The Association of Aging With Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease

Little is known about aging in von Willebrand disease (VWD). It is uncertain whether VWD patients experience an age-related increase in von Willebrand factor (VWF) levels, and if so, it is unknown whether normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the association of age with VWF levels and bleeding risk in patients with type 1 VWD. This is a retrospective chart review of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinic visits. Data collected included VWF antigen level and condensed molecular and clinical markers for the diagnosis and management of Type 1 (MCMDM-1) VWD bleeding assessment tool (BAT) bleeding score based on bleeding symptoms during the previous 3 years. Thirty-nine patients participated in the study, and 32 were female. The average age of participants was 41.8 ± 18.0 years. The mean VWF antigen level was 0.83 ± 0.37 IU/mL, and the mean bleeding score was 2.51 ± 2.90. The bleeding score was inversely associated with age, β = −0.080 (SE = 0.023), P < .01. There was a nonsignificant association between VWF antigen levels and age. To our knowledge, this is the first report showing an association between aging and decreased bleeding symptoms in patients with type 1 VWD. Determining whether or not bleeding risk is reduced in older patients with type 1 VWD is essential for optimal clinical management. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of health-care dollars. These findings warrant further investigation.

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The Effects of Aging on Von Willebrand Factor Levels and Bleeding Risk in Type 1 Von Willebrand Disease

Blood ◽

10.1182/blood.v128.22.2584.2584 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2584-2584 ◽

Cited By ~ 1

Author(s):

Craig D. Seaman ◽

Margaret V. Ragni

Keyword(s):

Research Funding ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Antigen Level ◽

Cross Sectional ◽

Age Related ◽

Bleeding Score ◽

Effects Of Aging ◽

Von Willebrand

Introduction: Little is known about aging in von Willebrand disease (VWD). While it has been well established that von Willebrand factor (VWF) levels increase with age among healthy adults, it is uncertain if VWD patients experience an age related increase in VWF levels, although limited data suggests so. Furthermore, it is unknown if normalization of VWF levels with aging ameliorates bleeding risk. We aimed to determine the effects of aging on VWF levels and bleeding risk in patients with type 1 VWD. Methods: This is a cross-sectional study of patients with type 1 VWD presenting to the Hemophilia Clinic of Western Pennsylvania for regularly scheduled clinical visits. Exclusion criteria included concomitant hereditary bleeding disorder. Blood samples were obtained to determine VWF antigen level, VWF ristocetin cofactor activity, and factor VIII activity. A bleeding score was obtained using the condensed MCMDM-1 VWD bleeding assessment tool (BAT); however, we calculated the bleeding score based on bleeding symptoms over the previous three years. The prophylactic use of DDAVP or VWF concentrate prior to surgery was not included in the determination of the bleeding score. Descriptive statistics for continuous variables included mean, median, range, and standard error. Frequencies and percentages were used for categorical variables. Simple linear regression was used to predict the association of age with VWF antigen level and bleeding score. Results: The average age of participants was 43.5 ± 5.28 years (median 38, range 22 to 85). Twelve of 14 patients were female. The mean VWF antigen level was 0.97 ± 0.10 IU/mL (median 0.88, range 0.58 to 1.56). The mean bleeding score was 1.64 ± 0.52 (median 1, range 0 to 6). Four of 12 female patients reported use of estrogen containing oral contraceptives. None reported pregnancy. A simple linear regression was calculated to predict bleeding score based on age. Average bleeding score was inversely proportion to age, with a decrease of 0.057 (-0.107, 0.006) for each year of age, p =0.03. There was no significant correlation between VWF antigen level and age, with an increase in average VWF antigen level of 0.003 (-0.009, 0.014) for each year of age, p =0.60. Discussion: To our knowledge, this is the first report showing age-related amelioration of bleeding symptoms in patients with type 1 VWD. Prior studies have reported contradictory findings, some reporting that bleeding symptoms do not lessen with aging in patients with type 1 VWD. Several studies may be confounded by study design, including the method of BAT administration. Determining the bleeding score using lifetime bleeding symptoms may not be reflective of present day bleeding risk (i.e. an older patient with a remote history of moderate to severe bleeding without bleeding symptoms for several years). We found no association between aging and VWF antigen levels, which may, in part, be related to the small sample size. Determining whether or not bleeding risk is reduced in elderly type 1 VWD patients is essential for optimal clinical management. If older type 1 VWD patients have experienced normalization of VWF levels, and no longer have an increased risk of bleeding, administration of DDAVP or VWF concentrate may be harmful. Thrombosis risk increases with aging, and providing DDAVP or VWF concentrate unnecessarily may increase thrombosis risk, especially among patients with underlying CVD, CVD-related risk factors, or concomitant hypercoagulable states. Moreover, VWF concentrate is costly, and unwarranted use represents a significant waste of healthcare dollars. For these reasons, we plan a multicenter, cross-sectional study (VWD Aging and Bleeding Correlation Study, VWD-ABC) to further investigate the effects of aging on VWF levels and bleeding risk in patients with type 1 VWD. Disclosures Ragni: OPKO: Research Funding; Tacere Benitec: Consultancy; Biogen: Consultancy, Research Funding; Novo Nordisk: Research Funding; Alnylam Pharmaceuticals: Consultancy, Research Funding; Baxalta: Research Funding; Genentech: Research Funding; Biomarin: Consultancy; CSL Behring: Research Funding; Shire: Consultancy; SPARK: Research Funding; Vascular Medicine Institute: Research Funding.

