Willebrand Starsi
Willebrand Starsi
Willebrand Starsi
Abstract:
Von Willebrand disease (VWD) is the most common bleeding disorders and especially milder type 1 VWD
might not be cared for in specialty clinics. Von Willebrand factor (VWF) levels rise with age, but
the rise of these levels do not necessarily correlate with bleeding risk. A recent bleeding history
combined with recent labs are important for hemostatic management decision during surgical
interventions. Antifibrinolytics appear safe in the elderly population, while DDAVP should be used
cautiously. Where needed, factor concentrates present a great treatment option.
Acquired von Willebrand syndrome (AVWS) is vastly underrecognized, but likely to surface in the
aging, especially in the setting of co-morbidities such as plasma cell dyscrasias. IVIG can be an
effective treatment in this scenario, but potentially increases thrombotic risk.
COI notes: JNP is a paid consultant for TeraImmune RKJ has been a paid consultant for Biomarin,
Pfizer and Genentech/Roche, has been an educational speaker for Genentech/Roche and Takeda and is
receiving research funding from Genentech.
Author contributions and disclosures: J.P and R.K-J co-wrote this publication
Affiliations:
1. Division of Hematology/Oncology, Department of Medicine, Larner College of Medicine at the
University of Vermont, Burlington, VT
2. Division of Clinical Pathology, Department of Medicine, Larner College of Medicine at the
University of Vermont, Burlington, VT
3. Washington Center for Bleeding Disorders, Seattle, WA
4. Division of Hematology, Department of Medicine, University of Washington, Seattle, WA
Corresponding Author:
Rebecca Kruse-Jarres, MD, MPH
701 Pike Str., Ste 1900
Seattle, WA 98101
rkj@wacbd.org
Conflicts of Interest:
Von Willebrand disease (VWD) is the most common bleeding disorders and especially milder
type 1 VWD might not be cared for in specialty clinics. Von Willebrand factor (VWF) levels rise
with age, but the rise of these levels do not necessarily correlate with bleeding risk. A recent
bleeding history combined with recent labs are important for hemostatic management decision
during surgical interventions. Antifibrinolytics appear safe in the elderly population, while
DDAVP should be used cautiously. Where needed, factor concentrates present a great
treatment option.
Acquired von Willebrand syndrome (AVWS) is vastly underrecognized, but likely to surface in
the aging, especially in the setting of co-morbidities such as plasma cell dyscrasias. IVIG can be
an effective treatment in this scenario, but potentially increases thrombotic risk.
I. Introduction
Managing inherited and acquired bleeding disorders in older patients (age > 65 years) requires
a holistic approach that incorporates each patient’s underlying comorbidities and risk factors
for treatment related complications. Von Willebrand disease (VWD) is the most prevalent
inherited bleeding disorder (0.8-1%)(1, 2) and most patients with milder disease are likely not
receiving care in specialty bleeding disorder center.(3) Acquired von Willebrand syndrome
(AVWS) is associated with lympho- or myeloproliferative disorders, solid tumors, autoimmune
disorders and conditions altering cardiac circulation. It is likely underreported and recognized
increasingly with advancing age of the patient. (4) Herein, we highlight things to consider when
caring for an older patient with a congenital or acquired von Willebrand disorder.
A 77-year-old woman with type 1 VWD, hypertension and osteoarthritis presents for
preoperative recommendations for a hip replacement. She was diagnosed with type 1 VWD in
her early twenties when her von Willebrand factor (VWF) antigen (VWF:Ag) was 27 IU/dL and
her VWF ristocetin cofactor activity (VWF:RCo) was 29 IU/dL. She has a remote history of
bleeding consistent with type 1 VWD including epistaxis in childhood that was successfully
treated with cauterization and desmopressin (DDAVP), as well as heavy menstrual bleeding that
improved after starting combined oral contraception. In the last several years, she has not had
atypical bleeding such as prolonged epistaxis or easy bruising. She underwent laparoscopic
cholecystectomy 5 years ago without hemostatic prophylaxis and had no abnormal bleeding.
Her last documented VWF levels were when she was 42 years old with a VWF:Ag of 42 IU/dL
and VWF:RCo of 44 IU/dL.
