The Diagnosis, Evaluation and Management of von
Willebrand Disease
Evidence Tables
Evidence Table 1. Recommendation
I.B.
If answers to probe
questions I.B.18 are positive, obtain relevant specific information.
Grade B, level IIb
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Drews CD, Dilley AB,
Lally C, Beckman MG, Evatt B. Screening questions to identify women with von
Willebrand disease. J Am Med Womens Assoc 2002;57(4):217218. |
Emory Hospital Clinic 102
women who had VWD, some had menorrhagia |
Case/control retrospective telephone
survey |
Survey and known case status;
presumed control status. |
Presence of ≥6 symptoms in 80% of
women who had VWD and 8% of women who did not have VWD. |
CDC funded. |
Sramek A, Eikenboom JC,
Briet E, Vandenbroucke JP, Rosendaal FR. Usefulness of patient interview in
bleeding disorders. Arch Intern Med 1995 Jul;155(13):14091415. |
Hematology Clinic, The Netherlands
Sample comprised 18- to 65-year-old persons:
- 222 had a previously diagnosed
bleeding disorder (95 mild VWD, 54 platelet dysfunction, 73 hemophilia A or
B)
- 134 referred for bleeding
symptoms but with normal hemostasis tests
- 341 healthy volunteers
|
Survey compared to gold standard
evaluation of "elaborate" interview |
Survey and indepth interview were
compared to blood work. |
Bleeders vs. referral control:
- Tonsillectomy, 16.2 odds.
- Muscle bleeding, 3.4 odds.
- Joint bleeding, 2.5 odds.
- Nose bleeds, 2.2 odds (observed
but not useful).
Multivariate positive:
- Family history of bleeding with
trauma.
- Bleeding at delivery (not
helpful).
Bleeders vs. healthy volunteers:
- Positive family history, 97.5
odds.
- Minor trauma or muscle bleeding,
9.5 odds.
- Joint bleeding, 5.8 odds.
- Absence of menorrhagia, 1.8
odds.
|
Unknown sponsor. |
CDC, Centers for Disease Control and Prevention Back to Top
Evidence Table 2. Recommendation
II.B
Initial tests for
diagnosing or excluding VWD include the following three tests: VWF:RCo, VWF:Ag,
and FVIII activity. Grade B, level III
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Favaloro EF, Bonar R,
Kershaw G, Siufi J, Hertzberg M, Street A, Lloyd J, Marsden K. Laboratory
diagnosis of von Willebrand’s disorder: quality and diagnostic
improvements driven by peer review in a multilaboratory test process.
Haemophilia 2004,10:232242. |
45 laboratories in Australia, New
Zealand, and Southeast Asia |
Assessing testing proficiency in
diagnostic tests for VWD using 8 VWD testing sample sets from normals or VWD
subjects during 2003 |
Comparison of test results for
patients who have and do not have VWD. |
Initial diagnosis of VWD is usually
correct (~90% accurate). Subtype diagnosis is aided by VWF:CB assay,
clinical history, and possibly repeat testing. |
All 45 labs measured FVIII, 42
measured VWF:Ag, 32 measured VWF:RCo, and 23 measured VWF:CB to diagnose or
classify VWD. Only 3 performed VWF multimer analysis. |
Favaloro EJ, Thom J,
Baker R. Assessment of current diagnostic practice and efficacy in testing for
von Willebrand's disorder: results from the second Australasian
multilaboratory survey. Blood Coagul Fibrinolysis 2000
Dec;11(8):729737. |
19 laboratories in Australia, New
Zealand, and Southeast Asia |
Assessment of testing proficiency in
diagnostic tests for VWD using 7 VWD testing sample sets from normals (1) or
from VWD subjects (n = 7) |
Comparison of test results for
patients who have or do not have VWD. |
Continued problems with
nonidentification of functional VWF discordance in type 2 VWD,
misidentification of functional VWF in type 1 VWD, and difficulties in
discriminating types 1 and 3 VWD. Increase in use of latex immunoassay
and automated VWF:RCo testing noted. |
All 19 labs measured FVIII and
VWF:Ag, 18 measured VWF:RCo, and 7 measured VWF:CB to diagnose or classify VWD.
Concluded that testing should comprise FVIII:C, VWF:Ag, and either/or
both VWF:RCo and VWF:CB. |
Gill JC, Endres-Brooks
J, Bauer PJ, Marks WJ, Jr., Montgomery RR. The effect of ABO blood group on the
diagnosis of von Willebrand disease. Blood 1987 Jun;69(6):16911695. |
Adult blood donors in southeast
Wisconsin |
Cohort of blood donors (n = 1,117)
to define levels of VWF:Ag relative to ABO groups |
ABO blood group and VWF:Ag. |
Level of VWF:Ag is affected by ABO
blood type. Group O is lowest in VWF:Ag. |
Study of 142 persons with known VWD
showed that 88% of patients who had type 1 VWD (n = 114) had blood group O (vs.
45% expected frequency). VWD diagnoses were based on measuring VWF:Ag,
VWF:RCo, and FVIII, with supplemental VWF multimer assay. |
Rodeghiero F, Castaman
G, Dini E. Epidemiological investigation of the prevalence of von
Willebrand’s disease. Blood 1987Feb;69(2): 454459. |
Italian children who were 1114
years old from 2 communities (n = 1,218 participants) |
Populationbased cohort using
questionnaire about personal and family history of bleeding, and blood sample
for testing |
Blood group (ABO) and VWF:RCo as
primary laboratory measures, with supplemental VWF:Ag, FVIII, and VWF multimer
analysis for selected cases. Family history of bleeding over 3
generations. |
Prevalence is 10/1,218 = 0.82 with
allowance for different reference ranges for blood group O vs. non‑O.
Suggest using ristocetin cofactor for screening in those who have
bleeding problems even if usual screening is normal. |
Small sample for a rare condition.
Of those who had findings consistent with VWD (all had type 1 VWD), nearly all
had minimally or borderline decreased VWF:RCo. |
VWF, von Willebrand factor; VWF:Ag, von Willebrand
factor antigen; VWF:CB, von Willebrand factor collagen-binding activity;
VWF:RCo, von Willebrand factor ristocetin cofactor activity Back to Top
Evidence Table 3. Recommendation
II.C.1.a
The first set of
additional tests may include evaluation of ratio of VWF activity (VWF:RCo
and/or VWF:CB) to VWF:Ag (only in laboratories that have defined reference
ranges for the ratio(s)) Grade B, level III
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Dean JA, Blanchette VS,
Carcao MD, Stain AM, Sparling CR, Siekmann J, Turecek PL, Lillicrap D, Rand ML.
von Willebrand disease in a pediatric-based populationcomparison of type
1 diagnostic criteria and use of the PFA-100® and a von
Willebrand factor/collagen-binding assay. Thromb Haemost 2000
Sep;84(3):401-409. |
53 children (1.517 years old)
registered at Bleeding Disorders Clinic of Hospital for Sick Children, Toronto,
and 47 relatives Control group was 58 healthy children (2.517
years old) |
Compared diagnostic criteria for VWD
from Hospital for Sick Children with ISTH provisional consensus criteria |
Bleeding history and laboratory
testing, including an assessment of the sensitivity of PFA-100®
and VWF:CB for diagnosis of VWD. |
Used ratio of VWF:Ag/ VWF:CB >3
as criterion for type 2 VWD.
13 patients had ratio >3, and 12 of
these had type 2 VWD by criteria and the other had severe type 1 VWD.
PFA-100® had higher sensitivity than bleeding time for VWD, and
VWF:CB performed as well as VWF:RCo. The Hospital for Sick Children
criteria were more sensitive than the provisional ISTH criteria for diagnosing
VWD. |
Study not designed to evaluate
diagnostic validity of ratio in diagnosis, but reported results for ratio.
Used ratio of VWF:Ag/ VWF:CB and did not report the ratio of
VWF:RCo/VWF:Ag. |
Favaloro EJ, Bonar R,
Kershaw G, Sioufi J, Hertzberg M, Street A, Lloyd J, Marsden K. Laboratory
diagnosis of von Willebrand's disorder: quality and diagnostic improvements
driven by peer review in a multilaboratory test process. Haemophilia 2004
May;10(3):232-242. |
45 laboratories from Australia, New
Zealand, Southeast Asia participating in multilaboratory surveys for VWD |
2 sets of 4 masked samples,
including both normal and VWD plasma, were sent to each laboratory for
evaluation using each laboratory’s tests for diagnosis of VWD |
Laboratory testing including
VWF:RCo, VWF:Ag, and FVIII activity in approximately 95% of laboratories. |
Ratio of VWF:Ag/VWF: RCo >2
utilized for presumptive diagnosis in type 2A sample. Ratio >2 not
obtained by 7 laboratories. |
Study not designed to evaluate
diagnostic validity of ratio in diagnosis, but reported results for ratio.
