The Diagnosis, Evaluation and Management of von
Willebrand Disease
Management of VWD
Introduction
Therapies to prevent or control bleeding in persons
who have VWD follow three general strategies. The first strategy is to increase
plasma concentration of VWF by releasing endogenous VWF stores through
stimulation of endothelial cells with DDAVP. The second approach is to replace
VWF by using human plasma-derived, viral-inactivated concentrates. The third
strategy employs agents that promote hemostasis and wound healing but do not
substantially alter the plasma concentration of VWF. The three treatment
options are not mutually exclusive, and patients may receive any one or all
three classes of agents at the same time. The appropriateness of therapeutic
choice is dependent on the type and severity of VWD, the severity of the
hemostatic challenge, and the nature of the actual or potential bleeding.
Because some persons who have VWF:RCo >30 IU/dL manifest clinical bleeding,
persons not having a definite diagnosis of VWD but who have low VWF and a
bleeding phenotype may merit treatment or prophylaxis of bleeding in certain
clinical situations.196 Infusions
of VWF to prevent bleeding episodesknown as prophylaxisare less
frequently required in patients who have severe VWD in contrast to patients who
have severe hemophilia. The CDC Universal Data Collection Project Web site (http://www2a.cdc.gov/ncbddd/htcweb/)
reports that 45 percent of patients who have severe hemophilia A use some type
of prophylaxis, either continuous or intermittent, compared with 10 percent of
patients who have severe VWD. Risks and benefits of prophylaxis should be
carefully weighed when considering long-term therapy for VWD.211,212 Treatment of VWD in the United
States varies widely and frequently is based on local experience and physician
preference. Few standard recommendations exist to guide therapy for VWD.6,7,9 This
guidelines document presents recommendations regarding the management and
prevention of bleeding in persons who have VWD and reviews the strength of
evidence supporting those recommendations.
Therapies To Elevate VWF: Nonreplacement Therapy
DDAVP (Desmopressin: 1-desamino-8-D-arginine
vasopressin)
Mechanism of action of DDAVP. DDAVP is a
synthetic derivative of the antidiuretic hormone, vasopressin. DDAVP has been
used to treat VWD for 25 years, and its pharmacology, mechanism of action, and
indications have been reviewed extensively.213215 DDAVP stimulates the release
of VWF from endothelial cells through its agonist effect on vasopressin V2
receptors.213,214,216 The mechanism by which DDAVP
increases plasma concentration of VWF is probably through cyclic AMP-mediated
release of VWF from endothelial cell Weibel-Palade bodies.216,217 FVIII levels also increase
acutely after administration of DDAVP, although the FVIII storage compartment
and the mechanism of release by DDAVP have not been fully elucidated to
date.11,218 DDAVP induces the release of tissue
plasminogen activator (tPA).219,220 However, the secreted tPA is
rapidly inactivated by plasminogen activator inhibitor (PAI-1) and does not
appear to promote fibrinolysis or bleeding after DDAVP treatment.
DDAVP dosing and administration. Table 11
displays published reports of DDAVP effects on laboratory assays of VWF and
FVIII in normal persons and persons who have various subtypes of VWD.64,92,99,221232 When administered
intravenously to normal persons as well as to patients who have VWD or mild
hemophilia, DDAVP consistently increases plasma VWF and FVIII from twofold to
greater than fivefold over baseline levels.92,218,223,225227,230,231 Children under the age of 2 have
a significantly lower response rate than older children.230 Two controlled prospective studies in
healthy volunteers form the basis for DDAVP dosing recommendations.225,227 Maximal FVIII response was determined
at 0.3 micrograms/kilogram in both studies, while maximal VWF release data were
determined at 0.2 and 0.3 micrograms/ kilogram in the two studies,
respectively. Based on these data, standard dosing of DDAVP is 0.3
microgram/kilogram given intravenously in 3050 mL of normal saline over
30 minutes, with peak increments of FVIII and VWF 30 to 90 minutes
postinfusion.218,223,225,233 Nasal administration of high-dose
desmopressin acetate (Stimate®) is often effective for minor
bleeding, but intravenous administration is the preferred route for surgical
bleeding prophylaxis and for treatment of major hemorrhage.
A retrospective review of DDAVP administration to 56
children who had nonsevere type 1 VWD found a 91 percent response rate, defined
as FVIII and VWF activity increase of twofold, to at least 30 IU/dL.230 In a small case series of VWD
patients, the consistency of FVIII increases and the response of the bleeding
time after a second test dose of DDAVP was within 1020 percent of the
initial value.231 Evidence shows
that response to DDAVP diminishes with repeated doses, probably due to
depletion of the VWF storage compartment.218,227 However, when DDAVP was given in four
daily doses to 15 patients who had type 1 VWD, an increase in FVIII activity of
at least twofold was found in 100 percent of the patients after the first
administration, in 80 percent after the second, in 87 percent after the third,
and in 74 percent after the fourth administration.226
Consistency of response to DDAVP has been studied
using 24-hourly dosing for three to four daily doses.226,227 A series of 15 type 1 VWD
patients showed a mean rise of VWF:RCo to fivefold above baseline following the
first dose of DDAVP, significantly decreased response to fourfold following the
second daily dose, and no significant change in response among the second to
fourth doses.226 The proportion
of VWD patients attaining at least a twofold rise in FVIII activity following
the second to fourth daily doses80 percent following the second daily
dose of DDAVP to 74 percent following the fourth dosewas substantially
higher than that for hemophilia A patients (55 to 37 percent). There is no
published evidence regarding response to DDAVP given every 12 hours to compare
with daily dosing of DDAVP. In addition to tachyphylaxis, hyponatremia may
complicate repeated DDAVP dosing, and fluid restriction as well as serum sodium
monitoring are recommended.
DDAVP can also be administered subcutaneously or
intranasally.225,227,233 The effective subcutaneous dose is
identical to intravenous dose, but the subcutaneous preparation is not
available in the United States. The preparation of DDAVP for nasal instillation
(Stimate®) contains 150 micrograms per metered nasal puff (0.1
mL of a 1.5 mg/mL solution). The dose is one puff for persons who weigh <50
kg and two puffs (one to each nostril) for persons weighing 50 kg or more.
Although the intra- and intersubject coefficient of variation for
reproducibility of nasal spray effect is good, nasal absorption is variable,
and all patients who have VWD and are responsive to intravenous DDAVP should
undergo a trial of Stimate® to measure FVIII and VWF response
before using it.225 When used for
epistaxis, Stimate® ideally is delivered into the nonbleeding
nostril. Persons who have inadequate plasma responses to intravenous DDAVP will
not respond to Stimate®.
There is also a nasal formulation of DDAVP (for
enuresis) that contains 10 micrograms per puff (about 7 percent of the
Stimate® concentration); however, this preparation is not
suitable for treatment of VWD. Patients and parents must be carefully
instructed regarding the two concentrations of nasal DDAVPthe one used
for bleeding (1.5 mg/mL), and the one used for antidiuretic hormone replacement
(diabetes insipidus) and bedwetting (0.1 mg/mL)to avoid accidental
underdosing for VWD.
Monitoring of VWD patients receiving DDAVP.
Treatment of patients who have VWD with DDAVP should be based on results of a
therapeutic trial, ideally one performed in a nonbleeding state and before
clinical use.
