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.

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

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.

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.

How I treat low von Willebrand factor levels.

Partial quantitative deficiency of plasma von Willebrand factor (VWF) is responsible for the majority of cases of von Willebrand disease (VWD), the most common inherited human bleeding disorder. International consensus guidelines recommend that patients with reduced plasma VWF antigen (VWF:Ag) levels and bleeding phenotypes be considered in 2 distinct subsets. First, patients with marked reductions in plasma VWF levels (<30 IU/dL) usually have significant bleeding phenotypes and should be classified with "type 1 VWD." In contrast, patients with intermediate reduced plasma VWF levels (in the range of 30-50 IU/dL) should be considered in a separate category labeled "low VWF levels." These patients with low VWF commonly display variable bleeding phenotypes and often do not have VWF gene sequence variations. Because the pathophysiology underlying low VWF levels remains largely undefined, diagnosis and management of these patients continue to pose significant difficulties. In this article, we present a number of clinical case studies to highlight these common clinical challenges. In addition, we detail our approach to establishing a diagnosis in low VWF patients and discuss strategies for the management of these patients in the context of elective surgery and pregnancy.

A case of inherited type 1 and type 2A von Willebrand disease confirmed by diagnostic exome sequencing.

A 10-year-old male and his family members visited a pediatric hematology clinic due to coagulopathy. Laboratory tests indicated von Willebrand disease (vWD) in all the family members. We conducted diagnostic exome sequencing for confirmation. The patient was confirmed to be a compound heterozygote for vWD: c.2574C > G (p.Cys858Trp) from his father (known variant of vWD type 1) and c.3390C > T (p.Pro1127_Gly1180delinsArg) from his mother (variant known to result in exon 26 skipping in vWD type 2A). He was managed with factor VIII and von Willebrand factor complex concentrate during palatoplasty due to bleeding despite pre-operative desmopressin injection. The operation was completed successfully.

Validation Study of the Composite Score to Identify Von Willebrand Disease in Children.

BACKGROUND: The diagnosis of type 1 von Willebrand disease (VWD) presents a diagnostic challenge in children. In fact, 25% or more of children with VWD may be diagnosed only after they experience postoperative bleeding. We previously described a 4-variable composite score that has 92.5% sensitivity and 95% specificity for diagnosing VWD in children with known VWD when 2 of 4 criteria are positive: (1) Tosetto bleeding score ≥ 1; (2) family history of VWD; (3) personal history of iron deficiency anemia; and/or (4) positive James early bleeding score. The purpose of this study was to prospectively validate a composite score of ≥ 2 for identifying children with VWD. PROCEDURE: Children without a previously diagnosed bleeding disorder presenting for hematology evaluation were enrolled. Sensitivity, specificity, positive, and negative predictive value of the composite score was determined. RESULTS: A total of 193 subjects were enrolled from 12 participating centers were included in the analysis. Forty-seven children had type 1 VWD, including 11 with von Willebrand Ristocetin Cofactor (VWF):RCo < 30 IU/dL, 14 subjects with a VWF:RCo 30 to 39 IU/dL, and 22 with a VWF:RCo 40 to 49 IU/dL. Including all 4 variables, a composite score of ≥ 2 had a sensitivity of 63.6% to 76.0%, specificity of 33.5% to 35.1%, negative predictive value of 76.9% to 93.8%, and positive predictive value of 5.5% to 25%. CONCLUSIONS: The negative predictive value of the composite score was robust, especially at lower VWF:RCo suggesting that VWD testing could be eliminated in nearly a third of children referred for VWD testing.

FVIII/VWF ratio is not a reliable predictor of VWD in children.

Adults with von Willebrand Disease (VWD) are known to have a ratio of factor VIII activity (FVIII:C) to von Willebrand factor antigen (VWF:Ag) greater than 1. We, however, noted healthy children with ratios that are unexpectedly high. Though the FVIII:C/VWF:Ag ratio differs significantly between healthy children and VWD patients in some age groups, the substantial overlap of observed ranges suggests that a ratio threshold-based screening approach alone cannot reliably discriminate between these groups. The diagnostic performance of this ratio is poor for VWD in children, which may decrease its value as a screening tool in the pediatric population.

Low von Willebrand factor: sometimes a risk factor and sometimes a disease.

A sufficiently low level of von Willebrand factor (VWF) predisposes to bleeding that can be quite serious, and low VWF is a diagnostic feature of von Willebrand disease (VWD) type 1, which is characterized by partial quantitative deficiency of VWF. Recent groundbreaking studies of patients with VWD type 1 have delineated several pathophysiologic mechanisms that determine the plasma concentration of VWF, but the relationship between VWF level and the likelihood of bleeding remains less well understood. In part, this problem reflects the broad range of VWF levels in the population, so that the distinction between "normal" and "low" is arbitrary. The risk of bleeding certainly increases as the VWF level decreases, but the relationship is not very strong until the VWF level is very low. Furthermore, mild bleeding symptoms are common in apparently healthy populations and have many causes other than defects in VWF, which can make it impossible to attribute bleeding to any single factor, such as low VWF. These difficulties might be resolved by an epidemiologic approach to VWF and other risk factors for bleeding, analogous to how physicians manage multiple risk factors for cardiovascular disease or venous thromboembolism.