Guideline sources The following summarized guidelines for the evaluation and management of von Willebrand disease are prepared by our editorial team based on guidelines from the National Hemophilia Foundation (NHF/ISTH/WFH/ASH 2021) and the British Society for Haematology (BSH 2014). 1 2 3 4 4 4 5 5 6 Definition vWD is an inherited bleeding disorder that results in defective platelet adhesion and aggregation. 4 Epidemiology In most cases, vWD results from a mutation in the gene coding for vWF, a key glycoprotein in both primary and secondary hemostasis. Mutations may lead to a quantitative deficiency of vWF (70-80%), dysfunction of vWF (20%), or absence of vWF (<5%). 4 Pathophysiology Laboratory-defined vWD affects approximately 1% of the population. However, the symptomatic prevalence is estimated at 10 persons per 100,000 population. 5 Disease course https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 1/6 6/29/23, 3:44 AM Von Willebrand disease Pathway Clinical manifestations of abnormal hemostasis may include epistaxis, bleeding from minor wounds, hematomas, menorrhagia, postpartum hemorrhage, increased bleeding after surgery or dental extractions, intra-articular bleeding and life-threatening gastrointestinal bleeding from angiodysplasia. 4 Prognosis and risk of recurrence Most patients with vWD have mild bleeding and require only episodic treatment. Women with vWD may have a higher risk of postpartum hemorrhage and peripartum mortality. 5 6 Calculator Pathway Diagnostic criteria for von Willeb Von Willebrand disease Management Guidelines 1. Screening and diagnosis Indications for screening: use a validated bleeding assessment tool as an initial screening test to determine patients requiring specific blood testing in patients with a low probability of vWD (such as seen in the primary care setting). B Show 2 more Screening of family relatives: consider testing first-degree relatives with or without a positive bleeding history when a diagnosis of vWD is made. C Diagnostic criteria: Diagnose vWD in patients with mucocutaneous bleeding in whom vWF activity is < 0.3 units/mL. B Classify patients with a history of mucocutaneous bleeding and vWF activity 0.3-0.5 units/mL as having primary hemostatic bleeding with reduced von Willebrand, factor rather than vWD. B 2. Diagnostic investigations Clinical history: use a bleeding score (e.g. Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis bleeding assessment tool) to standardize history taking. B Initial laboratory tests: As per ASH 2021 guidelines, consider obtaining newer assays measuring the platelet- binding activity of vWF (such as vWF:glycoprotein-IbM, vWF:glycoprotein-IbR) over the vWF ristocetin cofactor assay (automated or nonautomated assay) for the diagnosis of vWD. C Show 4 more https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 2/6 6/29/23, 3:44 AM Von Willebrand disease Pathway As per BSH 2014 guidelines, measure factor VIII, vWF activity and vWF antigen as initial investigations for patients with suspected vWD. A Additional laboratory tests: diagnose type 2 vWD in patients with a ratio of vWF factor activity to vWF factor antigen < 0.6. B Ristocetin-induced platelet aggregation testing: Obtain a ristocetin-induced platelet aggregation test in all patients with reduced ratio of vWF factor activity to vWF factor antigen, and in patients in whom thrombocytopenia is present. B Platelet agglutination at low ristocetin concentrations suggests a pathological enhancement of the VWF - GPIb interaction, which is characteristic of type 2B vWD and platelet-type pseudo-vWD. Multimer analysis: As per ASH 2021 guidelines, consider obtaining either vWF multimer analysis or vWF collagen binding/vWF antigen for the diagnosis of type 2 vWD in patients with suspected type 2A, 2B or 2M vWD requiring additional testing. C As per BSH 2014 guidelines, obtain multimer analysis to distinguish between types 2A and 2M. B Show 2 more Genetic testing: As per ASH 2021 guidelines: Consider obtaining targeted genetic testing over low-dose ristocetin-induced platelet agglutination for the diagnosis of type 2B vWD in patients with suspected type 2A or 2B vWD requiring additional testing. C Consider obtaining either vWF FVIII binding or targeted genetic testing (when available) in patients with suspected type 2N vWD requiring additional testing. C As per BSH 2014 guidelines, consider obtaining genetic analysis to clarify diagnosis and aid management, for example, to identify an explanatory mutation if the phenotypic analysis does not clarify the type of vWD. B 3. Medical management Desmopressin trial: As per ASH 2021 guidelines, consider administering a trial of desmopressin and treating based on the results in patients with baseline vWF level of < 0.30 IU/mL, if desmopressin is a valid treatment option (primarily type 1 vWD). Avoid initiating desmopressin in the absence of desmopressin trial results in these patients. C Show 3 more As per BSH 2014 guidelines, perform a trial of desmopressin in patients with type 1, 2A, 2M, and 2N vWD. Measure vWF antigen, activity and factor VIII at baseline, 30-60 minutes, and 4-6 hours. B Show 3 more Management of acute bleeding: https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 