Although the pattern of DDAVP responsiveness is fairly
consistent within VWF subtypes, population results should not be used to plan
treatment of individual patients (see Table 11). VWF:RCo and FVIII activities
should be measured in all VWD patients at baseline and within 1 hour after
administering DDAVP. Additional assay of VWF:RCo and FVIII, 24 hours
after DDAVP, will evaluate for shortened survival and should be considered for
patients who have a history of poor response to treatment.41
According to conservative definitions of laboratory
response, the majority of patients who have type 1 VWD respond adequately to
DDAVP (Table 11). Single infusions of DDAVP for common bleeding
episodessuch as epistaxis, simple dental extraction, or
menorrhagiado not usually require laboratory monitoring. Patients should
be monitored for VWF:RCo activity as well as FVIII activity around major
surgeries or major bleeding events. For major surgeries or bleeding events,
patients who have VWD should be referred to hospitals with in-house or daily
laboratory availability of FVIII and VWF:RCo activity assays. Care should be
taken to monitor serum electrolytes, especially after surgery or multiple doses
of DDAVP. Adult patients, especially those who are elderly, should be evaluated
for CVD before using DDAVP because myocardial infarction rarely has been
precipitated by DDAVP therapy in patients who have hemophilia or uremia.234236
Table 11. Intravenous DDAVP Effect on Plasma
Concentrations of FVIII and VWF in Normal Persons and Persons Who Have VWD
Group/reference |
N |
Mean increase (fold)* |
Type of
evidence |
VWF:RCo |
VWF:Ag |
FVIII |
Normals |
|
|
|
|
|
Mannucci et al. 1981227 |
10 |
N/A |
3.3 |
4.5 |
Case series |
Lethagen et al. 1987225 |
10 |
N/A |
2.7 |
3.7 |
Case series |
VWD |
|
|
|
|
|
Type 1 |
|
|
|
|
|
Mannucci et al. 1981227 |
15 |
N/A |
3.6 |
5.5 |
Case series |
de la Fuente et al. 1985223 |
13 |
5.0 |
4.5 |
5.7 |
Case series |
Mannucci et al. 198892 |
7 |
9.5 |
9.0 |
10.3 |
Case series |
Rodeghiero et al. 1989231 |
14 |
N/A |
N/A |
7.8 |
Case series |
Mannucci et al. 1992226 |
15 |
5.1 |
4.8 |
4.3 |
Case series |
Revel-Vilk et al. 2003230 91% response rate† |
56 |
|
|
|
Retrospective
review |
Federici et al. 2004224 27% response rate† |
26 |
3.1 |
N/A |
3.3 |
Case series |
Type 1 Vicenza (ultra-large multimers) |
|
|
|
|
|
Mannucci et al.198892 |
6 |
9.1 |
8.3 |
10.2 |
Case series |
Rodeghiero et al. 1989231
|
5 |
N/A |
N/A |
10 |
Case series |
Type 1, Severe |
|
|
|
|
|
(VWF:RCo <10 IU/dL OR Bleeding Time >15 min OR FVIII <20 IU/dL) |
|
|
|
|
|
Revel-Vilk et al. 2003230 36% response rate† |
14 |
N/A |
N/A |
N/A |
Retrospective
review |
Federici et al. 2004224 27% response rate† |
26 |
3.1 |
N/A |
1.4 |
Case series |
Type 1, Severe with normal platelet VWF |
|
|
|
|
|
Rodeghiero et al. 1988232 |
14 |
N/A |
N/A |
7.8 |
Case series |
Mannucci et al. 198599 6/6 with increase in FVIII, VWF:RCo
and VWF:Ag |
6 |
N/A |
N/A |
N/A |
Case series |
Type 1, "Platelet low" |
|
|
|
|
|
Mannucci et al. 198599 7/7 with increase in FVIII; 0/7
with increase in VWF:RCo or VWF:Ag |
7 |
N/A |
N/A |
N/A |
Case series |
Rodeghiero et al. 1989231 2/2 with increase in FVIII; VWF
response not reported |
2 |
N/A |
N/A |
2.1 |
Case series |
Type 2A |
|
|
|
|
|
de la Fuente et al. 1985223 86% response rate† |
7 |
6.4 |
4.9 |
4.9 |
Case series |
Revel-Vilk et al. 2003230 40% response rate, results given
for responders only |
5 |
4.2 |
N/A |
2.9 |
Retrospective
review |
Federici et al. 2004224 7% response rate† |
15 |
2.6 |
N/A |
3.4 |
Case series |
Type 2B |
|
|
|
|
|
Casonato et al. 199064 |
4 |
2.3 |
3.5 |
3.0 |
Case series |
McKeown et al. 1996229 |
3 |
3.2 |
3.2 |
3.6 |
Case series |
Castaman and Rodeghiero 1996222 |
33 |
Normalized in 18/33 |
Normalized in 33/33 |
Normalized in 33/33 |
|
Type 2M |
|
|
|
|
|
Federici et al. 2004224 14% response rate† |
21 |
3.3 |
N/A |
3.0 |
Case series |
Type 2N |
|
|
|
|
|
Mazurier et al. 1994228 |
8 |
1.4 |
2.2 |
9.7 |
Case series |
Federici et al. 2004224 75% response rate† |
4 |
3.8 |
N/A |
6.6 |
Case series |
Type 3 |
|
|
|
|
|
Castaman et al. 1995221 0% response rate† |
6 |
1.8 |
8.6 |
2.5 |
Case series |
* Data are given as mean fold increase in plasma
factor compared to baseline after a single administration of DDAVP. Mean fold
increases were calculated from original data, where possible, if not included
in the manuscript. † Response defined as twofold increase AND to at
least 30 IU/dL VWF:RCo and FVIII. FVIII, factor VIII (8); N/A, not
available; VWF:Ag, VWF antigen; VWF:RCo, von Willebrand factor (VWF) ristocetin
cofactor.
Pharmacokinetics of VWF and FVIII after
DDAVP. After stimulation with DDAVP, released VWF and FVIII circulate with
an apparent half-life characteristic of the patient's own proteins, or
approximately 810 hours for both proteins in normal individuals.218 Type 2 VWF proteins that are released
by DDAVP will increase in concentration but retain their intrinsic molecular
dysfunction.237 For this reason,
DDAVP has been efficacious in only a minority of patients who have types 2A or
2M VWD. Therefore, monitoring is necessary to document adequate correction of
VWF:RCo. Type 2N VWF lacks FVIII stabilization; consequently, patients who have
2N VWF will release FVIII and the abnormal VWF protein as expected, but the
survival of released FVIII may be severely decreased, with an apparent plasma
half-life as low as 2 hours, depending on the mutation.168,228 Emerging information suggests that
some individuals who have type 1 VWD have accelerated plasma clearance of VWF
and may benefit from trial testing of VWF:RCo 24 hours after a dose of
DDAVP.40,238
Following infusion of DDAVP into patients with type 2B
VWD, VWF multimers of larger but still somewhat less than normal molecular
weight can be detected in plasma after 15 to 30 minutes, with persistence
throughout 4 hours of study.63,168,237,239 Although formal pharmacokinetic
studies have not been reported for type 2B VWD, VWF:RCo activity increases were
less than that seen in type 1 VWD with an apparent half-life of approximately 4
hours.63,229 Bleeding time response to DDAVP in
type 2B VWD is inconsistent.222,229
Clinical response to DDAVP in VWD. The
clinical effectiveness of DDAVP to prevent or control bleeding depends, in
large part, on the plasma VWF:RCo or FVIII activity achieved after drug
administration, which in turn depends primarily on the basal levels of plasma
FVIII and VWF:RCo and to a lesser extent on the underlying qualitative VWF
defect.64,92,99,221232 Table 12 and
Evidence Tables 712 summarize
published data on clinical response when using DDAVP in conjunction with common
surgical procedures.136,218,221223,230,232,240250 All data were derived from
retrospective studies and small case series; there are no randomized clinical
trials of the use of DDAVP in persons who have VWD.