The rise in VWF levels with aging may be related to an increase in inflammation and underlying
comorbidities as VWF is an acute phase reactant; in the WiN study of 333 patients with type 1
VWD, the association between aging and rising VWF was not present after adjusting for
comorbidities.(11) It is also possible that the underlying mutation driving VWD impacts whether
VWF levels are responsive to age and inflammation as VWF levels appear to be minimally
impacted by aging in forms of type 2 VWD. (12)
Desmopressin (DDAVP)
DDAVP increases endogenous VWF levels transiently and can result in hyponatremia and
tachyphylaxis with ongoing use regardless of the age of the patient. Due to these limitations,
alternative hemostatic agents such as VWF factor products are favored following procedures
that require higher VWF levels for hemostatic control beyond the initial perioperative period
(>24-48 hours). This is particularly important in patients that require longer healing times due
to advanced age and/or underlying comorbidities.
In general, the use of DDAVP is not favored in older patients with VWD or mild hemophilia A
because of a theoretical increased risk for adverse events. Careful consideration must be given
to the patient’s comorbidities and sensitivity to fluid shifts and risk for seizure. Theoretically,
DDAVP may increase the risk of thrombosis in older patients especially in the setting of a rising
FVIII levels, however there is minimal data available to support this theoretical concern. Case
reports have documented arterial thrombotic events following DDAVP infusion, but these
events occurred in patients with strong underlying risk factors. (13-15) DDAVP has not been
shown to increase the risk of venous or arterial thrombosis in populations without bleeding
disorders at high risks for thrombotic events such as in the perioperative setting, as well as
following intracranial hemorrhage while on antiplatelet therapy(16) or with concurrent alcohol
abuse(17). Until more data is available in older patients with bleeding disorders, DDAVP should
be used cautiously particularly in the setting of elevated baseline FVIII levels, underlying cardiac
risk factors, or sensitive to fluid shifts.
Antifibrinolytics
Although there are limited data on the use of antifibrinolytics in older patients with bleeding
disorders, there are significant safety data showing no increased risk of thrombosis in older
patients without bleeding disorders including in the setting of traumatic injuries(18),
orthopedic(19-21) and cardiac surgeries(22). A meta-analysis of over 40,000 non-surgical
patients showed no increased risk of thrombosis, including stroke, myocardial infarction,
pulmonary embolism and deep vein thrombosis with tranexamic acid.(23) Notably, patients
without bleeding disorders typically receive antifibrinolytics for shorter durations, but a recent
trial of patients with hematologic malignancies did not show an increased risk of thrombosis
after an average of two weeks of tranexamic acid.(24) Given the available extensive and
reassuring safety data that included older populations, antifibrinolytics are an excellent option
for older patients with bleeding disorders.
The 2021 combined guidelines on VWD from ISTH, ASH and WFH suggest “reconsidering” rather
than removing a diagnosis of type 1 VWD when VWF levels rise with age, especially since the
correlation between rising VWF levels and risk of bleeding has not been established.(26) In the
absence of bleeding symptoms the decision to reconsider or remove the diagnosis of VWD for
this patient should be considered and should be one of shared decision-making as per the 2021
ISTH, ASH and WFH combined guidelines.
II. Case Two: Thrombotic event following intravenous immunoglobulin (IVIG) for acquired von
Willebrand syndrome (AVWS)
A 72-year-old man with obesity and AL amyloidosis complicated by cardiomyopathy and chronic
renal insufficiency on maintenance daratumumab presented with hematochezia after
undergoing biopsies during a colonoscopy. He denied any abnormal bleeding earlier in life but
had noticed increased bruising over the last year. Coagulation testing revealed a prolonged
activated partial thromboplastin time (aPTT) of 50s (reference range 26-37s) with a normal
prothrombin time (PT) and fibrinogen. Subsequent testing showed normal coagulation factors
except for a FVIII of 13 IU/dL, VWF:Ag of 10 IU/dL and a VWF:RCo below the limit of detection.
A pharmacokinetic study receiving a 100% corrective dose of a plasma derived VWF:FVIII
concentrate showed initial increase of VWF:Ag and RCo, but a significantly decreased half-life
(Figure 1) and he was diagnosed with acquired von Willebrand syndrome (AVWS).
The patient received 500 mg/kg of intravenous immunoglobulin (IVIG) with subsequent
normalization of his VWF:Ag, VWF:RCo and FVIII (Figure 2). Repeat colonoscopy showed
bleeding at the site of prior biopsies, which resolved after receiving IVIG. The patient was
discharged and continued to require IVIG once per month.. In retrospect, the patient had
increased bruising and an elevated aPTT for at least two years prior to diagnosis of AVWS.
