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1.
Haemophilia ; 30(1): 161-168, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38013388

RESUMO

INTRODUCTION: VWD diagnosis is challenging requiring multiple VWF activity tests using many individual assays. We have developed an ELISA-based VWF Multiplex Activity Assay (VWF-MAA) to address this concern; however, the ability of the VWF-MAA to discriminate between type 1 VWD, variant VWD, and normal subjects has not been evaluated. AIM: To evaluate the VWF-MAA and its ability to differentiate between type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding. METHODS: A total of 177 plasma samples from the Zimmerman Program: Comparative Effectiveness in the Diagnosis of VWD were evaluated from 11 centres across the US and Canada. The VWF-MAA was compared to Versiti Blood Research Institute (VBRI) and Local Center (LC) assigned VWD diagnosis. RESULTS: Overall, 129/177 (72.9%) were correctly assigned as normal (non-VWD), type 1, or variant VWD compared to the VBRI assigned diagnosis. VWF-MAA assigned non-VWD accurately in 29/57 (50.9%) samples, and type 1 VWD accurately in 93/110 (84.6%) samples. Considering LC diagnosis where there was agreement with VWF-MAA and not VBRI diagnosis, type 1 VWD was accurate in 105/110 (95.5%) samples. Bland-Altman analysis demonstrated good correlation between laboratory methods. VWD, types 2A, 2B, 1C VWD were also assigned by the VWF-MAA. CONCLUSIONS: We demonstrate that the VWF-MAA has utility in differentiating type 1 VWD, variant VWD and normal subjects in individuals undergoing an initial laboratory evaluation for bleeding.


Assuntos
Doença de von Willebrand Tipo 1 , Doença de von Willebrand Tipo 2 , Doenças de von Willebrand , Humanos , Fator de von Willebrand/análise , Doença de von Willebrand Tipo 1/diagnóstico , Doenças de von Willebrand/diagnóstico , Hemorragia , Canadá , Doença de von Willebrand Tipo 2/diagnóstico
2.
J Thromb Haemost ; 22(3): 666-675, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38040335

RESUMO

BACKGROUND: As knowledge of the human genome has advanced, so too has the recognition that interpretation of the pathogenic nature of sequence variants can be challenging. The von Willebrand factor (VWF) gene exhibits a significant degree of sequence variability, and the first VWF variant associated with type 1 von Willebrand disease (VWD), c.4751 A>G, p.Y1584C, was described in 2003. However, since that time, the pathogenic nature of this variant has remained unclear, being assigned properties ranging from a risk factor to a pathogenic variant. OBJECTIVES: To provide additional evaluation on the interpretation of pathogenicity for this common VWF variant. METHODS: Fifty-eight subjects with only the p.Y1584C variant were recruited from 2 cohort studies (the Zimmerman Program and the Canadian type 1 VWD study). Clinical and laboratory phenotypes were assessed. RESULTS: The prevalence of the p.Y1584C variant in our cohorts was 23- to 27-fold higher than that in large normal population databases. Significantly more p.Y1584C subjects had an abnormal bleeding score when compared to Y1584 individuals. In comparison with a group of 35 subjects without the p.Y1584C variant, subjects with the variant had lower mean VWF:antigen and VWF:ristocetin cofactor values and significantly higher VWF propeptide/VWF:antigen ratios suggestive of enhanced clearance. CONCLUSION: Collectively, the results of this analysis suggest that p.Y1584C is likely pathogenic, however, due to influences such as incomplete penetrance, variable expressivity, and other genetic modifiers like ABO blood group, the straightforward assignment of pathogenicity to this variant is inevitably challenging.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Humanos , Fator de von Willebrand/genética , Fator de von Willebrand/análise , Canadá , Doença de von Willebrand Tipo 1/diagnóstico , Fenótipo , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética
5.
Transfus Apher Sci ; 62(5): 103766, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37550093

