Keywords
von Willebrand disease - von Willebrand factor - age - bleeding score
Introduction
von Willebrand disease (VWD) is a quantitative or qualitative defect in von Willebrand
factor (VWF). It is the most common inherited bleeding disorder and is estimated to
affect up to 1% of the population, although the symptomatic prevalence if 10-fold
less.[1] Bleeding manifestations are often mucocutaneous, and excessive bleeding occurs with
hemostatic challenges, such as invasive procedures and surgery.[2] The severity of disease is assessed with the use of bleeding assessment tools (BATs),
which provide an objective measure of bleeding symptoms.[3]
[4] Bleeding symptoms are treated with DDAVP (1-desamino-8-D-arginine vasopressin) and
VWF concentrates. In addition, VWD-specific therapy is necessary periprocedurally
to ensure adequate hemostasis.[5]
The management of periprocedural VWD-specific therapy is sometimes problematic in
older patients. The plasma concentration of many coagulation proteins, including VWF,
increases with age. While it has been established that VWF levels increase with age
in a healthy population, emerging research demonstrates this occurs in certain subtypes
of VWD, too. When VWF levels increase over time to normal (i.e., VWF:antigen [Ag]
greater than or equal to 0.50 IU/mL), hematologists are faced with the dilemma whether
or not VWF-specific therapy is indicated at the time of surgery. If VWD patients with
normalized VWF levels are no longer at an increased risk of bleeding then periprocedural
VWD-specific therapy may lead to thrombotic complications, especially given the increased
risk of cardiovascular disease in older patients; thus, should be omitted. In this
article, we will review the current state of the literature regarding this topic to
identify what is known and what research remains to be done to optimize care in this
patient population.
Clinical Vignette
A 67-year-old female presents to clinic for preoperative hematology clearance. She
has a history of DDAVP-responsive type 1 VWD, and she is scheduled to undergo a laparoscopic
sigmoid colectomy for recurrent diverticulitis. She has not been seen in the clinic
for more than 20 years. Her lowest recorded VWF:Ag level and VWF:ristocetin cofactor
(RCo) activity were 0.41 and 0.38 IU/mL, respectively, more than 30 years ago. Her
lifelong bleeding score determined with the condensed molecular and clinical markers
for the diagnosis and management of type 1 (MCMDM-1) BAT is 7 based on a history of
easy bruising, epistaxis, menorrhagia requiring estrogen containing hormonal therapy,
and excessive bleeding following wisdom teeth extraction. She denies any recent bleeding
symptoms in the past several years; however, she is postmenopausal and has not required
any invasive procedures during that time. VWF levels are repeated, and the VWF:Ag
level is 0.95 IU/mL, and the VWF:RCo activity is 0.90 IU/mL. Factor VIII (FVIII) activity
is 1.61 IU/mL. She is not receiving any exogenous estrogen therapy. Other pertinent
medical history includes hypertension, type II diabetes mellitus, obesity, and remote
tobacco abuse. Is VWD-specific therapy necessary perioperatively, and if so, what
are the specific dosing recommendations?
Effect of Age on von Willebrand Factor in the General Population
Effect of Age on von Willebrand Factor in the General Population
The plasma concentration of many coagulation proteins, including fibrinogen, FVII,
FVIII, FIX, and FXII, increases with age. Correspondingly, markers of coagulation
activation, prothrombin fragment 1 + 2, thrombin–antithrombin III complex, and D-dimer,
are elevated.[6] Similarly, VWF levels increase with age. VWF is an acute phase reactant: 35% of
the variability in VWF levels is explained by environmental (cigarette smoke), physiological
(hormonal, exercise, and age), and pathological (inflammation, atherosclerosis, and
liver disease) factors, the incidence of which are increased in older adults.[7] An Italian prospective study compared 74 centenarians and 110 controls (55 less
than 45 years of age), excluding chronic disorders (malignancy, diabetes, cardiovascular,
kidney disease, etc.) and reported VWF:Ag levels were significantly higher among centenarians.