Only 1 sample with type 2 VWD assessed; no type 2B or 2M plasma
tested. |
Federici AB, Canciani
MT, Forza I, Cozzi G. Ristocetin cofactor and collagen binding activities
normalized to antigen levels for a rapid diagnosis of type 2 von Willebrand
disease. Single center comparison of four different assays. Thromb Haemost 2000
Dec;84(6):1127-1128. |
Single laboratory study to evaluate
VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag to distinguish type 1 from type 2 VWD |
72 previously diagnosed VWD patients
who had type 1 or type 2A, 2B, or 2M VWD 27 normal blood donors served
as controls |
Laboratory testing including
homemade and commercial ("ELISA VWF Activity" by Shield) VWF:RCo, and homemade
and commercial ("Immunozyme VWF:CB" by ImmunoBaxter) VWF:CB kits. |
Ratio of both VWF:RCo/VWF:Ag and
VWF:CB/VWF:Ag using homemade assays was sensitive (92% and 88%, respectively)
and specific (84% and 95%) for diagnosis of type 2 VWD. Cutoff for
ratios for normal subjects was 0.7. Neither commercial kit was
sensitive, although both were specific. |
Study designed to evaluate the
utility of VWF activity/antigen ratios for diagnosis of types 2A, 2B, or 2M
VWD. Usefulness of ratio depends on the particular assay used in a
given laboratory. |
Hillery CA, Mancuso DJ,
Sadler JE, Ponder JW, Jozwiak MA, Christopherson PA, Cox GJ, Paul SJ,
Montgomery RR. Type 2M von Willebrand disease: F606I and I662F mutations in the
glycoprotein Ib binding domain selectively impair ristocetinbut not
botrocetin-mediated binding of von Willebrand factor to platelets. Blood 1998
Mar;91(5):1572-1581. |
2 families with disproportionately
low VWF:RCo/VWF:Ag |
Identified 2 families, from large
screening study, with decreased VWF:RCo/VWF:Ag |
Laboratory testing including VWF:RCo
using fresh platelets and ristocetin, VWF:Ag using Laurell electrophoresis, VWF
multimer gel electrophoresis. Gene sequencing in 2 families. |
Identified 2 families as having type
2M VWD using ratio of VWF:RCo/ VWF:Ag more than 2 SD lower than 681 previously
tested individuals and confirmed by gene sequencing. |
Study not designed to evaluate
diagnostic validity of ratio in diagnosis, but reported results for ratio.
Only 2 families studied. |
Mancuso DJ, Kroner PA,
Christopherson PA, Vokac EA, Gill JC, Montgomery RR. Type 2M: Milwaukee1
von Willebrand disease: an inframe deletion in the Cys509-Cys695 loop of
the von Willebrand factor A1 domain causes deficient binding of von Willebrand
factor to platelets. Blood 1996;88:2559. |
3 generations of a family with 5
affected members and 681 VWD control subjects who had VWF:Ag <50 and normal
VWF multimers |
Clinical and laboratory evaluation
of patients who had type 1 VWD and family who had type 2M VWD |
Laboratory testing including VWF:RCo
using platelets and VWF:Ag using Laurell immunoelectrophoresis. Confirmed
abnormality in family members affected by gene sequencing. |
Ratio of VWF:RCo/ VWF:Ag for 681
control subjects with type 1 VWD reported as ~0.781.27. Family
members who had type 2M VWD had ratio of <0.4. |
Study provides ratio of
VWF:RCo/VWF:Ag for large numbers of patients who have type 1 VWD to establish
reference range for ratio for this group. At present, however, very
few laboratories use this method for VWF:Ag determination. |
Nitu-Whalley IC, Riddell
A, Lee CA, Pasi KJ, Owens D, Enayat MS, Perkins SJ, Jenkins PV. Identification
of type 2 von Willebrand disease in previously diagnosed type 1 patients: a
reappraisal using phenotypes, genotypes and molecular modelling. Thromb Haemost
2000 Dec;84(6):9981004. |
111 patients who had type 1 VWD at
the Royal Free Haemophilia Centre; subgroup of 30 identified with
VWF:RCo/VWF:Ag<0.7 |
Evaluation to determine whether some
patients who had previously diagnosed type 1 VWD may have type 2 VWD |
Laboratory testing including VWF:RCo
using fresh platelets and ristocetin, and also using mouse anti-VWF binding
site for GPIb receptor in ELISA format (VWF:Ac). ELISA used for
VWF:Ag. Gene sequencing in selected patients. |
Ratio of VWF:RCo/ VWF:Ag was <0.7
in 7 (of 17) kindreds using assay with fresh platelets. VWF activity
using ELISA for GPIb binding site (VWF:Ac) detected only 1 of these 7 kindreds.
Used gene sequencing to confirm patients who had type 2 VWD. |
Study not designed to evaluate
diagnostic validity of ratio in diagnosis, but reported results for ratio.
VWF:RCo/VWF:Ag ratio <0.7 more sensitive for diagnosis of type 2A, 2B,
or 2M VWD than VWF:Ac/VWF:Ag (binding to GPIb) for detection of type 2 VWD.
Small numbers of patients. |
ELISA, enzyme-linked immunosorbent assay; GPIb,
glycoprotein Ib; ISTH, International Society on Thrombosis and Haemostasis;
PFA-100®, platelet function analyzer; VWF, von Willebrand
factor; VWF:Ac, von Willebrand factor activity; VWF:Ag, von Willebrand factor
antigen; VWF:CB, von Willebrand factor collagen-binding activity; VWF:RCo, von
Willebrand factor ristocetin cofactor activity Back to
Top
Evidence Table 4. Recommendation
II.C.1.d
The first set of
additional tests may include VWF collagen binding activity (VWF:CB)
Grade B, level IIb
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Favaloro EJ. Collagen
binding assay for von Willebrand factor (VWF:CBA): detection of von
Willebrand’s disease (VWD), and discrimination of VWD subtypes, depends
on collagen source. Thromb Haemost 2000 Jan;83(1):127135. |
Plasma samples from
wellcharacterized VWD patients who had type 1 VWD (n = 8) and type 2
variant VWD (n = 9) |
Comparison of multiple types of
collagen for VWF:CB assay, and comparison to standard VWD tests, including
VWF:RCo |
Compared discriminant power of
different collagens and power for differentiating type 1 from type 2 VWD. |
Depending on the type of collagen,
when optimized and used in conjunction with the VWF:Ag assay, the VWF:CB assay
has better discriminant power for differentiating type 1 vs. type 2 VWD than
does the VWF:RCo assay. |
Very small sample size; not
prospective. |
Favaloro EJ, Bonar R,
Kershaw G, Siufi J, Hertzberg M, Street A, Lloyd J, Marsden K. Laboratory
diagnosis of von Willebrand’s disorder: quality and diagnostic
improvements driven by peer review in a multilaboratory test process.
Haemophilia 2004;10:232242. |
45 laboratories in Australia, New
Zealand, and Southeast Asia |
Assessment of testing proficiency
for diagnostic tests for VWD, using 8 VWD testing sample sets from normal
subjects or persons who had VWD during 2003 |
Comparison of test results for
patients who had and did not have VWD. |
Initial diagnosis of VWD was usually
correct (~90%). Subtype diagnosis was aided by VWF:CB assay in
addition to other assays, clinical history, and possibly repeat testing. |
All 45 labs measured FVIII, 42
measured VWF:Ag, 32 measured VWF:RCo, and 23 measured VWF:CB to diagnose or
classify VWD. Only 3 performed VWF multimer analysis. |
Favaloro EJ, Henniker A,
Facey D, Hertzberg M. Discrimination of von Willebrands disease (VWD) subtypes:
direct comparison of von Willebrand factor collagen binding assay (VWF:CBA)
with monoclonal antibody (MAB) based VWF-capture systems. Thromb Haemost
2000;84:541547. |
Patients known to have type 1 (n =
9) VWD and type 2A and 2B (n = 11) VWD |
Comparison of laboratory testing for
diagnostic accuracy |
Compared VWF:CB assay with
platelet-based ristocetin cofactor assay and MAB-based ristocetin cofactor
assay systems. |
VWF:CB assay was better than either
platelet-based ristocetin cofactor or commercial GPIb-binding MAB assay for
identifying type 2 VWD defects. |
Very small sample size; not
prospective. |
GPIb, glycoprotein Ib; MAB, monoclonal antibody;
VWF:Ag, von Willebrand factor antigen; VWF:CB, von Willebrand factor
collagenbinding activity; VWF:RCo, von Willebrand factor ristocetin
cofactor activity Back to Top
Evidence Table 5. Recommendation
II.C.2
Studies in selected
patients, especially those who have a discordantly low FVIII activity compared
to VWF levels and who are suspected of having type 2N VWD, should include a
FVIII binding assay (VWF:FVIIIB). Grade B, level IIb
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Mazurier C, Meyer D.
