A novel platelet-type von Willebrand disease mutation (GP1BA p.Met255Ile) associated with type 2B “Malmö/New York” von Willebrand disease

2016 ◽  
Vol 116 (12) ◽  
pp. 1070-1078 ◽  
Author(s):  
Cécile Lavenu-Bombled ◽  
Corinne Guitton ◽  
Arnaud Dupuis ◽  
Marie-Jeanne Baas ◽  
Céline Desconclois ◽  
...  
Keyword(s):  
New York ◽  
Von Willebrand Disease ◽  
Bleeding Complications ◽  
Loss Of Function ◽  
Gain Of Function ◽  
Mild Phenotype ◽  
Biological Assays ◽  
Expression Studies ◽  
Similar Phenotype ◽  
Von Willebrand

SummaryInteraction between von Willebrand factor (VWF) and platelet GPIbα is required for primary haemostasis. Lack or loss-of-function in the ligand-receptor pair results in bleeding complications. Paradoxically, gain-of-function mutations in VWF or GPIbα also result in bleeding complications as observed in type 2B von Willebrand disease (VWD) and platelet-type- (PT-) VWD, respectively. A similar phenotype is observed with increased ristocetin-induced platelet agglutination and disappearance of the highest molecular weight multimers of VWF. We evaluated a patient with a bleeding disorder and a biological presentation compatible with type 2B VWD. VWF and platelet functional assays, sequencing of the VWF and GP1BA genes, and expression studies in HEK cells were performed. Sequencing of the VWF gene in the propositus revealed a heterozygous p.Pro1266Leu mutation previously found in type 2B VWD Malmö/New York. These variants are characterised by a mild phenotype and a normal VWF multimer composition suggesting the presence of a second mutation in our propositus. Sequencing of the GP1BA gene revealed a heterozygous c.765G>A substitution changing Met at position 255 of GPIbα to Ile. This new mutation is located in the β-switch domain where five other gain-of-function mutations have been reported in PT-VWD. Expression of GPIbα Ile255 in HEK GPIb-IX cells resulted in enhanced VWF binding compared to wild-type, similar to known PT-VWD mutations (p.Val249, p.Ser249 and p.Val255) indicating that it contributes to the propositus defects. This first report associating PT-with type 2B VWD illustrates the importance of combining biological assays with genetic testing to better understand the clinical phenotype.

scholarly journals Successful management of multiple pregnancies in a family with varying severity of Von Willebrand disease

2018 ◽  
Vol 11 (4) ◽  
pp. 192-194
Author(s):  
Patrick Harrington ◽  
Pippa Kyle ◽  
Jacky Cutler ◽  
Bella Madan
Keyword(s):  
Von Willebrand Factor ◽  
Von Willebrand Disease ◽  
The Other ◽  
Severe Phenotype ◽  
Mild Phenotype ◽  
History Of ◽  
Specialist Treatment ◽  
Factor Concentrate ◽  
Von Willebrand ◽  
Willebrand Factor

We present the obstetric history of a family of three sisters with Von Willebrand disease, managed in our centre over the course of nine successful pregnancies. The abnormalities result from inheritance of an exon 50 skipping mutation in the Von Willebrand factor gene, resulting from consanguinity. Two of the sisters were identified as having a severe phenotype with a Von Willebrand factor level of less than 5 IU/dl, with the other having a mild phenotype. Of the sisters with a severe phenotype, one had a number of prenatal complications and required early onset prophylaxis with Von Willebrand factor concentrate, whilst the other had a less complicated clinical course, only requiring Von Willebrand factor concentrate to cover labour. The sister with mild Von Willebrand disease had a rise in Von Willebrand factor levels during pregnancy and required no specialist treatment. The report highlights the markedly different clinical courses that can occur in patients with Von Willebrand disease and the different approaches to management.

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

2008 ◽  
Vol 100 (05) ◽  
pp. 797-802 ◽  
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.

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

2009 ◽  
Vol 155 (1) ◽  
pp. 68-72 ◽  
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

Founder von Willebrand factor haplotype associated with type 1 von Willebrand disease

Blood ◽  
2003 ◽  
Vol 102 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Lee A. O'Brien ◽  
Paula D. James ◽  
Maha Othman ◽  
Ergul Berber ◽  
Cherie Cameron ◽  
...  
Keyword(s):  
Von Willebrand Factor ◽  
Structural Changes ◽  
Significant Proportion ◽  
Thiol Group ◽  
Homology Model ◽  
Von Willebrand Disease ◽  
Expression Studies ◽  
Von Willebrand ◽  
Willebrand Factor

