Type 1 von Willebrand Disease in a Pediatric Patient Caused by a Novel Heterozygous Deletion of Exons 1 to 6 of the von Willebrand Factor Gene: A Case Report.

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.

Longitudinal bleeding assessment in von Willebrand disease utilizing an interim bleeding score.

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.

Disruption of the glomerular basement membrane associated with nutcracker syndrome and double inferior vena cava in Noonan syndrome: a case report.

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.

Social participation is reduced in type 3 Von Willebrand disease patients and in patients with a severe bleeding phenotype.

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.

Dramatic Response to Pramipexole in Delayed-Onset Parkinsonism from Osmotic Demyelinating Syndrome.

Background: Delayed parkinsonism and dystonia are recognized phenomena in osmotic demyelinating syndrome (ODS). Dopamine receptor agonists and levodopa have been reported to benefit select patients. Case report: We report a patient with ODS with severe pseudobulbar deficits, parkinsonism and dystonia, poorly responsive to levodopa, who experienced a remarkable improvement with pramipexole. Discussion: A marked response to pramipexole with lack of response to levodopa suggests a pre-synaptic source for his deficits coupled with injuries to non-nigral compensatory structures. Highlights: This case highlights a dramatic response of osmotic demyelination-induced parkinsonism/dystonia to pramipexole. A lack of response to levodopa suggests deficits in the pre-synaptic nigral as well as non-nigral compensatory structures.

Use of Tranexamic Acid for the Treatment of Mittelschmerz in a Patient with Type 1 von Willebrand Disease and Recurrent Hemorrhagic Cysts.

BACKGROUND: Tranexamic acid reduces blood loss in patients with bleeding diatheses and is used in a number of gynaecologic and non-gynaecologic conditions CASE: We discuss the case of a 27-year-old woman with type 1 von Willebrand disease, who presented with a two-year history of severe mittelschmerz secondary to recurrent hemorrhagic cysts. The patient refused oral contraception and reported that traditional analgesia did not significantly alleviate symptoms. We theorized that the underlying von Willebrand disease compounded the degree of hemorrhage into her recurrent cysts. As such, a trial of mid-cycle tranexamic acid was offered, which drastically improved her symptoms. CONCLUSION: We report that the use of mid-cycle tranexamic acid in patients with recurrent haemorrhagic cysts can lower ovulation-associated pain.

von Willebrand factor and factor VIII levels after desmopressin are associated with bleeding phenotype in type 1 VWD.

The bleeding phenotype of patients with type 1 von Willebrand disease (VWD) is very heterogeneous. We hypothesized that this heterogeneity may partly be explained by variability in response of von Willebrand factor (VWF) and factor VIII (FVIII) levels to stress during hemostatic challenges. We therefore investigated whether VWF and FVIII levels after administration of desmopressin, which mimic in vivo hemostatic response during hemostatic challenges, explain the heterogeneity in bleeding phenotype of patients with type 1 VWD. We performed a retrospective cohort study in 122 patients with type 1 VWD. All patients received a test dose of desmopressin shortly after diagnosis. Patients' mean age was 47 ± 14 years, and the mean Tosetto bleeding score was 10 ± 7. Higher FVIII activity during the complete time course after desmopressin administration (1, 3, and 5-6 hours), and higher VWF and FVIII levels combined at 3 hours after desmopressin administration, were associated with a lower bleeding score: ß = -0.9 (-1.7; -0.1) and ß = -1.2 (-1.9; -0.5), respectively, adjusted for age, sex, body mass index (BMI), and comorbidities. Patients with FVIII activity in the highest quartile 3 hours after desmopressin administration had a much lower bleeding score compared with patients in the other 3 quartiles (ß = -5.1 [-8.2; -2.0]) and also had a lower chance of an abnormal bleeding score (odds ratio = 0.2 [0.1-0.5]), both adjusted for age, sex, BMI, and comorbidities. In conclusion, VWF and FVIII levels after desmopressin administration, which mimic hemostatic response to hemostatic challenges, are associated with the bleeding phenotype of patients with type 1 VWD. This may partly explain the variability in bleeding phenotype of these patients.

Case of Hemorrhagic Moyamoya Disease Associated with Von Willebrand Disease.

BACKGROUND: Association of moyamoya disease (MMD) with von Willebrand disease (vWD) is extremely rare. CASE DESCRIPTION: We first report a 27-year-old female case of MMD concurrent with vWD type 1, which presented as hemorrhagic stroke. The patient underwent a revascularization surgery with perioperative replacement therapy of von Willebrand factor and coagulation factor VIII. No hemorrhagic complications occurred. CONCLUSIONS: The patient overcame postoperative transient neurological events and fully recovered. We discuss appropriate perioperative supplementation of coagulation factors for a revascularization surgery for MMD with vWD.

Outgrowing the laboratory diagnosis of type 1 von Willebrand disease: A two decade study.

Von Willebrand Factor (VWF) levels are known to increase with age in the general population, but that effect is unclear in von Willebrand disease (VWD) patients. Thus, it is important to assess the trends of VWF levels with age, and the extent and rate of their normalization in patients with VWD. In a retrospective cohort study, we reviewed the medical records of 126 patients between 1996 and 2016 who met the NHLBI diagnostic criteria for type 1 VWD or "Low VWF" (LVWF). We followed all their historically documented VWF antigen (VWF:Ag), VWF activity (VWF:RCo), and Factor VIII (FVIII) levels longitudinally over time, correlating data with clinical setting at time of testing. The average duration of follow-up was 10.5 ± 3.7 years (SD). Out of the total study population, 27.8% achieved the primary outcome of complete normalization (CN) of both VWF:Ag and VWF:RCo levels, including 19.6% and 32.5% of those with VWD and LVWF, respectively. Linear regression demonstrated statistically significant positive trends of VWF:Ag, VWF:RCo, FVIII with time, calculated at 2.4, 1.4, and 1.4 U dL-1/year, respectively (P < .001 each). In the largest study population of VWD patients to date whose levels were followed longitudinally, there is a statistically significant rise in VWF:Ag, VWF:RCo, and FVIII levels observed with time. CN of both VWF:Ag and VWF:RCo levels was observed in almost a third of patients with VWD or LVWF, over an average of 10 years. Whether the bleeding phenotype also improves is unclear and requires further study.