Factor VIII binding assay of von Willebrand factor and the diagnosis of type 2N
von Willebrand diseaseresults of an international survey. On behalf of
the Subcommittee on von Willebrand Factor of the Scientific and Standardization
Committee of the ISTH. Thromb Haemost 1996 Aug;76(2):270274. |
56 laboratories from across the
world that specialize in VWD or hemophilia A |
Survey |
None. |
Few sites do VWF:FVIIIB assays, but
this is required to differentiate type 2N VWD from mild hemophilia A.
Testing should be done in specialized centers. |
Study does not address the
epidemiology of type 2N VWD but focuses on the methodology of testing. |
Rodgers SE, Lerda NV,
Favaloro EJ, Duncan EM, Casey GJ, Quinn DM, Hertzberg M, Lloyd JV.
Identification of von Willebrand disease type 2N (Normandy) in Australia: a
cross-laboratory investigation using different methods. Am J Clin Pathol 2002
Aug;118(2):269276. |
101 selected patients who had
suspected or known FVIII defects 5 specialized centers in
Australia |
After preliminary testing, samples
from 31 patients were selected for detailed testing in 2 reference
laboratories |
Two-stage and one-stage FVIII
assays, VWF:Ag, VWF:RCo, VWF:CB, and VWF:FVIIIB. Mutation detection by
DNA sequencing to confirm diagnosis of type 2N VWD. |
8 patients with type 2N VWD
identified.
VWF:FVIIIB or a 2-stage assay for FVIII activity could
discriminate type 2N VWD. 1-stage assay did not perform as well as
2-stage assay. |
Not many laboratories perform a
2stage FVIII assay. |
Schneppenheim R, Budde
U, Krey S, Drewke E, Bergmann F, Lechler E, Oldenburg J, Schwaab R. Results of
a screening for von Willebrand disease type 2N in patients with suspected
haemophilia A or von Willebrand disease type 1. Thromb Haemost 1996
Oct;76(4):598602. |
Unrelated patients from Germany who
were previously diagnosed as having either hemophilia or VWD |
Assess screening program in 376
patients:
- 177 diagnosed with hemophilia
- 199 diagnosed with type 1
VWD
Compare frequency of type 2N VWD for the 2
groups |
FVIII:C, VWF:Ag, VWF:FVIIIB, and VWF
multimers. DNA sequencing to detect type 2N VWD mutations. |
5 patients thought to have
hemophilia A and 13 patients thought to have type 1 VWD were reclassified as
having type 2N VWD. VWF:FVIIIB should be performed to distinguish type
2N VWD from hemophilia A and other types of VWD. |
Results for this population
(patients at a hemostasis clinic) may not be representative of new patient
referrals. |
FVIII, [blood clotting] factor VIII; VWF:Ag, von
Willebrand factor antigen; VWF:CB, von Willebrand factor collagen-binding
activity; VWF:FVIIIB, von Willebrand factor: factor VIII binding assay;
VWF:RCo, von Willebrand factor ristocetain cofactor activity
Back to Top
Evidence Table 6. Recommendation
IV.C
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 IIa
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
de la Fuente B, Kasper
CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate
hemophilia A and von Willebrand's disease to treatment with desmopressin. Ann
Intern Med 1985 Jul;103(1):614. |
40 patients who had hemophilia A, 21
who had VWD, 5 hemophilia carriers, and 2 who had acquired FVIII inhibitors
Bleeding history and laboratory criteria for subjects |
Prospective, open-label,
nonrandomized, controlled clinical trial Informed consent given
Patient’s baseline as his/her own control |
One dose of DDAVP, 0.3 mcg/kg in 50
mL normal saline, was infused over 15 minutes. FVIII and VWF levels
drawn at 0, 0.25, 0.5, 1, 3, 5, and 24 hours. |
For patients who had VWD:
- Rise in VWF:RCo activity from
<0.2 to >10-fold baseline value.
- Rise in VWF:Ag from 0.25 to
>10-fold baseline value.
- Rise in FVIII activity from 0.2
to 8-fold baseline value.
|
This study established the value of
baseline testing because it showed that the magnitude of response could not be
predicted by baseline VWF values. 10 of 21 patients who had VWD were
in a nonbleeding state at the time of study. |
Federici AB, Mazurier C,
Berntorp E, Lee CA, Scharrer I, Goudemand J, Lethagen S, Nitu I, Ludwig G,
Hilbert L, et al. Biologic response to desmopressin in patients with severe
type 1 and type 2 von Willebrand disease: results of a multicenter European
study. Blood 2004 Mar;103(6):20322038. |
66 patients who had
well-characterized VWD defined by laboratory criteria and life-long bleeding
history:
- 26 patients had type 1 VWD
- 40 patients had type 2 VWD
Each patient had received replacement therapy
on at least 2 occasions |
Prospective, open-label,
nonrandomized, controlled clinical trial Patient’s baseline as
his/her own control Informed consent given |
One dose of DDAVP 0.3 mcg/kg in
50100mL normal saline, infused over 30 minutes. Blood drawn at
0, 0.5, 1, 2, and 4 hours. Bleeding time measured at 0 and 2
hours. |
VWF:Ag, VWF:RCo, FVIII activity, and
BT were measured. This study showed a wide degree of responses that
could not be predicted a priori. Because of stringent patient response
criteria, only 27% of persons who had type 1 VWD, 7% of persons who had type 2A
VWD, 14% of persons who had type 2M VWD, and 75% of persons who had type 2N VWD
responded for all criteria. |
Response was defined as at least a
3-fold increase in FVIII and VWF:RCo activities AND reaching at least 30 IU/dL
AND BT of 12 minutes or less. |
Mannucci PM, Canciani
MT, Rota L, Donovan BS. Response of factor VIII/von Willebrand factor to DDAVP
in healthy subjects and patients with haemophilia A and von Willebrand's
disease. Br J Haematol 1981 Feb;47(2):283293. |
15 patients who had VWD 9
patients who had mild hemophilia 10 healthy normal controls
Controlled preanalytic conditions |
VWF:Ag and FVIII activities were
measured 0, 1, 2, 4 and 6 hours after a standard dose of DDAVP Normal
controls had been given a range of dose-response prior to patient studies to
determine study dose |
DDAVP, 0.4 mcg/kg, was given over 30
minutes according to published protocol. |
VWD patients' percentage increase in
plasma VWF over baseline was similar to that of healthy controls and patients
who had hemophilia, on average. Tachyphylaxis occurred in some but not
all patients. |
Demonstrates that type 1 VWD often
responds to DDAVP and that tachyphylaxis is variable. |
Mannucci PM, Lombardi R,
Bader R, Vianello L, Federici AB, Solinas S, Mazzucconi MG, Mariani G.