VWF:Ag levels were 0.77, 0.99, and 2.45 among O blood group and 1.15, 1.52, and 2.85
among non-O blood group younger controls (less than 45 years of age), older controls
(45 years of age or older), and centenarians, respectively. Interestingly, using a
laboratory database-established cut-off value of 17%, the proportion of individuals
with a reduction in high molecular weight multimers (HMWM) was 0% in younger controls,
25% in older controls, and 51% in centenarians.[8] HMWMs are the most hemostatically active multimers. A decrease in the proportion
of HMWMs present may counteract any increase in coagulation activity seen with rising
VWF levels. A cross-sectional study of 123 women showed that VWF:Ag levels and VWF:RCo
activity increased by an average of 0.17 and 0.15 IU/mL, respectively, per decade
of life.[9] This is counterintuitive to the expectation that the decline in estrogen in postmenopausal
females is paralleled by a reduction in VWF levels. Recently, a cross-sectional study
of 207 patients showed increasing VWF levels with age is greatly influenced by ABO
blood type.[10] Elderly individuals (age 55–87) with blood type O were observed to have a 1.25-fold
increase in mean VWF:Ag levels, 1.68 ± 0.62 versus 0.98 ± 0.32 IU/mL, p < 0.001, compared with young individuals (age 1–17). Whereas, elderly individuals
with blood type non-O demonstrated a 1.71-fold increase in mean VWF:Ag levels, 0.85 ± 0.25
versus 1.11 ± 0.38 IU/mL, p = 0.002, compared with young individuals. This suggests ABO, and possibly other non-VWF
loci, contribute to age-related changes in VWF levels. Finally, when interpreting
the results of studies investigating changes in VWF levels, it is important to keep
in mind that VWF assays may not be completely reliable and have demonstrated an interlaboratory
coefficient of variation as high as 30%.[11]
Effect of Age on von Willebrand Factor in von Willebrand Disease
Effect of Age on von Willebrand Factor in von Willebrand Disease
While it has been established that VWF levels increase with age in a healthy population,
emerging research demonstrates this occurs in VWD, too, and has been described in
several observational studies ([Table 1]). A Canadian retrospective cohort study of 31 patients with type 1 VWD (historical
VWF:Ag level and/or VWF:RCo activity less than 0.50 IU/mL) reported VWF:Ag levels
and VWF:RCo activity increased by 0.30 IU/mL (95% confidence interval [CI], 0.21–0.39)
and 0.20 IU/mL (95% CI, 0.13–0.27), respectively, per decade.[12] The average duration of follow-up was 11 years, and during this time, the mean VWF:Ag
level increased from 0.44 to 0.71 IU/mL, p < 0.001, and the mean VWF:RCo activity increased from 0.34 to 0.56 IU/mL, p < 0.001. In all, 58% of the patients had VWF:Ag levels and VWF:RCo activity that
increased into the normal range. A similar retrospective cohort study looked at the
relationship between age and VWF levels in 126 patients with a diagnosis of type 1
VWD (historical VWF:Ag level and/or VWF RCo activity less than 0.30 IU/mL) or “low
VWF” (historical VWF:Ag level and/or VWF:RCo activity 0.30–0.49 IU/mL).[13] VWF:Ag levels and VWF:RCo activity increased 0.024 and 0.014 IU/mL, p < 0.001 each, respectively, per year. The average duration of follow-up was 10.5
years. Normalization of VWF:Ag levels and VWF:RCo activity occurred in 27.8% of patients.
A third retrospective cohort study of 195 patients with type 1 VWD demonstrated a
0.14 ± 0.033 and 0.096 ± 0.02 IU/mL, p < 0.05 each, increase in mean VWF:Ag levels and VWF:RCo activity, respectively, between
the first and last measurements during a 6.6-year median duration of follow-up.[14] In a subgroup analysis of 143 patients with mild disease (VWF:Ag level and VWF:RCo
activity 0.30–0.49 IU/mL) and 52 patients with moderate to severe disease (VWF:Ag
level and VWF:RCo activity less than 0.30 IU/mL), an increase in VWF levels was restricted
to those with mild disease. Among patients with mild disease, 94% experienced normalization
of VWF:Ag levels and VWF:RCo activity at last follow-up compared with only 6% of patients
with moderate to severe disease.
