Patterns of Bleeding in Males with Von Willebrand Disease

Abstract Abstract 1129 Background: Von Willebrand disease (vWD) is the most common inherited bleeding disorder in the United States, affecting about 1–2 % of the population. It is generally inherited as an autosomal dominant trait and is equally prevalent in males and females. Though this disorder usually manifests as mucosal bleeding, it is well known that there is a wide variation in clinical severity. The symptoms of vWD are usually more obvious in women because of menstruation and labor/delivery; and may be significantly under recognized in men. The pattern of bleeding and presentation at diagnosis in males has previously only been described in a small population of type 1 vWD patients (pts). Patients and Methods: We performed a retrospective chart review of active male pts with vWD receiving care at the Comprehensive Hemophilia Treatment Center. Clinical information such as age at diagnosis, initial symptom prompting the diagnosis and clinical bleeding history was obtained. Invasive procedures were reviewed for bleeding complications and relevant hematological intervention. Relevant laboratory data like PT, PTT, von Willebrand antigen (vWF:Ag), von Willebrand ristocetin cofactor (vWF:RCoF) and factor VIII activity (FVIII:C) was noted. Results: We identified a total of 140 male subjects with the diagnosis of vWD. Of the 140, 85 were evaluable with complete data. The mean age of the pts at the time of the study is 19 years (yrs) (1–79 yrs). 76/85 (89%) are type 1, 6/85 (7%) type 2 and 2/85 (4%) type 3 vWD. The mean age at diagnosis was 9.7 yrs (0.5–60 yrs) with 62/85 (73%) being diagnosed at age ≤ 10 yrs. The most common initial presentations leading to the diagnosis of vWD were epistaxis (25/85; 29%), a positive family history (24/85; 28%), prolonged preoperative (preop) PTT (14/85; 16%), easy bruising (10/85; 12%) and postoperative (postop) bleeding (5/85; 6%) pts. The mean lab values of vWF:Ag 48 IU/dl, vWF:RCoF 45 IU/dl and FVIII:C 62 IU/dl. 25/85 (29%) pts have one of the above parameters measuring < 30 IU/dl. Among those who ever experienced bleeding, the most common manifestations were epistaxis (30/85; 35%), easy bruising (10/85; 12%), postop bleeding (10/85; 8%), hemarthrosis (4/85; 5%), hematuria and oral bleeds (3/85; 4% each). A total of 48 surgical procedures occurred, consisting of 18 dental procedures, 13 tonsillectomy/adenoidectomy (T/A), 7 circumcisions, 5 joint surgeries, 2 port placements and 1 each of cystoscopy, orchiopexy and heart surgery. Bleeding complications were common 10/48 (21%): 5 with dental procedures, 2 each with T/A and circumcision and 1 with cystoscopy; all occurring in the absence of prophylactic treatment and 2/10 (20%) complications requiring transfusion of blood products. Conclusions: In our study which included types 1, 2 and 3 vWD pts, the majority of male subjects were symptomatic at the time of diagnosis, whereas about 40% were brought to attention due to a positive family history or an abnormal preop screening test. As opposed to previous reports, postop bleeding was a rare initial presentation in our larger cohort, possibly due to improved preop screening and earlier diagnosis. The most common pattern of bleeding amongst the symptomatic pts was mucosal, in the form of epistaxis and easy bruising. Bleeding complications can occur with invasive procedures, so aggressive use of DDAVP or clotting factor concentrates is warranted in a pt with known diagnosis of vWD. Disclosures: No relevant conflicts of interest to declare.

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Major haemorrhage related to surgery in patients with type 1 and possible type 1 von Willebrand disease

Thrombosis and Haemostasis ◽

10.1160/th-07-12-0757 ◽

2008 ◽

Vol 100 (05) ◽

pp. 797-802 ◽

Cited By ~ 13

Author(s):

Alicia Blanco ◽

Roberto Chuit ◽

Susana Meschengieser ◽

Ana Kempfer ◽

Cristina Farías ◽

...

