Management of VWD

VWD is an inherited autosomal disorder of deficient (type 1 or 3) or dysfunctional (type 2 variants) VWF. It is characterized primarily by mucocutaneous bleeding, excessive hemorrhage after invasive procedures, and, less commonly, by soft tissue hematomas and joint bleeding in the more severe types.¹  There are excellent clinical guidelines published to facilitate the diagnosis and management of the various types of VWD.²  The general approach to management of VWD depends upon increasing the circulating concentration of functional VWF and/ or using adjunctive therapies to preserve or enhance clot formation. Desmopressin acetate (DDAVP) or estrogens can increase endogenous levels. VWF concentrates purified from plasma or synthesized by recombinant technology will raise functional VWF levels. Other therapies that can inhibit fibrinolysis or enhance local clot formation are also effective adjuncts. Women with VWD are more symptomatic than men due to heavy menstrual bleeding and childbirth issues. Patients with Type 3 disease may benefit from prophylactic treatment with VWF but 5%–15% are also at risk for inhibitor formation when exposed to VWF concentrates.

Desmopressin (1-desamino-8-D-arginine vasopressin) is a synthetic derivative of the human antidiuretic hormone vasopressin. First described as a treatment for VWD in 1977,³  DDAVP raises VWF levels through its action on vasopressin V2 receptors, which increase VWF and factor VIII (FVIII) secretion from Weibel-Palade bodies inside endothelial cells into the circulation⁴  (Table 1). Definitions of adequate response vary, but to be effective, VWF:RCo and FVIII:C levels should increase at least 2- to 3-fold and to levels >50%. These definitions can be arbitrary and responses may not be adequate for all clinical situations. It is important to perform a trial with a standard DDAVP dose administered intravenously, subcutaneously, or intranasally after baseline levels of VWF:Ag, VWF:RCo, and FVIII:C are drawn to document the patient's adequate responsiveness before using the drug in a specific bleeding situation. It is important to use the appropriate intranasal preparation specifically for bleeding disorders with doses of 150 μg/spray and not formulations for enuresis or diabetes insipidus, which are much lower and ineffective at releasing adequate VWF. Subsequent measurements at multiple time points will give the best information about immediate response and VWF half-life to screen for variants that are rapidly metabolized, such as type 1C.⁵ Table 1 outlines DDAVP trial procedures. Patients with type 1C may have an excellent response shortly after DDAVP administration, but the multimers are cleared very rapidly, thus limiting the effectiveness of this therapy.⁶  Immediate potential complications of DDAVP include flushing, hypotension/hypertension, gastrointestinal upset, and headache. Repeated dosing of this antidiuretic-hormone-mimicking drug can lead to hyponatremia and seizures; therefore, most clinical centers limit doses to no more than 2 or 3 consecutive days. Restriction of free water will help prevent symptomatic low sodium levels. At our center, we provide a chart to assist patients and parents in determining fluid intake amounts (Table 2). Doses are typically 24 hours apart because more frequent administration can lead to tachyphylaxis and hyponatremia. DDAVP is the treatment of choice for 70%–80% of patients with VWD, including most type 1 patients and some patients with type 2A and 2M. When adequate VWF response is proven with a DDAVP trial, it can be used for prevention and treatment of most bleeding episodes. Although some responses have been seen in other type 2 patients, they are usually either too small or not sufficiently sustained to be effective. DDAVP is not effective in type 3 patients and is usually considered contraindicated in type 2B patients because it may promote thrombocytopenia, although it has been effective in selected type 2B patients.²  DDAVP is not recommended for patients under age 2 due to poor response.⁷ 

Combined oral contraceptives (COCs) containing higher-dose estrogens increase the endogenous production of VWF.⁸  For many women with VWD, COCs control menstrual flow adequately and likely work through additional local mechanisms on the endometrium because they are also helpful for patients with type 3 disease in whom VWF levels are not increased.⁹ 

Patients who do not respond adequately to desmopressin or are to undergo major surgical procedures may require VWF clotting factor concentrates. This includes all patients with type 3 disease and most with type 2 and severe type 1 disease. Currently available VWF products in the United States are listed in Table 3. Other brands are available in Europe, but dosing is essentially the same for all. All are plasma-derived human factors containing VWF and FVIII in various ratios that have been purified and virally inactivated. Although there remains a theoretical risk of infectious disease transmission, their safety records are excellent. In the United States, these products are dosed in RCo units; in Europe in FVIII:C units. Both VWF:RCo and FVIII:C levels are expected to rise with infusions but, over time, the FVIII:C levels may rise higher than desired due to stabilization of endogenous FVIII by the infused VWF and due to higher concentrations of FVIII in some VWF concentrates. This can produce an increased risk of thrombosis, especially in elderly patients if FVIII:C levels rise above 200%–250%. In type 3 patients, the immediate availability of FVIII is necessary for treatment of acute hemorrhage or emergency surgery because FVIII:C levels will not rise for 6-8 hours if pure VWF is infused. See Table 4 for VWF dosing and treatment guidelines for various procedures.