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Toward Personalized Treatment for Patients with Low von Willebrand Factor and Quantitative von Willebrand Disease

Seminars in Thrombosis and Hemostasis ◽

10.1055/s-0041-1722864 ◽

2021 ◽

Vol 47 (02) ◽

pp. 192-200

Author(s):

James S. O'Donnell

Keyword(s):

Von Willebrand Factor ◽

Bleeding Risk ◽

Von Willebrand Disease ◽

Personalized Treatment ◽

Treatment Plans ◽

Type 3 ◽

Von Willebrand ◽

Willebrand Factor

AbstractThe biological mechanisms involved in the pathogenesis of type 2 and type 3 von Willebrand disease (VWD) have been studied extensively. In contrast, although accounting for the majority of VWD cases, the pathobiology underlying partial quantitative VWD has remained somewhat elusive. However, important insights have been attained following several recent cohort studies that have investigated mechanisms in patients with type 1 VWD and low von Willebrand factor (VWF), respectively. These studies have demonstrated that reduced plasma VWF levels may result from either (1) decreased VWF biosynthesis and/or secretion in endothelial cells and (2) pathological increased VWF clearance. In addition, it has become clear that some patients with only mild to moderate reductions in plasma VWF levels in the 30 to 50 IU/dL range may have significant bleeding phenotypes. Importantly in these low VWF patients, bleeding risk fails to correlate with plasma VWF levels and inheritance is typically independent of the VWF gene. Although plasma VWF levels may increase to > 50 IU/dL with progressive aging or pregnancy in these subjects, emerging data suggest that this apparent normalization in VWF levels does not necessarily equate to a complete correction in bleeding phenotype in patients with partial quantitative VWD. In this review, these recent advances in our understanding of quantitative VWD pathogenesis are discussed. Furthermore, the translational implications of these emerging findings are considered, particularly with respect to designing personalized treatment plans for VWD patients undergoing elective procedures.

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Von Willebrand Factor Levels Do Not Increase with Age in Patients with Type 1 Von Willebrand Disease.