RESUMO

BACKGROUND: Genetic variations influence the Von Willebrand Factor plasma level and function. This study aims to evaluate the frequency and clinical phenotype effects of eight single nucleotide polymorphism candidates in four genes (VWF, STXBP5, CLEC4M, and ABO) in Iranian patients with VWD type 1. METHOD: The study recruited 50 patients with VWD type 1 and 100 healthy individuals. The demographic data from all participants were collected, and the High-Resolution Melting technique was used to determine the frequency of specific single nucleotide polymorphisms. Bleeding scores were also obtained from all patients to assess how these genetic variations might affect the severity of their bleeding symptoms. RESULTS: The study found notable variations in the occurrence of certain SNPs (rs7853989 and rs8176743 for ABO gene and rs1063856 and rs1063857 for VWF gene) between the control group and the patients. Additionally, the study discovered that two SNPs (rs868875 for CLEC4M gene and rs9390459 for STXBP5 gene) were significantly linked to the severity of bleeding, and two others (rs868875 for CLEC4M gene and rs8176746 for ABO gene) were associated with reduced levels of VWF antigen in the patients. CONCLUSION: According to this study, the above-selected SNPs can cause variations in VWF plasma levels in patients with VWD type 1. Furthermore, the effects of SNPs on bleeding phenotype prove the role of these SNPs in the severity of bleeding manifestations in patients.


Assuntos
Doença de von Willebrand Tipo 1 , Fator de von Willebrand , Humanos , Hemorragia , Irã (Geográfico) , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Doença de von Willebrand Tipo 1/diagnóstico , Doença de von Willebrand Tipo 1/genética , Fator de von Willebrand/análise , Fator de von Willebrand/genética
6.
J Thromb Haemost ; 21(5): 1112-1122, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36754679

RESUMO

BACKGROUND: Enhanced von Willebrand factor (VWF) clearance from plasma is associated with von Willebrand disease (VWD). However, the genetic background of this disease mechanism is not well defined. OBJECTIVE: To determine VWF variants that are associated with reduced VWF survival. METHODS: Two hundred fifty-four patients with VWD (type 1 = 50 and type 2 = 204) were investigated, and the results were compared with 120 healthy controls. The patients were comprehensively characterized for phenotypic and genetic features. The ratio of VWF propeptide (VWFpp)/VWF antigen (VWFpp ratio) was used to establish in each patient the VWF clearance state. RESULTS: Out of 92 variants associated with type 1 (7 were novel) and type 2 VWD, 19 had a VWFpp ratio ranging from 1.7 to 2.2, 24 had a VWFpp ratio between 2.3 and 2.9, and 24 variants had a ratio of ≥3. The VWFpp median ratio in healthy controls was 0.98 (0.55-1.6) so that a cut-off value of >1.6 was considered an indicator of accelerated VWF clearance from plasma. An enhanced VWF clearance was observed in 34% of type 1 cases, 100% of type 1 Vicenza cases, 81% of 2A cases, 77% of 2B cases, 88% of 2M cases, and 36% of 2N cases. CONCLUSIONS: An accelerated VWF clearance was found in most patients with type 2A, 2B, and 2M VWD, with a lower proportion of type 1 and 2N. Sixty-seven different variants alone or in combination with other variants were associated with an increased VWFpp ratio. The variants with the highest VWFpp ratio were mostly located in the D3-A1 VWF domains.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Humanos , Fator de von Willebrand/genética , Fator de von Willebrand/química , Precursores de Proteínas , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética , Doença de von Willebrand Tipo 1/diagnóstico , Doença de von Willebrand Tipo 1/genética
7.
Blood Adv ; 7(8): 1477-1487, 2023 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-36121439

RESUMO

Type 1 von Willebrand disease (VWD) is associated with a reduction in qualitatively normal von Willebrand factor (VWF). Current diagnostic guidelines only take into consideration the contribution of basal VWF levels, despite a lack of correlation with bleeding severity. Defects in stimulated VWF release, which occurs after hemostatic challenge, may contribute to bleeding in type 1 VWD, but the pathogenic mechanisms are poorly defined. In this study, a layered multiomic approach including messenger RNA (mRNA) and microRNA (miRNA) sequencing was used to evaluate transcriptome-wide differences between type 1 VWD- and control-derived endothelial colony forming cells (ECFCs) during basal and stimulated VWF release. ECFCs from 8 patients with type 1 VWD and 4 other patients were included in this study as controls. VWF protein analysis revealed heterogenous responses to stimulation among type 1 VWD and control ECFCs. During basal VWF release, 64 mRNAs and 7 miRNAs were differentially regulated between type 1 VWD and control ECFCs, and 65 putatively pathogenic miRNA-mRNA interactions were identified. During stimulated VWF release, 190 mRNAs and 5 mRNAs were differentially regulated between type 1 VWD and control ECFCs, and 110 putatively pathogenic miRNA-mRNA interactions were identified. Five gene ontology terms including coagulation, regulation of cell shape, and regulation of cell signaling were also differentially regulated in type 1 VWD ECFCs during stimulated release. To our knowledge, we have shown for the first time that transcriptome-wide differences exist between type 1 VWD and control ECFCs. These differences may contribute to bleeding in type 1 VWD, and further investigation may reveal novel biomarkers and therapeutic targets.