Keyword(s):

Family History ◽

Surgical Procedures ◽

Tooth Extraction ◽

Positive Family History ◽

Major Haemorrhage ◽

Von Willebrand Disease ◽

Bleeding Complications ◽

Laboratory Test Results ◽

Von Willebrand

SummaryPatients with von Willebrand disease (VWD) frequently bleed under a challenge. The aim of our study was to identify predictive markers of perioperative major haemorrhage in type 1 (VWF:RCo = 15–30 IU dl-1) and possible type 1 (VWF:RCo = 31–49 IU dl-1)VWD patients. We recorded perioperative bleeding complications previous to diagnosis and laboratory parameters in 311 patients with 498 surgical procedures. The patients were grouped according to the absence (A) or presence (B) of perioperative major haemorrhages. Eighty-one patients (26%) and 87 surgical procedures (17.5%) presented major haemorrhages associated with surgeries. There was no difference between the percentage of type 1 and possible type 1 VWD patients who had major haemorrhages (32.6% and 24.8% respectively; p=ns). No difference in the prevalence of O blood group, age, gender, positive family history and laboratory test results (FVIII and VWF) was observed, independent of the haemorrhagic tendency. Bleeding after tooth extraction was the most frequent clinical feature observed in patients with perioperative major haemorrhages. The bleeding score and the number of bleeding sites (≥3) were not predictors of major haemorrhage associated with surgery. Caesarean section and adenotonsillectomy showed the highest frequency of major haemorrhages (24.6% and 22.3%, respectively). In conclusion, type 1 and possible type 1VWD patients showed similar incidence of perioperative major haemorrhages. Laboratory tests and positive family history did not prove to be effective at predicting major haemorrhages in patients that had either type 1 or possible type 1 VWD. The history of bleeding after tooth extraction could define risk factors of major haemorrhage.

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Incidence of Bleeding Complications in Pediatric Patients with Type 1 von Willebrand Disease Undergoing Adenotonsillar Procedures

The Journal of Pediatrics ◽

10.1016/j.jpeds.2009.01.051 ◽

2009 ◽

Vol 155 (1) ◽

pp. 68-72 ◽

Cited By ~ 32

Author(s):

Char M. Witmer ◽

Lisa Elden ◽

Regina B. Butler ◽

Catherine S. Manno ◽

Leslie J. Raffini

Keyword(s):

Pediatric Patients ◽

Von Willebrand Disease ◽

Bleeding Complications ◽

Von Willebrand

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The Power of a Standardized Bleeding Score in Diagnosing Pediatric Type 1 Von Willebrand Disease.

Blood ◽

10.1182/blood.v114.22.1293.1293 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1293-1293

Author(s):

Paul D Marcus ◽

Kidan G Nire ◽

Linda Grooms ◽

Jennifer Klima ◽

Sarah O'Brien

Keyword(s):

Platelet Function ◽

Predictive Value ◽

Care Setting ◽

Tertiary Care ◽

Bleeding Disorder ◽

Von Willebrand Disease ◽

The Mean ◽

Bleeding Score ◽

Von Willebrand

Abstract Abstract 1293 Poster Board I-315 INTRODUCTION Type I von Willebrand disease (VWD) is the most common inherited bleeding disorder. Repetitive testing of von Willebrand factor (VWF) levels is necessary before the diagnosis can be safely ruled out, as VWF levels fluctuate in response to genetic and environmental factors. A predictive bleeding score (BS) could reveal individuals that may benefit from repetitive testing and those for whom repetitive testing is unlikely to be of benefit. While a standardized questionnaire (the Vicenza score) was developed to evaluate hemorrhagic symptoms, it was never prospectively validated for a pediatric population in a tertiary care setting. SUBJECTS The study targeted children, ages 0 to 17 years, referred to the Hemostasis and Thrombosis Center (HTC) of Nationwide Children's Hospital for a coagulation evaluation as a result of bleeding symptoms, family history of a bleeding disorder and/or abnormal coagulation labs found during pre-operative screening. Children were excluded if they had a previously diagnosed bleeding disorder, if their caregiver did not speak English or if the child did not undergo VWF:Ag and VWF:RCo testing. METHODS Prior to the diagnosis or exclusion of a bleeding disorder in the child, caregivers consented to answer the questionnaire over the telephone. Descriptions of the Vicenza score are available online (http://www.euvwd.group.shef.ac.uk/bleed_score.htm). LABORATORY TESTING A single VWF:Ag or VWF:RCo <30 IU/dL was classified as “Definite Type 1 VWD” while levels from 30-50 IU/dL were classified as “Low VWF” (http://www.nhlbi.nih.gov/guidelines/vwd). Platelet function analysis (PFA-100) screened for platelet function defects, with some patients undergoing follow-up platelet aggregation studies and/or platelet electron microscopy. Laboratory studies from other institutions were excluded from analysis. Patients' medical records were reviewed after hematologic evaluation, and the resultant data was analyzed with STATA 10.1 (Stata Corp., College Station, TX). RESULTS A total of 104 children (52 females and 52 males) with a mean age of 7.53 years (range 1 month to 17 years) were included. At least one hemorrhagic symptom was present in 99 of the 104 children (95%) with the mean number of symptoms being 2.87 (range 0 to 7). The mean Vicenza score was 3.24 (range -1 to 13). Of the 104 children, 8 met criteria for “Definite Type 1 VWD,” 23 met criteria for “Low VWF,” 14 were diagnosed with a “Platelet Function Defect,” and 2 children had bleeding secondary to Ehlers Danlos syndrome. Children with non-bleeding disorders (e.g. Factor XII deficiency) or no laboratory evidence of a bleeding disorder were classified as “No Bleeding Disorder.” In general, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive diagnostic likelihood ratio of the bleeding questionnaire demonstrated poor predictive value in our patient population with the exception of high specificity in ruling out “Definite Type 1 VWD” (Table). The NPV was comparably high with both qualitative (>2 bleeding symptoms) and quantitative (BS ≥2) criteria. CONCLUSIONS The Vicenza score, previously validated in adults and in a pediatric primary care setting, appears to have limited predictive value in a pediatric tertiary care setting when evaluating patients with platelet function defects or low VWF levels. While the Vicenza score has a high NPV to exclude “Definite Type 1 VWD,” the use of simpler qualitative criteria is similarly predictive. Disclosures No relevant conflicts of interest to declare.