Table 1
Effect of age on von Willebrand factor in von Willebrand disease
|
Study type
|
Author
|
Patient population
|
Results
|
|
Retrospective cohort study
|
Rydz et al
Canada
|
31 patients with type 1 VWD (historical VWF:Ag level and/or VWF:RCo activity less
than 0.50 IU/mL)
Mean age at last observation 46 years (range 30–74 y)
|
VWF:Ag levels increased 0.30 IU/mL (95% CI, 0.21–0.39) per decade
Mean VWF:Ag level increased from 0.44 to 0.71 IU/mL, p < 0.001, over an average duration of follow-up of 11 years
VWF:Ag levels increased into the normal range in 58% of patients
|
|
Abou-Ismail et al
United States
|
126 patients with type 1 VWD (historical VWF:Ag level and/or VWF:RCo activity less
than 0.30 IU/mL) or “low VWF” (historical VWF:Ag level and/or VWF:RCo activity 0.30–0.49 IU/mL)
Mean age at last observation 43.5 ± 21.5 years
|
VWF:Ag levels increased 0.024 IU/mL, p < 0.001, per year
VWF:Ag levels normalized in 27.8% of patients during an average duration of follow-up
of 10.5 years
|
|
Borghi et al
Italy
|
143 patients with mild type 1 VWD disease (VWF:Ag level and VWF:RCo activity 0.30–0.49 IU/mL)
and 52 patients with moderate to severe type 1 VWD (VWF:Ag level and VWF:RCo activity
less than 0.30 IU/mL)
Mean age at first observation 28.7 y (range 0.4–74.5 y)
|
VWF:Ag levels increased 0.14 ± 0.033 IU/mL, p < 0.05, between the first and last measurements during a 6.6-year median duration
of follow-up
VWF:Ag levels did not increase in patients with moderate to severe type 1 VWD
VWF:Ag levels normalized in 94% of patients with mild type 1 VWD compared with 6%
of patients with moderate to severe type 1 VWD
|
|
Cross-sectional study
|
Sanders et al
Netherlands
|
664 patients with moderate to severe VWD (historical VWF:Ag level and/or VWF:RCo activity
less than 0.30 IU/mL)
Mean age 71 years (range 65–85) in patients 65 years of age and older and 43 years
(range 16–64) in patients less than 65 years of age
|
VWF:Ag levels were higher among 71 VWD patients 65 years of age and older compared
with 593 VWD patients less than 65 years of age, 0.38 and 0.30 IU/mL, p = 0.033
VWF:Ag levels increased 0.035 IU/mL (95% CI, –0.6 to 7.6) per decade among 40 patients,
age 65 or older, with type 1 VWD
VWF:Ag levels did not increase among 26 patients, age 65 or older, with type 1 VWD
|
|
Flood et al
United States
|
310 patients with a historical diagnosis of type 1 VWD
|
172 of 310 (36%) patients with a historical diagnosis of type 1 VWD had normal VWF:Ag
levels when repeated at enrollment (median VWF:Ag level was 0.76 IU/mL)
|
|
Atiq et al
Netherlands
|
333 patients with type 1 VWD.
Mean age 47 ± 15 years
|
VWF:Ag levels increased 0.03 IU/mL (95% CI, 0.01–0.04) per decade
VWF:Ag levels increased from 0.36 IU/mL (95% CI, 0.23–0.49) in patients without comorbidities
to 0.44 IU/mL (95% CI, 0.29–0.62) in patients with one comorbidity to 0.67 IU/mL (95%
CI, 0.39–0.90) in patients with two comorbidities
|
Abbreviations: CI, confidence interval; VWD, von Willebrand disease; VWF:Ag, von Willebrand
factor:antigen; VWF:RCo, von Willebrand factor:ristocetin cofactor.
In contrast to the previously described retrospective studies, the Willebrand in the
Netherlands (WiN) study was a cross-sectional study of patients with moderate to severe
VWD (historical VWF:Ag level and/or VWF:RCo activity less than 0.30 IU/mL). Sanders
et al reported VWF:Ag level and VWF:RCo activity per decade age increases of 0.035 IU/mL
(95% CI, –0.6 to 7.6) and 0.095 IU/mL (95% CI, 3.7–15.3), respectively, among 40 elderly
patients, age 65 or older, with type 1 VWD.[15] There was no age-related increase in VWF levels among 26 elderly patients with type
2 VWD: VWF:Ag level –1.6 IU/mL (95% CI, –10.3 to 7.2) and VWF:RCo 0.5 IU/mL (95% CI,
–2.8 to 3.7). In the same study, VWF:Ag levels were higher among 71 VWD patients 65
years of age and older compared with 593 VWD patients less than 65 years of age, 0.38
and 0.30 IU/mL, p = 0.033. A similar large multicenter study in the United States, the Zimmerman Program,
enrolled patients with an institutional diagnosis of VWD.[16] VWF levels were repeated at the time of enrollment, and 172 of 310 (36%) patients
with a historical diagnosis of type 1 VWD had normal VWF levels. The median VWF:Ag
level was 0.76 IU/mL, and the median VWF:RCo activity was 0.72 IU/mL.