Blood ◽

10.1182/blood.v104.11.4028.4028 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4028-4028

Author(s):

Hong I. Tarng ◽

Lynne Taylor ◽

Barbara A. Konkle

Keyword(s):

Factor Viii ◽

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Test Results ◽

Age Related ◽

One Year ◽

Von Willebrand ◽

Willebrand Factor ◽

Over Time

Abstract A number of inherited and acquired factors modulate von Willebrand factor antigen (VWF:Ag) levels, including blood type, race, activity and stress level, thyroid hormone status, and, in women, time in menstrual cycle. In reported studies a positive correlation between VWF:Ag and/or factor VIII levels and age has been demonstrated, with an increase of 5 – 6 IU/dL per decade (Conlan MG et al, 1993; Kamphuisen PW et al, 1998). Those studies have primarily assessed VWF and factor VIII as risk factors for ischemic heart disease, cerebrovascular disease, and venous thromboembolism. None of the subjects had von Willebrand disease (VWD). Their VWF:Ag levels were in the higher normal or elevated range. The purpose of this study was to determine whether there is a relationship between age and VWF:Ag level in patients with Type 1 VWD. We collected the data from 36 patients who were diagnosed with type 1 VWD and followed at the Penn Comprehensive Hemophilia and Thrombosis Program up to a period of 13 years (See Table 1 below). For each patient, date of birth, VWF:Ag levels with corresponding test dates were collected by reviewing the medical histories and the lab results. Test results obtained during pregnancy, DDAVP testing, or during prophylaxis or therapy for bleeding control were excluded. One year was set as the observation period, so the adjacent VWF:Ag levels that were tested less than one year were excluded from the dataset. When two test results were available on a patient within a one-year period, the lower test result was used. To investigate whether there was a relationship between VWF:Ag levels and age, cross-sectional analyses (across each visit) and longitudinal analyses were performed using scatter plots, Spearman and Pearson correlations, and regression analysis. No significant increase in VWF:Ag levels with age was demonstrated. The fact that we did not find an increase in VWF:Ag levels over time in our patients could be due to the relatively small number of patients studied or could reflect a subtype of VWD, due to our selection criteria. Only patients with abnormal values were included. Some patients have a prior diagnosis of VWD and bleeding symptoms, but have normal values when tested. Since these patients are adults, this may be due, at least in part, to an age-related increase. Type 1 VWD may occur secondary to decreased VWF synthesis and/or clearance. It is possible that age-related effects on VWF levels will differ depending on the underlying factor(s) resulting in a lower VWF level. Further studies correlating a patient’s values longitudinally with the underlying pathophysiology of their disease would aid in our understanding of their bleeding risks over time. Patient # Age at Last Visit, range (mean) Females (%) Race % (Cauc/AA/Other) VWF:Ag mean 36 17–70 (34) 89 78/19/3 49%

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Epidural Analgesia Use in Women with Von Willebrand Disease

Blood ◽

10.1182/blood.v124.21.1529.1529 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1529-1529

Author(s):

Leslie Skeith ◽

M. Dawn Goodyear ◽

Natalia Rydz ◽

Man-Chiu Poon

Keyword(s):