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Experience with Epidural Anesthesia in Pregnant Women with Von Willebrand Disease.

Blood ◽

10.1182/blood.v104.11.1026.1026 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1026-1026

Author(s):

Jay Varughese ◽

Alice J. Cohen

Keyword(s):

Pregnant Women ◽

Von Willebrand Factor ◽

Epidural Anesthesia ◽

Postpartum Hemorrhage ◽

Postoperative Bleeding ◽

Von Willebrand Disease ◽

Bleeding Complications ◽

Von Willebrand ◽

Willebrand Factor

Abstract Von Willebrand Disease (vWD) is an autosomal dominant inherited bleeding disorder that is characterized by epistaxis, mucosal and postoperative bleeding, menorrhagia and postpartum hemorrhage. In particular, there is a paucity of safety data for, and thus a reluctance to use, epidural anesthesia (EA) for delivery. We thus conducted a review of all women followed with vWD in a referral hemophilia clinic who had ≥ 1 pregnancy. Thirty-three subjects were screened; 31/33 (94%) had type 1 and 2/33 (6%) had type 2A vWD. There were 59 term pregnancies (range 1–3 per patient), and 5 fetal losses (in 4 patients). Of the term pregnancies, 16/59 (27%) were delivered by Caesarian Section (C-Section), complicated by postpartum hemorrhage in 3 (19%); 43/59 (73%) were delivered by normal spontaneous vaginal delivery (NSVD), complicated by hemorrhage in 21 (49%) (p=0.05). EA was administered during 14 (13 with type 1 vWD) of 59 (24%) of the deliveries, all without DDAVP, plama-derived factor VIII-von Willebrand factor containing concentrates or blood products, and in no patient were bleeding complications encountered at the site of EA nor were there any neurologic complications. Conclusion: Postpartum hemorrhage was a common complication in patients with vWD, more after NSVD than C-Section. In a selected subset, EA was safely administered without bleeding complications, possibly due to pregnancy induced increase in factor VIII:C and von Willebrand factor activity counteracting the tendency to bleed. Larger series and prospective studies should be performed to confirm the safety of EA and the relationship to coagulation factor levels in pregnant women with vWD.

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Bleeding Score as a Preoperative Predictor of Postoperative Bleeding in Type 1 Von Willebrand Disease.

Blood ◽

10.1182/blood.v108.11.1019.1019 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1019-1019 ◽

Cited By ~ 4

Author(s):

Laura R. Goldberg ◽

Margaret V. Ragni

Keyword(s):