Assuntos
MicroRNAs , Doença de von Willebrand Tipo 1 , Humanos , Doença de von Willebrand Tipo 1/genética , Fator de von Willebrand/metabolismo , Células Endoteliais/metabolismo , Hemorragia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Perfilação da Expressão Gênica , MicroRNAs/genética
8.
Lab Med ; 54(4): 434-438, 2023 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-36468906

RESUMO

A 6-year-old boy was referred to a hematologist due to excessive mucocutaneous bleeding. Diagnostic assessment for von Willebrand disease (VWD) was indicated and included both coagulation and genetic testing. Laboratory testing revealed proportionally decreased von Willebrand factor (VWF) glycoprotein Ib-binding activity (23.6%) compared to VWF antigen (24.7%), similarly decreased VWF collagen-binding activity (24.2%), and normally distributed VWF multimers, with decreased intensity of all fractions. Diagnosis of type 1 VWD was established. Genetic analysis by means of next-generation sequencing (NGS) of VWF and coagulation factor VIII genes did not identify any causative mutations. Additionally, multiplex ligation-dependent probe amplification (MLPA) of VWF gene exons revealed a heterozygous deletion of exons 1 to 6, which is reported in type 1 VWD for the first time. Application of MLPA was crucial for revealing the genetic basis of type 1 VWD in this case, which would have remained undetected if only NGS was used.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Masculino , Humanos , Criança , Fator de von Willebrand/genética , Fator de von Willebrand/análise , Doença de von Willebrand Tipo 1/diagnóstico , Doença de von Willebrand Tipo 1/genética , Doença de von Willebrand Tipo 1/complicações , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/genética , Doenças de von Willebrand/complicações , Hemorragia , Éxons/genética
10.
Hematology Am Soc Hematol Educ Program ; 2022(1): 618-623, 2022 12 09.
Artigo em Inglês | MEDLINE | ID: mdl-36485079

RESUMO

Most people with von Willebrand disease (VWD) have a partial quantitative deficiency of plasma von Willebrand factor (VWF) or type 1 VWD. In contrast to type 2 and type 3 VWD, laboratory assays will not always establish the diagnosis in type 1 VWD. This is because plasma VWF levels in type 1 VWD, especially those with levels closer to 50 IU/dL, overlap with the general population. Assessment is further complicated by increased plasma VWF levels in response to physiologic stressors or aging. Diagnosis of those with type 1 VWD with plasma VWF levels 30 to 50 IU/dL (previously referred to as "low VWF") requires expert assessment of bleeding phenotype as well as an understanding of the limitations of both bleeding assessment tools (BATs) and laboratory testing. Using the available evidence and highlighting research gaps, we discuss common dilemmas facing providers relating to assessment of adolescents, transition from pediatrics to adult care, and older individuals with type 1 VWD.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Humanos , Criança , Doença de von Willebrand Tipo 1/diagnóstico , Fator de von Willebrand/genética , Hemorragia , Fenótipo
11.
Semin Thromb Hemost ; 48(6): 739-749, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36223773

RESUMO

BACKGROUND: Reduced or dysfunctional von Willebrand factor (VWF) may lead to von Willebrand disease (VWD), which is a common inherited bleeding disorder. VWD is classified into three major types: type 1 is a partial quantitative deficiency of VWF, type 3 is a complete quantitative deficiency of VWF, and type 2 consists of qualitative abnormalities of VWF. To arrive at a correct VWD diagnosis, multiple tests and a correct interpretation of these tests are needed. AIM: The aim of the present study was to gain insight into the approach of laboratories toward VWD diagnosis. METHODS: Data from four samples of the external quality assessment (EQA) VWF surveys of the ECAT (External Quality Control for Assays and Tests) were evaluated. Furthermore, results were analyzed of a questionnaire that was sent to hemostasis laboratories about VWD diagnostic approaches. RESULTS: For most EQA samples, the majority of participants indicated the correct classification. However, 6 to 60% indicated another classification. For all samples, significant differences in VWF results were observed between the correct and incorrect classifications. The questionnaire demonstrated that the testing approach varied between the laboratories, especially for parameters that were essential for discrimination between VWD type 1 and healthy individuals, as well as the cutoff values used to discriminate VWD types 1 and 2. CONCLUSIONS: Diagnosis of VWD is heterogeneous in diagnostic approach, guidelines, and cutoff values within large ranges of VWF results between laboratories. Harmonization of approaches and increased accuracy of VWF measurements may help to establish a correct diagnosis.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Hemostasia , Humanos , Laboratórios , Inquéritos e Questionários , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand
12.
Reprod Biol ; 22(4): 100700, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36240670