Heterogeneity of type I von Willebrand disease: evidence for a subgroup with an
abnormal von Willebrand factor. Blood 1985 Oct;66(4):796802. |
17 patients who had VWD from 13
kindreds Patients had positive bleeding history and met standard
laboratory criteria; most severe patients were studied |
VWF:Ag, VWF:RCo, and FVIII activity
pre-/post-DDAVP Details not given of bleeding state at time of
study |
DDAVP, 0.4 mcg/kg, was given over 30
minutes according to published protocol. |
Response for plasma VWF:RCo differed
according to baseline platelet VWF concentration. |
Supports the utility of a DDAVP test
dose, and associates an inadequate response with qualitative VWF defects. |
Rodeghiero F, Castaman
G, Di Bona E, Ruggeri M. Consistency of responses to repeated DDAVP infusions
in patients with von Willebrand's disease and hemophilia A. Blood 1989
Nov;74(6):19972000. |
22 patients who had
well-characterized VWD were studied on 2 occasions; median time interval was 14
months 13 affected family members were studied on 1 occasion each
Bleeding history was not given |
Retrospective analysis
Comparison of DDAVP response data on 2 occasions in 22 patients
Comparison of 2 or more family members on 1 occasion in 7 kindreds
Informed consent given |
One dose of DDAVP, 0.4 mcg/kg in 100
mL normal saline, was infused over 30 minutes. FVIII activity was
measured at 0, 0.5, 1, 2, and 4 hours. BT was measured at 0, 0.5, and
2 hours. |
Consistent response, with delta of
less than 20%. |
This study established the value of
baseline testing because it showed consistent responses on repeated infusions
within patients and between patients within a kindred. |
BT, bleeding time; DDAVP, 1-desamino-8-D-arginine
vasopressin (desmopressin, a synthetic analog of vasopressin); FVIII, [blood
clotting] factor VIII; VWF, von Willebrand factor; VWF:Ag, von Willebrand
factor antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity
Back to Top
Evidence Table 7. Recommendation
VI.A
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 IIa
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Castaman G, Lattuada A,
Mannucci PM, Rodeghiero F. Factor VIII:C increases after desmopressin in a
subgroup of patients with autosomal recessive severe von Willebrand disease. Br
J Haematol 1995 Jan;89(1):147151. |
6 selected patients who had
"autosomal recessive" severe VWD |
Prospective, nonrandomized,
controlled trial |
One dose of DDAVP 0.4 mcg/kg was
infused over 30 minutes. BT and blood tests were measured at 0, 0.5, 1
hour. VWF assays were performed on some parents. |
4/6 patients showed some rise in
FVIII:C and VWF:Ag. 3/6 patients showed a small rise in VWF:RCo but no
change in BT. 1 patient successfully underwent dental extraction. |
Cases had variant type 3 VWD, as all
had some measurable baseline VWF:Ag. One or both parents were
unavailable for the study in 2/6 cases. |
Castaman G, Rodeghiero
F. Desmopressin and type IIB von Willebrand disease. Haemophilia
1996;2:7377. |
Cases of type 2B VWD treated with
DDAVP |
Literature review |
Effects of DDAVP on FVIII, VWF:Ag,
VWF:RCo, VWF multimers, BT, and platelet counts were tabulated. |
31 cases were found in 10 reports:
- In 18/23 cases, VWF:RCo was
normal postDDAVP.
- BT was shortened, sometimes to
normal.
- 5 cases underwent 4 major
operations and 3 dental extractions.
- In 5/6 procedures, platelet
counts were low postprocedure without excessive bleeding.
|
BT was normal after DDAVP in 5 of
the 7 surgical procedures tabulated. |
de la Fuente B, Kasper
CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate
hemophilia A and von Willebrand's disease to treatment with desmopressin. Ann
Intern Med 1985 Jul;103(1):614. |
21 subjects who had VWD:
- 13 had type 1 VWD
- 7 had type 2A VWD
- 1 had type 2B VWD
|
Prospective, open-label,
nonrandomized, controlled clinical trial, with patients’ baselines as
controls |
One dose of DDAVP 0.3 mcg/kg infused
over 15 minutes. FVIII and VWF levels drawn at 0, 0.25, 0.5, 1, 3, 5,
and 24 hours. BT measured pre- and post-DDAVP. |
3 subjects (1 had type 1 VWD, 2 had
type 2A VWD) who were treated for minor bleeding episodes had excellent
clinical responses and laboratory evidence of DDAVP responsiveness. |
BT was normal in 2 subjects and
shortened but not to normal in 1 subject who had type 2A VWD.
See also
comments in Evidence Table 6 for Recommendation IV.C. |
Mariana G, Ciavarella N,
Mazzucconi MG, Antoncecchi S, Solinas S, Ranieri P, Pettini P, Agrestini F,
Mandelli F. Evaluation of the effectiveness of DDAVP in surgery and in bleeding
episodes in haemophilia and von Willebrand's disease. A study on 43 patients.
Clin Lab Haematol 1984;6(3):229238. |
20 patients who had type 1 or type 2
VWD 5 were treated for 8 episodes of mild to moderate bleeding |
Open-label, nonrandomized controlled
study of DDAVP infusion, as well as tranexamic acid (oral or intravenous) in 7
of the 8 episodes |
One or more doses of DDAVP 0.3 or
0.4 mcg/kg infused intravenously over 2030 minutes. Baseline BT,
FVIII:C, VWF:RCo. VWF:RCo and FVIII:C at 1 hour postinfusion. |
5 patients showed good clinical
responses in all 8 episodes. |
Cases varied as to type of bleeding
(epistaxis, muscle hematoma, menometrorrhagia, placental detachment), number
and dose of DDAVP infusions, and use of tranexamic acid. |
Revel-Vilk S, Schmugge
M, Carcao MD, Blanchette P, Rand ML, Blanchette VS. Desmopressin (DDAVP)
responsiveness in children with von Willebrand disease. J Pediatr Hematol Oncol
2003 Nov;25(11):874879. |
75 children who had VWD:
- 70 had type 1 VWD, (43 males, 27
females)
- 5 had type 2A VWD
|
Retrospective, single institution
review of records (19892001) |
One dose of DDAVP 0.3 mcg/kg infused
over 20 minutes, with pre- and postinfusion blood sampling for FVIII:C and
VWF:RCo. |
DDAVP responsiveness was
agerelated. 26 of 28 DDAVP responders had good clinical outcomes
with DDAVP treatment. |
All cases, except hematuria,
received tranexamic acid for bleeding episodes.
Details on types of
bleeding in the good outcomes category were not reported. |
BT, bleeding time; DDAVP, 1-desamino-8-D-arginine
vasopressin (desmopressin, a synthetic analog of vasopressin); FVIII, [blood
clotting] factor VIII; FVIII:C, factor VIII coagulant activity; VWF, von
Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von
Willebrand factor ristocetin cofactor activity Back to
Top
Evidence Table 8. Recommendation
VI.C
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 III
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
de la Fuente B, Kasper
CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate
hemophilia A and von Willebrand's disease to treatment with desmopressin. Ann
Intern Med 1985 Jul;103(1):614. |
13 patients who had type 1 VWD
7 patients who had type 2A VWD 1 patient who had type 2B VWD |
Prospective, open-label,
nonrandomized, controlled clinical trial |
5 patients had dental surgery with
DDAVP x 1 and epsilon aminocaproic acid for 35 days. 4 patients
had minor surgery with DDAVP. |
5/5 dental patients had good
hemostasis with VWF:RCo 22115 IU/dL (only 1 <50 IU/dL).
4/4
surgical patients had good hemostasis with VWF:RCo 57132 IU/dL. |
9/9 patients who had dental
extractions/ minor surgeries had good hemostasis; 8/9 patients achieved 50
IU/dL VWF:RCo. |
Federici AB, Sacco R,
Stabile F, Carpenedo M, Zingaro E, Mannucci PM. Optimising local therapy during
oral surgery in patients with von Willebrand disease: effective results from a
retrospective analysis of 63 cases. Haemophilia 2000 Mar;6(2):7177. |
63 consecutive patients who had VWD:
- 31 had type 1
- 22 had type 2
- 10 had type 3
|
Retrospective, single-center review
of using a standard regimen for 4 years |
All subjects underwent intravenous
DDAVP trial with 0.3 mcg/kg. Response was defined as an increase to 3x
baseline VWF:RCo and FVIII to a minimum of 30 IU/dL and a BT of 12 minutes or
less. Topical and oral tranexamic acid x 7 days, plus DDAVP
subcutaneous x 1 in responsive patients who had type 1 and 2A VWD, plus topical
fibrin glue x 1 if >2 extractions or >4 periodontal flaps, +/
Haemate-P® x 1 for some patients who had type 2B and type 3
VWD. |
Good hemostatic control in all but 2
cases (1 type 2B VWD, 1 type 3 VWD) who required additional therapy.