AbstractTo date, no dominant mutation has been identified in a significant proportion of patients with type 1 von Willebrand disease (VWD). In this study, we examined 70 families as part of the Canadian Type 1 VWD Study. The entire VWF gene was sequenced for 1 index case, revealing 2 sequence variations: intron 30 (5312—19A>C) and exon 28 at Tyr1584Cys (4751A>G). The Tyr1584Cys variation was identified in 14.3% (10 of 70) of the families and was in phase with the 5312—19A>C variation in 7 (10.0%) families. Both variants were observed in 2 of 10 UK families with type 1 VWD, but neither variant was found in 200 and 100 healthy, unrelated persons, respectively. Mean von Willebrand factor antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and factor VIII coagulant activity (FVIII:C) for the index cases in these families are 0.4 U/mL, 0.36 U/mL, and 0.54 U/mL, respectively, and VWF multimer patterns show no qualitative abnormalities. Aberrant VWF splicing was not observed in these patients, and both alleles of the VWF gene are expressed as RNA. Molecular dynamic simulation was performed on a homology model of the VWF-A2 domain containing the Tyr1584Cys mutation. This showed that no significant structural changes occur as a result of the substitution but that a new solvent-exposed reactive thiol group is apparent. Expression studies revealed that the Tyr1584Cys mutation results in increased intracellular retention of the VWF protein. We demonstrate that all the families with the Tyr1584Cys mutation share a common, evolved VWF haplotype, suggesting that this mutation is ancient. This is the first report of a mutation that segregates in a significant proportion of patients with type 1 VWD.

scholarly journals Complications of Hysterectomy in Women with Von Willebrand Disease.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3399-3399
Author(s):  
Andra H James ◽  
Evan R Myers ◽  
Chad Cook ◽  
Ricardo Pietrobon
Keyword(s):  
Case Reports ◽  
Postoperative Bleeding ◽  
Case Series ◽  
The United States ◽  
Von Willebrand Disease ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Bleeding Complications ◽  
Risk Of Bleeding ◽  
Von Willebrand

Abstract Background: Case reports and small case series suggest that women with von Willebrand disease (VWD) are at a very high risk of bleeding complications with hysterectomy. Because the procedure may be beneficial to women who suffer from heavy menstrual bleeding, an understanding of the true risks involved is essential for appropriate decision making. Objectives: To estimate the incidence of bleeding and other complications in women with VWD who undergo hysterectomy. Methods: The United States Nationwide Inpatient Sample (NIS) from the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality for the years 1988–2004 was queried for all hysterectomies for nonmalignant conditions. Data were analyzed based on the NIS sampling design. Bivariate analyses were used to examine the differences between women with and without VWD. Multivariate analysis was used to adjust for potential confounders among women who underwent hysterectomy for heavy menstrual bleeding. Results: 545 of the 1,358,133 hysterectomies were to women with VWD. Women with VWD were significantly more likely to experience intraoperative and postoperative bleeding (2.75% versus 0.89%, p < 0.001) and require transfusion (7.34% versus 2.13%, p < 0.001) than women without VWD. One woman with VWD died (odds ratio = 28.49). Conclusions: While the risk of bleeding complications from hysterectomy in women with VWD is smaller than previously reported, women with VWD did experience significantly more bleeding complications than women without VWD. Nonetheless, for women who have completed childbearing, the risks of hysterectomy may be acceptable.

Protein-Z-Mangel bei ungeklärter Neigung zu Thrombosen, Blutungen oder Aborten

2012 ◽  
Vol 32 (S 01) ◽  
pp. S95-S97
Author(s):  
H. Radtke ◽  
A. Jainz ◽  
F.-P. Schmidt ◽  
H. Kiesewetter
Keyword(s):  
Factor V Leiden ◽  
Disease Type ◽  
Von Willebrand Disease ◽  
Bleeding Complications ◽  
Factor V ◽  
Protein Z ◽  
Factor V Leiden Mutation ◽  
Vein Occlusion ◽  
Retinal Branch Vein Occlusion ◽  
Von Willebrand

SummaryA protein Z deficiency is presumably related with a threefold risk of venous and arterial thrombosis. Mucosal bleedings and post-operative haematomas can occur more frequently. This is seen in an increased in vivo bleeding time without other plasmatic coagulation disorders or thrombopathies. Pregnancy complications, especially abortions before the 15th week of gestation, are described as well. Patients, methods: Since May 2011 the plasmatic concentration of protein Z has been tested in 684 patients of the Hämostaseologicum. Results: In 74 patients a protein Z deficiency has been found. In other 45 patients protein Z was reduced because of the intake of phenprocoumon or coumadin. Of the 74 patients with diminished protein Z concentration 39 were marginally decreased (protein Z 1000–1500 μg/l). Of the 35 patients with a protein Z concentration <1000 μg/l 12 had had a thrombosis before (6 strokes, 3 DVT or PE, 1 arterial thrombosis, 1 retinal branch vein occlusion, 1 acute hearing loss). 7 had arterial hypertension, 2 suffered from diabetes mellitus. Of the patients who had a thrombosis 6 had a heterozygous factor V Leiden mutation. 10 had a microcirculation disorder (Raynaud’s phenomenon), 4 had had bleeding complications before, 3 had a von Willebrand disease type I, 6 patients had had abortions and 4 were healthy. Of the 39 patients with protein Z concentrations between 1000 and 1500 μg/l 18 had experienced a thrombosis before (9 DVT or PE, 3 myocardial infarctions, 1 CHD, 3 strokes, 1 retinal branch vein occlusion, 1 PAOD I, 1 tinnitus). 5 additionally had arterial hypertension. 13 suffered from Raynaud’s phenomenon, of which 7 had a hypotension. Of the patients with thromboses 3 had a heterozygous factor V Leiden mutation and one a protein C deficiency. 7 patients had had an abortion before. Bleeding complications were seen in 4 patients, of which 3 suffered from von Willebrand disease type 1.