RESUMO

Von Willebrand Disease (VWD) is a heritable disorder caused by defects of the Von Willebrand Factor (VWF), leading to deficiencies in coagulation and also angiogenesis. Women affected by VWD frequently show bleeding concerning the reproductive tract and may present with increased rates of miscarriages. We used a porcine model representing VWD type 1 and type 3 as well as the wildtype. Samples were obtained from the reproductive tract of non-pregnant sows and sows pregnant at time of placentation. Relative expression of the genes CALR, CCN2, CXCL8, ECE1, EDN1, F8, IGFBP7, and LGALS3 was analyzed. CCN2 and FVIII proteins were additionally analyzed using immunohistochemistry. In uterus and ovary significant upregulation of CCN2 was seen in non-pregnant pigs affected by VWD. This might be caused by the higher VEGFA-levels in these pigs and could have an influence angiogenesis. During pregnancy, CCN2 expression increased in wildtype pig uteri but hardly changed in those of pregnant pigs affected by VWD, presumably because the expression level in the latter pigs already was significantly increased before pregnancy. F8 expression was significantly reduced in uterus and ovary of VWD-affected pigs. VWF is known to protect FVIII from decomposition and a lack of VWF leads to lower levels of FVIII. Our results suggest that a reduced F8 expression primarily might contribute to those reduced FVIII levels in VWD-affected pigs. Additional significant results involving the pregnant pigs were detected for CALR, EDN1, and LGALS3. These genes are promising candidates for more detailed future studies.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Gravidez , Feminino , Suínos , Animais , Doenças de von Willebrand/genética , Fator de von Willebrand/genética , Fator de von Willebrand/química , Fator de von Willebrand/metabolismo , Indutores da Angiogênese , Galectina 3
13.
J Thromb Haemost ; 20(10): 2246-2254, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35780487

RESUMO

BACKGROUND: Assessment of bleeding phenotype is critically important in the diagnosis of von Willebrand disease (VWD). Despite advances in bleeding assessment tools (BATs), standardized tools to evaluate bleeding following diagnosis (interim bleeding) are lacking. OBJECTIVES: We assessed the clinical utility of an interim bleeding protocol in a multicenter, international study involving patients with VWD. METHODS: The enrolment ISTH BAT formed the original bleeding score (0 BS). At follow-up, the International Society on Thrombosis and Haemostasis BAT was repeated but included only interval bleeding (Interim BS, 1 BS). Both scores were annualized (0 BS/yr, 1 BS/yr). BS were analyzed by VWD subtype, plasma VWF level, sex, and age. RESULTS: Interim BS discriminated by subtype, with significantly increased 0 BS and 1 BS in patients with type 3 VWD. In patients with type 1 VWD, a positive or negative 0 BS did not predict future bleeding, with similar 1 BS/yr (median 1.0 vs. 0.7, p = .2). Despite significantly higher 0 BS in females with type 1 VWD than males (median 7 vs. 5, p = .0012), 1 BS were not significantly different (median 4 vs. 4, p = .16). While 0 BS were lower in children than adults with type 1 VWD, interim BS were similar (median 5 vs. 3, p = .5; 1BS/yr, median 1 vs. 0.8, p = .7). Interestingly, in those with plasma von Willebrand factor:ristocetin cofactor levels >50 IU/dl, interim BS rates were similar to those 30-50 IU/dl (1 BS/yr 0.8 vs. 1.3, p = .5). CONCLUSION: This study provides both a new approach to longitudinal bleeding assessment and insights into the evolution of bleeding in VWD.