Family History ◽

Postoperative Bleeding ◽

Von Willebrand Disease ◽

Chi Square ◽

Exact Test ◽

Bleeding Score ◽

Chi Square Analysis ◽

Bleeding History ◽

Von Willebrand

Abstract Type 1 Von Willebrand Disease (VWD) is the most common congenital bleeding disorder, affecting 1% of the population, and caused by a quantitative deficiency of Von Willebrand Factor (VWF). In addition to mucosal bleeding, VWD patients often suffer postoperative bleeding, leading to significant morbidity. Thus, a preoperative diagnosis could potentially reduce postoperative bleeding. Because symptoms correlate poorly with VWD assays, subject to extragenic effects and lab variability, diagnosis is difficult. The bleeding score (BS) is a simple quantitative tool recently developed to rate bleeding symptom severity, with 99% specificity for VWD. To determine the potential utility of BS in predicting postoperative bleeding in VWD, we evaluated preoperative BS by retrospective review of type 1 VWD patients who suffered postoperative bleeding prior to diagnosis. Preoperative clinical bleeding symptoms and VWD assays, including VWF:RCo, VWF:Ag, and FVIII:C, were obtained. The severity of clinical bleeding symptoms present prior to surgery was rated by the 4-point BS scale: 0 = no/trivial; 1 = present; 2 = intervention required; 3 = replacement therapy. Statistical analysis was by chi square analysis and Fisher’s exact test for categorical data, and by student t test for continuous data. Of 260 registered type 1 VWD patients, 71 (27.3 %) experienced surgical bleeding prior to a diagnosis of VWD. Of these 56 (78.9%) were female, 48 (67.6%) were adults (≥ 18 yr), and 61 (85.9%) had a family bleeding history. The surgeries included general, gynecologic, genitourinary, and otolaryngologic procedures. The median preop BS, 3 in females and 4 in adults, was significantly higher than in males and children, each median 1, p<0.01, respectively. A BS ≥ 3 would have identified only 59.1% patients before surgery, but as many as 90.1%, if combined with one abnormal VWD test; 94.4%, with family bleeding history; or 97.2% with both family history and one abnormal VWD test. The proportion of children identified by BS was significantly lower than in adults, 26.1% vs 75.0 % with BS > 3, p = 0.001. Yet this significantly improved by combining BS with family history, 91.3% vs 95.8%, not different from adults, p = 0.591. We conclude that obtaining a preoperative BS and family bleeding history may reduce postoperative bleeding and promote timely diagnosis among individuals with type 1 VWD patients, particularly children. Preoperative Bleeding Score in Type 1 VWD Patients with Postoperative Bleeding Male Female Age < 18 Age ≥ 18 All N = 15 N = 56 N = 23 N = 48 N = 71 τp = .001, as compared with under 18 yr; σp = .007, as compared with males; ζ p > 0.5 as compared with age under 18 or males, respectively. BS≥1 10/15 (66.7%) 54/56 (96.4%) 18/23 (78.3%) 46/48 (95.8%) 64/71 (90.1%) BS≥3 4/15 (26.7%) 38/56 (67.8%)σ 6/23 (26.1%) 36/48 (75.0%)τ 42/71 (59.1%) BS≥5 2/15 (13.3%) 17/56 (30.3%) 2/23 (8.7%) 17/48 (35.4%) 19/71 (26.7%) Abnl VWF:RCo 8/15 (53.3%) 19/56 (33.9%) 6/23 (26.1%) 19/48 (39.6%) 27/71 (38.0%) Abnl VWD Test 11/15 (73.3%) 41/56 (73.2%) 16/23 (69.6%) 36/48 (75.0%) 52/71 (73.2%) Fam Bld History 15/15 (100%) 47/56 (83.9%) 21/23 (91.3%) 40/48 (83.3%) 61/71 (85.9%) BS≥3 ± Abnl VWD Test 13/15 (86.7%) 51/56 (91.1%) 18/23 (78.3%) 46/48 (95.8%) 64/71 (90.1%) BS≥3 ± Fam Hx 15/15 (100.0%) 52/56 (92.8%)ζ 21/23 (91.3%) 46/48 (95.8%)ζ 67/71 (94.4%) BS≥3 ± Fam Hx ± Abnl VWD Test 15/15 (100.0%) 54/56 (96.4%) 22/23 (95.6%) 47/48 (97.9%) 69/71 (97.2%)

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Von Willebrand Factor Collagen Binding Provides a Sensitive Screen for Identification of Type 2A and 2B Von Willebrand Disease

Blood ◽

10.1182/blood.v118.21.379.379 ◽

2011 ◽

Vol 118 (21) ◽

pp. 379-379

Author(s):

Veronica H Flood ◽

Joan Cox Gill ◽

Kenneth D Friedman ◽

Pamela A Christopherson ◽

Paula M. Jacobi ◽

...

Keyword(s):