The above findings indicate that VWF levels increase with age, and this increase may
be restricted to patients with “low VWF” and type 1 VWD; however, the reasons for
both are unclear. One reason for increasing VWF levels with age is the presence of
comorbid illnesses. As mentioned previously, VWF is an acute phase reactant, and 35%
of the variability of VWF levels is related to external factors, such as inflammation
and other related conditions. Atiq et al explored this matter in the WiN study.[17] Among 333 patients with type 1 VWD, hypertension, diabetes mellitus, cancer, and
thyroid dysfunction were found to be associated with increased VWF levels. Further,
as the number of comorbidities increased, so did VWF levels: VWF:Ag levels increased
from 0.36 IU/mL (95% CI, 0.23–0.49) in patients without comorbidities to 0.44 IU/mL
(95% CI, 0.29–0.62) in patients with one comorbidity to 0.67 IU/mL (95% CI, 0.39–0.90)
in patients with two comorbidities. In the study, VWF:Ag levels and VWF:RCo activity
increased 0.03 IU/mL (95% CI, 0.01–0.04) and 0.04 IU/mL (95% CI, 0.02–0.06), respectively,
per decade. Following adjustment for comorbidities, the age-related increase in VWF
levels was no longer observed. Future studies exploring the effect of inflammatory
biomarkers, such as C-reactive protein, on VWF levels in the context of comorbidities
is needed.
The variability in VWF levels with age may be limited to those with type 1 VWD, based
on the presence or absence of a VWF mutation. Pathogenic VWF gene mutations have been
identified in most cases of types 2 and 3 VWD, and several large population studies
have identified VWF mutations in approximately 65% of type 1 VWD cases, which occur
with greater frequency in more severe disease.[1]
[18]
[19] It is proposed that the presence of VWF mutations, and associated defects in VWF
synthesis and processing, prevent age-related increases in VWF levels in severe type
1 and types 2 and 3 VWD. Alternatively, it is surmised that age-related increases
in VWF levels are most commonly experienced in individuals without VWF mutations,
which typically occurs in patients with mild type 1 VWD, or “low VWF” (VWF:Ag level
0.30–0.50 IU/mL), where the decrease in VWF levels is probably explained by the effect
of non-VWF genetic loci on VWF secretion, clearance, and glycosylation. Heritability
accounts for approximately 65% of the variability in VWF levels with 5% of heritability
explained by the VWF gene and non-VWF genetic loci responsible for the remainder,
including the ABO locus, which accounts for 25% of variability in VWF levels, CLEC4M,
STAB2, and STXBP5, among others.[20] Hence, VWF mutations correlate with the severity of disease, and if the presence
of such determines whether or not an age-related increase in VWF levels is experienced,
this may afford hematologists a way to predict which patients with type 1 VWD will
experience an increase in VWF levels with age.
Effect of Age on Bleeding Symptoms in von Willebrand Disease
Effect of Age on Bleeding Symptoms in von Willebrand Disease
Whether or not an age-related increase in VWF levels results in reduced bleeding in
VWD is uncertain. An estrogen-related increase in VWF levels during hormonal therapy
or pregnancy improves bleeding symptoms, and increasing VWF levels with DDAVP prevents
periprocedural bleeding; however, it is hypothesized greater than normal VWF levels
may be necessary for adequate hemostasis with aging, so normalization of VWF levels
may not necessarily result in reduced bleeding.[21] This issue has been explored in a few studies ([Table 2]).