Assuntos
Doença de von Willebrand Tipo 1 , Doença de von Willebrand Tipo 3 , Doenças de von Willebrand , Feminino , Hemorragia/diagnóstico , Humanos , Masculino , Doença de von Willebrand Tipo 1/complicações , Doença de von Willebrand Tipo 1/diagnóstico , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand
14.
Haemophilia ; 28(5): 814-821, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35526239

RESUMO

INTRODUCTION: Desmopressin can be used to prevent bleeding in von Willebrand disease (VWD), but the relationship between desmopressin and von Willebrand factor activity (VWF:Act) has yet to be quantified. AIM: To quantify the relationship between desmopressin dose, its plasma concentration and the VWF:Act response in type 1 VWD patients. METHODS: Forty-seven VWD patients (median age 25 years, IQR: 19-37; median body weight 71 kg, IQR: 59-86) received an IV desmopressin dose of .3 mcg/kg. In total, 177 blood samples were available for analysis. We developed an integrated population pharmacokinetic-pharmacodynamic (PK-PD) model using nonlinear mixed effect modelling. Subsequently, we performed Monte Carlo simulations to investigate the efficacy of the current dosing regimen. RESULTS: A one-compartment PK model best described the time profile of the desmopressin concentrations. In the PD turnover model, the relationship between desmopressin plasma concentration and release of VWF:Act from the vascular endothelium was best described with an Emax model. Typically, VWF:Act increased 452% with an EC50 of .174 ng/ml. Simulations demonstrated that after .3 mcg/kg desmopressin intravenously, >90% patients with a VWF:Act baseline of ≥.20 IU/mL attain a VWF:Act >.5 IU/ml up to ≥4 h after administration. A capped dose of 30 mcg was sufficient in patients weighing over 100 kg. CONCLUSION: The relationship between desmopressin and VWF:Act was quantified in a PK-PD model. The simulations provide evidence that recently published international guidelines advising an intravenous desmopressin dose of .3 mcg/kg with a capped dose of 30 mcg > 100 kg gives a sufficient desmopressin response.


Assuntos
Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Adulto , Desamino Arginina Vasopressina/farmacologia , Desamino Arginina Vasopressina/uso terapêutico , Fator VIII/uso terapêutico , Humanos , Doença de von Willebrand Tipo 1/tratamento farmacológico , Doenças de von Willebrand/tratamento farmacológico , Fator de von Willebrand/uso terapêutico
15.
Haemophilia ; 28(5): 694-701, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35478475

RESUMO

INTRODUCTION: Type 1 and type 3 von Willebrand disease (VWD) are caused by partial and complete, quantitative deficiency of von Willebrand factor (VWF), respectively, and factor (F)VIII/VWF complex concentrates are used for haemostatic treatment. Emicizumab, mimics activated FVIII, reduces bleeding in haemophilia A patients. The effects of emicizumab on haemostasis in both types of VWD remain to be fully established, however. AIM: To examine the effects of emicizumab on thrombogenesis in type 1 and type 3 VWD. PATIENTS/METHODS: Perfusion chamber experiments under high shear conditions (2500 s-1 ) combined with immunostaining were performed using whole blood samples from patients with type 1 (VWF:Ag 25 U/dl) and type 3 VWD (<1.0 U/dl). RESULTS: The addition of FVIII (1 U/ml) to type 1 blood did not affect thrombus formation, whilst supplementation with VWF (1.6 U/ml) or FVIII/VWF (1 U/ml/1.6 U/ml) enhanced thrombogenesis to a similar extent. FVIII/VWF promoted thrombus formation significantly more than VWF alone, however, in type 3 blood. Emicizumab (100 µg/ml) augmented thrombus formation in type 3 blood compared to FVIII, and this potency seemed to be somewhat greater than that of VWF. Surface coverage of formed thrombus in type 3 VWD was less than that in type 1 VWD, but thrombus height was comparable in both. The addition of emicizumab to type 3 blood enhanced thrombin generation and fibrin formation compared to control IgG. CONCLUSION: Emicizumab promoted mechanisms of thrombus formation in vitro in type 3 and type 1 VWD, suggesting the possibility of alternative therapeutic protocols in these patients.