Whether DDAVP will be adequate for prophylaxis around
surgery or for treatment of bleeding events in persons who have type 1 VWD is
dependent on the severity of the hemostatic challenge and the time required for
healing. Major surgery requires hemostasis for 714 days,247,251256 whereas minor surgeries can
be treated adequately in 15 days.243,244,247,256 If treatment is necessary for more
than 3 days, VWF concentrate is usually given to supplement therapy with
DDAVP.244,247 Currently, however, expert opinions
are divided regarding the risk of delayed hemorrhage 510 days after a
bleeding challenge in VWD patients, e.g., those who have had tonsillectomy or
given birth. In small case series, persons who have type 1 VWD Vicenza manifest
an exaggerated response to DDAVP.41,92,231
Individuals who have type 2N VWD exhibit a brisk rise in plasma FVIII after
receiving DDAVP, but they have a mean FVIII half-life of only 3 hours because
of deficient FVIII stabilization by the defective VWF.228 Persons who have low platelet VWF or
type 2A VWD have a low likelihood of having a clinically relevant DDAVP
response, but they may warrant a DDAVP trial.224,231 Type 2B VWD previously was a
contraindication to DDAVP therapy because platelet counts usually fell after
DDAVP stimulation.257 However,
thrombocytopenia after DDAVP in type 2B VWD is usually transient and often is
not associated with bleeding or thrombosis.258 In patients who have type 2B VWD,
decrease in platelet count after DDAVP administration has been considered
"pseudothrombocytopenia" by some authors because it is related to platelet
agglutination in vitro rather than in vivo agglutination and clearance.63,239
Therefore, DDAVP may be cautiously considered for patients who have type 2B
VWD. Patients who have type 3 VWD almost never experience a clinically relevant
rise in VWF:RCo or FVIII activities, and DDAVP is not considered clinically
useful in these patients.224,230
Complications and toxicities of DDAVP. Minor
side effects of DDAVP are common and include facial flushing, transient
hypertension or hypotension, headache, or gastrointestinal upset,214,215,262 but these effects rarely limit
clinical use. Water retention after a dose of DDAVP, with an increase in
urinary osmolality, is universal; however, decreased serum sodium in otherwise
healthy adults is variable and is related to multiple doses.262,263 In the case of repeated dosing,
all patients should be instructed to limit fluid intake to maintenance levels
for 24 hours.264266
Prophylactic use of DDAVP complicates the management of fluids and electrolytes
for surgery or during childbirth. Seizures have been associated with
hyponatremia after DDAVP administration, primarily in young children.263,266 Most pediatric hematologists do not
use DDAVP in children under the age of 2 years.230,261,266
Myocardial infarction after treatment with DDAVP has
been reported, although rarely, in patients who have mild hemophilia A.234,236,267 DDAVP should be avoided in patients
who are at very high risk for cardiovascular or cerebrovascular disease,
especially the elderly, as underlying inhibition of plasminogen activation with
DDAVP-related vasoconstriction contributes additional prothrombotic effects in
these patients.268 Because of
reported complications in other patient populations, DDAVP should be used with
caution for brain, ocular, and coronary artery surgeries,235,269,270 and VWF concentrate replacement
generally is used in these settings. DDAVP does not appear to increase
myometrial contractility significantly; consequently, pregnancy is not an
absolute contraindication271274 but use of DDAVP is rarely
indicated (see "Pregnancy").
Table 12. Clinical Results of DDAVP Treatment in
Patients Who Have VWD*
Adult surgical
prophylaxis |
N |
Frequency |
Duration |
Other treatment |
Bleeding outcome |
Dental procedures63,64,221223,232,242,246248, 250,259,260 |
113 |
Once |
Once or twice |
Antifibrinolytics |
Excellent/good 109/113 |
Gynecologic218,223,246,247 |
9 |
Daily |
17 days |
Antifibrinolytics 2/7 |
Delayed bleeding in 2/9 requiring
extended DDAVP |
Surgery218,221,223,247,249,258,259 |
26 |
Daily |
15 days |
|
Excellent/good in 25/26 Hemorrhage
after 1 rhinoplasty |
Experience
in children |
N |
Frequency |
Duration |
Other treatment |
Bleeding outcome |
Primarily tonsillectomy
and adenoidectomy240,241,243245,249,250 |
146 |
Once or twice daily |
17 days |
Antifibrinolytics in most for 7
days |
Excellent/good in 125/146 |
Primarily
tonsillectomy/adenoidectomy261 |
119 |
NA† |
NA† |
NA† |
Excellent/good in 105/119 |
Otologic Surgery249 |
6 |
Daily |
2 days |
|
Excellent/good in 6/6 |
DDAVP, 1-desamino-8-D-arginine vasopressin
(desmopressin, a synthetic analog of vasopressin) * For additional detail
and information, see Evidence Tables
711. † NA, not available
Therapies To Elevate VWF: Replacement Therapy
As of January 2007, Humate-P® and
Alphanate SD/HT® are the only plasma-derived concentrates
licensed in the United States to replace VWF in persons who have VWD. One other
plasma derivativeKoate DVI®is licensed in the United
States to treat hemophilia and has been used off-label for VWD. These products
are not identical, have differing ratios of FVIII to VWF, and should not be
considered as interchangeable.275277 All of these products are
manufactured at U.S.-licensed facilities from pooled plasma collected from paid
donors.
Products that contain FVIII and little or no VWF are
generally not useful to treat VWD, but in rare circumstances these products may
be used to treat patients who have antibody-mediated AVWS.278 These products include the
plasma-derived concentrates Monoclate P®, Monarc
M®, and Hemofil M®; and recombinant products
Helixate FS®, Kogenate FS®,
Recombinate®, Advate®, and
ReFacto®.
Humate-P®, a lyophilized concentrate of
purified VWF and FVIII, contains other plasma proteins including fibrinogen and
albumin. In Humate-P®, the quantity of the large, most
hemostatically active multimers of VWF is decreased compared to fresh
plasma.279 When reconstituted at
the recommended volume, each milliliter of the product contains 50100
IU/mL VWF:RCo and 2040 IU/mL FVIII activity (Humate-P®
package insert). The median half-life of VWF:RCo activity was 10.3 hours
(range: 6.413.3 hours) in one study (see package insert) and 11.3 hours
in another study.251 The product
is indicated for use in adult and pediatric patients for treatment of
spontaneous and trauma-induced bleeding when use of DDAVP is thought or known
to be inadequate or contraindicated. Humate-P® has received FDA
approval for use in prophylactic management of surgery and invasive procedures
in patients with VWD.
Alphanate SD/HT® is a lyophilized
concentrate of VWF and FVIII, and other plasma proteins. It is prepared from
pooled human plasma by cryoprecipitation of FVIII, fractional solubilization,
and further purification employing heparin-coupled, cross-linked agarose. Upon
reconstitution to the recommended volume, each milliliter of product contains
40-180 IU/mL FVIII activity, and not less than 16 IU/mL VWF:RCo activity
(Alphanate SD/HT® package insert). The median half-life for
VWF:RCo activity was 6.91 hours (mean: 7.46 +/- 3.20 hours; range: 3.68 to
16.22 hours. Package Insert). The product is indicated for surgical and/or
invasive procedures in patients with VWD in whom either DDAVP is ineffective or
contraindicated. It is not indicated for patients with severe VWD (type 3)
undergoing major surgery.