Epidural Analgesia ◽

Von Willebrand Factor ◽

Safety Data ◽

Von Willebrand Disease ◽

Activity Levels ◽

Third Trimester ◽

Bleeding Score ◽

Von Willebrand ◽

Willebrand Factor

Abstract There is little safety data available on the use of epidural analgesia during pregnancy in women with von Willebrand disease (VWD), a common disorder comprising up to 0.1% of the population. Despite physiological increases in von Willebrand factor antigen and activity levels to normal or near levels during third trimester in Type 1 VWD patients, epidural analgesia use is varied and often withheld. We conducted a cross-sectional questionnaire in order to further characterize the local practice and provide additional safety data on epidural use in the VWD population. We invited all women with VWD followed by the Southern Alberta Rare Blood and Bleeding Disorders Comprehensive Care Program to participate in an online or paper questionnaire. The questionnaire was part of a larger study identifying pregnancy complications in VWD, with additional questions collected on the diagnosis and severity of VWD, epidural use and associated outcomes, as well as the perceived contraindications of epidural analgesia. All questions were pre-tested by hematologists, obstetricians and laypeople. With patient consent, supplemental data was collected from clinic and hospital records. We included patients who were 18 years of age or older with a diagnosis of VWD, defined as von Willebrand factor (VWF) antigen and activity levels less than 50 percent or a historical diagnosis, in combination with a bleeding score of 4 or more (condensed MCMDM-1 bleeding questionnaire). Patients were excluded if they had no past pregnancies, no mailing address, or had an alternative bleeding disorder. Confidence intervals for proportions were calculated using the Wilson’s score method. Of the 98 women with VWD who met the study inclusion criteria, 31 (32%) completed the questionnaire. There were 25 (81%) diagnosed with Type 1, 5 (16%) with Type 2, and 1 (3%) with Type 3 VWD. The mean bleeding score was 10.3 (SD 3.6). There were a total of 83 pregnancies (mean 2.7, range 1-6), with 60 deliveries assessed because of 20 pregnancy losses, 2 elective terminations, and 1 patient currently pregnancy. Of the 60 deliveries, the rate of epidural use was 28.3% (95% confidence interval 18.5-40.8, n=17). All epidural analgesia use was reported in women with Type 1 VWD. Of the 43 pregnancies without an epidural, the stated reasons were as follows: 10 because of concern for bleeding (23.3%), 25 because of personal preference (58.1%), 7 ‘other’ (16.3%), and 1 participant without a response (2.3%). In the 10 pregnancies where an epidural was not used due to bleeding concerns, 6 patients had Type 1 VWD and 1 patient had Type 2N VWD. The outcome of epidural use in the VWD population was reassuring, 2 women reported their epidural analgesia to be ineffective, and 4 women reported neurological symptoms such as numbness, tingling or weakness. All neurological symptoms were temporary with no persistent deficits or documented complication of bleeding. Due to the retrospective nature of this study, VWF antigen and activity levels at the time of delivery were not available, limiting the conclusions that can be made on the safety of epidural use based on VWF levels. It is our local practice to proceed with epidural analgesia if a patient’s VWF antigen and activity levels measured in third trimester are greater than 50%. For VWF levels less than 50%, epidural analgesia would only be considered with appropriate DDAVP or factor concentrate replacement. In summary, our local rate of epidural use was close to 30% in the VWD population, which was primarily composed of Type 1 VWD patients. Outcome data is reassuring, but a larger cohort study is needed to further quantify rare risks such as neuraxial bleeding. Disclosures No relevant conflicts of interest to declare.

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Type 2M vWD Resulting from a Lysine Deletion within a Four Lysine Residue Repeat in the A1 Loop of von Willebrand Factor

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613995 ◽

2000 ◽

Vol 84 (08) ◽

pp. 188-194 ◽

Cited By ~ 13

Author(s):

P. V. Jenkins ◽

C. Gaucher ◽

E. Meriane ◽

P. W. Collins ◽

K. J. Pasi ◽

...

Keyword(s):

Von Willebrand Factor ◽

Von Willebrand Disease ◽

Lysine Residue ◽

Antigen Level ◽

The Uk ◽

Von Willebrand ◽

Willebrand Factor ◽

Ristocetin Cofactor ◽

Ristocetin Cofactor Activity

SummaryType 1 von Willebrand disease is characterized by a decreased plasma concentration of functionally normal von Willebrand factor (vWF) whereas type 2M is characterised by an abnormal vWF displaying decreased affinity for platelets. In these two types of patients, the multimeric structure of vWF is normal.We report here the identification, in two unrelated families from the UK and Algeria, of an in-frame 3 bp deletion, at the heterozygous state, resulting in the deletion of a lysine residue within a four lysine repeat at position 642-645 of the mature vWF subunit (del K1405-1408 in prepro vWF). The patients who have a discrepancy between vWF antigen level and vWF ristocetin cofactor activity exhibited decreased ristocetin-induced binding but only a slight decrease in the percentage of high molecular weight (HMW) multimers in plasma.Recombinant vWF harbouring this deletion did not bind to platelet GPIb in the presence of ristocetin or botrocetin although the protein is multimerized. Consequently, this lysine deletion was considered as a type 2M vWD mutation.

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The Management of Bleeding Risk in Von Willebrand Disease: Should Blood Group O Make a Difference?

