04). The observed PK profiles were best described using a one-compartment model with allometric scaling. While increased with age, Cl was dependent on VWD type and sex. Inclusion resulted in a drop in interpatient variability in and Cl of 81.7 to 60.5% and 92.8 to 76.5%, respectively.

Conclusion:  A PK model was developed, describing VWF activity versus time profile after desmopressin administration in patients with VWD or low VWF. Interpatient variability in response was quantified and partially explained. This model is a starting point toward more accurate prediction of desmopressin dosing effects in VWD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1714349DOI Listing
October 2020

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

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

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

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

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

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

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

Conclusion: Neither the one-stage assay nor the chromogenic assay is superior in predicting bleeding phenotype. In addition, equivalent or discrepant FVIII results measured before desmopressin do not always predict FVIII assay results after desmopressin administration.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590113PMC
September 2020

Acquired haemophilia A after alemtuzumab therapy.

Haemophilia 2020 Nov 22;26(6):e337-e339. Epub 2020 Jul 22.

Department of Internal Medicine, Division of Nephrology and Transplantation, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/hae.14107DOI Listing
November 2020

A Novel Quantitative Method for Analyzing Desmopressin in Human Plasma Using Liquid Chromatography-Tandem Mass Spectrometry.

Ther Drug Monit 2020 12;42(6):880-885

Clinical Pharmacology and Hospital Pharmacy-Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Desmopressin (D-amino D-arginine vasopressin: dDAVP) is used for the treatment of patients with hemophilia A and Von Willebrand disease. Studies on the rationale of dosing are scarce and mainly focus on the underlying causes of the vast differences in desmopressin response among individuals. The aim of this study was to develop and validate a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the quantification of desmopressin in human plasma for identifying its pharmacokinetics and its therapeutic effect relationship in patients with bleeding disorder.

Methods: The method entails solid-phase extraction with ion exchange for sample clean-up, followed by an LC-MS/MS run. The technique has been validated for analytical selectivity as well as specificity, process efficiency, linearity, accuracy, imprecision, and stability.

Results: This method showed good selectivity because no significant chromatographic matrix interferences were observed. The determination coefficient (R) of the calibration curves was ≥0.990. Analyte accuracy ranged from 89.2% to 111.8%, and the between- and within-run imprecision was less than 9.3% in a plasma concentration and range from 60 to 3200 pg/mL. Samples were stable during 3 freeze/thaw cycles with an additional 120 hours of storage at room temperature (21°C-24°C) and 96 hours in the autosampler (10°C). The total run time was approximately 5 minutes.

Conclusions: The LC-MS/MS method presented enables quantification of desmopressin in human plasma, and it is sensitive, specific, efficient, accurate, and precise. This analytical technique is a valuable and useful tool to study the interpatient variability of pharmacokinetics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/FTD.0000000000000791DOI Listing
December 2020

Effect of antithrombotic stewardship on the efficacy and safety of antithrombotic therapy during and after hospitalization.

PLoS One 2020 25;15(6):e0235048. Epub 2020 Jun 25.

Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Although the benefits of antithrombotic drugs are indisputable to reduce thrombotic events, they carry a high risk of compromising patient safety. No previous studies investigated the implementation and (cost-) effectiveness of a hospital-based multidisciplinary antithrombotic team on bleeding and thrombotic outcomes. The primary aim of this study was to compare the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization.

Methods And Findings: A prospective, multicenter before-after intervention study was conducted in two Dutch hospitals. Adult patients hospitalized between October 2015 and December 2017 treated with anticoagulant therapy were included. The primary aim was to estimate the proportion of patients with a composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization. The intervention was the implementation of a multidisciplinary antithrombotic team focusing on education, medication reviews by pharmacists, implementing of local anticoagulant therapy guidelines based on national guidelines, patient counselling and medication reconciliation at admission and discharge. The primary endpoint was analysed using segmented linear regression. We obtained data for 1,886 patients: 941 patients were included in the usual care period and 945 patients in the intervention period. The S-team study showed that implementation of a multidisciplinary antithrombotic team over time significantly reduced the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs (-1.83% (-2.58% to -1.08%) per 2 month period).

Conclusions: This study shows that implementation of a multidisciplinary antithrombotic team over time significantly reduces the composite end point consisting of one or more bleeding episodes or one or more thrombotic event from hospitalization until three months after hospitalization in patients using anticoagulant drugs.

Trial Registration: Trialregister.nl NTR4887.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235048PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316339PMC
August 2020

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

Thromb Haemost 2020 Jul 1;120(7):1056-1065. Epub 2020 Jun 1.

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

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 ( < 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 (4,227) = 0.54,  = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0040-1710591DOI Listing
July 2020

COVID-19-associated immune thrombocytopenia.

Br J Haematol 2020 07 8;190(2):e61-e64. Epub 2020 Jun 8.

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

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/bjh.16850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276755PMC
July 2020

Bleeding symptoms in patients diagnosed as type 3 von Willebrand disease: Results from 3WINTERS-IPS, an international and collaborative cross-sectional study.

J Thromb Haemost 2020 09 25;18(9):2145-2154. Epub 2020 Aug 25.

Hematology and Transfusion Medicine, Department of Oncology and Oncohematology, L. Sacco University Hospital, University of Milan, Milano, Italy.

Background: Type 3 von Willebrand's disease (VWD) patients present markedly reduced levels of von Willebrand factor and factor VIII. Because of its rarity, the bleeding phenotype of type 3 VWD is poorly described, as compared to type 1 VWD.

Aims: To evaluate the frequency and the severity of bleeding symptoms across age and sex groups in type 3 patients and to compare these with those observed in type 1 VWD patients to investigate any possible clustering of bleeding symptoms within type 3 patients.

Methods: We compared the bleeding phenotype and computed the bleeding score (BS) using the MCMDM-1VWD bleeding questionnaire in patients enrolled in the 3WINTERS-IPS and MCMDM-1VWD studies.

Results: In 223 unrelated type 3 VWD patients, both the BS and the number of clinically relevant bleeding symptoms were increased in type 3 as compared to type 1 VWD patients (15 versus 6 and 5 versus 3). Intracranial bleeding, oral cavity, hemarthroses, and deep hematomas were at least five-fold over-represented in type 3 VWD. A more severe bleeding phenotype was evident in patients having von Willebrand factor antigen levels < 20 IU/dL at diagnosis in the two merged cohorts. In type 3 patients, there was an apparent clustering of hemarthrosis with gastrointestinal bleeding and epistaxis, whereas bleeding after surgery or tooth extraction clusters with oral bleeding and menorrhagia.

Conclusions: In the largest cohort of type 3 VWD patients, we were able to describe a distinct clinical phenotype that is associated with the presence of a more severe hemostatic defect.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jth.14886DOI Listing
September 2020