The National Heart, Lung, and Blood Institute (NHLBI) has issued the first guidelines for the diagnosis and management of von Willebrand's Disease. These recommendations were posted February 29 on the NHLBI's Web site and appear in the March issue of Haemophilia.

"Von Willebrand disease (VWD) is an inherited bleeding disorder that is caused by deficiency or dysfunction of von Willebrand factor (VWF), a plasma protein that mediates the initial adhesion of platelets at sites of vascular injury and also binds and stabilizes blood clotting factor VIII (FVIII) in the circulation," write William L. Nichols, Jr, MD, from Mayo Clinic in Rochester, Minnesota, and colleagues from the NHLBI von Willebrand Disease Expert Panel. "Therefore, defects in VWF can cause bleeding by impairing platelet adhesion or by reducing the concentration of FVIII. VWD is a relatively common cause of bleeding, but the prevalence varies considerably among studies and depends strongly on the case definition that is used."

The VWD Expert Panel developed these guidelines for diagnosis and management of VWD for practicing primary care and specialist clinicians, including family clinicians, obstetrician-gynecologists, and nurse practitioners, in addition to hematologists and laboratory medicine specialists.

In 2004, NHLBI began planning for the development of clinical practice guidelines for VWD, and in consultation with the American Society of Hematology, the Institute convened an Expert Panel on VWD. Members of the Expert Panel (1 basic scientist and 9 physicians) were selected for expertise in basic sciences, clinical and laboratory diagnosis, evidence-based medicine, and the clinical management of VWD.


Specific management recommendations, and their supporting level of evidence, are as follows:

* Testing before nonemergent treatment
o All persons suspected of having VWD should have a laboratory-confirmed diagnosis of the type and severity of VWD (grade C, level IV). Persons not definitely diagnosed with VWD but with VWF ristocetin cofactor activity (VWF:RCo) levels of 30 to 50 IU/dL and bleeding phenotype should receive treatment or prophylaxis of bleeding in certain clinical situations (grade B, level III). Persons with more than 10 IU/dL VWF:RCo and more than 20 IU/dL FVIII activity levels should be given a trial of desmopressin (1-desamino-8-D-arginine, DDAVP; sanofi-aventis) while in a nonbleeding state (grade B, level IIa).
* General management
o The goal of treatment of VWD is to stop bleeding or to provide prophylaxis for surgical procedures (grade C, level IV). Continued bleeding when VWF:RCo and FVIII activity are adequately replaced requires further evaluation for other bleeding causes (grade C, level IV). The long-term risks and benefits of long-term prophylaxis should be considered carefully (grade C, level IV). Hepatitis A and B immunization is indicated in individuals older than 2 years who have VWD (grade C, level IV).
o Persons with VWD should consult with a knowledgeable genetic counselor (grade C, level IV) and should be counseled to avoid aspirin, other nonsteroidal anti-inflammatory drugs (NSAIDs), and other platelet-inhibiting drugs (grade C, level IV). In persons receiving DDAVP, fluid restriction should be considered (especially for young children and in surgical settings) to avoid hyponatremia and seizures (grade C, level IV).
* Treatment of minor bleeding and prophylaxis for minor surgery
o Epistaxis and oropharyngeal, soft tissue, or minor bleeding should be treated with intravenous or nasal DDAVP, if appropriate (grade B, level IIa). VWF concentrate should be used to elevate VWF when response to DDAVP is inadequate, with dosing primarily based on VWF:RCo units and secondarily on FVIII units (grade C, level IV).
o For prophylaxis for minor surgery, initial treatment goals should be VWF:RCo and FVIII activity levels of at least 30 IU/dL and preferably higher than 50 IU/dL (grade B, level III). For minor surgery, target VWF:RCo and FVIII activity levels are at least
30 IU/dL and preferably higher than 50 IU/dL, maintained for 1 to 5 days (grade B, level III).
o In VWD, minor bleeding (eg, epistaxis, simple dental extraction, or menorrhagia) can be managed with DDAVP, and fluids can be restricted without laboratory monitoring unless high-dose desmopressin acetate (Stimate; CSL Behring) or DDAVP is used more than 3 times within 72 hours (grade C, level IV). In mild to moderate VWD, antifibrinolytics plus DDAVP are usually effective for oral surgery. For persons who cannot receive DDAVP or who bleed excessively despite combination therapy, VWF concentrate should be available (grade B, level IIb). Oral surgical topical agents (eg, fibrin sealant or bovine thrombin) may be useful adjuncts, and careful attention to hemostasis of an extraction socket and to suturing of sockets is also important (grade C, level IV).
* Treatment of major bleeding and prophylaxis for major surgery
o All treatment plans should be based on objective laboratory evaluation of response of VWF:RCo and FVIII activity levels to DDAVP or to VWF concentrate infusion (grade B, level IIb). All major surgery and bleeding events should be treated in hospitals with 24-hour/day laboratory availability and with clinical monitoring by a team including a hematologist and a surgeon who is expert in the management of bleeding disorders (grade C, level IV).
o For severe bleeding (eg, intracranial, retroperitoneal) or for prophylaxis of major surgery, initial target VWF:RCo and FVIII activity levels should be at least 100 IU/dL, followed by trough levels of more than 50 IU/dL for at least 7 to 10 days (grade B, level III). To decrease the risk for perioperative thrombosis, VWF:RCo levels should be 200 IU/dL or less, and FVIII activity should be less than or equal to 250 IU/dL (grade C, level IV). A preoperative trial infusion of VWF concentrate with pharmacokinetic laboratory monitoring should be considered for major surgical procedures in selected patients with type 3 VWD or acquired von Willebrand’s syndrome who are at risk for poor VWF recovery because of inhibitors (grade C, level IV).
* Specific recommendations are also given for management of menorrhagia and hemorrhagic ovarian cysts in women who have VWD, for management of pregnancy and childbirth in women who have VWD, and for acquired von Willebrand's syndrome.

