The VWF gene is located near the short arm of chromosome 12. It spans 178 kb and contains 52 exons [6]. VWF mutations that cause VWD include large deletions, frameshift mutations, nonsense mutations, and missense mutations. Mature VWF consists of 3 A and B domains, 2 C domains, and 4 D domains. The specific domain location of the VWF gene mutation often correlates with a particular VWD variant [7]. To date, 70 % of those with type 1 VWD, and nearly all of those with type 2 and 3 VWD, have detectable genetic abnormalities that cause the disease. Type 1 VWD usually involves single amino acid substitutions in the D3 domain. Type 2A VWD involves mutations in the D3 or A2 domains. Types 2B, 2M, and 2N VWD include mutations in the A1, A3, and D3 domains, respectively. Types 3 VWD usually involves nonsense and frameshift mutations and occurs throughout the VWF gene [3]. All VWD variants are inherited in an autosomal dominant fashion except for type 2N VWD and type 3 VWD, which are inherited autosomal recessively.

VWD is a disorder of primary hemostasis; therefore, bleeding manifestations are primarily mucocutaneous in origin. The most common bleeding symptoms include epistaxis, easy bruising, menorrhagia, gingival bleeding, gastrointestinal bleeding, and postoperative bleeding. VWD is often overlooked as a cause of menorrhagia; however, it is a common presenting symptom in women with VWD and should be considered in the appropriate clinical context. Angiodysplasia is uncommon, but usually associated with type 2 or 3 VWD, and should be considered in any VWD patient with chronic gastrointestinal bleeding [8]. The occurrence of hemarthroses and hematomas is uncommon except in the more severe forms of the disease, such as type 3 VWD. Bleeding commonly occurs following hemostatic challenge, such as surgery, dental extractions, menarche, and childbirth. With the latter, it is critical to recognize that while bleeding occurs early, it may persist as long as 6 weeks postpartum. Clinical bleeding symptoms are often variable within families, and even within the same person at different times.

Laboratory testing for the diagnosis and classification of VWD is imperfect (Table 6.1) [2]. VWF and FVIII are acute phase reactants; therefore, levels are increased with inflammation, trauma, and stress. Several other factors affect VWF levels, including estrogen, pregnancy, and blood type. In the appropriate clinical scenario, normal testing does not necessarily exclude the presence of VWD and may need to be repeated on multiple occasions.

Assays to measure VWF antigen (VWF:Ag), VWF ristocetin cofactor (VWF:RCo), and FVIII levels are the initial tests performed when VWD is suspected. These tests are commonly available at most hospitals. VWF:Ag is an immunoassay used to the measure the concentration of VWF in plasma. Most laboratories used enzyme-linked immunosorbent assay (ELISA) or automated latex immunoassay (LIA). VWF:RCo is an assay performed to measure the functional activity of VWF based on ristocetin-induced platelet agglutination (RIPA). Ristocetin is an antibiotic that triggers VWF-platelet binding. Despite significant intra- and inter-laboratory variation, VWF:RCo is still the most sensitive and specific test available for measuring VWF function [9]. FVIII levels are measured in a functional assay based on the activated partial thromboplastin time (aPTT) to determine coagulant activity. For all of the above tests, reference ranges vary by laboratory but the normal range is generally considered to be 0.50 IU/dL to 2.00 IU/dL.

