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The Diagnosis, Evaluation and Management of von Willebrand Disease

Evidence Tables

Evidence Table 1. Recommendation I.B.

If answers to probe questions I.B.1–8 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):217–218.	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):1409–1415.	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

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 2004,10:232–242.	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 multi–laboratory survey. Blood Coagul Fibrinolysis 2000 Dec;11(8):729–737.	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):1691–1695.	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): 454–459.	Italian children who were 11–14 years old from 2 communities (n = 1,218 participants)	Population–based 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

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 population—comparison 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 (1.5–17 years old) registered at Bleeding Disorders Clinic of Hospital for Sick Children, Toronto, and 47 relatives Control group was 58 healthy children (2.5–17 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 Immuno–Baxter) 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 ristocetin—but 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: Milwaukee–1 von Willebrand disease: an in–frame 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 ~0.78–1.27. 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):998–1004.	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

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):127–135.	Plasma samples from well–characterized 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;10:232–242.	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;84:541–547.	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 collagen–binding activity; VWF:RCo, von Willebrand factor ristocetin cofactor activity

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 disease—results 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):270–274.	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):269–276.	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 2–stage 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):598–602.	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

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):6–14.	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):2032–2038.	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 50–100mL 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):283–293.	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):796–802.	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):1997–2000.	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

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):147–151.	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;2:73–77.	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 post–DDAVP. 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):6–14.	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):229–238.	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 20–30 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):874–879.	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 (1989–2001)	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 age–related. 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

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):6–14.	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 3–5 days. 4 patients had minor surgery with DDAVP.	5/5 dental patients had good hemostasis with VWF:RCo 22–115 IU/dL (only 1 <50 IU/dL). 4/4 surgical patients had good hemostasis with VWF:RCo 57–132 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):71–77.	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):280–284.	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 7–10 days, for 38% of surgeries.	DDAVP for 10 minor surgeries, median 2 doses, range 1–6. VWF concentrate for 26 minor surgeries, median load 48 IU/dL (range 14–70); follow-up dose 26 IU/kg (range 24–37); median days of treatment 4 (range 1–16). 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):874–879.	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

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 1–5 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): 1365–1368.	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):304–310.	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: 2–3-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 10–30 IU/kg twice daily. Children who had type 2A VWD received 20–30 IU/dL once or twice daily. Children who had type 3 VWD received 20–50 IU/dL once or twice daily.	2/12 had postoperative bleeding and required CFC. No bleeding.	All children treated with DDAVP had a 2–3-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):280–284.	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 7–10 days, for 38% of surgeries.	DDAVP for 10 minor surgeries, median 1.5 days, range 1–6. VWF concentrate for 26 minor surgeries, median 4 days of treatment (range 1–16). 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):42–51.	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 1–4 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

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):147–151.	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):6–14.	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 3–5 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 66–115 IU/dL and 1 subject who had a small rise in VWF:RCo from 10–22 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):71–77.	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):229–238.	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):280–284.	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 7–10 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):163–167.	Patients who had severe type 1 VWD All subjects had VWF:RCo <3 IU/dL prior to DDAVP, and 36–110 IU/dL 30–60 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 6–8 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):6–12.	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

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):547–551.	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 5–7 days. 9/67 had delayed bleeding on days 5–12 (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):172–177.	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):33–39.	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 6.4–13.3 hours. Recovery of VWF:RCo, median 2.1 IU/dL per kg; range 1.1–2.74. Recovery of FVIII, median 2.69 IU/dL per kg; range 1.94–3.65.	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):169–176.	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):304–310.	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), (24–36 hours in 3/12), and a third/fourth dose at 5–7 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 5–7 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):1997–2000.	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 64–120 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):32–36.	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.

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 7–10 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):33–39.	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;9:688–695.	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 60–80 IU VWF:RCo/kg, followed by intermittent bolus maintenance infusions (40–60 IU VWF:RCo/ kg) at 8–12 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):173–179.	5 patients who had VWD	Prospective, open-label, nonrandomized clinical trial	5 surgeries treated with Koate, 20–100 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 (400–800 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):304–310.	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 (10–20 IU FVIII/kg for type 1 VWD and 20–50 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):224–230.	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 7–10 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):229–233.	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 31–51) 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 5–12.	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): 323–330.	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 60–80 VWF:RCo IU/kg; 30–40 IU/kg VWF:RCo every 12 hours for 5–7 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): 280–284.	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 12–48 hours, with or without tranexamic acid. Median duration of treatment 5 days (range 2–5). 10 treated with VWF concentrate. Mean preoperation dose 54 IU/kg. Followup mean, 47 IU/kg/day for median of 10 days (range 4–14).	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 5–10 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 Sep–Oct;24(5):298–303.	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 20–80 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 5–7 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):42–51.	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

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):643–644.	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):2707–2711.	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 8–21 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):345–349.		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):143–146.	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 21–177 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):891–892.	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