Blood ◽

10.1182/blood.v124.21.2829.2829 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2829-2829

Author(s):

Joan Cox Gill ◽

Veronica H Flood ◽

Pamela A Christopherson ◽

Daniel B Bellissimo ◽

Kenneth D Friedman ◽

...

Keyword(s):

Blood Group ◽

Von Willebrand Factor ◽

Sequence Variation ◽

Gene Sequence ◽

Von Willebrand Disease ◽

Sequence Change ◽

Bleeding Score ◽

Von Willebrand ◽

Willebrand Factor

Abstract Type 1 von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by a quantitative deficiency of von Willebrand factor (VWF) and excessive mucocutaneous bleeding. It is well known that von Willebrand factor (VWF) levels are significantly lower in persons with ABO blood group O and that there is a significantly higher prevalence of blood group O in patients with a diagnosis of type 1 VWD. This raises a question important to the clinical care of patients with low VWF; is there a difference in bleeding risk in patients with a deficiency of VWF on the basis of blood group O versus those with a deficiency of VWF due to a sequence variation in the VWF gene. To explore this question, we examined index cases enrolled in the Zimmerman Program for the Molecular and Clinical Biology of VWD with a quantitative deficiency of VWF including those with a phenotypic diagnosis of low VWF [von Willebrand factor antigen (VWF:Ag) or von Willebrand factor ristocetin cofactor activity (VWF:RCo)≤ 50 U/dL and >40 U/dL], type 1 VWD (VWF:Ag or VWF:RCo≤40 U/dL) and type 1C VWD (VWF:Ag ≤30 U/dL and VWF propeptide/Ag ratio >3 indicating increased clearance of VWF). VWF:Ag, VWF:RCo, VWF propeptide and multimer distribution were analyzed in the clinical hemostasis laboratory at the BloodCenter of Wisconsin. Full length VWF gene sequencing including intron-exon boundaries was performed for all index cases. Bleeding symptoms were scored utilizing the ISTH, MCMDM1 and PBQ bleeding assessment tools. Since there was a high correlation among bleeding scores with these three methods, the ISTH score was utilized for this analysis. Complete data were available for 91 subjects with low VWF, 161 subjects with type 1 VWD, 53 subjects with type 1C VWD and 74 normal control subjects. Median ages were not different among the diagnostic groups. As expected based on previous reports, the groups of VWD patients with lower VWF:Ag values (Mean±1SD) had an increased percentage of subjects with an identified sequence variation; low VWF group, VWF:Ag 50.4±8.4, 38% with sequence variation; Type 1 VWD, VWF:Ag 30.8±11.6, 70% with sequence variation; and Type 1C VWD, VWF:Ag 9.8±5.9, 83% with sequence variation. The low VWF group and the type 1 VWD groups both had a significantly increased frequency of subjects with blood group O (70 – 80%) vs. nonO (19-30%) in comparison to those with type 1C in whom the frequency of blood group O (57% ) vs. nonO (43%) was not different than that in the normal control population (43% O vs. 57% nonO). This suggests that the type 1 and low VWF groups have a significant proportion of subjects with low VWF on the basis of blood group O alone. Since those subjects with a diagnosis of low VWF or Type 1 VWD who have no identifiable sequence variation are more likely to be affected by blood group O alone, we examined the ISTH bleeding scores in subjects with similar VWF levels and blood group O with and without an identifiable VWF gene sequence variation. We found that there was no difference in the ISTH bleeding scores in blood group O subjects regardless of the presence of a VWF gene sequence variation; low VWF, no sequence change (N=45), median bleeding score 6.0 vs. 5.0 with sequence change (N=27); type 1 VWD, no sequence change (N=39), median bleeding score 5.0 vs. 5.0 with sequence change (N=73); type 1C VWD, no sequence change (N=6), median bleeding score 7.0 vs. 7.0 with sequence change (N=24). There were no differences in median bleeding scores in blood group O vs. nonO groups, and none in the nonO groups with or without sequence variation in any of the VWD phenotypic diagnostic categories. There were no significant differences in bleeding scores by gender in any of the diagnostic categories. In conclusion, we found no differences in ISTH bleeding scores in the groups of subjects most likely to have low VWF on the basis of blood group O alone, i.e., those with blood group O and no identifiable VWF gene sequence variation compared to those with VWF gene sequence variations. Thus, management of persons with VWF deficiency should be based on baseline VWF levels and not modified in those with blood group O. Disclosures No relevant conflicts of interest to declare.

