When considering a diagnosis of VWD, the differential diagnosis must be considered and includes acquired von Willebrand syndrome (AVWS), platelet-type VWD (PT-VWD), and hemophilia A. AVWS is the result of an acquired deficiency or defect of VWF and manifests with a mild to moderate bleeding disorder without a lifelong personal and family history of bleeding. AVWS has diverse pathology. The most common mechanism is proteolytic cleavage of VWF after shear stress–induced unfolding, as seen with aortic stenosis and ventricular assist devices, where as many as 79% of persons with aortic stenosis39 and up to 100% with left ventricular assist devices are affected.40 Other disease mechanisms include autoantibody formation that impairs VWF function or increases its clearance (autoimmune disease or lymphoproliferative disease), adsorption of HMW VWF multimers to malignant cells or platelets (myeloproliferative neoplasms and Wilm’s tumor), or decreased synthesis (hypothyroidism, valproic acid). The median age of diagnosis is 62 years, but the disorder may occur in any age-group (range 2–96 years).41 The approach to management of AVWS should focus on treatment of bleeding and induction of long-term remission. Treatment of bleeding will depend on the underlying mechanism of AVWS and may include a combination of DDAVP or VWF/FVIII concentrates, recombinant factor VIIa, antifibrinolytic agents, intravenous immunoglobulin, or plasmapheresis for AVWS associated with autoantibodies. Treatment of the underlying disorder (eg, aortic valve repair or treatment of a lymphoproliferative disorder) may result in remission of the AVWS.
Mild hemophilia A (caused by mutations in the F8 gene) and type 2N VWD can be difficult to differentiate clinically. Both present with reduced FVIII:C, and type 2N VWD may have normal or borderline low levels of VWF. Although the VWF:FVIIIB assay will distinguish between the 2 disorders, the test is not available in many centers. The pattern of inheritance may be helpful: hemophilia A is an X-linked disorder, whereas type 2N is autosomal recessive. Often, the diagnosis of type 2N VWD is suspected when genotyping of F8 does not identify a mutation in mild hemophilia A, when infused FVIII concentrates have a decreased half-life, or when DDAVP is associated with a brisk but short-lived response. In the absence of VWF:FVIIIB assay availability, genotyping of VWF will confirm the diagnosis, with missense mutations being located in exons 17–20 or 24–27.19
PT-VWD represents the phenocopy of type 2B VWD. The mutation is in the platelet receptor gene GPIBA and causes enhanced VWF-platelet binding. The disorders can be differentiated by RIPA plasma/platelet mixing studies or flow cytometry.42,43 However, these assays are technically challenging. In the absence of mutations in exon 28 of VWF, mutations in exon 2 of GPIBA may be identified in approximately 10% of persons misdiagnosed with type 2B VWD.
Patients with VWD present to medical attention in a number of ways: excessive post-trauma or surgical bleeding, recurrent mucocutaneous bleeding such as epistaxis, menorrhagia, gastrointestinal bleeding, or, in severe cases, recurrent hemarthroses and muscle hematomas. Irrespective of the presentation, the goal is to minimize and control bleeding. Therapeutic options can be divided into 3 main categories: (1) localized measures to stop bleeding; (2) pharmacologic agents with indirect hemostatic benefit; and (3) treatments that directly increase plasma VWF and FVIII levels. A combination of all 3 of these modalities can be used depending on the bleeding location and severity.
Localized measures to control bleeding in VWD will depend on the site of bleeding. Epistaxis can be particularly problematic for affected children, and patients should be armed with a step-wise action plan that escalates from pressure to packing and includes guidelines regarding how long to wait before seeking medical attention. In selected cases, nasal cautery may be required for prolonged or excessive epistaxis. Topical hemostatic agents such as gelatin foam/matrix, topical thrombin, and fibrin sealants are predominately used to achieve surgical hemostasis and may have a limited role in the treatment of VWD-associated bleeding. In the case of menorrhagia, hormonal treatments (ie, the combined oral contraceptive pill, OCP), levonorgestrel-releasing intrauterine systems, or endometrial ablation all effectively reduce menstrual blood loss through their local effects on the endometrial lining.44 In addition, older generations of OCP are associated with increases in VWF levels. This effect is mediated by the estrogen component and is evident with ethynylestradiol doses of 0.5 μg or higher. Lower estrogen doses, seen in currently used OCP, have little or no effect on VWF levels.11,45
Indirect therapies include the antifibrinolytic agents (eg, tranexamic acid and aminocaproic acid). These agents are used either as the sole therapy at the time of minor surgical and dental procedures, or as an adjunct in combination with DDAVP or VWF/FVIII concentrates. Antifibrinolytics are thought to be particularly useful for controlling mucosal bleeding in areas of high fibrinolytic activity: the oral cavity, gastrointestinal tract, or uterus. Tranexamic acid inhibits the conversion of plasminogen to plasmin, and is the more commonly used antifibrinolytic.11 Tranexamic acid can be administered either intravenously or orally at doses of 10 to 25 mg/kg, respectively. It is usually continued until bleeding is controlled or up to 7 to 10 days postoperatively. The most common adverse events associated with tranexamic acid are headache, back pain, and gastrointestinal side effects.46 Tranexamic acid is contraindicated in disseminated intravascular coagulation and bleeding from the upper urinary tract, where it can lead to urinary tract obstruction by clots.