Adverse reactions are rare but include allergic and
anaphylactic symptoms, urticaria, chest tightness, rash, pruritus, and
edema.253 If these reactions
occur, the infusion should be stopped, and appropriate treatment should be
given as required. The product should be used with caution in patients who have
known risk factors for thrombosis, as there have been a few reports of venous
thromboembolism associated with high levels of FVIII.280,281 Risk factors include old age,
previous thrombosis, obesity, surgery, immobility, hormone replacement therapy
(HRT), and use of antifibrinolytic therapy. If patients receive VWF replacement
therapy continuously for several days, it has been recommended that FVIII
levels be monitored to avoid unacceptably high levels.215,281
The products that contain VWF:RCo activity differ
significantly in their ratios of VWF:RCo to FVIII252,282,283 and one should not assume that
the dose or frequency of dosing is the same for all. The ratio of VWF:RCo to
FVIII for Humate-P® in various reports is 2.7, 2, and 1.6; for
Koate DVI®, the ratio is 1.2 and 0.8; and for
Alphanate®, the ratio is 0.5.251 These products also differ in their
relative levels of high-molecular-weight multimers. Koate DVI®,
in particular, has fewer large VWF multimers compared to Alphanate
SD/HT®, which has fewer than Humate-P® or normal
plasma.277,284,285
Cryoprecipitate, derived from plasma, historically has
been used to treat hemophilia A and VWD. Although cryoprecipitate is not
required to have a specified level of VWF, the final product must have on
average at least 80 units of FVIII per standard donor unit.286 Currently, cryoprecipitate is used
under rare circumstances to treat VWD, such as when potential exposure to
infectious agents can be limited by using directed donations to prepare the
product.287 However, the use of
cryoprecipitate is strongly discouraged by the National Hemophilia Foundation,
except in life-or limb-threatening situations when no VWF concentrate is
available, because cryoprecipitate is not virally inactivated.288 In developing countries, patients who
have VWD may have no other options, because virally inactivated plasma
concentrates are not available or are too expensive,283 but use of cryoprecipitate poses a
significant risk of transmitting disease.289
VWF concentrates are dosed primarily on the basis of
labeled VWF:RCo units and secondarily on the basis of labeled FVIII units. A
dosing trial with pharmacokinetic laboratory monitoring should be considered
before major surgery for selected patients with type 3 VWD or AVWS who are at
risk for poor VWF recovery because of inhibitors. Use of VWF concentrates to
prevent or control bleeding has been clinically efficacious, as shown on Table
13. The ultimate goal of surgical prophylaxis is to achieve a therapeutic level
of 100 IU/dL VWF:RCo and, at least for the first 3 days of treatment, a nadir
of 50 IU/dL VWF:RCo, as well as similar targets for FVIII.251,253256,290 Successful surgical hemostasis was
reported with the use of continuous infusion after initial bolus infusion at
rates of 12 U/kg/hr VWF:RCo.252
Replacement therapy, using a VWF concentrate, is
indicated for significant bleeding events or major surgery in patients who have
types 2 and 3 VWD as well as in patients who have type 1 VWD and are
unresponsive to DDAVP or require a protracted duration of therapy, or where
DDAVP is contraindicated (see above). The dose and duration of therapy are
dependent on the hemostatic challenge and expected duration required for
hemostasis and wound healing. Major surgery requires hemostasis for 714
days,247,251256 whereas minor surgeries can
be treated adequately in 15 days.243,244,247,256 Certain procedures can be managed
adequately by using a single infusion of 2040 U/kg VWF:RCo before the
procedure. Table 14 lists examples of major and minor surgical procedures.
Table 15 lists initial dosing recommendations for use of VWF replacement
therapy to prevent or treat bleeding. These recommendations are based on
published results (see Table 13) as well as consensus expert opinion. The
adequacy of courses of VWF replacement usually should be confirmed by
laboratory assessment of VWF:RCo and FVIII levels, although monitoring of
single infusions for treatment of outpatients may not be necessary. Duration of
VWF elevation after replacement therapy is highly variable in the surgical
setting. Thromboembolic events have been reported in patients who have VWD and
are in situations of high thrombotic risk and receiving VWF:RCo/FVIII complex
replacement therapy, especially in the setting of known risk factors for
thrombosis.280282 In all
patients who have VWD and are receiving VWF concentrate, attention should be
given to avoid exceeding maximal recommended levels of VWF:RCo and FVIII
activities (see Recommendation VII.D, below), perform proper thrombotic-risk
assessment, and institute appropriate preventive strategies. Recombinant VWF
has been prepared and evaluated in animal models292 but is not available for use in
humans.
Human platelets contain 1015 percent of total
blood VWF and platelet transfusions have been used successfully to treat
bleeding in VWD patients.293,294
Platelet transfusion therapy should be considered as an adjunctive source of
VWF, especially in patients with type 3 or platelet low VWD and platelet-type
VWD, to control bleeding that is non- or poorly responsive to replacement
therapy with VWF concentrate.
Table 13. Efficacy of VWF Replacement Concentrate for
Surgery and Major Bleeding Events*
Reference |
N |
Uses |
Loading dose†
(U/kg) |
Outcome |
Michiels et al. 2004255 |
5 |
Surgeries |
6080 |
100% ExcellentGood |
Thompson et al. 2004256 |
42 |
Surgeries |
82.3 |
100% ExcellentGood |
Gill et al. 2003291 |
53 |
Bleeding events |
67 |
98% ExcellentGood |
Lillicrap et al. 2002253 |
344/73 |
Bleeding events/surgeries |
55.3/69.1 |
99% ExcellentGood |
Nitu-Whalley et al. 2001247 |
10 |
Surgeries |
54 |
100% ExcellentGood |
Lubetsky et al. 1999254 |
3/9 |
Bleeding events/surgeries |
39.5 |
92.5% ExcellentGood |
Dobrkovska et al. 1998251 |
73 |
Surgeries |
80 C.I. |
99% ExcellentGood |
Hanna et al. 1994252 |
5 |
Surgeries |
25100 C.I.§ |
100% ExcellentGood |
Kreuz et al. 1994244 |
26/41 |
Bleeding events/surgeries |
1050§ |
100% ExcellentGood |
Scharrer et al. 1994290 |
66/70 |
Bleeding events/surgeries |
2080§ |
100% ExcellentGood |
* For additional detail and information,
see Evidence Table 12. †
Loading dose (VWF:RCo IU/dL) reported as median except for Lubetsky (mean).
Indicates that continuous infusion was used after the loading dose.
§ Loading dose (FVIII IU/dL).
Table 14. Suggested Durations of VWF Replacement for
Different Types of Surgical Procedures
Major surgery 714 days* |
Minor surgery 15 days* |
Other procedures, if uncomplicated,
single VWF treatment |
Cardiothoracic |
Biopsy: breast, cervical |
Cardiac catheterization |
Cesarean section |
Complicated dental extractions |
Cataract surgery |
Craniotomy |
Gingival surgery |
Endoscopy (without biopsy) |
Hysterectomy |
Central line placement |
Liver biopsy |
Open cholecystectomy |
Laparoscopic procedures |
Lacerations |
Prostatectomy |
|
Simple dental extractions |
*Individual cases may need longer or shorter
duration depending on the severity of VWD and the type of procedure.
Table 15. Initial Dosing Recommendations for VWF
Concentrate Replacement for Prevention or Management of Bleeding
Major
surgery/bleeding |
Loading dose:* |
4060 U/kg |
Maintenance dose: |
2040 U/kg every 8 to 24 hours |
Monitoring: |
VWF:RCo and FVIII trough and peak, at least
daily |
Therapeutic goal: |
Trough VWF:RCo and FVIII >50 IU/dL for
714 days |
Safety parameter: |
Do not exceed VWF:RCo 200 IU/dL or FVIII
250300 IU/dL |
May alternate with DDAVP for latter
part of treatment |
|
Minor
surgery/bleeding |
Loading dose:* |
3060 U/kg |
Maintenance dose: |
2040 U/kg every 12 to 48 hours |
Monitoring: |
VWF:RCo and FVIII trough and peak, at least
once |
Therapeutic goal: |
Trough VWF:RCo and FVIII >50 IU/dL for
35 days |
Safety parameter: |
Do not exceed VWF:RCo 200 IU/dL or FVIII
250300 IU/dL |
May alternate with DDAVP for latter
part of treatment |
|
*Loading dose is in VWF:RCo IU/dL.
Other Therapies for VWD
Antifibrinolytics. The antifibrinolytic drugs
aminocaproic acid and tranexamic acid are agents that inhibit the conversion of
plasminogen to plasmin, inhibiting fibrinolysis and thereby helping to
stabilize clots that have formed. Studies in hemophilia and in prostatectomy
provided the basis for initial trials of antifibrinolytic agents in VWD.295 The drugs can be used orally or
intravenously to treat mild mucocutaneous bleeding in patients who have VWD. In
patients who have mild to moderate VWD, tranexamic acid given topically in the
oral cavity ("swish and swallow or spit") every 6 hours has been used for
prophylaxis in dental surgery, in combination with applied pressure, other
topical agents, and suturing of surgical sites.242 The evidence for the effectiveness of
local application of these agents is based on clinical case series,296
but this route of administration is not currently approved by the U.S. Food and
Drug Administration (FDA). When DDAVP and/or VWF/FVIII concentrates are
indicated, the use of antifibrinolytic agents as adjuncts to DDAVP or VWF
concentrates has been helpful in controlling bleeding, such as in the oral
cavity36,221,223,232,242,246248 and in the gastrointestinal
and genitourinary tracts.