Depending on the results of the above tests, further testing may be indicated. While VWF:Ag and VWF:RCo levels less than 0.30 IU/dL are indicative of VWD based on the higher presence of genetic mutations in patients with these levels, generally VWF:Ag and VWF:RCo levels less than 0.50 IU/dL are considered clinically diagnostic of VWD. Decreased VWF:Ag levels and normal or comparably decreased VWF:RCo levels are consistent with type 1 VWD. Undetectable or nearly undetectable VWF:Ag and VWF:RCo levels along with significantly reduced FVIII levels are consistent with type 3 VWD. Type 2 VWD is suspected when VWF:RCo levels are decreased out of proportion to VWF:Ag levels. A ratio less than 0.5 to 0.7 can help distinguish type 2 VWD from type 1 VWD [10]. If type 2 VWD is suspected, multimer analysis is helpful in determining the specific subtype of type 2 VWD. Multimer analysis is done using agarose gel electrophoresis to separate out VWF proteins (multimers) by molecular weight followed by visualization with immunostaining. Loss of high molecular weight multimers is consistent with type 2A or 2B VWD. Type 2M and 2N have normal multimer analyses. Type 1 VWD has a reduced staining intensity, which affects all markers. In type 3 VWD, all markers are absent or barely visible. Differentiating between type 2A and 2B VWD can be done using the platelet count, which is often decreased in type 2B VWD, and RIPA. Ristocetin does cause VWD-platelet binding at low concentrations, less than 0.6 mg/mL; however, VWF hyperresponsiveness to ristocetin at these low concentrations in type 2B VWD results in increased VWF-platelet binding and platelet agglutination at rest. Other less commonly used tests, include the VWF: platelet binding assay, which will help distinguish type 2B VWD from platelet-type VWD; the VWF:collagen binding assay to assist in differentiating type 2A VWD from type 2M VWD; and the VWF:factor VIII binding assay to aid in diagnosing type 2N VWD.

Therapy for VWD is generally aimed at increasing VWF levels in type 1 VWD and replacing abnormal VWF in types 2 and 3 VWD. In type 1 VWD, VWF can be increased by stimulating the release of endogenous VWF from endothelial stores with DDAVP (1-desamino-8-D-arginine vasopressin) or by providing VWF replacement with the use of VWF-containing plasma concentrates . DDAVP is a synthetic analogue of vasopressin. It can be administered intranasally or intravenously. Nasal administration of DDAVP in the form of Stimate is indicated for minor bleeding, such as epistaxis, or minor wounds. One spray of 150 μg in one nostril is administered to patients weighing less than 50 kg, and one spray of 150 μg in each nostril (totaling 300 μg) is given for those weighing 50 kg or more. Intravenous DDAVP is administration in 50 mL of normal saline over 30 min at a dose of 0.3 μg/kg. This is reserved for more significant minor bleeding or minor surgical procedures, such as uncomplicated dental extractions. The maximum response to DDAVP is seen 30–90 min following administration. DDAVP is generally given every 24 h for a maximum of three doses before clinical responsiveness disappears due to exhaustion of endogenous VWF stores. Potential adverse effects of DDAVP include flushing, headache, nausea, allergic reaction, thrombosis, and water retention. In individuals receiving more than 1.5 L of fluids daily, such as in the postoperative setting, and more commonly in children, water retention can result in hyponatremia and seizures; therefore, it is very important to limit fluid intake to 1.5 L for 24 h after receiving DDAVP [11]. DDAVP is usually indicated for mild type 1 VWD. It is less commonly effective in type 2 VWD and is ineffective in type 3 VWD. Approximately 20 % of type 1 VWD and most type 2 and 3 VWD patients do not respond to DDAVP; therefore, it is recommended that all patients with type 1 VWD undergo a “DDAVP challenge” to assess response to DDAVP, in terms of VWF:Ag, VWF:RCo, and FVIII levels [12]. This should be done at least 3 weeks before anticipation of using DDAVP for a surgery. If the DDVAP challenge is undertaken in less than 3 weeks, VWF stores will not be able to replenished (tachyphylaxis), and response will be limited when it is needed.

Plasma-derived, virus-inactivated VWF-containing concentrates are indicated for VWD in patients unresponsive to DDAVP as well as significant bleeding or major surgical procedures, which will require treatment for longer than 3 days (due to tachyphylaxis). The most commonly used VWF-containing concentrates are Humate-P and Alphanate (Antihemophilic factor/von Willebrand complex [human]). The dosing and duration of therapy is largely empiric and based on expert opinion. Usual practice for surgery involves administering VWF concentrate 80 units/kg by IV slow push, followed by 50 units/kg every 8–12 h for 3–5 days thereafter. Potential adverse effects are uncommon but may include allergic reaction and thrombosis. Recently, the first plasma-free recombinant version of VWF has been studied in clinical trials with promising results and is currently awaiting FDA approval [13].

Other potential therapy includes antifibrinolytic agents , ε-aminocaproic acid and tranexamic acid, which are usually given as adjunctive therapy to DDAVP or VWF concentrates for effective control of mucosal bleeding, especially for menorrhagia or dental surgery. Their use may be limited by the potential to cause nausea.