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

Blood ◽  
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.

A Tiered Management Program To Conserve Replacement Therapy Resources for a Rural Population of Women with Type 2M von Willebrand Disease during Labor and Delivery.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3961-3961
Author(s):  
John T. Salter ◽  
Amy D. Shapiro ◽  
Matt Sulkin ◽  
Meadow Heiman ◽  
Anne Greist ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Replacement Therapy ◽  
Post Partum ◽  
Von Willebrand Disease ◽  
Bleeding Complications ◽  
Platelet Glycoprotein ◽  
Close Monitoring ◽  
Bleeding Events ◽  
Excessive Bleeding ◽  
Von Willebrand

Abstract Introduction: Type 2M Von Willebrand Disease (VWD) results from a mutation in the Von Willebrand factor (VWF) gene resulting in decreased or absent binding to platelet glycoprotein Ib. Bleeding episodes in type 2M VWD are variable, but can be severe or life-threatening; effective treatment requires administration of exogenous normal VWF. Pregnant women with type 2M VWD require close monitoring to prevent adverse bleeding events. Following a fatal post-partum hemorrhage in a woman from a large kindred with type 2M VWD, routine prophylactic doses of VWF were administered both pre- and postpartum to women with this disorder. This population is uninsured and utilized product is donated for their care. To determine if the amount of VWF could be safely reduced, a tiered risk stratification and replacement therapy program was developed to manage women with type 2M vWD during labor, delivery and the peuperium. We report the results of this tiered risk stratification in terms of the total product utilized and the rate of bleeding experienced. Methods: Between Jan–Mar 2007, we followed 7 Amish women from a large kindred with type 2M VWD (mutation 4120 C--&gt;T on exon 28). This rural community has limited access to sophisticated hematologic monitoring and is uninsured. Women were risk stratified into 1 of 3 tiers (T) based on their personal or immediate family history of bleeding with childbirth. A nurse provided peripartum monitoring via home visits on postpartum days 1, 3, 5, 10 with a portable hematocrit (Hct) machine. Women in T1 were at lowest risk and given VWF replacement only in the event of excessive bleeding or postpartum Hct &lt;30; T2 (intermediate risk) were given a single prophylactic VWF replacement dose immediately prior to delivery then monitored as T1; T3 received prophylactic VWF dose immediately prior to delivery, at 12 hours postpartum, then monitored by serial Hct per the other tiers. Women requiring Cesarean section were placed into T3 but treated with further VWF replacement due to the surgical intervention. Results: The 7 women fell into the following tiers; T1: 4; T2: 2; T3: 1. Of the 4 women in T1, none experienced excessive bleeding and no VWF therapy was required. In the 2 women in T2, there were no bleeding events requiring additional VWF. Postpartum Hct remained &gt;30 on all evaluations in T1 and 2. One woman was delivered by elective caesarean section for complicated twin pregnancy, and given VWF prior to surgery and once daily for three consecutive postoperative days. She had no bleeding complications, and maintained Hct &gt;30. Compared with the prior method of required pre- and post-partum prophylactic VWF administration regardless of tier or Hct, this pilot protocol safely decreased VWF usage in women assigned to T1 and 2 without adverse bleeding outcome or the need for transfusion. Conclusions: Women with type 2M VWD can be safely managed with a tiered risk stratification system and close postpartum clinical/Hct monitoring that utilizes conservative VWF replacement. For T1 and 2 this lead to a reduction in VWF administration of 83% compared with the prior method of mandatory pre- and postpartum VWF administration. This further translated into a substantial cost savings while still achieving safe hemostatic outcomes. Women at highest risk continue to receive prophylactic VWF pre- and postpartum to prevent serious hemorrhagic events.

Patterns of Bleeding in Males with Von Willebrand Disease

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1129-1129
Author(s):  
Manpreet K. Sandhu ◽  
Shailja Shah ◽  
Sari H Jacoby ◽  
Alice J. Cohen
Keyword(s):  
Family History ◽  
Positive Family History ◽  
Von Willebrand Disease ◽  
Bleeding Complications ◽  
Invasive Procedures ◽  
Dental Procedures ◽  
The Mean ◽  
Von Willebrand ◽  
Male Subjects

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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