The usual adult dose of aminocaproic acid is 45
g as a loading dose orally or intravenously (1 hour before invasive
procedures), and then 1 g per hour, intravenously or orally, or 46 g
every 46 hours orally, until bleeding is controlled, or for 57 days
postoperatively.215 Total daily
dose of aminocaproic acid is limited to 24 g per 24 hours to minimize potential
side effects. Weight-based dosing is required in children and can also be used
in adults (5060 mg/kg).215,296 Lower doses (25 mg/kg) may be
effective and can be used when gastrointestinal side effects interfere with
therapy. Tranexamic acid is given intravenously at a dose of 10 mg/kg every 8
hours.215 The oral form is not
currently available in the United States, and use of the intravenous form as an
oral rinse ("swish and swallow" approach) is not an FDA-approved indication.
The package insert for each drug should be consulted for more detailed guidance
and for a full list of risks and contraindications. Both drugs can cause nausea
and vomiting; less frequent but serious side effects include thrombotic
complications. Both drugs are excreted renally, and dose adjustment or
avoidance is advisable when significant renal insufficiency is present.
Disseminated intravascular coagulation (DIC) and/or bleeding from the renal
parenchyma or upper urinary tract are relative contraindications to
antifibrinolytic agents. Renovascular thrombi have followed use of fibrinolytic
agents in patients with DIC and have caused renal failure. Patients have also
experienced urinary tract obstruction with upper urinary tract bleeding related
to large clots in the renal pelvis or lower urinary tract. Changes in color
vision during therapy with tranexamic acid require cessation of the drug and
ophthalmologic examination.
Topical agents. Topical bovine thrombin
(Thrombin-JMI) is marketed in the United States as an aid to hemostasis for
topical therapy of accessible minor bleeding from capillaries and small
venules. Fibrin sealant (Tisseel VH®, consisting of human
thrombin, fibrinogen concentrate, and bovine aprotinin) is indicated as an
adjunct to hemostasis in certain surgical situations, but it is not effective
for the treatment of massive and brisk arterial bleeding. Fibrin sealants have
been used with good results as adjunctive therapy for dental surgery in persons
who have hemophilia or VWD.242,297 Topical collagen sponges are also
approved for control of bleeding wounds.298 Other topical agents approved for
limited indications include Coseal®, Bioglue®,
and Quickclot®; however, no reports of their use in treating VWD
could be found. Quickclot®, containing the mineral zeolite, was
approved recently for use with compression dressings for control of external
traumatic bleeding in the prehospital setting (e.g., battlefield). The added
benefit of topical agentswhen used with single or combination therapies
including antifibrinolytic drugs, DDAVP, and VWF/FVIII concentrateis
unproven. The topical use of plasma-derived bovine or human proteins imparts a
theoretical risk of disease transmission and of potential allergic and other
immune reactions. The use of fibrin sealants in addition to drugs and/or
concentrates may be viewed as optional adjunctive therapy for dental surgery
and for cases in which surface wound bleeding continues despite combined
therapy with drugs and concentrates. The safety of these topical agents in
therapy for VWD remains to be demonstrated.
Other Issues in Medical Management
All persons who have significant bleeding symptoms
related to VWD are likely to require human blood product administration and
should receive immunizations for hepatitis A and B as recommended for
individuals with hemophilia.299
Persons who have VWD should be counseled to avoid aspirin, other NSAIDs, and
other platelet-inhibiting drugs.300302
Treatment of AVWS
In an international registry of 189 cases of AVWS,
DDAVP produced clinical and laboratory improvement in one-third of cases,
although this effect was often short lived.117 If FVIII activity and the PTT were
abnormal, a good DDAVP response was less common than in hereditary VWD and was
often brief. In the international registry series, most patients who had AVWS
also received VWF/FVIII concentrates; the extent and duration of response was
varied. Therefore, VWF:RCo and FVIII levels must be measured pre- and
postinfusion of DDAVP or VWF/FVIII concentrates in patients who have AVWS to
determine the extent and duration of response and to guide subsequent dosage
and dosing intervals.117,157
In patients who had a previous inadequate response to
DDAVP and VWF/FVIII concentrates, intravenous immunoglobulin G (IGIV; 1 g/kg
daily for 2 days) given alone was effective in controlling bleeding and raising
VWF:RCo activity for 3 weeks in all eight patients who had excessive bleeding
and an IgG-monoclonal gammopathy of uncertain significance (MGUS).303 In the international registry series,
one-third of the 63 patients treated with high-dose IGIV had a good
response.117 The underlying
diagnoses of the responders were lymphoproliferative disorders (including
MGUS), solid tumors, and autoimmune diseases. An anti-VWF antibody could be
demonstrated in vitro in about two thirds of those responders. High dose IGIV
therapy in the setting of AVWS is an off-label use but should be considered
when DDAVP and VWF/FVIII concentrate therapy fail to control bleeding symptoms
adequately.304306 Some
patients who have immune-mediated AVWS have responded to plasmapheresis,
corticosteroids, and immunosuppressive agents.117 Because many patients in the
international registry series received multiple therapeutic modalities, the
independent contribution of each therapy to clinical improvement was
unclear.
When all other therapeutic modalities fail to control
bleeding adequately, the infusion of recombinant FVIIa may be considered, but
this agent should be used with caution. Little experience has been reported for
its use in treating VWD. A recent report described acute myocardial infarction
immediately after the second dose of 90 microgram/kilogram in a 50 year old man
who had hereditary type 2A VWD, gastrointestinal bleeding, and several risk
factors for, but no history of, coronary artery disease.307
Cardiac Valvular Diseases. Congenital or
acquired heart disease has been associated with AVWS.117,119,308 Elevated shear stress around a
stenotic valve or septal defect may promote the proteolysis and depletion of
high-molecular-weight VWF multimers.134 Patients who had associated aortic
stenosis or other cardiac valvular disorders infrequently responded to any of
the therapies described above.117,122 After surgical correction of the
cardiac defect, the multimer pattern has improved at least transiently in most
patients studied.119,122,308 Administration of VWF/FVIII
concentrate immediately preoperatively should be considered for patients who
demonstrate transient improvement in VWF activity with a test dose.
Angiodysplasia. Bleeding from
gastrointestinal angiodysplasia has been reported in persons who have
AVWS309 as well as in persons who
have various types of congenital VWD. For example, bleeding from angiodysplasia
is a classic presentation of AVWS associated with aortic stenosis122,310 and is often resistant to medical
therapy, requiring surgical correction of the valve defect to ameliorate
bleeding symptoms. In the absence of a correctable underlying etiology of
angiodysplasia and bleeding associated with AVWS or congenital VWD, management
of the condition can be challenging, as no single treatment modality is
successful in all cases.311
Thrombocytosis. Thrombocytosis, especially in
persons who have essential thrombocythemia, is associated with a relative
reduction in the proportion of high-molecular-weight multimers.125 Although the relation of this
abnormality to bleeding is inconsistent, treatment is aimed at reduction of the
platelet count.
Hypothyroidism. In contrast to the above
syndromes, AVWS that occurs in hypothyroidism is caused by decreased synthesis,
and the VWF multimer patterns are normal.312,313 A minority of patients who have
hypothyroidism have VWF levels below normal, and not all who have low VWF
levels have bleeding symptoms. The decrease in VWF is corrected by thyroid
hormone replacement.127,313
Management of Menorrhagia in
Women Who Have VWD
Menorrhagia is often the primary bleeding symptom in
women who have VWD.85,314,315 Menorrhagia, however, may be a
sign of a gynecological disorder rather than VWD.316 Therefore, a full gynecological
evaluation is required before therapy is initiated.316
Medical therapies that have been described to control
menorrhagia in women who have VWD include combined oral contraceptives,
tranexamic acid, DDAVP, and, most recently, the levonorgestrel-releasing
intrauterine system (Table 16). Data regarding the effectiveness of these
therapies are limited. The only published randomized clinical trial of DDAVP
for menorrhagia was small and failed to demonstrate efficacy compared to
placebo.317 The available data
show no evidence that DDAVP is more effective than other therapies used to
treat menorrhagia.318 Depending
on the woman's age, underlying gynecologic condition, and reproductive plans,
any of the therapies demonstrated to be effective for the treatment of
menorrhagia in women without VWD may be suitable, with the exception of NSAIDs,
which decrease platelet function and systemic hemostasis.319 In one retrospective review of 36
adolescent girls with VWD and menorrhagia, treatment using oral contraceptive
pills (OCPs) or intranasal DDAVP were equally efficacious.320
Table 16. Effectiveness of Medical Therapy for
Menorrhagia in Women Who Have VWD
Reference |
Population |
Treatment |
Controls |
Results |
Setting |
Kouides et al.