Local therapy alone in 47.6%. Local plus single dose DDAVP in
42.8%. Local plus VWF concentrate in 9.5%. |
Meticulous surgical technique by
experienced oral surgeons and close collaboration with expert hematologists are
likely to have contributed to the excellent outcomes. |
Nitu-Whalley IC,
Griffioen A, Harrington C, Lee CA. Retrospective review of the management of
elective surgery with desmopressin and clotting factor concentrates in patients
with von Willebrand disease. Am J Hematol 2001 Apr;66(4):280284. |
65 patients who had VWD and
underwent 103 operations |
Retrospective, single-center summary
of cases using similar regimens for 10 years |
Most patients had a DDAVP test
infusion preoperatively and were considered "responders" if FVIII/VWF >50
IU/dL. DDAVP x 1 or 2, or CFC. Tranexamic acid 4 x a day for
710 days, for 38% of surgeries. |
DDAVP for 10 minor surgeries, median
2 doses, range 16. VWF concentrate for 26 minor surgeries,
median load 48 IU/dL (range 1470); follow-up dose 26 IU/kg (range
2437); median days of treatment 4 (range 116). Bleeding
requiring further VWF concentrate in 4/36 minor surgeries. |
Most patients had a DDAVP test
infusion preoperatively, and tranexamic acid plus DDAVP was effective for those
patients. Dose and type of CFC were quite variable. |
Revel-Vilk S, Schmugge
M, Carcao MD, Blanchette P, Rand ML, Blanchette VS. Desmopressin (DDAVP)
responsiveness in children with von Willebrand disease. J Pediatr Hematol Oncol
2003 Nov;25(11):874879. |
70 children who had type 1 VWD; 5
children who had type 2A VWD |
Retrospective review; no control or
comparison group |
All subjects underwent intravenous
DDAVP (0.3 mcg/kg) treatment trial with laboratory response defined as increase
of 2x in VWF:RCo and to at least 30 IU/dL. Children were treated with
DDAVP for minor surgeries and additionally received tranexamic acid, except for
children with hematuria. |
26/28 children who had laboratory
responses had adequate clinical hemostasis when DDAVP was used to prevent or
treat bleeding. 6/8 children who did not respond to DDAVP challenge
also required VWF concentrate following unsuccessful use of DDAVP
clinically. |
In this study, children were defined
as laboratory responders if they increased VWF:RCo and FVIII at least 2-fold
over baseline and to at least 30 IU/dL. All cases, except in cases of
hematuria, used tranexamic acid along with DDAVP. |
BT, bleeding time; CFC, clotting factor concentrate;
DDAVP, 1-desamino-8-D-arginine vasopressin; FVIII, [blood clotting] factor
VIII; VWF:RCo, von Willebrand factor ristocetin cofactor activity
Back to Top
Evidence Table 9. Recommendation
VI.D
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
III
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Jimenez-Yuste V, Prim
MP, De Diego JI, Villar A, Quintana M, Rabanal I, Sastre N, Hernandez-Navarro
F. Otolaryngologic surgery in children with von Willebrand disease. Arch
Otolaryngol Head Neck Surg 2002 Dec;128(12): 13651368. |
41 children who had preoperative
confirmed diagnosis of type 1 VWD |
Prospective, single institution
controlled study |
37 children treated with DDAVP 0.3
mcg/kg, based on laboratory response to trial dosing. All treated
preoperatively and at 24 hours, and some daily up to 4 days. 4
children treated with Haemate-P® secondary to history of
seizures. All received tranexemic acid for 7 days. |
2/37 (5%) treated with DDAVP had
bleeding requiring intervention, not predicted by preoperative response to
trial dose. |
Mild hyponatremia was found in 24/24
given DDAVP for more than 1 day, and in 3/13 who were given DDAVP for 1 day.
Seizures occurred in 1/2 patients with severe hyponatremia, both after
2 doses. |
Kreuz W, Mentzer D,
Becker S, Scharrer I, Kornhuber B. Haemate-P® in children with
von Willebrand disease. Haemostasis 1994 Sep; 24(5):304310. |
Children who had VWD:
- 183 had type 1
- 1 had type 2A
- 14 had type 3
|
Retrospective review of data from a
single center |
DDAVP testing: 23-fold
increase in VWF:RCo, VWF:Ag, and FVIII. CFC: therapy based on
monitoring following 50 IU/kg. 64 surgeries, mostly tonsillectomy and
adenoidectomy. 12 children who underwent tonsillectomy and
adenoidectomy were given DDAVP twice daily for 3 days. 52 children
underwent surgery with Humate-P® for at least 3 days:
- Children who had type 1 VWD
received 1030 IU/kg twice daily.
- Children who had type 2A VWD
received 2030 IU/dL once or twice daily.
- Children who had type 3 VWD
received 2050 IU/dL once or twice daily.
|
2/12 had
postoperative bleeding and required CFC. No bleeding. |
All children treated with DDAVP had
a 23-fold increase in VWF:RCo, VWF:Ag, and FVIII activity.
Children treated with Humate-P® showed a halftime of 12
hours for FVIII, 10 hours for VWF:RCo. There was a 17% failure rate
(postoperative bleeding) for tonsillectomy and adenoidectomy surgery with
DDAVP, but no failures with Humate-P®. |
Nitu-Whalley IC,
Griffioen A, Harrington C, Lee CA. Retrospective review of the management of
elective surgery with desmopressin and clotting factor concentrates in patients
with von Willebrand disease. Am J Hematol 2001 Apr;66(4):280284. |
65 patients who had VWD and
underwent 103 operations |
Retrospective, single-center summary
of cases using similar regimens for 10 years |
Most patients had a DDAVP test
infusion preoperatively and were considered "responders" If FVIII/VWF >50
IU/dL. DDAVP x 1 or 2, or CFC. Tranexamic acid 4 x a day for
710 days, for 38% of surgeries. |
DDAVP for 10 minor surgeries, median
1.5 days, range 16. VWF concentrate for 26 minor surgeries,
median 4 days of treatment (range 116). Bleeding requiring
further VWF concentrate in 4/36 minor surgeries. |
Most patients had a DDAVP test
infusion preoperatively, and tranexamic acid plus DDAVP was effective for
patients who demonstrated increase in FVIII and VWF to >50 IU/dL on
preoperative DDAVP trial. Patients were routinely monitored for FVIII
activity following surgery (normal range achieved in all but 1 patient, who
achieved 38 IU/dL after DDAVP). Dose and type of CFC were quite
variable. |
Thompson AR, Gill JC,
Ewenstein BM, Mueller-Velten G, Schwartz BA. Successful treatment for patients
with von Willebrand disease undergoing urgent surgery using factor VIII/VWF
concentrate (Humate-P®). Haemophilia 2004
Jan;10(1):4251. |
Patients who had VWD:
- 16 had type 1 VWD
- 4 had type 2A VWD
- 5 had type 2B VWD
- 8 had type 3 VWD
- 6 had type 2M, 2N, or unknown
VWD
|
Prospective, multicenter,
open-label, nonrandomized clinical trial |
42 surgeries (17 minor).
VWF concentrate, mean loading dose 82.3 IU/dL. Median duration for
all 42 surgeries was 3 days. |
39 evaluable surgical events rated
Excellent/Good. |
Patients who had type 3 VWD were
treated for longer durations; no relationship between VWD type and loading or
maintenance dose. 17 minor surgeries presumably accounted for most or
all of the 16 cases treated 14 days. |
CFC, clotting factor concentrate; DDAVP,
1-desamino-8-D-arginine vasopressin; FVIII, [blood clotting] factor VIII; VWF,
von Willebrand factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von
Willebrand factor ristocetin cofactor avtivity Back to
Top
Evidence Table 10. Recommendation
VI.F
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 IIb
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Castaman G, Lattuada A,
Mannucci PM, Rodeghiero F. Factor VIII:C increases after desmopressin in a
subgroup of patients with autosomal recessive severe von Willebrand disease. Br
J Haematol 1995 Jan;89(1):147151. |
A single patient who had "autosomal
recessive" severe VWD Within a study of 6 patients who had severe
autosomal recessive VWD |
Single case report within a
prospective, nonrandomized, controlled trial |
Four doses of DDAVP (0.4 mcg/kg)
were infused over 30 minutes given every 6 hours, plus oral tranexamic acid (1
g, 3 times a day) for 5 days. |
Patients showed rise of VWF:Ag 0.5
to 9, VWF:RCo <3 to 11, and FVIII 19 to 70 IU/dL following DDAVP. 1
patient successfully underwent dental extraction without bleeding. |
Cases were variant type 3 VWD, as
all had some measurable baseline VWF:Ag. |
de la Fuente B, Kasper
CK, Rickles FR, Hoyer LW. Response of patients with mild and moderate
hemophilia A and von Willebrand's disease to treatment with desmopressin. Ann
Intern Med 1985 Jul;103(1):614. |
21 subjects who had VWD:
- 13 had type 1 VWD
- 7 had type 2A VWD
- 1 had type 2B VWD
|
Prospective, open-label,
nonrandomized, controlled clinical trial |
One dose of DDAVP (0.3 mcg/kg)
infused over 15 minutes.
