Clinical significance of slightly reduced von Willebrand factor activity.

Von Willebrand disease (VWD) is the most common congenital bleeding disorder, with a clinical presentation of mucocutaneous and surgical bleeding varying from mild to severe. It is inherited in an autosomal dominant or autosomal recessive manner. The disease is caused by quantitative or qualitative deficiency of the von Willebrand factor (VWF) and is classified as type 1, 2 (2A, 2B, 2M, 2N), and 3. Although type 1 VWD is the most common form of VWD, the f ormal cutoff for diagnosis remains a subject of debate. In our paper, we present results of studies regarding the clinical and laboratory importance of a new type of bleeding disorder called low VWF. The new guidelines for VWD diagnosis and management suggested that patients with historically type 1 VWD should be divided into 2 subsets: type 1 VWD with a VWF antigen level (VWF:Ag) of less than 30 IU/dl or less than 40 IU/dl, in which about 80% of patients exhibited VWF gene mutations, and low VWF with a VWF:Ag level of 30 to 50 IU/dl or 40 to 50 IU/dl, in which the causative mutation is detected in merely 40% of patients and in most families, inheritance is not dependent on the locus of VWF on chromosome 12. Previously, moderately reduced VWF levels (30-50 IU/dl) were considered a risk factor for bleeding, but not a true bleeding disorder, and this condition was named low VWF. Recently, it was documented in a large group of patients with type 1 VWD and low VWF that bleeding score does not correlate with VWF:Ag and bleeding symptoms in type 1 VWD (<30 IU/dl) and low VWF can change from infrequent and moderate to severe bleeds. Because the plasma concentration of VWF depends on many physiological and pathological factors that may mask the diagnosis of VWD, separation of the group of patients with low VWF (30-50 IU/dl) from those with type 1 VWD may delay or prevent them from receiving appropriate treatment. Diagnosis of VWD in each case, particularly those with a slight decrease in VWF (30-50 IU/dl), should be based primarily on the clinical manifestations and family history of hemorrhagic diathesis.

Higher rates of bleeding and use of treatment products among young boys compared to girls with von Willebrand disease.

There are limited observational studies among children diagnosed with von Willebrand Disease (VWD). We analyzed differences in bleeding characteristics by sex and type of VWD using the largest reported surveillance database of children with VWD (n = 2712), ages 2 to 12 years old. We found that the mean ages of first bleed and diagnosis were lowest among children with type 3 VWD. It was even lower among boys than girls among all VWD types, with statistically significant difference among children with type 1 or type 3 VWD. Children with type 3 VWD also reported higher proportions of ever having a bleed compared to other VWD types, with statistically higher proportions of boys compared to girls reporting ever having a bleed with type 1 and type 2 VWD. A similar pattern was observed with the use of treatment product, showing higher usage among type 3 VWD, and among boys than girls with type 1 and type 2 VWD. While there were no differences in life quality or in well-being status by sex, children with type 3 VWD showed a greater need for mobility assistance compared to children with type 1 and type 2 VWD. In an adjusted analysis among children with type 1 VWD, boys showed a significant association of ever bleeding [hazard ratio 1.4; P-value <.001)] compared to girls. Understanding phenotypic bleeding characteristics, well-being status, treatment, and higher risk groups for bleeding among pre-adolescent children with VWD will aid physicians in efforts to educate families about bleeding symptoms.

Clinical and laboratory variability in a cohort of patients diagnosed with type 1 VWD in the United States.

von Willebrand disease (VWD) is the most common inherited bleeding disorder, and type 1 VWD is the most common VWD variant. Despite its frequency, diagnosis of type 1 VWD remains the subject of debate. In order to study the spectrum of type 1 VWD in the United States, the Zimmerman Program enrolled 482 subjects with a previous diagnosis of type 1 VWD without stringent laboratory diagnostic criteria. von Willebrand factor (VWF) laboratory testing and full-length VWF gene sequencing was performed for all index cases and healthy control subjects in a central laboratory. Bleeding phenotype was characterized using the International Society on Thrombosis and Haemostasis bleeding assessment tool. At study entry, 64% of subjects had VWF antigen (VWF:Ag) or VWF ristocetin cofactor activity below the lower limit of normal, whereas 36% had normal VWF levels. VWF sequence variations were most frequent in subjects with VWF:Ag <30 IU/dL (82%), whereas subjects with type 1 VWD and VWF:Ag ≥30 IU/dL had an intermediate frequency of variants (44%). Subjects whose VWF testing was normal at study entry had a similar rate of sequence variations as the healthy controls (14%). All subjects with severe type 1 VWD and VWF:Ag ≤5 IU/dL had an abnormal bleeding score (BS), but otherwise BS did not correlate with VWF:Ag. Subjects with a historical diagnosis of type 1 VWD had similar rates of abnormal BS compared with subjects with low VWF levels at study entry. Type 1 VWD in the United States is highly variable, and bleeding symptoms are frequent in this population.