2000321 |
41 women known to have type 1
VWD |
Oral contraceptives |
No |
76% "ineffective" |
Patient survey |
Foster 1995322 |
25 women known to have VWD |
Oral contraceptives |
No |
88% "effective" |
Survey of hemophilia treatment
centers |
Greer et al. 1991323 |
7 women who had VWD |
Oral contraceptives |
No |
3 "good effect" 3 "slight
improvement" 1 "no effect" |
Retrospective review, single
hemophilia treatment center |
Kingman et al.
2004324 |
13 women who had VWD |
Levonorgestrel intrauterine
system |
No |
Periods "much better" in 100%
50% developed amenorrhea Increased hemoglobin concentrations |
Prospective, open label |
Kadir et al. 2002317 |
39 women known to have VWD |
DDAVP |
Placebo |
No significant difference |
Prospective, double-blind,
randomized trial |
Leissinger et al.
2001325 |
90 women who had a variety of
bleeding disorders |
DDAVP |
No |
92% "excellent" or "good" |
Prospective, open label |
Rodeghiero et al.
1996326 |
43 women who had VWD |
DDAVP |
No |
65% "very effective" 21%
effective 14% not effective |
Prospective, open label |
Mohri 2002327 |
3 women who had VWD |
Tranexamic acid |
No |
3 "well-controlled" |
Case series |
Greer et al. 1991323 |
2 women who had VWD |
Tranexamic acid |
No |
2 "no effect" |
Retrospective review, single
hemophilia treatment center |
In the adolescent or adult female who does not desire
pregnancy, but may desire future childbearing, the first choice of therapy
should be combined oral contraceptives. Combined oral contraceptives contain a
synthetic estrogen (ethinyl estradiol) and a progestin.328 The progestin prevents ovulation, and
the synthetic estrogen prevents breakthrough bleeding.329 A majority of studies have found that
combined oral contraceptives increase fibrinogen, prothrombin, factor VII,
FVIII, and/or VWF330332
and, consequently, promote hemostasis. It is not known whether the increase in
coagulation factors associated with combined oral contraceptives contributes to
the clinical response, but combined oral contraceptives do reduce menstrual
blood loss333 and increase
hemoglobin concentrations in women who have anemia.334336 Combined oral
contraceptives, used by tens of millions of women for prolonged periods of
time, have been proven to be safe for long-term use337 except in women with
thrombophilia.329 Although no
formal studies of the effects of the contraceptive patch on hemostasis have
been performed, the patch likely has effects similar to those of combined oral
contraceptives.338
For a woman who has VWD and would otherwise be a
suitable candidate for an intrauterine device, the second choice of therapy
should be the levonorgestrel-releasing intrauterine system. The
levonorgestrel-releasing intrauterine system is a progestin-impregnated
intrauterine device that is believed to reduce menstrual blood loss by opposing
estrogen induced growth of the endometrium or lining of the uterus.339
Women who do not respond to hormonal therapy and are
being considered for treatment with DDAVP or VWF concentrate should be referred
to a hemophilia treatment center or to a hematologist who has expertise in
hemostasis. Treatments specific for VWD (such as DDAVP or VWF concentrate), or
antifibrinolytic therapy, although they have not been proven to be effective
for menorrhagia, may be tried.
In addition to medical therapies, surgical therapies
have been used to treat menorrhagia in women who have VWD. Dilation and
curettage (D & C), while occasionally necessary to diagnose intrauterine
pathology, is not effective in controlling heavy menstrual bleeding.323 In two cases reported by Greer et
al.323 and two cases reported by
Kadir et al.,340 D & C
resulted in further blood loss.
Endometrial ablation, on the other hand, reduced
menstrual blood loss in seven out of seven women who had VWD.341 Three, however, ultimately required
hysterectomy, compared to 1234 percent of women who did not have VWD who
usually require hysterectomy.342346 Women who have VWD and
undergo hysterectomy may be at greater risk of perioperative bleeding
complications than other women, and bleeding may occur despite prophylactic
therapy.137,315 Hysterectomy carries the risk of
bleeding complications, but women who require the operation should not be
deprived of its benefits. Because menorrhagia is often the primary bleeding
symptom experienced by a woman who has VWD, hysterectomy offers the possibility
of the elimination of bleeding symptoms for menorrhagia and significant
improvement in quality of life.345,347,348
Hemorrhagic Ovarian Cysts
There are multiple case reports of women who have VWD
and have experienced hemorrhagic ovarian cysts.322,323,349353 Silwer, for example,
reported that 9 of 136 (6.8 percent) women who had VWD experienced this
problem.137 Ovulation is not
normally accompanied by any significant bleeding, but in a woman who has a
congenital bleeding disorder such as VWD, the potential exists for bleeding
into the peritoneal cavity or bleeding into the residual follicle, resulting in
a hemorrhagic ovarian cyst352 or
retroperitoneal hematoma.323
Acute treatment of hemorrhagic ovarian cysts with surgical therapy, tranexamic
acid, and factor replacement has been reported.323,351,352 Oral contraceptives have been used to
prevent recurrences.349,350,352
Pregnancy
Few options are available for the management of
menorrhagia or recurrent hemorrhagic ovarian cysts in women who have VWD and
desire pregnancy. Although data are limited to case reports, DDAVP,
antifibrinolytics, or VWF concentrate may be tried.322
Ideally, planning for pregnancy begins before
conception. Women who have VWD and are contemplating a pregnancy should be
aware that they may be at an increased risk of bleeding complications during
pregnancy354 and are definitely
at increased risk of postpartum hemorrhage.145 Before conception or during
pregnancy, women should be offered the opportunity to speak with a genetic
counselor regarding the inheritance of VWD355 and with a pediatric hematologist
regarding the evaluation of the infant after delivery.
Women who have type 1, type 2, or type 3 VWD and have
FVIII levels <50 IU/dL, VWF:RCo <50 IU/dL, or a history of severe
bleeding should be referred for prenatal care and delivery to a center that, in
addition to specialists in high-risk obstetrics, has a hemophilia treatment
center and/or a hematologist with expertise in hemostasis. Laboratory,
pharmacy, and blood bank support is essential. Before any invasive procedure,
such as chorionic villus sampling, amniocentesis, or cervical cerclage, women
who have VWD should have laboratory assays for FVIII and VWF:RCo in order to
receive appropriate prophylaxis.355,356 FVIII and VWF:RCo levels should
be obtained in the third trimester of pregnancy to facilitate planning for the
delivery.356 Before delivery, all
women who have VWD should meet with an anesthesiologist to plan for the
possible need for the administration of hemostatic agents, and/or alternatives,
if necessary, for regional anesthesia at the time of delivery.355 A pregnant woman carrying a baby at
risk for type 3 or severe types 1 or 2 VWD should be referred to a pediatric
hematologist to discuss neonatal testing and potential bleeding in the
infant.85,354,375
There are limited data on the use of DDAVP for VWD in
pregnancy. Mannucci reported using DDAVP for prophylaxis prior to procedures in
31 pregnant women "without mishap,"357 but specific data are not provided.