Molecular Weight ◽

High Molecular Weight ◽

Von Willebrand Disease ◽

Collagen Binding ◽

The Mean ◽

Von Willebrand ◽

Willebrand Factor ◽

Normal Controls ◽

High Molecular Weight Multimers

Abstract Abstract 379FN2 Collagen binding is an easily performed test of von Willebrand factor (VWF) function but its role in clinical evaluation is still debated. Analysis of multimer distribution, on the other hand, is time-consuming and technically challenging. We hypothesized that VWF antigen (VWF:Ag), ristocetin cofactor activity (VWF:RCo), and collagen binding (VWF:CB) could identify the subset of von Willebrand disease (VWD) cases in which multimer analysis would be informative. Subjects from the Zimmerman Program for the Molecular and Clinical Biology of VWD were analyzed for VWF:Ag, VWF:RCo, VWF:CB (with type III human placental collagen), multimer distribution, and full VWF exon sequencing. Normal controls as well as patients with type 1, 2A, 2B, 2M, and 2N VWD were analyzed. The mean VWF:CB/VWF:Ag ratio for subjects with normal multimers was 1.10, while the mean ratio for subjects with abnormal multimers was 0.51 (p<0.001). When results were restricted to those subjects with confirmed type 2A or type 2B mutations, however, the mean ratio for subjects with abnormal multimers decreased to 0.41 (p<0.001 compared to those with normal multimers). For the 146 normal controls with multimer results available, 2 had absence of the highest molecular weight multimers, but normal collagen binding, normal bleeding scores, and no evidence of a VWF gene mutation, suggesting that the multimer results represented assay artifact. 354 type 1 subjects were examined; of those, 12 had abnormal multimer patterns. 7 had loss of the high molecular weight multimers. Of these, 5 had known type 1 VWD mutations and normal VWF:CB/VWF:Ag ratios, possibly representing sample artifacts rather than a true multimer abnormality, as no multimer issues have been previously reported for these mutations. One had no mutation found and one had a type 2A mutation. 2 had a full spectrum of multimers with relatively increased staining of the lower molecular weight bands; both with novel A1 domain mutations that are currently under investigation. 3 had larger than normal multimers observed, all with normal VWF:CB/VWF:Ag ratios. Of the 342 type 1 subjects with normal multimers, only one had a VWF:CB/VWF:Ag ratio of <0.7, likely due to very low values (VWF:CB of 2 and VWF:Ag of 4). There were 36 type 2A subjects available for analysis. 27 had loss of high molecular weight multimers. Only 3 of those had VWF:CB/VWF:Ag ratios >0.7, but none of those subjects had VWF mutations consistent with type 2A VWD. 7 subjects had a shift from high to low molecular weight multimers, 4 with VWF:CB/VWF:Ag ratios >0.7 and either known type 1 mutations or novel VWF gene mutations. 2 subjects had normal multimer distribution, one with a type1 VWD mutation and one with a novel mutation. Characterization of these novel mutations is in progress. All the 17 type 2B subjects had loss of high molecular weight multimers and abnormal collagen binding, with a VWF:CB/VWF:Ag ratio <0.7. Interestingly, however, not all had a reduced VWF:RCo/VWF:Ag ratio, suggesting VWF:CB would be required in addition to VWF:RCo if multimer distribution was omitted in initial evaluation of this type of VWD. Of 18 type 2M subjects, only one had an abnormal multimer distribution. That subject had no mutations in the VWF coding sequence and normal VWF:CB, although the VWF:RCo/VWF:Ag ratio was low at 0.53. Repeat analysis of a new sample from this subject is pending. All 7 type 2N VWD subjects had normal multimers and VWF:CB/VWF:Ag ratios >0.7. In our population, with the exception of mutations that are yet to be characterized, the combination of VWF:Ag, VWF:RCo and VWF:CB was sufficient to categorize patients as normal, type 1, type 2A, 2B or 2M in the before multimer analysis. These findings suggest that VWF:CB is a sensitive screen for detection of an abnormal multimer distribution. Collagen binding is technically much easier to perform, allowing multimer analysis to be reserved for those cases with low VWF:RCo/VWF:Ag or low VWF:CB/VWF:Ag ratios. Disclosures: No relevant conflicts of interest to declare.

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Spectrum of Type 2 Von Willebrand Disease in the Zimmerman Program

Blood ◽

10.1182/blood.v124.21.472.472 ◽

2014 ◽

Vol 124 (21) ◽

pp. 472-472 ◽

Cited By ~ 1

Author(s):

Veronica H Flood ◽

Pamela A Christopherson ◽

Daniel B Bellissimo ◽

Joan Cox Gill ◽

Sandra L Haberichter ◽

...

Keyword(s):

