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Management of von Willebrand Disease
Therapies to prevent or control bleeding in persons who have VWD follow three general strategies. The first strategy is to increase plasma concentration of VWF by releasing endogenous VWF stores through stimulation of endothelial cells with DDAVP. The second approach is to replace VWF by using human plasma-derived, viral-inactivated concentrates. The third strategy employs agents that promote hemostasis and wound healing but do not substantially alter the plasma concentration of VWF. The three treatment options are not mutually exclusive, and patients may receive any one or all three classes of agents at the same time. The appropriateness of therapeutic choice is dependent on the type and severity of VWD, the severity of the hemostatic challenge, and the nature of the actual or potential bleeding. Because some persons who have VWF:RCo >30 IU/dL manifest clinical bleeding, persons not having a definite diagnosis of VWD but who have low VWF and a bleeding phenotype may merit treatment or prophylaxis of bleeding in certain clinical situations.196 Infusions of VWF to prevent bleeding episodes—known as prophylaxis—are less frequently required in patients who have severe VWD in contrast to patients who have severe hemophilia. The CDC Universal Data Collection Project Web site (http://www2a.cdc.gov/ncbddd/htcweb/) reports that 45 percent of patients who have severe hemophilia A use some type of prophylaxis, either continuous or intermittent, compared with 10 percent of patients who have severe VWD. Risks and benefits of prophylaxis should be carefully weighed when considering long-term therapy for VWD.211,212 Treatment of VWD in the United States varies widely and frequently is based on local experience and physician preference. Few standard recommendations exist to guide therapy for VWD.6,7,9 This guidelines document presents recommendations regarding the management and prevention of bleeding in persons who have VWD and reviews the strength of evidence supporting those recommendations.
Therapies To Elevate VWF: Nonreplacement Therapy
DDAVP (Desmopressin: 1-desamino-8-D-arginine vasopressin)
Mechanism of action of DDAVP. DDAVP is a synthetic derivative of the antidiuretic hormone, vasopressin. DDAVP has been used to treat VWD for 25 years, and its pharmacology, mechanism of action, and indications have been reviewed extensively.213-215 DDAVP stimulates the release of VWF from endothelial cells through its agonist effect on vasopressin V2 receptors.213,214,216 The mechanism by which DDAVP increases plasma concentration of VWF is probably through cyclic AMP-mediated release of VWF from endothelial cell Weibel-Palade bodies.216,217 FVIII levels also increase acutely after administration of DDAVP, although the FVIII storage compartment and the mechanism of release by DDAVP have not been fully elucidated to date.11,218 DDAVP induces the release of tissue plasminogen activator (tPA).219,220 However, the secreted tPA is rapidly inactivated by plasminogen activator inhibitor (PAI-1) and does not appear to promote fibrinolysis or bleeding after DDAVP treatment.
DDAVP dosing and administration. Table 11 displays published reports of DDAVP effects on laboratory assays of VWF and FVIII in normal persons and persons who have various subtypes of VWD.64,92,99,221-232 When administered intravenously to normal persons as well as to patients who have VWD or mild hemophilia, DDAVP consistently increases plasma VWF and FVIII from twofold to greater than fivefold over baseline levels.92,218,223,225-227,230,231 Children under the age of 2 have a significantly lower response rate than older children.230 Two controlled prospective studies in healthy volunteers form the basis for DDAVP dosing recommendations.225,227 Maximal FVIII response was determined at 0.3 micrograms/kilogram in both studies, while maximal VWF release data were determined at 0.2 and 0.3 micrograms/ kilogram in the two studies, respectively. Based on these data, standard dosing of DDAVP is 0.3 microgram/kilogram given intravenously in 30-50 mL of normal saline over 30 minutes, with peak increments of FVIII and VWF 30 to 90 minutes postinfusion.218,223,225,233 Nasal administration of high-dose desmopressin acetate (Stimate®) is often effective for minor bleeding, but intravenous administration is the preferred route for surgical bleeding prophylaxis and for treatment of major hemorrhage.