EACA given before and for 35 days
following dental procedure. |
Six dental procedures in 5 subjects
(4 type 1 VWD, 1 type 2A VWD). Excellent hemostasis in all 5 subjects,
including 4 subjects who had a rise in VWF:RCo to 66115 IU/dL and 1
subject who had a small rise in VWF:RCo from 1022 IU/dL. |
Pharmacokinetic studies of VWF:RCo,
VWF:Ag, FVIII activity, and FVIII:Ag following DDAVP in 13 patients who had VWD
showed rapid return almost to baseline values within 5 hours in 5 patients and
persistently elevated levels up to 5 hours in 8 patients. |
Federici AB, Sacco R,
Stabile F, Carpenedo M, Zingaro E, Mannucci PM. Optimising local therapy during
oral surgery in patients with von Willebrand disease: effective results from a
retrospective analysis of 63 cases. Haemophilia 2000 Mar;6(2):7177. |
63 consecutive patients who had VWD:
- 31 had type 1
- 22 had type 2
- 10 had type 3
|
Retrospective, single-center review
of using a standard regimen for 4 years |
Topical and oral tranexamic acid x 7
days, plus DDAVP subcutaneous x 1 in responsive patients who had type 1 and
type 2A VWD, plus topical fibrin glue x 1 if >2 extractions or >4
periodontal flaps, +/ Haemate-P® x 1 for some patients who
had type 2B and type 3 VWD. |
Good hemostatic control in all but 2
cases (1 type 2B VWD, 1 type 3 VWD), who required additional therapy. |
Meticulous surgical technique by
experienced oral surgeons and close collaboration with expert hematologists are
likely to have contributed to the excellent outcomes. |
Mariana G, Ciavarella N,
Mazzucconi MG, Antoncecchi S, Solinas S, Ranieri P, Pettini P, Agrestini F,
Mandelli F. Evaluation of the effectiveness of DDAVP in surgery and in bleeding
episodes in haemophilia and von Willebrand's disease. A study on 43 patients.
Clin Lab Haematol 1984;6(3):229238. |
9 patients who had type 1 or type 2
VWD |
Dental extractions performed on a
standard protocol |
12 dental extractions in 9 patients.
2 regimens: DDAVP 0.3 or 0.4 mcg/kg x1 infusion and tranexamic acid IV
for 12 hours and then 3 times a day to complete 7 days OR DDAVP given
preoperatively, at 24 hours, and when sutures were removed, and tranexamic acid
IV for 2 days and then orally for 6 days. Tranexamic acid IV (80
mg/kg/day) for 2 days and then orally (100 mg/kg/day) for 6 days. |
No bleeding. |
FVIII activity was measured pre/post
DDAVP in 5 patients who had VWD, and all had response to >100 U/dL. |
Nitu-Whalley IC,
Griffioen A, Harrington C, Lee CA. Retrospective review of the management of
elective surgery with desmopressin and clotting factor concentrates in patients
with von Willebrand disease. Am J Hematol 2001 Apr;66(4):280284. |
65 patients who had VWD and
underwent 103 operations, including 37 dental procedures |
Retrospective, single-center summary
of cases using similar regimens for dental surgery for 10 years |
Tranexamic acid 4x/day for 710
days, plus DDAVP x 1 or 2, or CFC. |
1 patient who had type 3 VWD re-bled
postoperatively. All others had good outcomes to initial treatment
plan. |
Most patients had a DDAVP test
infusion preoperatively, and tranexamic acid plus DDAVP was effective for those
patients. Dose and type of CFC were quite variable. |
Rodeghiero F, Castaman
G, Di Bona E, Ruggeri M, Lombardi R, Mannucci PM. Hyper-responsiveness to DDAVP
for patients with type 1 von Willebrand's disease and normal intra-platelet von
Willebrand factor. Eur J Haematol 1988 Feb;40(2):163167. |
Patients who had severe type 1 VWD
All subjects had VWF:RCo <3 IU/dL prior to DDAVP, and 36110
IU/dL 3060 minutes after infusion |
Prospective, nonrandomized,
open-label clinical trial Control: All subjects had bleeding with
previous dental extractions |
DDAVP: 0.4 mcg/kg 30 minutes prior
to and test dose 2 weeks prior to procedure. A second
dose was given at 68 hours. All subjects received tranexamic
acid 1 g 3 times a day orally. |
2/9 patients had delayed bleeding, 3
and 7 days after tooth extraction, necessitating an additional dose of
DDAVP. |
All patients had baseline VWF:RCo
<3 U/dL, VWF:Ag ≤10 U/dL, and FVIII activity ≤20 U/dL with
normal platelet VWF. Post-DDAVP: plasma VWF:RCo >65, VWF:Ag >35,
FVIII >65 U/dL, and normal BT were documented in all subjects. |
Saulnier J, Marey A,
Horellou MH, Goudemand J, Lepoutre F, Donazzan M, Gazengel C, Torchet M, Letang
C, Schuhmann C, et al. Evaluation of desmopressin for dental extractions in
patients with hemostatic disorders. Oral Surg Oral Med Oral Pathol 1994
Jan;77(1):612. |
15 patients who had VWD:
- 14 congenital (all responsive to
DDAVP) and
- 1 AVWS
16 patients who had hemophilia A 4
others |
Retrospective, multicenter summary
of cases using similar regimens for 5 years |
DDAVP x 1 infused preoperatively and
occasionally postoperatively plus antifibrinolytic, plus fibrin glue, in 1 of 3
centers. |
Postextraction bleeding in 1 case
(patient who had AVWS). |
Patients selected by response to
DDAVP:
- >30 percent FVIII level
postinfusion.
- VWD subtypes not specified.
- Contribution of fibrin glue not
evaluable.
|
AVWS, acquired von Willebrand syndrome; CFC, clotting
factor concentrate; DDAVP, 1-desamino-8-D-arginine vasopressin; EACA, epsilon
aminocaproic acid; FVIII, [blood clotting] factor VIII; VWF, von Willebrand
factor; VWF:Ag, von Willebrand factor antigen; VWF:RCo, von Willebrand factor
ristocetin cofactor activity Back to Top
Evidence Table 11. Recommendation
VII.A
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 IIb
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Allen GC, Armfield DR,
Bontempo FA, Kingsley LA, Goldstein NA, Post JC. Adenotonsillectomy in children
with von Willebrand disease. Arch Otolaryngol Head Neck Surg 1999
May;125(5):547551. |
Adenotonsillar procedures in 67
children who had VWD 59/67 children had preoperative DDAVP trials |
Retrospective cohort |
DDAVP given once
preoperatively. |
7/67 had immediate bleeding but none
required intervention; 2/7 went on to have delayed bleeding at 57 days.
9/67 had delayed bleeding on days 512 (mean 7.7); all were
admitted to hospital; 4 required cauterization (all tonsillectomy).
3/67 had substantial hyponatremia. 1/67 had seizures. |
Children who had VWD and delayed
bleeding had significantly lower response of VWF:RCo to DDAVP than children
without delayed bleeding (P <0.03). |
Derkay CS, Werner E,
Plotnick E. Management of children with von Willebrand disease undergoing
adenotonsillectomy. Am J Otolaryngol 1996 May;17(3):172177. |
12 children who had VWD and
underwent adenotonsillectomy |
Retrospective review |
DDAVP given preoperatively, at 12
hours and daily until eschar. |
2/12 had excessive bleeding, 1 at 3
hours postoperation requiring electrocautery and a single dose of
Humate-P® (DDAVP was continued), and 1 at day 10 requiring
operative intervention. 3/12 developed hyponatremia (Na <132).
1/12 received cryoprecipitate for tachyphylaxis. |
Surgical technique included Bovie
electrocautery in 7 and scissor dissection in 5 patients. Surgical
approach did not affect outcome. |
Dobrkovska
A, Krzensk U, Chediak JR. Pharmacokinetics, efficacy and safety of
Humate-P® in von Willebrand disease. Haemophilia 1998; (4 Suppl
3):3339. |
6 patients who had VWD |
Prospective pharmacokinetic
study |
Humate-P® bolus,
single infusion of VWF:RCo 80 IU/kg, FVIII 32 IU/kg. |
Median half-time of VWF:RCo, 11.3
hours; range 6.413.3 hours. Recovery of VWF:RCo, median 2.1
IU/dL per kg; range 1.12.74. Recovery of FVIII, median 2.69
IU/dL per kg; range 1.943.65. |
Variable recovery and half-life
indicate that laboratory monitoring is important to confirm adequate factor
levels and adjust therapy if necessary. |
97 patients who had VWD and were
treated with Humate-P®:
- 32 had type 1 VWD
- 5 had type 2A VWD
- 18 had type 2B VWD
- 28 had type 3 VWD
- 14 others, including 4 who had
AVWS
344 bleeding events; 73 surgeries; 93
invasive procedures, childbirth, or test infusions; 20 episodes of
prophylaxis |
Retrospective review of 97 Canadian
patients |
Humate-P®, specific
dosing not given. |
Excellent/good response in:
- 100% of patients who had type 1
VWD.