Assuntos
Trombose , Doença de von Willebrand Tipo 1 , Doença de von Willebrand Tipo 3 , Doenças de von Willebrand , Anticorpos Biespecíficos , Anticorpos Monoclonais Humanizados , Fator VIII/uso terapêutico , Humanos , Trombose/tratamento farmacológico , Doença de von Willebrand Tipo 3/tratamento farmacológico , Doenças de von Willebrand/tratamento farmacológico , Fator de von Willebrand/uso terapêutico
17.
BMC Nephrol ; 23(1): 65, 2022 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-35151252

RESUMO

BACKGROUND: Nutcracker syndrome (NCS) is characterized by compression of the left renal vein (LRV) between the aorta and the superior mesenteric artery. While rare, NCS was reported to be accompanied by double inferior vena cava (IVC). We herein report a case of Noonan syndrome (NS) with double IVC who presented with macrohematuria and proteinuria. CASE PRESENTATION: The patient was a 23-year-old man, who had been diagnosed with NS due to RIT1 mutation, after showing foamy macrohematuria 3 weeks previously. A physical examination revealed low-set ears and a webbed neck. A urinalysis showed hematuria and proteinuria, and urinary sediments showed more than 100 isomorphic red blood cells per high-power field. His proteinuria and albuminuria concentrations were 7.1 and 4.5 g/g⋅Cr, respectively. Three-dimensional contrast-enhanced computed tomography (CT) showed double IVC and narrowing of the LRV after interflow of the left IVC. The aortomesenteric angle on a sagittal reconstruction of the CT image was 14.7°. Cystoscopy revealed a flow of macrohematuria from the left ureteral opening. On Doppler ultrasonography, there was scant evidence to raise the suspicion of the nutcracker phenomenon. Since severe albuminuria continued, a left kidney biopsy was performed. Light microscopy showed red blood cells in Bowman's space and the tubular lumen. Electron microscopy revealed disruption of the glomerular basement membrane (GBM). Vulnerability of the GBM was suspected and a genetic analysis revealed a heterozygous mutation at c.4793 T > G (p.L1598R) in the COL4A3 gene. Screening for coagulation disorders revealed the factor VIII and von Willebrand factor (vWF) values were low, at 47.6 and 23%, respectively. A multimer analysis of vWF showed a normal multimer pattern and he was diagnosed with von Willebrand disease type 1. As the bleeding tendency was mild, replacement of factor VIII was not performed. His macrohematuria and proteinuria improved gradually without treatment, and his urinalysis results have been normal for more than 6 months. CONCLUSIONS: The present case showed macrohematuria and proteinuria due to NCS in NS with double IVC and von Willebrand disease type 1. The macrohematuria and proteinuria originated from glomerular hemorrhage because of vulnerability of the GBM due to COL4A3 mutation.


Assuntos
Hematúria/etiologia , Síndrome de Noonan/complicações , Proteinúria/etiologia , Síndrome do Quebra-Nozes/complicações , Veia Cava Inferior/anormalidades , Autoantígenos/genética , Colágeno Tipo IV/genética , Membrana Basal Glomerular/fisiopatologia , Hematúria/genética , Hematúria/fisiopatologia , Humanos , Masculino , Mutação , Proteinúria/genética , Proteinúria/fisiopatologia , Adulto Jovem , Doença de von Willebrand Tipo 1/complicações , Doença de von Willebrand Tipo 1/diagnóstico
18.
Haemophilia ; 28(2): 278-285, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34964530

RESUMO

INTRODUCTION: The negative impact of haemophilia on social participation is well established in previous studies, however, the impact of Von Willebrand disease (VWD) on social participation has not been studied. AIM: To compare the social participation of a large cohort of VWD patients in the Netherlands with the general Dutch population. In addition, to identify factors associated with social participation in VWD. METHODS: Patients participating in the "Willebrand in the Netherlands" study completed an extensive questionnaire on educational level, absenteeism from school or work, and occupational disabilities. RESULTS: Seven-hundred and eighty-eight VWD patients were included (mean age 38.9 years, 59.5% females), of whom 136 children < 16 years. Adult patients with type 3 VWD more often had a low educational level (52.9%) compared to type 1 (40.2%), type 2 VWD (36.8%) and the general population (36.4%) (p = .005). Moreover, in patients aged ≥16 years the days lost from school and/or work in the year prior to study inclusion differed significantly between the VWD types (p = .011). Using negative binomial regression analysis, the occurrence of bleeding episodes requiring treatment in the year preceding study inclusion was significantly associated with the number of days lost from school and/or work among patients aged ≥16 years. Multivariable logistic regression analysis showed that a higher total bleeding score, older age and presence of at least one comorbidity were significantly associated with occupational disability in patients aged ≥16 years. CONCLUSION: Our study shows that social participation was lower in type 3 VWD and VWD patients with a more severe bleeding phenotype.