Table 2
Effect of age on bleeding symptoms in von Willebrand disease
|
Study type
|
Author
|
Patient population
|
Results
|
|
Prospective cohort study
|
Tosetto et al
Italy
|
91 index cases (ICs) and 273 affected family members (AFMs) with a historical diagnosis
of type 1 VWD and 295 unaffected family members (UFMs) and 195 controls
Mean age 40 years (range 1–80) in index cases and 32 years (range 2–91) in affected
family members
Mean age 41 years (range 3–90) in unaffected family members and 40 years (range 8–78)
in controls
|
Trend for increasing bleeding score with age in IC and AFM, but not UFM or controls
using the expert administered MCMDM-1 VWD BAT at the time of diagnosis
Strong inverse relationship between bleeding score and VWF levels, p < 0.001
|
|
Cross-sectional study
|
Flood et al
United States
|
310 patients with a historical diagnosis of type 1 VWD
|
No correlation between VWF:Ag levels and bleeding score, although 24% of patients
had a normal bleeding score,
using the expert administered ISTH BAT
|
|
Sanders et al
Netherlands
|
664 patients with moderate to severe VWD (historical VWF:Ag level and/or VWF:RCo activity
less than 0.30 IU/mL)
Mean age 71 years (range 65–85) in patients 65 years of age and older and 43 years
(range 16–64) in patients less than 65 years of age
|
No difference in the median bleeding score among 71 VWD patients 65 years of age and
older (older patients) compared with 593 VWD patients less than 65 years of age (younger
patients), 12 versus 11, p = 0.154, and no difference in the median bleeding score between the two groups according
to VWD subtype, type 1 VWD, p = 0.293, and type 2 VWD, p = 0.238
No difference in reported bleeding symptoms in previous year between older and younger
type 1 VWD patients, 23 vs. 30%, p = 0.271
Reported bleeding symptoms in previous year was greater in older type 2 VWD patients
compared with younger patients, 59 vs. 39%, p = 0.046
|
|
de Wee et al
Netherlands
|
664 patients with moderate to severe VWD (historical VWF:Ag level and/or VWF:RCo activity
less than 0.30 IU/mL)
Median age 44 years (range 16–85) in males and 46 years (range 16–83) in females
|
0.8 increase in bleeding score every 10 years of age using the self-administered condensed
MCMDM-1 VWD BAT
|
|
Atiq et al
Netherlands
|
333 patients with type 1
Mean age 47 ± 15 years
|
Bleeding score 1.9 (95% CI, 0.1–3.8) higher and more frequent bleeding events in the
previous year, 29.2 vs. 18.4%, p = 0.030, among type 1 VWD patients with comorbid illnesses
|
Abbreviations: BAT, bleeding assessment tool; CI, confidence interval; ISTH, International
Society on Thrombosis and Haemostasis; MCMDM-1, molecular and clinical markers for
the diagnosis and management of type 1; VWD, von Willebrand disease; VWF:Ag, von Willebrand
factor:antigen; VWF:RCo, von Willebrand factor:ristocetin cofactor.
The multicenter, prospective MCMDM-1 VWD study in Europe enrolled patients with an
institutional diagnosis of type 1 VWD.[22] There was no specific VWF level identified for inclusion in the study; however,
the median VWF:Ag level and VWF:RCo activity were 0.33 and 0.34 IU/mL, respectively,
in 144 index cases, and 0.36 and 0.35 IU/mL, respectively, in 273 affected family
members. The median VWF:Ag level and VWF:RCo activity were normal in unaffected family
members and controls. The study demonstrated a trend for increasing bleeding score
with age in index cases and affected family members, but not unaffected family members
or controls, using the expert-administered MCMDM-1 VWD BAT at the time of diagnosis.
Also, the study showed the existence of a strong inverse relationship between bleeding
score and VWF levels, p < 0.001. In contrast, in the previously discussed Zimmerman Program, using the expert-administered
International Society on Thrombosis and Haemostasis BAT, Flood et al found no correlation
between VWF:Ag levels and bleeding score in patients with type 1 VWD, although 24%
of patients had a normal bleeding score.[16]
In the previously discussed WiN study, using the MCMDM-1 VWD BAT, Sanders et al found
no difference in the median bleeding score between elderly VWD patients, 65 years
of age and older, and younger VWD patients, less than 65 years of age, 12 versus11,
p = 0.154, respectively.[15] Nor was there any difference in the median bleeding score when the two groups were
compared separately according to VWD subtype, type 1 VWD, p = 0.293, and type 2 VWD, p = 0.238. In addition, at the time of inclusion in the study, patients were asked
to report bleeding symptoms experienced during the previous year that required VWD-specific
treatment. There was no difference in reported bleeding symptoms between older and
younger type 1 VWD patients, 23% versus 30%, p = 0.271. In contrast, older type 2 VWD patients reported more bleeding symptoms than
young patients, 59% versus 39%, p = 0.046. Similar to the general population, gastrointestinal bleeding was more common
in older patients. In the same cohort of patients, using the self-administered condensed
MCMDM-1 VWD BAT, de Wee et al reported a 0.8 increase in bleeding score every 10 years
of age.[23]
[24] Again, from the WiN study, using the condensed MCMDM-1 VWD BAT, Atiq et al reported
a total bleeding score of 1.9 (95% CI, 0.1–3.8) higher and more frequent bleeding
events in the previous year, 29.2% versus 18.4%, p = 0.030, among type 1 VWD patients with comorbid illnesses.[17] These differences were not seen in patients with type 2 VWD.