- 100% of patients who had type 2A
VWD.
- 99% of patients who had type 2B
VWD.
- 95% in patients who had type 3
VWD.
- 95% in thosewho had conditions
including AVWS and other.
|
Adverse events were rare and not
serious. |
Federici AB. Clinical
diagnosis of von Willebrand disease. Haemophilia 2004 Oct;10 (Suppl
4):169176. |
26 patients who had type 1 VWD
40 patients who had type 2 VWD |
Prospective, controlled trial, not
randomized |
DDAVP 0.3 mcg/kg, with laboratory
monitoring of response. |
Very variable DDAVP response,
between and within VWD subtypes. |
Well-designed nonrandomized clinical
trial. Study demonstrated lack of a priori prediction of response to
DDAVP and lower response rate in type 1 VWD than previously suspected.
Study supports need for baseline trial. |
Kreuz W, Mentzer D,
Becker S, Scharrer I, Kornhuber B. Haemate-P® in children with
von Willebrand’s disease. Haemostasis 1994 Sep;24(5):304310. |
12 children who had type 1 VWD and
tonsillectomy and adenoidectomy |
Case series |
DDAVP, all based upon preoperation
trial. DDAVP administered twice daily for 3 days. |
2/12 required VWF concentrate
replacement for bleeding. |
Children in whom DDAVP treatment
failed were successfully treated with Haemate-P®. |
Manno CS, Bulter RB,
Cohen AR. Successful management of patients with type 1 von Willebrand's
disease with desmopressin acetate for tonsillectomy (abstract). Haemophilia
1998;4:288. |
13 children who had type 1 VWD and
tonsillectomies or adenoidectomies |
Retrospective cohort |
DDAVP 0.3 mcg/kg IV, preoperation,
12 hours (12/13), (2436 hours in 3/12), and a third/fourth dose at
57 days (11/13). Epsilon aminocaproic acid in 50%. |
13/13 had no bleeding or other
treatment. |
2 infusions of DDAVP on day of
surgery and 1 followup at 57 days may be adequate for tonsillectomy and
adenoidectomy in children who have VWD and are responsive to DDAVP. |
Rodeghiero F, Castaman
G, Di Bona E, Ruggeri M. Consistency of responses to repeated DDAVP infusions
in patients with von Willebrand's disease and hemophilia A. Blood 1989
Nov;74(6):19972000. |
14 patients who had severe type 1
VWD and normal platelet VWF |
Case series |
DDAVP, 0.4 mcg/kg. All had
preoperation trial. |
14/14 increased VWF:RCo from <3
to 64120 IU/dL. No bleeding complications. |
Case series showed efficacy of DDAVP
in patients who have severe type 1 VWD and positive trial responses. |
Shah SB, Lalwani AK,
Koerper MA. Perioperative management of von Willebrand's disease in
otolaryngologic surgery. Laryngoscope 1998 Jan;108(1 Pt 1):3236. |
8 had type 1 VWD 3 had type
2A VWD 4 children had tonsillectomy and adenoidectomy; 1 child had
adenoidectomy alone |
Case series |
DDAVP preoperation and at 24 hours.
IV then oral antifibrinolytic therapy. |
5/5 children who had
tonsilloadenectomy procedures had no bleeding. |
Importance of meticulous surgical
technique was emphasized. Delayed therapy with DDAVP was not given,
but sample size is very small. |
AVWS, acquired von Willebrand syndrome; DDAVP,
1-desamino-8-D-arginine vasopressin (desmopressin, a synthetic analog of
vasopressin); FVIII, [blood clotting] factor VIII; VWF, von Willebrand factor;
VWF:RCo, von Willebrand Factor ristocetin cofactor activity Back to Top
Evidence Table 12. Recommendation
VII.C
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 III
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Dobrkovska
A, Krzensk U, Chediak JR. Pharmacokinetics, efficacy and safety of
Humate-P® in von Willebrand disease. Haemophilia 1998;(4 Suppl
3):3339. |
6 patients who had VWD (2 each had
type 1, 2A, 3) for prospective pharmacokinetic study |
Prospective pharmacokinetic
study |
Pharmacokinetic studies were
performed for each patient given 80 IU/kg VWF:RCo and 32 IU/kg FVIII. |
Median plasma values for VWF:RCo,
VWF:Ag, and FVIII were maintained above 50 IU/dL for 48 hours. |
|
73 patients who had VWD and were
having surgery |
Retrospective data collection |
VWF concentrate
(Humate-P®) 80 IU/kg bolus and continuous infusion. |
72/73 Excellent/good
hemostasis. |
Duration of therapy for surgery not
given. |
Gill JC, Ewenstein BM,
Thompson AR, Mueller-Velten G, Schwartz BA, for the Humate-P®
study group. Successful treatment of urgent bleeding in von Willebrand disease
with factor VIII/VWF concentrate (Humate-P®): use of the
ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy.
Haemophilia 2003;9:688695. |
33 patients who had congenital VWD
(9 type 1, 4 type 2A, 4 type 2B, 12 type 3, 4 unspecified VWD), treated for
urgent bleeding episodes (n = 53 episodes) |
Prospective open-label,
nonrandomized study of patients from 19 participating centers |
Initial Humate-P®
bolus 6080 IU VWF:RCo/kg, followed by intermittent bolus maintenance
infusions (4060 IU VWF:RCo/ kg) at 812 hour intervals for 3 days,
with supplemental daily dosing if needed up to 7 days total, with target nadir
above 50 IU/dL VWF:RCo. |
91% of patients (48 bleeding
episodes) had complete followup. Efficacy 98% excellent/good for 53
bleeding episodes. |
|
Hanna WT, Bona RD,
Zimmerman CE, Carta CA, Hebert GZ, Rickles FR. The use of intermediate and high
purity factor VIII products in the treatment of von Willebrand disease. Thromb
Haemost 1994 Feb;71(2):173179. |
5 patients who had VWD |
Prospective, open-label,
nonrandomized clinical trial |
5 surgeries treated with Koate,
20100 IU/kg load and continuous infusion. |
5/5 had no surgical bleeding. |
All patients treated with Koate and
maintaining VWF:RCo >50 IU/dL had excessively high VWF:Ag (400800
IU/dL) and 2/5 had FVIII activity >400 IU/dL. |
Kreuz W, Mentzer D,
Becker S, Scharrer I, Kornhuber B. Haemate-P® in children with
von Willebrand’s disease. Haemostasis 1994 Sep;24(5):304310. |
Children who had congenital VWD (183
type 1, 1 type 2A, 14 type 3) as well as valproate-associated acquired von
Willebrand syndrome (91 children) |
Retrospective review, single
center |
41 surgeries in patients who had
congenital VWD, treated with Haemate-P® (38 type 1, 3 type 3)
generally for at least 3 days once or twice daily (1020 IU FVIII/kg for
type 1 VWD and 2050 IU FVIII/kg for type 3 VWD). |
Excellent/Good 41/41. |
Most surgeries were oral procedures
(tonsillectomy and adenoidectomy). 17% failure rate with DDAVP but
none with Haemate-P®. |
Lillicrap D, Poon MC,
Walker I, Xie F, Schwartz BA. Efficacy and safety of the factor VIII/von
Willebrand factor concentrate, Haemate-P/Humate-P: ristocetin cofactor unit
dosing in patients with von Willebrand disease. Thromb Haemost 2002
Feb;87(2):224230. |
Patients who had type 1, 2, or 3
VWD |
Retrospective data review |
73 surgeries, types not
specified. VWF concentrate (Humate-P®), loading dose
mean 69.1 VWF:RCo IU/kg |
Excellent/Good 72/73. |
Trough levels not given.
10% of surgeries were treated 710 days (the rest fewer).
Presumably these were the major surgeries, but not specified. Only
55% of surgery patients were treated more than 1 day. |
Lubetsky A, Schulman S,
Varon D, Martinowitz U, Kenet G, Gitel S, Inbal A. Safety and efficacy of
continuous infusion of a combined factor VIII-von Willebrand factor (vWF)
concentrate (Haemate-P®) in patients with von Willebrand
disease. Thromb Haemost 1999 Feb;81(2):229233. |
8 patients who had various types of
VWD |
Retrospective review |
9 surgeries in 8 patients.