Sequence Variation ◽

Von Willebrand Disease ◽

Sequence Variations ◽

Platelet Binding ◽

The Mean ◽

Bleeding Score ◽

Von Willebrand ◽

Index Cases

Abstract While von Willebrand disease (VWD) is the most common inherited bleeding disorder, most patients have quantitative defects in von Willebrand factor (VWF). The qualitative variants, collectively termed type 2 VWD, are less common, but also in general more severe than type 1 VWD. However, despite a common laboratory phenotype of decreased VWF:RCo/VWF:Ag ratio for types 2A, 2B, and 2M VWD, the clinical phenotype is highly variable. We examined index cases and affected family members enrolled in the Zimmerman Program with a phenotypic diagnosis of type 2 VWD. All subjects had factor VIII (FVIII), VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), and multimer distribution analyzed in a central laboratory. For calculation of mean VWF:RCo values, a level of 5 was assigned to subjects with VWF:RCo below the laboratory lower limit of detection of 10 IU/dL. A platelet binding assay was also performed using a gain of function GPIb containing 2 mutations that enable spontaneous binding to VWF in the absence of ristocetin (VWF:GPIbM). Full length VWF gene sequencing was performed for all index cases. Targeted sequencing was performed for family members to ascertain the presence or absence of sequence variations found in the index case. Bleeding symptoms were quantified using the ISTH bleeding assessment tool and reported as bleeding scores (BS). Mean FVIII, VWF:Ag, VWF:RCo, and BS are listed in the table below for each type 2 variant. For type 2A VWD, 113 subjects have been enrolled to date. All had an abnormal multimer distribution with loss of high molecular weight multimers. 6 type 2A subjects had a VWF:RCo/VWF:Ag ratio of ≤0.7. The lowest VWF:RCo levels were seen in the type 2A cohort with 60% <10. 98% of type 2A subjects had an identified sequence variation on full length sequencing. 25% had the p.R1597W sequence variation and an additional 4 subjects had p.R1597Q. The mean bleeding score for the subjects with sequence variations at 1597 was 10.6. 11% of subjects had p.R1374H, which correlated with a higher mean bleeding score of 12.4. Mean bleeding score for the remainder of the type 2A subjects was lower, at 6.6, suggesting that differences in VWF genetics may account for differences in phenotype, despite the common type 2A laboratory presentation of reduced VWF:RCo and loss of high molecular weight multimers. 44 type 2B subjects have been enrolled to date, all with abnormal multimer distribution and either documented abnormal VWF-platelet binding or a presence of a known type 2B sequence variation. Sequence variations were found in 100% of subjects. The most common sequence variations were p.V1316M (20%), p.R1306W (18%), p.R1341Q (11%), and p.H1268Y (9%). Mean VWF:RCo/VWF:Ag ratios ranged from 0.32-1.12, suggesting that a normal VWF:RCo/VWF:Ag ratio cannot completely exclude the possibility of type 2B VWD. Most (94%) had increased VWF:GPIbM. Subjects with p.V1316M and p.R1306W/Q sequence variations had lower VWF:RCo compared to subjects with p.R1341Q/W but mean bleeding scores did not differ. 59 type 2M subjects have been enrolled to date. Mean VWF:RCo/VWF:Ag ratio was 0.46 (range 0.14-0.7). Sequence variations were found in 93% of subjects. R1374C was found in 13 members from one family. While mean VWF levels were similar to the entire 2M group, a wide range in VWF:Ag and VWF:RCo/VWF:Ag ratio was observed, accompanied by a corresponding range in BS from 0-8. This suggests that other modifiers of phenotype may be present aside from the VWF sequence variation. 11 type 2N subjects have been enrolled to date, all with low VWF binding to FVIII. Sequence variations were found in 100% of this cohort. R854Q was present in 89% of subjects. Bleeding scores were highest for homozygous 2N sequence variations. Overall, the mean BS for type 1 VWD subjects was 6.3, the mean BS for type 2 VWD subjects was 7.5, and the mean BS for type 3 VWD subjects was 16.8. Types 2A and 2N had higher bleeding scores on average than type 2B, and type 2M subjects had on average the lowest bleeding scores. Although heterogeneity was seen across all the type 2 variants, both laboratory testing and genetic testing are useful in categorizing and phenotyping type 2 VWD. Table. FVIII (mean) VWF:Ag (mean) VWF:RCo (mean) BS (mean) Type 2A 47 34 12 8.7 Type 2B 45 36 23 7.1 Type 2M 62 54 21 5.4 Type 2N 30 69 76 8.3 Disclosures Montgomery: Immucor: Patents & Royalties.

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Outcomes in Patients With Hemophilia and von Willebrand Disease Undergoing Invasive or Surgical Procedures

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029616658116 ◽

2016 ◽

Vol 23 (2) ◽

pp. 148-154 ◽

Cited By ~ 10

Author(s):

John Chapin ◽

Jaqueline Bamme ◽

Fraustina Hsu ◽

Paul Christos ◽

Maria DeSancho

Keyword(s):