Spectrum of Von Willebrand's disease in Punjab: clinical features and types.

BACKGROUND: Von Willebrand's disease (VWD) is a common inherited bleeding disorder caused by quantitative deficiency (Type-1 & Type-3 VWD) or qualitative defect of Von Willebrand's Factor (Type-2 VWD). Regarding VWD limited studies are available in Pakistan. The current study was aimed to determine the clinical presentation and frequency of types of VWD. METHODS: A cross sectional study was carried out from 16th December 2012 to 15th December 2013 on fifty one patients of VWD. RESULTS: Patients were diagnosed on the basis of prolonged bleeding time, abnormal APTT, reduced level of VWF: Ag, FVIII, VWF: RCo and ratio of VWF: RCo/VWF Ag. Among them 26 (50.98%) were male and 25 (49.02%) were female. Type3 VWD (94.12%) was found to be the commonest type. Two (3.92%) cases of type-2 VWD and only one (1.96%) case of type-1 VWD were identified. Easy bruising was the most commonly observed clinical presentation, 21 (41.18%) patients, followed by epistaxis 7 (13.73%), gum bleed 4(7.84%) menorrhagia 5(9.80%), haemarthosis 2(3.92%), haematoma formation 5 (9.80%), bleeding after circumcision 2 (3.92%), bleeding after surgery 2 (3.92%) and umbilical cord bleeding 3 (5.88%). Consanguineous marriages were reported in parents of 42 (82.4%) patients. Family history of bleeding disorder was reported in 44 (86.27%) of cases. CONCLUSION: Type-3 VWD was found to be the commonest type which can be attributed to the fact that type-3 VWD is transmitted through autosomal recessive pattern of inheritance and consanguineous marriages are highly practiced in our society leading to high frequency of this form of VWD. Easy bruising and epistaxis were concluded to be the most common clinical presentation. Menorrhagia was found to be common in the females of child bearing age.

No increase in bleeding identified in type 1 VWD subjects with D1472H sequence variation.

The diagnosis of von Willebrand disease (VWD) is complicated by issues with current laboratory testing, particularly the ristocetin cofactor activity assay (VWF:RCo). We have recently reported a sequence variation in the von Willebrand factor (VWF) A1 domain, p.D1472H (D1472H), associated with a decrease in the VWF:RCo/VWF antigen (VWF:Ag) ratio but not associated with bleeding in healthy control subjects. This report expands the previous study to include subjects with symptoms leading to the diagnosis of type 1 VWD. Type 1 VWD subjects with D1472H had a significant decrease in the VWF:RCo/VWF:Ag ratio compared with those without D1472H, similar to the findings in the healthy control population. No increase in bleeding score was observed, however, for VWD subjects with D1472H compared with those without D1472H. These results suggest that the presence of the D1472H sequence variation is not associated with a significant increase in bleeding symptoms, even in type 1 VWD subjects.

Bleeding tendency and efficacy of anti-haemorrhagic treatments in patients with type 1 von Willebrand disease and increased von Willebrand factor clearance.

Accelerated clearance of von Willebrand factor (VWF) has been recently identified as a major pathophysiologic mechanism inducing low VWF in some patients with von Willebrand disease (VWD). The frequency of bleeding and the best treatment of these patients have never been evaluated prospectively in large series of patients. It was the aim of the present study to prospectively evaluate clinical events of 60 heterozygous patients with VWD Vicenza (VWD-VI) carrying R1205H VWF mutation and 23 with C1130F mutation, both characterised by markedly increased VWF clearance. During 71 months of follow-up, 65% of patients with VWD-VI and 61% with C1130F required treatment. The rate of spontaneous bleeding requiring consultation/treatment was 7.5/100 patients-year in patients with C1130F mutation vs. 1.9/100 patients-year in those with R1205H (p=0.004). This difference persisted also by multivariate analysis adjusted for sex, age and blood group (hazard ratio [HR]=3.3 for C1130F, 95% confidence interval [CI] 1.16-9.27) and females were at greater risk of bleeding (HR=3, 95%CI 1.01-9.93) because of menorrhagia. Only 3/15 (20 %) women in fertile age with VWD-VI compared to 8/9 (89 %) with C1130F mutation required consultation/treatment for menorrhagia (iron supplementation, combined oral contraceptives, tranexamic acid). Almost all dental extractions, minor surgeries and deliveries occurring during follow-up were successfully managed with desmopressin. Major surgery required factor VIII/VWF concentrates, but a few cases benefited from desmopressin. In conclusion, similar to patients with type 1 VWD, also in patients with increased VWF clearance desmopressin maintains a major therapeutic role.