Bleeding score in Type 1 von Willebrand disease patients using the ISTH-BAT questionnaire.

BACKGROUND: Bleeding assessment tools have evolved in the last decade to standardize the assessment of the severity of bleeding symptom in a consistent way. In 2010, the International Society on Thrombosis and Hemostasis-Bleeding Assessment Tool (ISTH-BAT) was developed and validated. AIMS: Our aim was to administer ISTH-BAT questionnaire to the Omani patients with type 1 VWD and obtain the bleeding score (BS). We also studied the severity of their bleeding symptoms and correlated it with the BS as well as with the laboratory parameters. METHODS: Forty-eight type I VWD index cases and 52 normal subjects were interviewed and the ISTH-BAT questionnaire administered. The BS was calculated based on a history of bleeding symptoms from 12 different sites according to the standard ISTH-BAT questionnaire. Laboratory parameters were obtained from patient's medical records. RESULTS: The mean age of this cohort was 27 years (range, 6-49) with 60% being females. The median time to administer this questionnaire was 10 minutes with an interquartile range (IQR) from 8 to 17 minutes. Overall, the median BS was 7 (IQR; 2,11) although individual scores ranged between 0 and 36. The BS was negatively correlated with VWF: Ag, VWF: RCo, and VWF: CB and the Spearman's correlation coefficient "rho" was, respectively, -0.15, -0.08, and -0.22. CONCLUSION: The ISTH-BAT BS is designed to reflect the severity of bleeding. Our results demonstrate the inherent variability of this bleeding pattern. We also found that the ISTH-BAT BS significantly correlated with VWF: Ag and VWF: CB.

Revascularization Operation for Moyamoya Disease with Concurrent von Willebrand Disease.

BACKGROUND: Although extracranial-intracranial (EC-IC) bypass is an effective treatment strategy for symptomatic moyamoya disease, surgeons need to be cautious regarding the possibility of postoperative hemorrhagic complications in patients with a concurrent coagulation disorder. Here, we describe a case of EC-IC bypass for moyamoya disease concurrent with von Willebrand disease type 1. CASE DESCRIPTION: Following perioperative replacement of the von Willebrand factor, the patient showed an uneventful and uncomplicated clinical course. CONCLUSION: This is the first reported case of EC-IC bypass being performed for moyamoya disease in a patient with concurrent von Willebrand disease. We emphasize the importance of appropriate management with replacement of the von Willebrand factor during the perioperative period to avoid hemorrhagic complications.

Gingival bleeding and mild type 1 von Willebrand disease.

Oral bleeding is a frequently reported symptom of von Willebrand disease (VWD) and evaluated by several VWD bleeding scores. Gingival bleeding is also known to be a leading symptom of plaque-induced gingivitis and untreated periodontal disease. This study evaluates whether mild type 1 VWD is associated with an increased susceptibility to gingival bleeding. In this case-control study, 50 patients and 40 matched controls were periodontally examined, answered a questionnaire, and underwent professional teeth cleaning. Compared with the controls, the VWD patients more frequently reported periodontal symptoms, such as bleeding (34 vs. 20%, P = 0.141) and swelling (54 vs. 32.5%, P = 0.538) of the gingiva, and these patients had their teeth professionally cleaned less often (58 vs. 77.5%, P = 0.051). However, there was less gingival bleeding, as determined by the gingival bleeding index, in the VWD patients compared with the controls (10 vs. 12.2%, P = 0.047); the amount of bleeding on probing was similar between the VWD patients and the controls (17 vs. 17.2%, P = 0.723). Gingival bleeding in VWD patients may be triggered by gingival inflammation, but it is not a genuine symptom of mild type 1 VWD.

Is gingival bleeding a symptom of patients with type 1 von Willebrand disease? A case-control study.

BACKGROUND: Von Willebrand disease (VWD) is the most common inherent bleeding disorder resulting in prolonged bleeding time. Gingival bleeding is a frequently reported symptom of VWD. However, gingival bleeding is also known as a leading symptom of plaque-induced gingivitis and untreated periodontal disease. Gingival bleeding in VWD patients (VWD) may be triggered by gingival inflammation and not a genuine symptom. Thus, this study evaluated whether type 1 VWD determines an increased susceptibility to gingival bleeding in response to the oral biofilm. METHODS: Fifty cases and 40 controls were examined haematologically (VWF antigen, VWF Ristocetin cofactor, factor VIII activity) and periodontally [Gingival Bleeding Index (GBI), bleeding on probing (BOP), Plaque Control Record (PCR), periodontal inflamed surface area (PISA), vertical probing attachment level]. RESULTS: GBI was significantly higher in controls (12.2%) than in VWD (10%). The study failed to find a significant difference regarding BOP between VWD (17%) and controls (17.2%). Multiple regressions identified PCR and PISA to be associated with GBI and BOP. VWD was negatively associated with GBI. Smoking and number of remaining teeth was negatively associated with BOP. CONCLUSION: VWD is not associated with a more pronounced inflammatory response to the oral biofilm in terms of GBI and BOP.