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Combined Hereditary Disorders of Haemophilia B Leyden (-6 G → A) and Type 1 von Willebrand Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650544 ◽

1996 ◽

Vol 76 (02) ◽

pp. 151-155 ◽

Cited By ~ 4

Author(s):

Gilles Pernod ◽

Christine Vinciguerra ◽

Christine Gaucher ◽

Claudine Mazurier ◽

Benoît Polack ◽

...

Keyword(s):

Bleeding Risk ◽

Von Willebrand Disease ◽

Factor Ix ◽

Haemophilia B ◽

Age Related ◽

Hereditary Disorders ◽

Paternal Grandmother ◽

Von Willebrand ◽

Willebrand Factor

SummaryMultiple coagulation disorders are unusual. We report here a combination of haemophilia B Leyden with type 1 von Willebrand disease (vWD) affecting different members of the same family. Haemophilia B Leyden was due to a -6 G → A mutation within the promoter of the factor IX gene and was responsible for a mild haemophilia in the father of the proband. The proband and her sister (age 4 and 6) exhibited a twofold lower level of factor IX activity (0.4 IU/ml) than the paternal grandmother (0.95 IU/ml). The differences in FIX levels in the three carriers of the same -6 G → A mutation suggest the implication of an age-related mechanism responsible for the increase in factor IX plasma level. Haemophilia B Leyden patient and carriers suffered also from a mild von Willebrand disease. The diagnosis of this associated type 1 vWD was performed by assaying plasma von Willebrand factor together with multimer electrophoretic studies and DDAVP test. The inheritance of this vWD was investigated by haplotype analysis of the vWF gene. Individuals affected by such an association are actually asymptomatic, but per- and post-operative bleeding risk remains to be evaluated.

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Bleeding Symptoms and von Willebrand Factor Levels: 30-Year Experience in a Tertiary Care Center

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/1076029619866916 ◽

2019 ◽

Vol 25 ◽

pp. 107602961986691

Author(s):

Chatphatai Moonla ◽

Benjaporn Akkawat ◽

Yaowaree Kittikalayawong ◽

Autcharaporn Sukperm ◽

Mukmanee Meesanun ◽

...

Keyword(s):

Von Willebrand Factor ◽

Care Center ◽

Tertiary Care ◽

Bleeding Risk ◽

Binding Activity ◽

Von Willebrand Disease ◽

Von Willebrand ◽

Willebrand Factor

Correlations between bleeding symptoms and von Willebrand factor (VWF) levels may help to predict hemorrhagic severity in the Westerners with von Willebrand disease (VWD), but data in Asians are lacking. In this study, Thai patients with VWF levels <50 IU/dL without any secondary causes were enrolled from 1988 to 2018 to determine the relationship between VWF levels and hemorrhagic manifestations. According to the current concept, we reclassified VWD and low VWF by VWF levels ≤30 and 30 to 50 IU/dL, respectively. Type 2 VWD was diagnosed if VWF activity to antigen ratio was ≤0.6. Bleeding severity was determined by the condensed MCMDM-1VWD bleeding score (BS). Among 83 patients, VWF activities showed negative correlations with BS ( P = .001), which were higher in type 2 (median: 7, interquartile range [IQR]: 5-11) compared with type 1 VWD (median: 3, IQR: 2-4) and low VWF (median: 4, IQR: 2-8). Bleeding symptoms were indistinguishable between type 1 VWD and low VWF using the 30 IU/dL cutoff point. However, VWF ristocetin cofactor activity or gain-of-function mutant glycoprotein Ib binding activity <36.5 IU/dL and VWF collagen binding activity <34.5 IU/dL could predict increased bleeding risk (BS ≥3) by 92.3% specificity and 70.0% sensitivity ( P < .0001).

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