"Aside from needs for better information about VWD prevalence and the relationship of low VWF levels to bleeding symptoms or risk, there are needs for enhancing knowledge and improving clinical and laboratory diagnostic tools for VWD," the authors of the guidelines conclude. "Furthermore, there are needs for better knowledge of and treatment options for management of VWD and bleeding or bleeding risk."

The development of this report was entirely funded by the NHLBI, National Institutes of Health. Some of the guidelines authors have disclosed financial relationships with CSL Behring, GTI-Diagnostics, AstraZeneca, Mayo Clinic, and Baxter. All of the other guidelines authors have disclosed no relevant financial relationships.

Clinical Context

VWD is an inherited disorder that promotes bleeding through a combination of decreased platelet adherence at the site of vascular injury along with a reduced concentration of FVIII. The prevalence of VWD varies widely based on patient characteristics, but the general prevalence of VWD in routine screening of the general population has been between 0.6% and 1.3%.

There are currently no guidelines for the diagnosis and management of VWD in the United States. In 2004, the NHLBI began planning for an expert panel to review these issues. The panel examined evidence collected before 1996, and their recommendations are presented in the Study Highlights section of this CME.
Study Highlights

* VWD is divided into 1 of 3 types:
o In type 1 VWD, patients have a low level of VWF and may have lower than normal levels of FVIII. This is the mildest and most common form of VWD, accounting for approximately 75% of patients with VWD.
o In type 2 VWD, VWF levels may be normal, but the factor is ineffective or inefficient in promoting hemostasis. There are 4 subtypes of type 2 VWD, and treatment varies according to the subtype of disease.
o In type 3 VWD, patients usually have no VWF and low levels of FVIII. Type 3 is the most serious form of VWD, but it is very rare.
* A history of bleeding is usually the first evidence of the presence of VWD. Symptoms usually involve the skin and mucous membranes, although menorrhagia is a frequent symptom of VWD and may be its first manifestation.
* There is no single ideal laboratory test to diagnose VWD. Initial tests for patients with excessive bleeding should include a complete blood count, activated partial thromboplastin time, and prothrombin time. Plasma levels of fibrinogen may also be ordered.
* If no obvious cause of excessive bleeding, such as thrombocytopenia, is found on these studies, clinicians may order VWF antigen, VWF:RCo, and FVIII levels. If any of these tests yield abnormal results, referral to a specialty center may be indicated for additional testing such as FVIII binding or DNA sequencing of the VWF gene. The interpretation of these tests can be complicated, and more testing may be required.
* Assays to assess anti-VWF antibodies are not as advanced as those used to diagnose hemophilia A.
* Children older than 2 years with VWD should receive vaccination against hepatitis A.
* Treatment of VWD is focused on the cessation of acute bleeding or the prevention of bleeding during surgical procedures.
* Patients with VWD should be cautioned against the use of aspirin or other NSAIDs.
* DDAVP stimulates release of VWF from endothelial cells, and the intranasal or intravenous forms of DDAVP may be used to treat cases of minor bleeding.
* The antifibrinolytic drugs aminocaproic acid and tranexamic acid can also be used to treat mild mucocutaneous bleeding in VWD.
* Concentrates of VWF can be effective for cases of bleeding recalcitrant to treatment with DDAVP. Products that contain FVIII but not VWF are usually not helpful in treating symptomatic VWD.
* 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 more than 50 IU/dL, and these levels should be maintained for 1 to 5 days.
* For severe bleeding 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 to 10 days. However, to reduce the risk for thrombosis, VWF:RCo levels should not exceed 200 IU/dL, and FVIII activity should not exceed 250 IU/dL.
* Women with menorrhagia and VWD should undergo a full gynecologic examination. The initial choice of treatment for these women is oral contraceptives, followed by the levonorgestrel-releasing intrauterine system.
* Women with VWD who are pregnant should be managed by specialists in high-risk pregnancy. Among these patients, the VWF:RCo and FVIII levels should be maintained at least 50 IU/dL before delivery with use of DDAVP or VWF concentrate. These levels should be maintained for at least 3 to 5 days postpartum.

Pearls for Practice

* Initial laboratory tests for patients with suspected VWD include VWF antigen, VWF:RCo, and FVIII levels.
* The initial choice of treatment for women with VWD and menorrhagia is oral contraceptives.

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