A retrospective review of DDAVP administration to 56 children who had nonsevere type 1 VWD found a 91 percent response rate, defined as FVIII and VWF activity increase of twofold, to at least 30 IU/dL.230 In a small case series of VWD patients, the consistency of FVIII increases and the response of the bleeding time after a second test dose of DDAVP was within 10-20 percent of the initial value.231 Evidence shows that response to DDAVP diminishes with repeated doses, probably due to depletion of the VWF storage compartment.218,227 However, when DDAVP was given in four daily doses to 15 patients who had type 1 VWD, an increase in FVIII activity of at least twofold was found in 100 percent of the patients after the first administration, in 80 percent after the second, in 87 percent after the third, and in 74 percent after the fourth administration.226
Consistency of response to DDAVP has been studied using 24-hourly dosing for three to four daily doses.226,227 A series of 15 type 1 VWD patients showed a mean rise of VWF:RCo to fivefold above baseline following the first dose of DDAVP, significantly decreased response to fourfold following the second daily dose, and no significant change in response among the second to fourth doses.226 The proportion of VWD patients attaining at least a twofold rise in FVIII activity following the second to fourth daily doses—80 percent following the second daily dose of DDAVP to 74 percent following the fourth dose—was substantially higher than that for hemophilia A patients (55 to 37 percent). There is no published evidence regarding response to DDAVP given every 12 hours to compare with daily dosing of DDAVP. In addition to tachyphylaxis, hyponatremia may complicate repeated DDAVP dosing, and fluid restriction as well as serum sodium monitoring are recommended.
DDAVP can also be administered subcutaneously or intranasally.225,227,233 The effective subcutaneous dose is identical to intravenous dose, but the subcutaneous preparation is not available in the United States. The preparation of DDAVP for nasal instillation (Stimate®) contains 150 micrograms per metered nasal puff (0.1 mL of a 1.5 mg/mL solution). The dose is one puff for persons who weigh <50 kg and two puffs (one to each nostril) for persons weighing 50 kg or more. Although the intra- and intersubject coefficient of variation for reproducibility of nasal spray effect is good, nasal absorption is variable, and all patients who have VWD and are responsive to intravenous DDAVP should undergo a trial of Stimate® to measure FVIII and VWF response before using it.225 When used for epistaxis, Stimate® ideally is delivered into the nonbleeding nostril. Persons who have inadequate plasma responses to intravenous DDAVP will not respond to Stimate®.
There is also a nasal formulation of DDAVP (for enuresis) that contains 10 micrograms per puff (about 7 percent of the Stimate® concentration); however, this preparation is not suitable for treatment of VWD. Patients and parents must be carefully instructed regarding the two concentrations of nasal DDAVP—the one used for bleeding (1.5 mg/mL), and the one used for antidiuretic hormone replacement (diabetes insipidus) and bedwetting (0.1 mg/mL)—to avoid accidental underdosing for VWD.
Monitoring of VWD patients receiving DDAVP. Treatment of patients who have VWD with DDAVP should be based on results of a therapeutic trial, ideally one performed in a nonbleeding state and before clinical use.
Although the pattern of DDAVP responsiveness is fairly consistent within VWF subtypes, population results should not be used to plan treatment of individual patients (see Table 11). VWF:RCo and FVIII activities should be measured in all VWD patients at baseline and within 1 hour after administering DDAVP. Additional assay of VWF:RCo and FVIII, 2-4 hours after DDAVP, will evaluate for shortened survival and should be considered for patients who have a history of poor response to treatment.41
According to conservative definitions of laboratory response, the majority of patients who have type 1 VWD respond adequately to DDAVP (Table 11). Single infusions of DDAVP for common bleeding episodes—such as epistaxis, simple dental extraction, or menorrhagia—do not usually require laboratory monitoring. Patients should be monitored for VWF:RCo activity as well as FVIII activity around major surgeries or major bleeding events. For major surgeries or bleeding events, patients who have VWD should be referred to hospitals with in-house or daily laboratory availability of FVIII and VWF:RCo activity assays. Care should be taken to monitor serum electrolytes, especially after surgery or multiple doses of DDAVP. Adult patients, especially those who are elderly, should be evaluated for CVD before using DDAVP because myocardial infarction rarely has been precipitated by DDAVP therapy in patients who have hemophilia or uremia.234-236
Table 11. Intravenous DDAVP Effect on Plasma Concentrations of FVIII and VWF in Normal Persons and Persons Who Have VWD
* Data are given as mean fold increase in plasma
factor compared to baseline after a single administration of DDAVP. Mean fold
increases were calculated from original data, where possible, if not included
in the manuscript.