3/6 6/29/23, 3:44 AM Von Willebrand disease Pathway Administer a vWF-FVIII concentrate or a combination of high purity FVIII and high purity vWF concentrates for treatment of acute bleeding or emergency surgery. A Use desmopressin in preference to blood-derived products, whenever possible (e.g., minor bleed or surgery), if previously shown to be effective. B Prevention of recurrent bleeding: As per ASH 2021 guidelines, consider initiating long-term prophylaxis in patients with vWD with a history of severe and frequent bleeding. C As per BSH 2014 guidelines: Consider initiating prophylaxis in patients with vWD of any type in whom there is recurrent bleeding. B Use intermediate purity FVIII-VWF or high purity VWF concentrates for prophylaxis. B Antithrombotic therapy: consider initiating the necessary antiplatelet or anticoagulant therapy in patients with vWD and CVD requiring antiplatelet or anticoagulant therapy. C Show 2 more 4. Perioperative care Perioperative care: As per ASH 2021 guidelines, consider targeting both FVIII and vWF activity levels of 0.50 IU/mL for at least 3 days after major surgery. Avoid using only FVIII 0.50 IU/mL as a target level for at least 3 days after surgery. C Show 2 more As per BSH 2014 guidelines, monitor factor VIII levels regularly in patients undergoing major and most minor surgical procedures. B 5. Specific circumstances Pregnant patients: As per ASH 2021 guidelines, avoid using desmopressin in patients with preeclampsia and with CVD. D Show 5 more As per BSH 2014 guidelines, deliver all women with type 2 and type 3 vWD, and women with type 1 vWD in whom vWF levels are unlikely to normalize, in an obstetric unit with close collaboration between hematology, obstetric, anesthetic and neonatal teams and access to 24-hour monitoring of factor VIII and vWF. B Show 4 more Patients with heavy menstrual bleeding: consider initiating either hormonal therapy (combined hormonal contraception or levonorgestrel-releasing intrauterine system) or tranexamic acid over desmopressin for the treatment of patients with vWD with heavy menstrual bleeding not wishing to conceive. C Show 7 more https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 4/6 6/29/23, 3:44 AM Von Willebrand disease Pathway 6. Patient education General counseling: Counsel patients about desmopressin therapy including strategies to mitigate risks associated with hyponatremia (such as free water restriction and education about signs and symptoms of hyponatremia that should lead to prompt medical evaluation) and CVD. E Educate patients about the risks and benefits of using antiplatelet agents or anticoagulant therapy to inform shared decision-making. E Clinical findings Symptoms Past medical history Easy bleeding Endometriosis Easy bruising Gastrointestinal bleeding Gum bleeding No history of migraines Heavy periods Ovarian cyst Nosebleed Pulmonary hypertension Rectal bleeding Uterine fibroids Tendency toward prolonged bleeding Uterine polyps Past surgical history Past obstetric history Postoperative bleeding Postpartum hemorrhage Musculoskeletal exam Family history Hemarthrosis vWD Lab findings Integument exam Normal INR Ecchymosis Prolonged PTT Petechiae Endoscopic findings Hematological findings Angiodysplasia Anemia Blood group O Normal blood platelet count bleeding time vWF activity Likelihood Ratios Pertinent positives The following findings increase the probability of von Willebrand disease in adults. 6 Finding LR+ Value https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 5/6 6/29/23, 3:44 AM Von Willebrand disease Pathway Increased MCMDM-1VWD score ( 4) 7.6 Pertinent negatives The following findings decrease the probability of von Willebrand disease in adults. 6 Finding LR- Value MCMDM-1VWD score not increased (< 4) 0.01 References 1. Nathan T Connell, Veronica H Flood, Romina Brignardello-Petersen et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021 Jan 12;5 1 301 325. Open 2. Laffan MA, Lester W, O'Donnell JS et al. The diagnosis and management of von Willebrand disease: a United Kingdom Haemophilia Centre Doctors Organization guideline approved by the British Committee for Standards in Haematology. Br J Haematol. 2014 Nov;167 4 453 65. Open 3. Paula D James, Nathan T Connell, Barbara Ameer et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021 Jan 12;5 1 280 300. Open 4. Leebeek FW, Eikenboom JC. Von Willebrand's Disease. N Engl J Med. 2016 Nov 24;375 21 2067 2080. Open 5. Chapin J. Von Willebrand disease in the elderly: clinical perspectives. Clin Interv Aging. 2018 Aug 31;13 1531 1541. Open 6. James AH, Jamison MG. Bleeding events and other complications during pregnancy and childbirth in women with von Willebrand disease. J Thromb Haemost. 2007 Jun;5 6 1165 9. Open 7. M Bowman, G Mundell, J Grabell et al. Generation and validation of the Condensed MCMDM 1VWD Bleeding Questionnaire for von Willebrand disease. J Thromb Haemost. 2008 Dec;6 12 2062 6. Open 8. Maha Othman, Paolo Gresele. Guidance on the diagnosis and management of platelet-type von Willebrand disease: A communication from the Platelet Physiology Subcommittee of the ISTH. J Thromb Haemost. 2020 Aug;18 8 1855 1858. Open https://web.pathway.md/diseases/recVWH7rXbAYl1Nms 6/6