Cryoprecipitate prepared from donor plasma is enriched with VWF and FVIII per unit volume compared with fresh-frozen plasma. These units are derived from blood donors and are tested for communicable diseases, but they are not virally inactivated and thus are not considered optimal therapy. Cryoprecipitate should be used only in emergencies if VWF concentrates are not readily available. Each unit of cryoprecipitate contains ∼80-100 units of FVIII. Doses of cryoprecipitate for VWD would be ∼30-60 FVIII units/kg daily¹⁰  until such time as VWF concentrates could be obtained or the patient transferred to a facility that has access to them.

Natural thrombus dissolution can be inhibited by the antifibrinolytic agents aminocaproic acid or tranexamic acid. Aminocaproic acid is a potent competitive inhibitor of plasminogen activators and, to a lesser degree, inhibits plasmin itself. Tranexamic acid, a synthetic lysine derivative, binds to the lysine-receptor-binding sites on plasmin, thus preventing its attachment to fibrin monomers and retarding clot dissolution. Antifibrinolytic agents can be used locally, such as in a mouthwash, ingested orally, or injected intravenously. They have been most effective as adjuncts to DDAVP or clotting factor concentrates in mucocutaneous sites such as with tonsillectomy, tooth extraction,¹¹  and also as a single agent for heavy menstrual bleeding.¹² 

Bovine thrombin, recombinant human thrombin, and a fibrin sealant composed of human thrombin, fibrinogen, and bovine aprotinin are all agents that enhance thrombus formation at specific sites of application. They have been most effective when combined with raising VWF levels or with other hemostatic therapies in oral cavity procedures.¹¹  Possible side effects include thrombosis if thrombin gains access to the circulation or antibody formation to thrombin or, in bovine thrombin, the contaminant factor V, which can lead to serious bleeding. Rarely, patients will develop allergic reactions to the proteins (Table 5).

Heavy menstrual bleeding is often the primary symptom of women with VWD. Available treatment options are similar to those for women without bleeding disorders who experience heavy menstrual flow. Combined oral contraceptives containing an estrogen, typically ethinyl estradiol, and a progestin will variably raise the levels of selected coagulation factors, including VWF,¹³  but may not always provide relief from heavy menstrual bleeding.¹⁴  For women who also desire contraception, COCs may be the treatment of choice. For girls <18 years old who may not wish to take hormones, off-label use of a fibrinolytic inhibitor such as tranexamic acid 3 times daily may be effective in curbing menstrual flow.^12,15  Chi et al¹⁶  studied the effects of a levonorgestrel-releasing intrauterine device (Mirena) on women with bleeding disorders, including 13 women with VWD, all of whom reported a significant improvement in their quality of life and decrease in their blood flow.¹⁶  Desmopressin treatment of heavy menstrual bleeding has had mixed results, with some study subjects reporting excellent or good control of excessive bleeding¹⁷  and others considering it no more effective than placebo.¹⁸  VWF concentrates are another option, with infusions as needed during menstrual cycles if initial measures fail; however, there exist little data to support their effectiveness. For the most refractory cases or for those women who no longer wish to preserve their fertility, endometrial ablation has been successful in some.¹⁹  There are still women who choose hysterectomy to enhance quality of life, even with its attendant perioperative bleeding risks.

For best outcomes, pregnancies in a woman with VWD should be planned before conception with input from the hematologist, obstetrician, anesthesiologist, and genetics counselor to ensure that the patient is adequately informed about her risks of hemorrhage before and after delivery and the methods of pain control available to her. Her infant is also at risk for side effects from the mother's treatment and there is the possibility of the infant inheriting this genetic disease.