Pharmacokinetics of VWF and FVIII after DDAVP. After stimulation with DDAVP, released VWF and FVIII circulate with an apparent half-life characteristic of the patient's own proteins, or approximately 8-10 hours for both proteins in normal individuals.218 Type 2 VWF proteins that are released by DDAVP will increase in concentration but retain their intrinsic molecular dysfunction.237 For this reason, DDAVP has been efficacious in only a minority of patients who have types 2A or 2M VWD. Therefore, monitoring is necessary to document adequate correction of VWF:RCo. Type 2N VWF lacks FVIII stabilization; consequently, patients who have 2N VWF will release FVIII and the abnormal VWF protein as expected, but the survival of released FVIII may be severely decreased, with an apparent plasma half-life as low as 2 hours, depending on the mutation.168,228 Emerging information suggests that some individuals who have type 1 VWD have accelerated plasma clearance of VWF and may benefit from trial testing of VWF:RCo 2-4 hours after a dose of DDAVP.40,238
Following infusion of DDAVP into patients with type 2B VWD, VWF multimers of larger but still somewhat less than normal molecular weight can be detected in plasma after 15 to 30 minutes, with persistence throughout 4 hours of study.63,168,237,239 Although formal pharmacokinetic studies have not been reported for type 2B VWD, VWF:RCo activity increases were less than that seen in type 1 VWD with an apparent half-life of approximately 4 hours.63,229 Bleeding time response to DDAVP in type 2B VWD is inconsistent.222,229
Clinical response to DDAVP in VWD. The clinical effectiveness of DDAVP to prevent or control bleeding depends, in large part, on the plasma VWF:RCo or FVIII activity achieved after drug administration, which in turn depends primarily on the basal levels of plasma FVIII and VWF:RCo and to a lesser extent on the underlying qualitative VWF defect.64,92,99,221-232 Table 12 and Evidence Tables 7-12 summarize published data on clinical response when using DDAVP in conjunction with common surgical procedures.136,218,221-223,230,232,240-250 All data were derived from retrospective studies and small case series; there are no randomized clinical trials of the use of DDAVP in persons who have VWD.
Whether DDAVP will be adequate for prophylaxis around surgery or for treatment of bleeding events in persons who have type 1 VWD is dependent on the severity of the hemostatic challenge and the time required for healing. Major surgery requires hemostasis for 7-14 days,247,251-256 whereas minor surgeries can be treated adequately in 1-5 days.243,244,247,256 If treatment is necessary for more than 3 days, VWF concentrate is usually given to supplement therapy with DDAVP.244,247 Currently, however, expert opinions are divided regarding the risk of delayed hemorrhage 5-10 days after a bleeding challenge in VWD patients, e.g., those who have had tonsillectomy or given birth. In small case series, persons who have type 1 VWD Vicenza manifest an exaggerated response to DDAVP.41,92,231 Individuals who have type 2N VWD exhibit a brisk rise in plasma FVIII after receiving DDAVP, but they have a mean FVIII half-life of only 3 hours because of deficient FVIII stabilization by the defective VWF.228 Persons who have low platelet VWF or type 2A VWD have a low likelihood of having a clinically relevant DDAVP response, but they may warrant a DDAVP trial.224,231 Type 2B VWD previously was a contraindication to DDAVP therapy because platelet counts usually fell after DDAVP stimulation.257 However, thrombocytopenia after DDAVP in type 2B VWD is usually transient and often is not associated with bleeding or thrombosis.258 In patients who have type 2B VWD, decrease in platelet count after DDAVP administration has been considered "pseudothrombocytopenia" by some authors because it is related to platelet agglutination in vitro rather than in vivo agglutination and clearance.63,239 Therefore, DDAVP may be cautiously considered for patients who have type 2B VWD. Patients who have type 3 VWD almost never experience a clinically relevant rise in VWF:RCo or FVIII activities, and DDAVP is not considered clinically useful in these patients.224,230
Complications and toxicities of DDAVP. Minor side effects of DDAVP are common and include facial flushing, transient hypertension or hypotension, headache, or gastrointestinal upset,214,215,262 but these effects rarely limit clinical use. Water retention after a dose of DDAVP, with an increase in urinary osmolality, is universal; however, decreased serum sodium in otherwise healthy adults is variable and is related to multiple doses.262,263 In the case of repeated dosing, all patients should be instructed to limit fluid intake to maintenance levels for 24 hours.264-266 Prophylactic use of DDAVP complicates the management of fluids and electrolytes for surgery or during childbirth. Seizures have been associated with hyponatremia after DDAVP administration, primarily in young children.263,266 Most pediatric hematologists do not use DDAVP in children under the age of 2 years.230,261,266
Myocardial infarction after treatment with DDAVP has been reported, although rarely, in patients who have mild hemophilia A.234,236,267 DDAVP should be avoided in patients who are at very high risk for cardiovascular or cerebrovascular disease, especially the elderly, as underlying inhibition of plasminogen activation with DDAVP-related vasoconstriction contributes additional prothrombotic effects in these patients.268 Because of reported complications in other patient populations, DDAVP should be used with caution for brain, ocular, and coronary artery surgeries,235,269,270 and VWF concentrate replacement generally is used in these settings. DDAVP does not appear to increase myometrial contractility significantly; consequently, pregnancy is not an absolute contraindication271-274 but use of DDAVP is rarely indicated (see "Pregnancy").