Our patient presented with gastrointestinal bleeding, which may be more common in cases of
AVWS secondary to plasma cell dyscrasias based on an international registry(28) of patients
with AVWS from multiple causes including from mechanical destruction of VWF with loss of
high molecular weight multimers and altered clearance in the setting of aortic valve stenosis,
mitral valve regurgitation, and left ventricular assist devices.(4) In some cases, AVWS will
resolve with treatment of the underlying disease such as following valve replacement.(29, 30)
In patients with underlying plasma cell dyscrasias, autoantibodies increase clearance of VWF
and can persist despite adequate treatment of the plasma cell dyscrasia. VWF containing
concentrates and DDAVP are only transiently effective (return to baseline within 4 hours), but
intravenous immunoglobulin (IVIG) can lead to more sustained VWF levels (peak at 4 days and
return to baseline in 21 days) in AVWS from plasma cell dyscrasias. (31) This seems to be more
reliable in AVWS related to IgG monoclonal gammopathy of unknown significance (MGUS) over
IgM MGUS, where responses to IVIG have been varied.(31, 32) IVIG can be given 3-4 days prior
to surgery (suggested dose of 1 g/kg/day for 2 days) or can be given every 3 weeks (suggested
dose 1g/kg) to sustain chronic higher VWF levels to prevent bleeding. In our experience, doses
and dose intervals can be titrated to response. Thalidomide (33) and
lenalidomide/dexamethasone (34) have been used successfully to treat gastrointestinal
bleeding in AVWS. Rituximab has been used with inconsistent response. (35, 36)
Approximately one year after diagnosis of AVWS, his IVIG dose was increased to 1.5 g/kg in an
attempt to increase his nadir VWF:RCo. Shortly thereafter, he represented with a sub-massive
pulmonary embolism (acute onset dyspnea and chest pain) two days after receiving IVIG. His
FVIII was 314 IU/dL four days prior to the thrombotic event. The patient also reported
decreased mobility over the prior year related to chronic knee and back osteoarthritis. He was
started on a heparin drip and bridged to warfarin with a goal INR of 2-3. Warfarin was selected
given the patient’s renal insufficiency and risk of acute bleeding if his VWF:RCo were to decline
while on anticoagulation. His IVIG dose was switched to twice per month instead of monthly
and was reduced to 0.2 g/kg to maintain lowest (nadir) VWF:RCo at or above 30 IU/dL while
avoiding "overshooting" FVIII above 200 IU/dL after redosing IVIG.
III. Case Three: Managing antiplatelet therapy in a patient with type 1 VWD and coronary
artery disease
An 82-year-old man with type 1 VWD, hyperlipidemia, tobacco use and insulin dependent
diabetes mellitus presented with acute onset chest pain with an elevated troponin and
electrocardiogram changes consistent with an acute ST elevation myocardial infarction. At
baseline, the patient experienced easy bruising, intermittent epistaxis and bleeding following
surgery and trauma. His most recent VWF:RCo was 32 IU/dL, VWF:Ag 30 IU/dL and FVIII of 65
IU/dL. Prior to undergoing left heart catheterization, the patient received a VWF factor product
to achieve VWF:RCo >50 IU/dL. Catheterization revealed a left anterior descending (LAD)
infarction requiring angioplasty and stent placement. The cardiologist asks whether the patient
may receive dual antiplatelet therapy for one year.
Treatment of elderly patients with acquired or congenital von Willebrand disorders should be
tailored to each individual and incorporate the patient’s comorbidities and treatment
preferences. Some risk factors for adverse events from hemostatic therapies increase with age,
such as the risk of thrombosis due to rising clotting factors. Other side effects may also be more
common with advanced age, such as the risk of seizures and inability to tolerate fluid shifts with
DDAVP for older patients with mild hemophilia A, VWD, or AVWS. Acquired bleeding disorders
should also be considered for older patients present with new bleeding and/or coagulation
abnormalities.