Assuntos
Doença de von Willebrand Tipo 1 , Doença de von Willebrand Tipo 3 , Doenças de von Willebrand , Adolescente , Adulto , Feminino , Hemorragia/complicações , Humanos , Masculino , Fenótipo , Participação Social , Doença de von Willebrand Tipo 1/complicações , Doença de von Willebrand Tipo 3/complicações , Doenças de von Willebrand/complicações , Fator de von Willebrand/genética
19.
Haemophilia ; 28(1): 109-116, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34874087

RESUMO

INTRODUCTION: Obesity is associated with endothelial dysfunction, haemostatic and fibrinolytic disturbances, however the impact of obesity on von Willebrand factor (VWF) is unclear. AIM: The aim of this study was to test our hypothesis that the prevalence of obesity is higher among participants with low VWF (LVWF) compared to type 1 von Willebrand disease (T1VWD). METHODS: A retrospective review of the ATHNdataset as of March 2018 was performed. Participants were categorized as T1VWD if their VWF ristocetin cofactor activity was 30 IU/dL and LVWF if the values were 30-50 IU/dL, and by the NIH definitions for body mass index (BMI) for adult participants (≥ 18 years of age) or BMI z-score for paediatric participants (< 18 years). RESULTS: The prevalence of obesity was not significantly different between adults with T1VWD (n = 186) and LVWF (n = 362) (32% vs 36%; p = .345). The mean factor VIII (FVIII) increased with increasing BMIs in both groups. In the paediatric cohort (T1VWD, n = 583; LVWF, n = 1702), there was no difference in the prevalence of obesity, but BMI was positively correlated with mean FVIII (p < .001). Children < 10 years were 27.6% more likely to be diagnosed with T1VWD compared to > 10 years. CONCLUSION: Among participants in the ATHNdataset, the prevalence of obesity was similar among those with LVWF and T1VWD. However, higher BMI levels were associated with elevated FVIII. Further research is needed to evaluate the impact of obesity on bleeding phenotype and treatment practices.


Assuntos
Hemostáticos , Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Adolescente , Criança , Fator VIII , Humanos , Obesidade/complicações , Obesidade/epidemiologia , Estudos Retrospectivos , Doenças de von Willebrand/complicações , Doenças de von Willebrand/epidemiologia , Fator de von Willebrand
20.
Semin Thromb Hemost ; 48(2): 219-228, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34749402

RESUMO

Type 1 von Willebrand disease (VWD) is the most common subtype of VWD, comprising 75% of VWD patients. We provide a systematic review of type 1 VWD in pregnancy. Our objective was to evaluate the rate of postpartum hemorrhage (PPH) in patients with known type 1 VWD. The primary outcome was rate of PPH. Primary PPH was defined as a cumulative blood loss ≥1,000 mL, or blood loss accompanied by signs and symptoms of hypovolemia within 24 hours postpartum or requiring blood products. Secondary PPH was defined as significant bleeding 24 hours to 12 weeks postpartum. Relevant articles published in English pertaining to VWD and pregnancy were identified without any time or study limitations. Seven articles (n = 144 pregnancies) met inclusion criteria. The rate of primary PPH was 4/144 (2.8%). The secondary PPH rate was reported in four studies, and occurred in 7/48 pregnancies (14.6%), ranging from 2 to 19 days postpartum. In conclusion, according to this systematic review, the frequency of primary PPH in pregnancies with known type 1 VWD is 2.8%. This is similar to the overall PPH rates of 3% reported in the literature. Although the sample size was small, secondary PPH occurred in almost 15% of pregnancies, while in the overall obstetrical population this occurs in approximately 1% of cases. Patients with known type 1 VWD may not be at increased risk of primary PPH, though they appear to bear increased risk of secondary PPH.


Assuntos
Hemorragia Pós-Parto , Doença de von Willebrand Tipo 1 , Doenças de von Willebrand , Feminino , Humanos , Hemorragia Pós-Parto/etiologia , Gravidez , Doenças de von Willebrand/complicações , Doenças de von Willebrand/diagnóstico , Fator de von Willebrand
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