Mean loading dose 39.5 VWF:RCo IU/dL (range 3151) followed by
continuous infusion 2 IU/kg/hr. Trough level maintained above 50 IU/dL
VWF:RCo. Mean duration of therapy 9.1 days, range 512. |
1/8 with excessive surgical bleeding
(total hip replacement with 2,400 mL blood loss with inadequate levels of
VWF:RCo). |
Troughs and durations were reported
for this study. |
Michiels JJ, Berneman
ZN, van der Planken M, Schroyens W, Budde U, van Vliet HDM. Bleeding
prophylaxis for major surgery in patients with type 2 von Willebrand disease
with an intermediate purity factor VIIIVWF concentrate
(Haemate-P®). Blood Coagul Fibrinolysis. 2004 Jun; 15(4):
323330. |
5 patients who had type 2 VWD |
Prospective, nonrandomized,
open-label clinical trial |
Major surgery. VWF
concentrate based on pharmacokinetic studies to maintain trough VWF:RCo and
VWF:CB above 60 IU/dL: yielding recommendations for load 6080 VWF:RCo
IU/kg; 3040 IU/kg VWF:RCo every 12 hours for 57 days. |
Successful. No
bleeding? |
The meaning of the word successful
in the manuscript was not defined, but it is presumed to mean no bleeding.
Dosing was based on pharmacokinetic data. |
Nitu-Whalley I,
Griffioen A, Harrington C, Lee CA. Retrospective review of the management of
elective surgery with desmopressin and clotting factor concentrates in patients
with von Willebrand disease. Am J Hematol 2001Apr;66(4): 280284. |
27 persons who had type 1, 2, or 3
VWD |
Retrospective review |
Monitoring with FVIII levels.
DDAVP response measured by increase to at least 50 IU/dL. Major
surgery. 3 treated with DDAVP every 1248 hours, with or without
tranexamic acid.
Median duration of treatment 5 days (range 25).
10 treated with VWF concentrate. Mean preoperation dose 54
IU/kg. Followup mean, 47 IU/kg/day for median of 10 days (range
414). |
DDAVP: Poor response following
rhinoplasty that was treated for only 24 hours; hematoma following
hysterectomy. VWF concentrate: hemorrhage on day 2 after caesarean
section. |
All major surgeries treated for
510 days to levels >50 IU/dL had good outcomes. 3 patients
treated for 1 or 2 days with bleeding complications. |
Scharrer I, Vigh T,
Aygoren-Pursun E. Experience with Haemate-P® in von
Willebrand’s disease in adults. Haemostasis 1994
SepOct;24(5):298303. |
Adult patients who had types 1, 2A,
2B, or 3 VWD (140 total; numbers of each type of VWD not specified) 66
treated for bleeding events, and 70 treated for a variety of minor and major
surgical events |
Retrospective review |
Haemate-P® initial
doses 2080 IU FVIII/kg, with maintenance infusions at 12-hour intervals
(recommended), with target nadir levels 50 IU FVIII and VWF:RCo
(recommended). |
100% Excellent/Good. |
21 patients participated in
pharmacokinetic studies with Haemate-P® bolus infusion (40 IU
FVIII/kg) and demonstrated VWF:RCo increments with half-life 57
hours. |
Thompson AR, Gill JC,
Ewenstein BM, Mueller-Velten G, Schwartz BA. Successful treatment for patients
with von Willebrand disease undergoing urgent surgery using factor VIII/VWF
concentrate (Humate-P®). Haemophilia 2004
Jan;10(1):4251. |
Patients who had VWD:
- 16 had type 1 VWD
- 4 had type 2A VWD
- 5 had type 2B VWD
- 8 had type 3 VWD
- 6 had type 2M, 2N, or unknown
VWD
|
Prospective, multicenter,
open-label, nonrandomized clinical trial |
42 surgeries. VWF
concentrate, mean loading dose 82.3 IU/dL. |
39 evaluable surgical events rated
Excellent/Good. |
Patients who had type 3 VWD were
treated for longer durations. No relationship was found between VWD
type and loading or maintenance dose. |
DDAVP, 1-desamino-8-D-arginine vasopressin; FVIII,
[blood clotting] factor VIII; VWF, von Willebrand factor; VWF:Ag, von
Willebrand factor antigen; VWF:CB, von Willebrand factor collagen-binding
activity; VWF:RCo, von Willebrand factor ristocetin cofactor activity
Back to Top
Evidence Table 13. Recommendation
X.B
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 Treatment of AVWS for
discussion of this non-FDA-approved use). Grade B, level
IIa
Citation |
Population |
Study Design |
Intervention |
Results |
Comments |
Arkel YS, Lynch J,
Kamiyama M. Treatment of acquired von Willebrand syndrome with intravenous
immunoglobulin. Thromb Haemost 1994 Oct;72(4):643644. |
1 person who had AVWS, type 2A, with
MGUS |
Case report on person with prior
brief response to DDAVP |
IGIV 400 mcg/kg/day x 4 days prior
to oral surgery. No other therapy. |
Normalization of VWF:RCo, FVIII:C,
VWF:Ag, by day 3 postinfusion. Maintained to day 17. |
References include 3 previous case
reports of effective therapy of AVWS with IGIV. |
Federici AB, Stabile F,
Castaman G, Canciani MT, Mannucci PM. Treatment of acquired von Willebrand
syndrome in patients with monoclonal gammopathy of uncertain significance:
comparison of three different therapeutic approaches. Blood 1998
Oct;92(8):27072711. |
AVWS in 10 subjects who had
MGUS |
Open-label, controlled crossover
trial of IGIV infusion |
Sequential treatment with:
- Intravenous DDAVP.
- Intravenous FVIII/VWF concentrate
at 40 IU/kg.
- IGIV at 1 g/kg/day x 2 days.
|
Brief responses only to DDAVP and
FVIII/VWF concentrate. Good to excellent sustained response to
IGIV. |
Laboratory monitoring pre- and
postinfusion, up to 821 days for IGIV. Only IgG isotype, and not
IgM isotype, MGUS patients who had AWVS responded to IGIV (8/8 vs. 0/2,
respectively). |
Federici AB,
Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H, Meyer D, Rodeghiero
F, Sadler JE. Acquired von Willebrand syndrome: data from an international
registry. Thromb Haemost 2000 Aug;84(2):345349. |
|
Literature search for published
cases |
Tabulation of previously published
cases. |
266 case reports found. |
Definition of AVWS
included acquired bleeding syndrome plus laboratory evidence, by prescribed
assays, of decreased VWF activity. |
186 persons who had AVWS |
International registry of previously
unpublished cases |
Tabulation of data from detailed
questionnaires on cases submitted by ISTH members |
In 186 new cases submitted by 54
members, high-dose IGIV was effective in 21 of 63 cases (13/21 had positive
anti-VWF assay). |
Macik BG, Gabriel DA,
White GC, High K, Roberts H. The use of high-dose intravenous gamma-globulin in
acquired von Willebrand syndrome. Arch Pathol Lab Med 1988
Feb;112(2):143146. |
2 persons who had AVWS:
- 1 had MGUS
- 1 had splenic B-cell
lymphoproliferative disorder
|
Case reports of patients who had
prior poor response to DDAVP or FVIII/VWF concentrate |
IGIV 1g/kg/day x 2 days before
surgery, with no other therapy.
Laboratory monitoring to 28 days or 177
days. |
By day 2, normal levels of VWF:RCo,
VWF:Ag, and FVIII:C were achieved, and sustained for 21177 days,
respectively. |
Anti-VWF was measurable in case 1.
Case 2 apparently was cured by splenectomy. |
van Genderen PJ,
Terpstra W, Michiels JJ, Kapteijn L, van Vliet HH. High-dose intravenous
immunoglobulin delays clearance of von Willebrand factor in acquired von
Willebrand disease. Thromb Haemost 1995 May;73(5):891892. |
1 person who had AVWS, type 2A, with
MGUS |
Case report with laboratory
studies |
Assays of VWF half-life pre- and
post-IGIV therapy. |
VWF:RCo half-life <1 hour pre-,
and 14 hours post IGIV. |
Increased binding of IgG fraction
from patient plasma to immobilized VWF was shown. |
AVWS, acquired von Willebrand syndrome; DDAVP,
1-desamino-8-D-arginine vasopressin (desmopressin, a synthetic analog of
vasopressin); FVIII, [blood clotting] factor VIII; FVIII:C, factor VIII
coagulant activity; IgG, immunoglobulin G; IGIV, immune globulin intravenous
(also known as IVIG); IgM, immunoglobulin M; ISTH, International Society on
Thrombosis and Haemostasis; MGUS, monoclonal gammopathy of uncertain
significance; VWF, von Willebrand factor; VWF:Ag, von Willebrand factor
antigen; VWF:RCo, von Willebrand factor ristocetin cofactor activity
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