Based on the above studies, it appears bleeding symptoms are not lessened with age,
and in fact, may worsen; however, certain study-specific limitations, which may affect
the validity of these findings, require further discussion. First, none of the studies
investigated, as their first objective, the effect of age on bleeding symptoms in
patients with type 1 VWD. Second, BAT administration may not have accurately reflected
current bleeding risk due to the cumulative score effect. For example, a patient may
have had a significant number of bleeding symptoms in early adulthood corresponding
to a high bleeding score; however, even if bleeding manifestations lessen, or completely
resolve with age, the bleeding score will remain unchanged. This may prevent a proper
assessment of the patient's current bleeding phenotype. Lastly, comorbidities, such
as liver disease, kidney disease, malignancy, etc., occur with increased incidence
in older adults and affect non-VWD-related bleeding risk; thus, they may serve as
potential confounders. It is not surprising that patients with comorbid illnesses
experienced more frequent bleeding, regardless of VWF:Ag level, in the Atiq et al
study.[16] To counter some of these limitations, our group performed a retrospective cohort
study of 43 patients with an institutional diagnosis of type 1 VWD.[25] No specific VWF level was identified for inclusion in the study. VWF levels and
the condensed MCMDM-1 BAT were performed during routine clinic visits. The bleeding
score was determined as an interim BAT, based on bleeding symptoms present during
the prior 3 years, rather than lifelong. There was no association between VWF levels
and age; however, the mean VWF:Ag level was 0.83 ± 0.37 IU/mL, and the mean VWF:RCo
activity was 0.59 ± 0.34 IU/mL. This may have been confounded by the fact that 34%
of patients were receiving estrogen containing hormonal therapy. The bleeding score
was found to be inversely associated with age. The bleeding score decreased 0.080,
p < 0.01, per year of life. Comorbidities were not assessed.
Clinical Vignette Conclusion
Clinical Vignette Conclusion
Based on the patient's recent lack of bleeding symptoms, current normal VWF levels,
and cardiovascular risk factors, periprocedural VWD-specific therapy was omitted.
The patient underwent an uncomplicated laparoscopic sigmoid colectomy. Postoperative
pharmacologic venous thromboprophylaxis was not recommended. The patient experienced
no bleeding or thrombotic events. The patient was recommended to have VWF levels checked
prior to future invasive procedures to determine the need for VWD-specific therapy
on a case-by-case decision.
Conclusion
Based on the current state of the literature, VWF levels increase with age in patients
with “low VWF” and type 1 VWD, thus may be more likely to occur in patients without
a pathogenic VWF mutation, and may be the consequence of comorbid illnesses. Whether
normalization of VWF levels results in amelioration of bleeding symptoms is uncertain.
In the case we present, it appears at least some patients as they age may tolerate
invasive procedures without VWD-specific therapy. Whether with age, a new “supernormal”
VWF level is necessary for hemostasis, and if so, what the value is, remains unclear.
The current findings are conflicting, possibly due to study-specific differences,
patient-specific characteristics, primary study objectives, method of BAT administration,
and confounding due to comorbid illnesses.
Determining whether or not bleeding risk is reduced in aging type 1 VWD patients is
essential to providing hematologists the knowledge needed to deliver appropriate medical
care to affected patients. Aging patients commonly undergo invasive procedures. If
older type 1 VWD patients have experienced normalization of VWF levels, and no longer
have an increased risk of bleeding, administration of VWD-specific therapy may be
harmful, especially among patients with underlying cardiovascular disease or related
risk factors, and unnecessarily costly. For these reasons, further investigation into
the effect of age on VWF levels and bleeding risk in VWD patients is sorely needed.
Ideally, large, multicenter cross-sectional or prospective observational studies of
type 1 VWD patients measuring current bleeding symptoms while accounting for non-VWD-related
bleeding risks are desired, and our institution will be leading a multicenter, cross-sectional
study to begin this task.