Hormonal changes throughout pregnancy are responsible for the rise in production of VWF and FVIII to levels twice the baseline in normal women.²⁰  This physiologic rise is probably the primary reason that women with type 1 VWD tend to do well with pregnancy and delivery without any intervention: many women will reach the normal range of activity by the second trimester. FVIII:C and VWF:RCo should be checked before any invasive procedures and in the third trimester to ensure levels of >50% activity, the level at which vaginal or cesarean section delivery have been shown to be safe.²¹  If procedures are required early in pregnancy before hemostatic levels of VWF:RCo and FVIII:C being achieved, DDAVP can be effective and safe in women previously shown to respond to the drug.²²  At our center, we typically use VWF concentrates if prophylaxis is indicated during pregnancy and at delivery. Regional anesthesia can be permitted with VWF:RCo and FVIII:C levels >50% without undue consequence.²¹  In women known before pregnancy to have VWD, the adjusted odds ratio of primary postpartum hemorrhage was 3.41.²³  VWF and FVIII levels begin to fall even by day 3 postpartum in healthy women and return to baseline levels by day 14.²⁴  For women with VWD, this fall can be associated with significant postpartum hemorrhage.²³  The average time of presentation of postpartum hemorrhage in women with VWD is 15.7 days²⁵ ; therefore, patients may require prophylaxis for 2 weeks or more. Women should be counseled to report any increase in postpartum bleeding swiftly to their hematologist to obtain treatment with either DDAVP or factor supplements to prevent significant hemorrhage. Other options include fibrinolytic inhibitors. Lactating mothers should exercise some caution with medications. Little is reported about the excretion of DDAVP in breast milk in bleeding disorder patients. Tranexamic acid is present in concentrations ∼1/100 of the serum level (per package insert) and its effect on infants is unknown.

Women with type 2 VWD present a greater challenge throughout gestation and delivery. A rise in VWF:Ag levels is not always accompanied by an adequate rise in VWF:RCo activity, often necessitating VWF factor concentrates at delivery and with invasive procedures during pregnancy.²⁵  Perhaps the greatest challenge occurs in women with type 2B VWD, with its gain-of-function mutation. Because VWF levels rise throughout pregnancy, binding of the mutant VWF to platelets can increase platelet clearance to further depress platelet counts. It is not uncommon for platelet counts to fall to levels of 20 000/μL or less, creating a worse situation than before pregnancy. These women may require platelet transfusions and VWF concentrates to support hemostasis around delivery and in the postpartum period until platelet counts rise.²⁶  Unfortunately, patients with very low platelet counts are usually considered ineligible to receive regional anesthesia.

Type 3 VWD women will have no rise in VWF:Ag or VWF:RCo and thus must receive VWF concentrates with any invasive procedure during pregnancy, at the time of delivery, and into the postpartum period to prevent hemorrhage.²⁷ 

The success of prophylactic factor infusions for severe hemophilia A has been extrapolated to those patients with severe clinical forms of VWD. In 2005, published results of years of prophylaxis in a Swedish cohort of 35 patients revealed its success at preventing joint disease if treatment is begun at an early age and also reduced the occurrence of epistaxis and gastrointestinal bleeding.²⁸  This prompted the formation of the von Willebrand Disease Prophylaxis Network (VWD PN), which has collected data from 20 centers in 10 countries on 61 subjects. The most common reasons for prophylaxis need were recurrent epistaxis and joint bleeding, which were seen primarily in younger patients, and heavy menstrual bleeding or gastrointestinal bleeding in older patients. The VWD PN report was comprised of 34 patients with type 3, 5 patients with type 1, 10 patients with type 2A, 8 patients with type 2B, and 2 patients with type 2M VWD. The greatest effect of the 1-3 times weekly infusions of 40-60 RCo U/kg VWF concentrates was the reduction in joint bleeding of nearly 90%. It was also effective at reducing episodes of epistaxis, intensity of heavy menstrual bleeding, and, in the older populations, gastrointestinal bleeding. Gastrointestinal bleeding required higher doses closer to 60 RCo U/kg of VWF concentrate for improvement. There have been no thrombotic complications of these regular VWF infusions, but antibodies to VWF appeared in 1 of 59 evaluable patients.²⁹  A standardized bleeding score >10 may be a means of identifying patients with the highest risk of spontaneous hemorrhage who would benefit from a prophylaxis regimen.³⁰ 