DDAVP, in the lower doses used to treat diabetes insipidus, however, is
generally thought to be safe for mother and fetus. In a review of 53 cases of
women who were pregnant and used DDAVP, administered in doses of 7.5100
micrograms a day for diabetes insipidus, no adverse maternal or neonatal
effects were attributable to the medication.274 In an in vitro placenta model, DDAVP
did not cross the placenta in detectable amounts.274
Tranexamic acid crosses the placenta358 but has been used to treat bleeding
during pregnancy in a limited number of cases without adverse fetal
effects.359364 Data
regarding aminocaproic acid in pregnancy are limited, but aminocaproic acid was
not found to be teratogenic in rabbits.365 In cases of its use during pregnancy,
no adverse fetal effects have been reported.366
Miscarriage and Bleeding During Pregnancy
In the general population, miscarriage is common, and
1213.5 percent of diagnosed pregnancies result in spontaneous
abortion.367,368 Although
detailed data were not provided, in a study of 182 females who had severe VWD,
Lak et al.85 reported that
miscarriage was no more frequent than in the general population. Other studies,
however, have found a higher incidence of miscarriage among women who have VWD
compared to controls145 or
compared to the background rate.322,354 Bleeding complications during
pregnancy other than miscarriage have been reported.322,323,369371 Kadir et al.354 found that 33 percent of women who
had VWD bled during their first trimester.
Childbirth
Table 17 summarizes nine case series reporting
pregnancy outcomes in women who had VWD, including rates of miscarriage,
peripartum prophylaxis, postpartum hemorrhage, and perineal hematoma.
Prophylaxis included cryoprecipitate, fresh frozen plasma, DDAVP, and factor
replacement.
No large prospective studies correlate VWF:RCo and
FVIII levels with the risk of bleeding at the time of childbirth, but the
opinion of experts is that VWF:RCo and FVIII levels of 50 IU/dL should be
achieved before delivery323 and
maintained for at least 35 days afterward.9,215,323,354356 There is no consensus on
levels of VWF:RCo and FVIII that are safe for regional anesthesia,372 but if VWF:RCo and FVIII levels are
≥50 IU/dL and the coagulation screen is normal, regional anesthesia may be
considered safe.354
DDAVP may be used to raise factor levels in
responders, but care must be taken in its administration at the time of
childbirth. Women commonly receive 12 liters or more of fluid at the time
of a vaginal delivery and 23 liters or more at the time of cesarean
delivery. Fluids containing oxytocin, which also causes fluid retention,
combined with DDAVP may result in fluid retention and life-threatening
hyponatremia. Chediak and colleagues reported complications of fluid retention
in two women who received DDAVP at the time of childbirth. One woman who
received three doses 18 hours apart developed severe hyponatremia (sodium level
of 108 mEq/L) and experienced grand mal seizures.371
Table 17. Pregnancies in Women Who Have VWD
Study |
Population |
Miscarriage |
Prophylaxis |
Postpartum hematoma |
Perineal |
Burlingame et al.
2001369 |
5 pregnancies in 2 women |
None |
FVIII concentrates for 1/5 |
1/5 |
None |
Lak et al. 200085 |
100 women who had type 3 VWD and had
delivered at least 1 child |
Rate not "higher than
the
general Iranian population" |
FFP Cryo FVIII
concentrates |
15/100 (15%) of women |
Not reported |
Caliezi et al.
1998370 |
2 pregnancies in 1 woman who had
type 3 VWD |
None |
FVIII concentrates for 2/2 |
1/2 on day 15 from episiotomy |
None |
Kadir et al. 1998354 |
84 pregnancies in 31 women |
18 of 72 pregnancies not
terminated |
10/54 with "no bleeding
complications" |
10/54 (18%) primary* 6/54 (11%)
required transfusion 11/54 (20%) secondary† |
3/54 |
Foster 1995322 |
69 pregnancies in 31 women who had
VWD unresponsive to DDAVP |
15 of 68 pregnancies not
terminated |
25/55 (46%) of those for whom data
were available FVIII concentrates (9) Cryo (8) FFP (1) |
In women who had type 2A, 2B, or 3
VWD, 6/18 who were treated; 3/4 who were not treated |
Not reported |
Ramsahoye et al.
1995376 |
24 pregnancies in 13 women |
None reported (1 fetal demise at 38
weeks) |
5 cesarean deliveries:
- Cryo for 2/5
- FVIII (Haemate-
P®) for 2/5
- DDAVP for 1/5 19 vaginal
deliveries:
- Cryo for 3/19
- FVIII (Haemate-P®,
NHS 8Y) for 2/19
|
3/24 (12.5%) primary* 6/24 (25%)
secondary† 2/6 secondary† had been treated |
None |
Greer et al. 1991323 |
14 deliveries in 7 women who had
VWD |
Not reported |
Cryo (9) |
5/9 who were treated (1 primary*, 3
secondary†, 1 both); 2/5 who were not treated (2 primary*) |
1/14 |
Chediak et al.
1986371 |
10 pregnancies in 6 women who had
VWD |
3 of 10 pregnancies |
Cryo for 5/7 deliveries DDAVP
for 2/7 deliveries |
4/5 "massive" |
1 had "lumbar hematomas" |
Conti et al. 1986377 |
5 deliveries in 5 women who had
VWD |
None |
None |
2/5 "late" |
None |
Cryo, cryoprecipitate; DDAVP,
1-desamino-8-D-arginine vasopressin (desmopressin, a synthetic analog of
vasopressin); FFP, fresh frozen plasma; FVIII, FVIII concentrate; Haemate
P®, European equivalent of Humate-P®; NHS 8Y,
National Health Services (United Kingdom) factor VIII concentrate (8Y); VWD,
von Willebrand disease. * Primary, postpartum hemorrhage within the first
24 hours after delivery † Secondary, postpartum hemorrhage after 24
hours after delivery
Because NSAIDs, commonly prescribed for pain after
childbirth, may decrease platelet function and systemic hemostasis,319
alternative analgesics should be considered.
Postpartum Hemorrhage
Postpartum hemorrhage is an anticipated problem among
women who have VWD. By the end of gestation, an estimated 1020 percent of
a woman's blood volume, or at least 750 mL/minute, flows through the
uterus.373 After delivery of the
infant and placenta, the uterus must contract, and the uterine vasculature must
constrict to prevent exsanguination.374 Failure of the uterus to contract is
the single most important cause of postpartum hemorrhage.374 Nonetheless, women who have VWD are
at an increased risk of postpartum hemorrhage compared to controls.137,145,321 Multiple case series document an
increased incidence of postpartum hemorrhage in women who have VWD (see Table
17).
Perineal hematoma, a rare complication of vaginal
birth, occurs with some frequency in women who have VWD. Greer et al.323 reported one hematoma in 13 vaginal
deliveries, and Kadir and colleagues354 reported three hematomas in 49
vaginal deliveries. This is a relatively high frequency compared to a rate of
only 2.2/1,000 in a cohort of 26,187 spontaneous or operative vaginal
deliveries.378
In women who have VWD, vaginal bleeding is frequently
reported to occur more than 23 weeks postpartum. The duration of bleeding
after delivery in a normal patient is a median of 2127 days.379381 However, the VWF levels that
are elevated during pregnancy return to baseline within 721 days,382,383 predisposing women who have VWD
to delayed postpartum hemorrhage. In the absence of a bleeding disorder,
delayed or secondary postpartum hemorrhage is rare and occurs following less
than 1 percent of deliveries.384,385 In contrast, 2025 percent
of women who had VWD had delayed postpartum hemorrhage, making delayed
postpartum hemorrhage 1520 times more common among these women compared
to normal subjects.354,376
Among the published series of cases of women who were
pregnant and had VWD (Table 17), multiple cases of postpartum hemorrhage
occurred despite prophylaxis. The average time of presentation of postpartum
hemorrhage in women who have VWD was estimated to be 15.7 ± 5.2 days
after delivery.386 The
implication is that women who have VWD may require frequent evaluationand
possibly prophylaxisfor 2 weeks or more postpartum. Weekly contact with
these women is recommended during the postpartum period.356
Management Recommendations
The recommendations are graded according to criteria
described in the "Introduction" and in
Table 1. Evidence tables are provided
for recommendations given a grade of B and having two or more references.
- Testing Prior to Treatment
- Before
treatment, all persons suspected of having VWD should have a
laboratory-confirmed diagnosis of type and severity of VWD. This recommendation
does not preclude treatment that may be indicated for urgent or emergency
situations, despite the absence of confirmatory laboratory data.