Retrospective Chart Review ◽

Adverse Outcomes ◽

Von Willebrand Disease ◽

Interdisciplinary Management ◽

Invasive Procedures ◽

Acute Bleeding ◽

Management Guidelines ◽

Delayed Bleeding ◽

Dental Procedures ◽

Von Willebrand

Adults with hemophilia A (HA), hemophilia B (HB), and von Willebrand disease (VWD) frequently require surgery and invasive procedures. However, there is variability in perioperative management guidelines. We describe our periprocedural outcomes in this setting. A retrospective chart review from January 2006 to December 2012 of patients with HA, HB, and VWD undergoing surgery or invasive procedures was conducted. Type of procedures, management including the use of continuous factor infusion, and administration of antifibrinolytics were reviewed. Adverse outcomes were defined as acute bleeding (<48 hours), delayed bleeding (≥48 hours), transfusion, inhibitor development, and thrombosis. We identified 59 patients with HA and HB. In all, 24 patients had severe hemophilia and 12 had mild/moderate hemophilia. Twelve patients had inhibitors. There were also 5 female carriers of HA and 6 patients with VWD. There were 34 major surgeries (26 orthopedic, 8 nonorthopedic) and 129 minor surgeries. Continuous infusion was used in 55.9% of major surgeries versus 8.5% of minor surgeries. Antifibrinolytics were administered in 14.7% of major surgeries versus 23.2% of minor surgeries. In all, 4 patients developed acute bleeding and 10 patients developed delayed bleeding. Delayed bleeding occurred in 28.6% of genitourinary procedures and in 16.1% of dental procedures. Five patients acquired an inhibitor and 2 had thrombosis. In conclusion, patients with HA, HB, or VWD had similar rates of adverse outcomes when undergoing minor surgeries or major surgeries. This finding underscores the importance of an interdisciplinary management and procedure-specific guidelines for patients with hemophilia and VWD prior to even minor invasive procedures.

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Bleeding Outcomes in People with Von Willebrand Disease Receiving Antithrombotic Therapy

Blood ◽

10.1182/blood-2021-152919 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3196-3196

Author(s):

Aisling Barrett ◽

Catherine Bergin ◽

Mary Byrne ◽

Kevin Ryan ◽

Niamh M O'Connell ◽

...

Keyword(s):

Antithrombotic Therapy ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Cumulative Exposure ◽

Bleeding Complications ◽

Gi Bleeding ◽

Von Willebrand

Abstract Aging brings additional challenges in the management of people with von Willebrand Disease (VWD). Plasma von Willebrand Factor (VWF) levels may increase but the impact on bleeding phenotype is unclear. With the development of age-related comorbidities, the use of antiplatelet (AP) or anticoagulant (AC) therapies may be warranted. As highlighted in the 2021 international VWD guidelines, limited evidence exists regarding the bleeding risk and safety of AP/AC use in people with VWD. 1 We sought to address this knowledge gap through a retrospective review of a large cohort of people with VWD attending a tertiary referral center. The records of all patients aged >50 years (y) attending our center registered with VWD were retrospectively reviewed. We identified all individuals treated with AP and/or AC, recording the indication for and duration of therapy. We also recorded disease subtype, baseline and most recent plasma VWF levels and bleeding on AP and/or AC. Bleeding episodes were stratified according to the World Health Organization (WHO) Bleeding Scale. From 255 eligible patients, 18 patients (7 male, 11 female) were identified who received AP and/or AC over a period of 22y. The median age at commencement was 60.2 years (range 40.0-74.5). 15 patients had Type 1 with baseline levels 30-50 IU/dL, (median VWF antigen, VWF:Ag, 57.5, range 39-87 IU/dL; median VWF ristocetin cofactor levels, VWF:RCo, 43, range 35-54 IU/dL). 3 patients had type 2 VWD (median VWF:Ag 64, range 27-90 IU/dL; median VWF:RCo of 16, range 10-66 IU/dL). The type of AP/AC used and indications for treatment are outlined in Table 1. Overall, 12 patients were treated with AP and 7 with AC therapy (19 therapies in total as one patient received first aspirin then warfarin therapy). The cumulative exposure to AP therapy was 61.9y with a median exposure time of 3.2y/patient (range 0.3-14.1y). Duration of AC therapy was shorter, with a cumulative exposure of 17.6y and a median of 1.5 y/patient (range 0.3-6.3y). Overall, 85.7% of patients on AC therapy had at least one episode of bleeding (6/7; 10 episodes total) in contrast to 58.3% of patients on AP (7/12; 12 episodes total). Of these 22 episodes, 5 (22.7%) were grade 1 bleeding. Grade 2 bleeding (iron deficiency or gastrointestinal (GI), gynecological or genitourinary bleeding) occurred in 5 patients (41.7%) treated with AP and 4 patients (57.1%) on AC (total of 14 episodes). 1 episode of grade 3 bleeding occurred in both the AP (8.3%) and AC (14.3%) group (GI bleeding requiring transfusion and abdominal hematoma respectively). The single grade 4 bleed was an intracranial hemorrhage (ICH) and occurred in a patient with type 2 VWD (VWF:RCo 10 IU/dL) on warfarin for atrial fibrillation; this required prothrombin complex concentrate, VWF concentrate, neurosurgical intervention and cessation of AC. Bleeding complications resulted in discontinuation of therapy in 2 patients (11.1%) treated; the individual with ICH and a patient with type 1 VWD on warfarin (baseline VWF:RCo 43 IU/dL) due to recurrent GI bleeding. No patients treated with AP therapy required discontinuation of use. The overall rate of major bleeding (WHO grade >/=3) in our study was 11.4 events/100 patient-years in VWD patients receiving AC therapy, in comparison to the rate of bleeding in the general population using AC of 7.2 events per 100 patient-years. 2 For patients with type 1 VWD, plasma VWF levels were seen to increase during follow up (median 8.5y, VWF:Ag median +13 IU/dL, VWF:RCo +18 IU/dL), resulting in plasma VWF levels >50 IU/dL for 66.6% of patients in this cohort. Despite this, bleeding while on AP and/or AC was still experienced in 8/10 patients whose levels had normalized, necessitating cessation in one instance. In conclusion, this study provides important insights into the use of AP and/or AC in patients with VWD. Bleeding rates were higher in patients treated with AC therapy than AP resulting in cessation of therapy in 28.6% of those on AC. Bleeding events still occurred despite normalization of plasma VWF levels in patients with type 1 VWD. These data highlight the need for close follow up of patients with VWD whilst on antithrombotic therapy, particularly AC. 1. Connell NT et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv 2021;5(1):301-325. 2. Shoeb M, Fang M. Assessing Bleeding Risk in Patients Taking Anticoagulants. J Thromb Thrombolysis 2013;35(3):312-319. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Prevalence, Clinical Characteristics and Outcome of Von Willebrand Disease in Oman