Table 1: Changes in Coagulation Factors with Age
Clotting Factor Changes with Aging
Fibrinogen Increases(46, 47)
Thrombin Unaffected
FV Increases(48)
FX Unaffected
FVII Increases(46, 48)
FVIII Increases(46)
FIX Increases(48)
FXI Increases(48)
FXII Depends on the reference (unaffected vs increases)
FXIII Increases(49)
VWF VWF Ag increases with age, especially in those that are blood type Non-O(5, 6, 50)
Protein C Protein C Ag increases with aging (~4% by decade); in women this is primarily seen
after menopause(51)
Protein S Increases with age; lower and more variable increase in women due to increased
total protein S but no change in free protein S (increase in C4b-BP levels with
normal aging); may be impacted by serum lipids (higher protein S a/w higher
cholesterol and triglyceride levels)(52, 53)
PAI-1 Increases (especially in association with myocardial infarction, obesity and insulin
resistance, atherosclerosis, malignancy, inflammation and psychological stress)(54)
D Dimer Increases (especially in association with comorbidities such as infection, heart
disease and malignancy)(55)
Platelet count Decreased (more pronounced in males)(56)
Platelet Increases(57)
Activation
Bleeding time Shortens(57)
Table 2: VWF Products licenses to treat VWD in the U.S.
Product Indication Dosage (adults)* Approximate Reference
VWF:RCo:
FVIII ratio in
vial
Plasma derived
Alphanate Surgical and/or invasive Pre-operative 1.2:1 (58, 59)
procedures in adult and dose of 60 IU
pediatric patients with VWF:RCo/kg body
von Willebrand Disease weight;
in whom desmopressin subsequent doses
(DDAVP) is either of 40-60 IU
ineffective or VWF:RCo/kg body
contraindicated. It is not weight.
indicated for patients
with severe VWD (Type
3) undergoing major
surgery
Humate P (1)Treatment of (Target peak 2.4:1 (60, 61)
spontaneous and plasma VWF:RCo
trauma-induced bleeding level – baseline
episodes, and (2) plasma VWF:RCo
Prevention of excessive level)/in vivo
bleeding during and after recovery in patient
surgery. This applies to x body weight
patients with severe (BW) in kg
VWD as well as patients
with mild to moderate
VWD where the use of
desmopressin is known
or suspected to be
inadequate
Wilate (1) On-demand Required IU = 1:1 (62)
treatment and control of body weight (BW)
bleeding episodes, (2) in kg x desired
Perioperative VWF:RCo rise (%)
management of bleeding (IU/dL) x 0.5 (IU/kg
per IU/dL)
Recombinant
Vonvendi (1)On-demand treatment Give 12 to 24 n/a (63)
and control of bleeding hours prior to
episodes. (1) surgery
(2)Perioperative to allow the
management of endogenous factor
bleeding. (1) VIII levels to
(3)Routine prophylaxis to increase to at least
reduce the frequency of 30 IU/dL (minor
bleeding episodes surgery)or 60
in patients with severe IU/dL (major
Type 3 von Willebrand surgery)
disease receiving
on-demand therapy
*Plasma derived VWF/FVIII concentrates can be dosed based on the FVIII or VWF in the vial and
it is important to specify that the dosing is given based on the VWF:RCo units in the vial.
Table 3: Acquired Factor Deficiencies Associated with Bleeding
Prolonged
Normal aPTT
Prolonged aPTT & PT Prolonged aPTT, nl PT PT,
& PT*
nl aPTT
Deficiency Fibrinogen FII FV(64) FX(65) FVIII FIX FXI FVII FXIII(66-68)
Pre- - DIC - Liver - Inhibitor - Amyloidosis - Inhibitor - Inhibitor - Inhibitor - Liver - Inhibitor
disposing - Liver disease disease - Topical - Liver - DIC - DIC - DIC disease - Liver disease
factors - Trauma - Sepsis bovine disease - AVWS - Liver - Liver - Sepsis - Post op
- MGUS, MM(69) - Vitamin K thrombin - Vitamin K with disease disease - Vitamin K - Cardiovascular
- Asparaginase(70) deficiency - Antibiotics deficiency reduced - Vitamin K deficiency bypass
FVIII deficiency - Vitamin K - Inflammatory
antagonist bowel disease
50
40
30
IU/DL
20
10
0
PRE 30 MIN 1 HOUR 4 HOURS
POST POST POST
FIGURE 2: RESPONSE TO IVIG
(500 MG/KG)
VWF:RCo VWF:Ag FVIII
60
50
40
30
IU/DL
20
10
0
PRE DAY 1 DAY 3 DAY 7
Figure 3: Receiving IVIG 1 gm/kg
250
200
150
100
50
0
3/12/2019 4/12/2019 5/12/2019 6/12/2019 7/12/2019 8/12/2019 9/12/2019 10/12/2019 11/12/2019
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