Type 3 VWD patients who make no VWF can form alloantibodies to exogenously provided VWF, rendering future transfused concentrates ineffective and, in rare cases, dangerous by producing anaphylactic reactions with exposure.³¹  In contrast to FVIII antibodies, because assays for anti-VWF antibodies are not standardized, they can be difficult to measure. Treatment of these patients can be quite challenging and this topic has been reviewed recently.³²  Bypassing agents such as recombinant factor VIIa (rFVIIa) has been successful with either bolus dosing or continuous infusion.³³  Combining both rFVIIa and rFVIII was successful in enabling delivery of an infant and recovery of the mother after childbirth.³⁴  Despite the shortened half-life of FVIII in the absence of its stabilizer, VWF, high-dose infusions of recombinant FVIII can maintain hemostatic levels of FVIII:C. Successful immune tolerance induction similar to that seen with inhibitors to FVIII has been reported.³⁵ 

Recombinant FVIII and factor IX have been available for many years, but only recently has rVWF been studied in clinical trials. In a pharmacokinetic and safety study, rVWF-rFVIII compared favorably to plasma-derived VWF-FVIII. Recovery, as measured by VWF:RCo activity assay, was quite similar, but rVWF-rFVIII infusions produced a slightly lower VWF:Ag level, demonstrating a greater specific activity of rVWF compared with the same amount of pdVWF. This higher ratio of activity is due to the increased relative amount of ultra-large-molecular weight multimers in the recombinant product that was not exposed to metalloproteinases (ADAMTS13) in vitro during production. In theory, this could lead to thrombotic complications, but studies of the patient plasma samples after infusion revealed rapid cleavage by ADAMTS13 to standard VWF multimer size.³⁶  Another interesting finding was the stabilization of endogenous FVIII by the rVWF that produced a secondary rise in FVIII:C levels. This may allow the infusion of only rVWF if there is no immediate need for FVIII:C to avoid the excessive rise in FVIII:C when plasma-derived concentrates are infused for several doses. Acute bleeding situations in type 3 patients may require both molecules initially for best hemostasis, but this has not been tested clinically. Therapeutic trials with rVWF are ongoing.

Thrombocytopenia is a significant problem in patients with VWD type 2B, resulting from increased binding to the platelet receptor GPIb at the A1 domain of VWF. Aptamers are oligonucleotides that can block the binding of proteins such as the interaction between the VWF A1 domain and the platelet GPIb receptor. Desmopressin is known to produce a drop in platelet counts if given to patients with type 2B VWD. An infusion of an aptamer ARC1779 blunted or blocked this fall in platelet count³⁷  and, in a different trial, led to a rise in baseline platelet count and VWF:RCo and FVIII:C levels, suggesting a possible novel treatment for this subtype of VWD patient.³⁸ 

Recombinant human IL-11 (rhIL-11) or oprelvekin (Neumega) is a US Food and Drug Administration (FDA)–approved drug indicated for the prevention of severe thrombocytopenia after myelosuppressive chemotherapy in nonmyeloid malignancies. It also raises levels of VWF. rIL-11 given subcutaneously as an experimental therapy was effective in reducing menstrual flow, as measured by pictorial blood assessment chart, in women with VWD and refractory heavy menstrual bleeding.³⁹  Side effects seen were conjunctival erythema, mild fluid retention, and some injection site bruising. Further studies are planned for this intriguing treatment.

Gene therapy may be feasible, even with this very large molecule, and has been reported in a cell model.⁴⁰  Realistically, this potential therapy is many years away.

Despite significant advances in our understanding of the molecular aspects of VWD, approaches to therapy have not changed much in >20 years. As we progress in understanding the basis for quantitative deficiencies in type 1 disease, we may be able to increase production in ways different from our current treatments. Newer treatment strategies may focus on enhancing endogenous production and release or prolonging the half-life of VWF infusions for prolonged efficacy and convenience of patients.

The authors thank our hemostasis staff for their tireless efforts in caring for bleeding disorder patients: Julie Thomas, Kelly Dawson, Shelley Ploch, Johnna Oleis, Lyndsey Rollins, Pamela Krueger, and Kim Blittle.

Conflict-of-interest disclosures: A.T.N. has served on the board of directors or an advisory committee for Alexion, Baxter Pharmaceuticals, and the American Board of Internal Medicine and has received research funding from NovoNordisk. R.F.S. has received research funding from Grifols and NovoNordisk and has received honoraria from Grifols, CSL Behring, and Kedrion. Off-label drug use: Oral contraceptives for VWD.

Anne T. Neff, MD, Vanderbilt University; Phone: (615)936-0381; Fax: (615)343-3694; email: anne.neff@Vanderbilt.Edu.