Blood ◽

10.1182/blood-2019-123915 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4939-4939

Author(s):

Shamsa Alkaabi ◽

Aala Alzadjali ◽

Mustafa Wasifuddin ◽

Ibrahim Suliman Masoud Alghaithi ◽

Murtadha Al-Khabori ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Clinical Characteristics ◽

Positive Family History ◽

Von Willebrand Disease ◽

Advisory Committees ◽

Type Iii ◽

History Of ◽

Bleeding Score ◽

Von Willebrand

Introduction: Von Willebrand Disease (VWD) is the second most common inherited bleeding disorder. There is paucity of the literature describing the prevalence and clinical characteristics of VWD in this part of the world. The aim of the current study is to detect the prevalence, describe the spectrum of the different types of VWD, their mode of presentation, bleeding phenotype and outcome in Oman. Methods: A retrospective cross-sectional study was carried out in the 2 available referral tertiary care facilities in Oman namely; Sultan Qaboos University and the Royal Hospitals. The study included all children and adults diagnosed with VWD in Oman until June 2019. The patients were subtyped as per the International Society of Thrombosis and Haemostasis (ISTH) criteria. Data was collected from the electronic hospital systems in both hospitals. Out of 700 entries of VWD in both hospitals, only 140 were true cases and 560 were tested negative but wrongly labelled. Patients or their next of ken were called and interviewed to obtain the necessary information that was not documented in the electronic system. Results: A total of 140 patients are confirmed to have VWD giving a prevalence of 1:20000. Fifty eight patients are males (41.5%), 82 patients are females (58.5%). Sixty six patients have type I (47%), 38 patients have type II (27%) and 36 patients have type III (26%). The majority of patients 90 (64%) were diagnosed before the age of 20 years and 62 of them (68%) had positive family history of the disease. The most common presentation was recurrent unexplained bruising. As expected, patients with type III tend to have a significant bleeding phenotype with a bleeding score more than 5 in adults and 3 for paediatric patients. All of them were admitted to hospital at some point electively (for surgery) or for bleeding control, however, they were not put on prophylaxis. None of the patients had serious or intra-cranial bleeding. Conclusion: Von Willebrand Disease is not uncommon in Oman with an overall prevalence of 1:20000, however, it is much less than what was originally reported in previous studies in developing countries and the WFH website. The majority of patients are type 1 and have a positive family history of the disease. The disease is more common in females. All patients with type III have abnormal bleeding score and required VW factor replacement at one point. None of the patients had a serious bleed and they are not on prophylaxis. Keywords: Von Willebrand disease, Prevalence, Oman. Disclosures Al-Khabori: AstraZeneca: Honoraria; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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