Grade
C, level IV85,136142
- Persons
who do not have a definite diagnosis of VWD but who have VWF:RCo levels of
3050 IU/dL and have a bleeding phenotype may merit treatment or
prophylaxis of bleeding in certain clinical situations.
Grade B, level
III196
- Persons
with >10 IU/dL VWF:RCo and >20 IU/dL FVIII activity levels should undergo
a trial of DDAVP while in a nonbleeding state. Persons with levels below these
thresholds are less likely to demonstrate clinical or laboratory responses to
DDAVP, but a DDAVP trial should still be considered in these individuals.
Grade B, level IIa99,223,224,227,231 See Evidence Table 6.
- General
Management
- Treatment
of persons who have VWD is aimed at cessation of bleeding or prophylaxis for
surgical procedures.
Grade C, level IV1,7,9
- Continued
bleeding, despite adequately replaced VWF:RCo and FVIII activity levels,
requires evaluation of the person for other bleeding etiologies, including
anatomic.
Grade C, level IV
- Long-term
prophylaxis is currently under investigation in an international cooperative
study, and the long-term risks and benefits should be considered carefully.
Grade C, level IV211,212
- Individuals who are more than 2 years of
age, who have VWD and have not already been vaccinated, should be immunized
against hepatitis A and B.
Grade C, level IV299
- Persons
who have VWD should have the opportunity to talk to a knowledgeable genetic
counselor.
Grade C, level IV355
- At
diagnosis, persons who have VWD should be counseled to avoid aspirin, other
NSAIDs, and other platelet-inhibiting drugs.
Grade C, level IV300302
- Restriction of fluids to maintenance
levels should be considered in persons receiving DDAVP (especially for young
children and in surgical settings) to avoid the occurrence of hyponatremia and
seizures.
Grade C, level IV264266
- Treatment of
Minor Bleeding and Prophylaxis for Minor Surgery
- Epistaxis
and oropharyngeal, soft tissue, or minor bleeding should be treated with
intravenous or nasal DDAVP, if appropriate, based on trial testing.
Grade B, level IIa221223,230,246 See Evidence Table 7
- If
elevation of VWF is necessary and response to DDAVP is inadequate, VWF
concentrate should be used, with dosing primarily based on VWF:RCo units and
secondarily on FVIII units.
Grade C, level IV247,253
- For
prophylaxis for minor surgery, initial treatment should be expected to achieve
VWF:RCo and FVIII activity levels of at least 30 IU/dL and preferably >50
IU/dL.
Grade B, level III223,230,242,247 See Evidence Table 8
- For minor
surgery, VWF:RCo and FVIII activity levels of at least 30 IU/dL and preferably
>50 IU/dL should be maintained for 15 days.
Grade B, level
III243,244,247,256 See Evidence Table 9.
- For
persons who have VWD, management of minor bleeding (e.g., epistaxis, simple
dental extraction, or menorrhagia) with DDAVP and proper fluid restriction can
be performed without laboratory monitoring unless Stimate® or
DDAVP is used more than three times within 72 hours.
Grade C, level
IV263,320
- For
persons who have mild to moderate VWD, antifibrinolytics combined with DDAVP
are generally effective for oral surgery. VWF concentrate should be available
for persons who cannot receive DDAVP or who bleed excessively despite this
combined therapy.
Grade B, level IIb221,223,232,242,246248
See Evidence Table 10.
- Topical
agents, such as fibrin sealant or bovine thrombin, may be useful adjuncts for
oral surgery in persons who have VWD. Careful attention to hemostasis of an
extraction socket and to suturing of sockets is also important in oral surgery
in persons who have VWD.
Grade C, level IV242,297
- Treatment of
Major Bleeding and Prophylaxis for Major Surgery
- All
treatment plans should be based on objective laboratory determination of
response of VWF:RCo and FVIII activity levels to DDAVP or to VWF concentrate
infusion.
Grade B, level IIb136,231,240,241,244,245,247,249,251256,290,291
See Evidence Tables 11 and
12.
- Whenever
possible, all major surgeries and bleeding events should be treated in
hospitals with a 24-hour/day laboratory capability and with clinical monitoring
by a team including a hematologist and a surgeon skilled in the management of
bleeding disorders.
Grade C, level IV
- For severe
bleeding (e.g., intracranial, retroperitoneal) or for prophylaxis of major
surgery, initial target VWF:RCo and FVIII activity levels should be at least
100 IU/dL. Subsequent dosing should maintain VWF:RCo and FVIII levels above a
trough of 50 IU/dL for at least 710 days.
Grade B, level
III244,247,251256,290,291
See Evidence Table 12.
- To
decrease risk of perioperative thrombosis, VWF:RCo levels should not exceed 200
IU/dL, and FVIII activity should not exceed 250 IU/dL.
Grade C, level
IV280282
- For major
surgical procedures in selected patients with type 3 VWD or AVWS who are at
risk for poor VWF recovery because of inhibitors, a pre-operative trial
infusion of VWF concentrate with pharmacokinetic laboratory monitoring should
be considered.
Grade C, level IV
- Management of
Menorrhagia and Hemorrhagic Ovarian Cysts in Women Who Have VWD
- Women who
have menorrhagia or abnormal vaginal bleeding should have a full gynecological
evaluation before therapy.
Grade C, level IV316
- In the
adolescent or adult woman who does not desire pregnancy, but may desire future
childbearing, the first choice of therapy for menorrhagia should be combined
oral contraceptives.
Grade B, level III322
- In the
adolescent or adult woman who does not desire pregnancy, but may desire future
childbearing, the first choice of therapy to prevent hemorrhagic ovarian cysts
should be combined oral contraceptives.
Grade C, level IV349,350,352
- If a woman
would otherwise be a suitable candidate for an intrauterine device, the second
choice of therapy for menorrhagia should be the levonorgestrel intrauterine
system.
Grade B, level IIb324
- For the
woman who desires pregnancy, DDAVP, antifibrinolytics, or VWF concentrate may
be tried to control menorrhagia.
Grade C, level IV322
- Dilation
and curettage is not usually effective to manage excessive uterine bleeding in
women who have VWD.
Grade C level IV323,340
- Management of
Pregnancy and Childbirth in Women Who Have VWD
- Women
planning for pregnancy should have, before conception, an evaluation with a
hematologist and a high-risk obstetrician, both of whom are skilled in the
management of VWD.
Grade C, level IV355
- Women who
have type 1, type 2, or type 3 VWD, with FVIII or VWF:RCo levels <50 IU/dL
or a history of severe bleeding:
- Should be
referred to a center that has high-risk obstetrics capabilities and with
expertise in hemostasis for prenatal care, delivery, termination of pregnancy,
or management of miscarriage.
Grade C, level IV
- Should
receive prophylaxis with DDAVP or VWF concentrate before invasive procedures.
Grade C, level IV355,356
- Should
achieve VWF:RCo and FVIII levels of at least 50 IU/dL before delivery and
maintain that level for at least 35 days afterward.
Grade C,
level IV9,215,323,354,356
- If VWF:RCo
and FVIII levels can be monitored and maintained above 50 IU/dL during labor
and delivery, and no other coagulation defects are present, then regional
anesthesia may be considered.
Grade C, level IV354
- Because
coagulation factors return to prepregnancy levels within 1421 days after
delivery, health care providers should be in close contact with women during
the postpartum period.
Grade C, level IV356
- Acquired von
Willebrand Syndrome
- Individuals who have AVWS and who require
surgery should be considered for a pharmacokinetic trial of therapy with DDAVP
and/or VWF concentrate, with monitoring of VWF:RCo and FVIII levels, to
evaluate for possible accelerated clearance of VWF.
Grade C, level
IV117,157
- For
persons who have AVWS and who bleed excessively despite therapy with DDAVP and
VWF concentrate, treatment with high-dose IGIV should be considered, especially
in IgG isotype MGUS (see "Acquired von Willebrand
Syndrome" for discussion of this non-FDA-approved use).
Grade B,
level IIa117,303306
See Evidence Table 13.
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