Table 12. Clinical Results of DDAVP Treatment in Patients Who Have VWD*
DDAVP, 1-desamino-8-D-arginine vasopressin
(desmopressin, a synthetic analog of vasopressin)
Therapies To Elevate VWF: Replacement Therapy
As of January 2007, Humate-P® and Alphanate SD/HT® are the only plasma-derived concentrates licensed in the United States to replace VWF in persons who have VWD. One other plasma derivative—Koate DVI®—is licensed in the United States to treat hemophilia and has been used off-label for VWD. These products are not identical, have differing ratios of FVIII to VWF, and should not be considered as interchangeable.275-277 All of these products are manufactured at U.S.-licensed facilities from pooled plasma collected from paid donors.
Products that contain FVIII and little or no VWF are generally not useful to treat VWD, but in rare circumstances these products may be used to treat patients who have antibody-mediated AVWS.278 These products include the plasma-derived concentrates Monoclate P®, Monarc M®, and Hemofil M®; and recombinant products Helixate FS®, Kogenate FS®, Recombinate®, Advate®, and ReFacto®.
Humate-P®, a lyophilized concentrate of purified VWF and FVIII, contains other plasma proteins including fibrinogen and albumin. In Humate-P®, the quantity of the large, most hemostatically active multimers of VWF is decreased compared to fresh plasma.279 When reconstituted at the recommended volume, each milliliter of the product contains 50-100 IU/mL VWF:RCo and 20-40 IU/mL FVIII activity (Humate-P® package insert). The median half-life of VWF:RCo activity was 10.3 hours (range: 6.4-13.3 hours) in one study (see package insert) and 11.3 hours in another study.251 The product is indicated for use in adult and pediatric patients for treatment of spontaneous and trauma-induced bleeding when use of DDAVP is thought or known to be inadequate or contraindicated. Humate-P® has received FDA approval for use in prophylactic management of surgery and invasive procedures in patients with VWD.
Alphanate SD/HT® is a lyophilized concentrate of VWF and FVIII, and other plasma proteins. It is prepared from pooled human plasma by cryoprecipitation of FVIII, fractional solubilization, and further purification employing heparin-coupled, cross-linked agarose. Upon reconstitution to the recommended volume, each milliliter of product contains 40-180 IU/mL FVIII activity, and not less than 16 IU/mL VWF:RCo activity (Alphanate SD/HT® package insert). The median half-life for VWF:RCo activity was 6.91 hours (mean: 7.46 +/- 3.20 hours; range: 3.68 to 16.22 hours. Package Insert). The product is indicated for surgical and/or invasive procedures in patients with VWD in whom either DDAVP is ineffective or contraindicated. It is not indicated for patients with severe VWD (type 3) undergoing major surgery.
Adverse reactions are rare but include allergic and anaphylactic symptoms, urticaria, chest tightness, rash, pruritus, and edema.253 If these reactions occur, the infusion should be stopped, and appropriate treatment should be given as required. The product should be used with caution in patients who have known risk factors for thrombosis, as there have been a few reports of venous thromboembolism associated with high levels of FVIII.280,281 Risk factors include old age, previous thrombosis, obesity, surgery, immobility, hormone replacement therapy (HRT), and use of antifibrinolytic therapy. If patients receive VWF replacement therapy continuously for several days, it has been recommended that FVIII levels be monitored to avoid unacceptably high levels.215,281
The products that contain VWF:RCo activity differ significantly in their ratios of VWF:RCo to FVIII252,282,283 and one should not assume that the dose or frequency of dosing is the same for all. The ratio of VWF:RCo to FVIII for Humate-P® in various reports is 2.7, 2, and 1.6; for Koate DVI®, the ratio is 1.2 and 0.8; and for Alphanate®, the ratio is 0.5.251 These products also differ in their relative levels of high-molecular-weight multimers. Koate DVI®, in particular, has fewer large VWF multimers compared to Alphanate SD/HT®, which has fewer than Humate-P® or normal plasma.277,284,285
Cryoprecipitate, derived from plasma, historically has been used to treat hemophilia A and VWD. Although cryoprecipitate is not required to have a specified level of VWF, the final product must have on average at least 80 units of FVIII per standard donor unit.286 Currently, cryoprecipitate is used under rare circumstances to treat VWD, such as when potential exposure to infectious agents can be limited by using directed donations to prepare the product.287 However, the use of cryoprecipitate is strongly discouraged by the National Hemophilia Foundation, except in life-or limb-threatening situations when no VWF concentrate is available, because cryoprecipitate is not virally inactivated.288 In developing countries, patients who have VWD may have no other options, because virally inactivated plasma concentrates are not available or are too expensive,283 but use of cryoprecipitate poses a significant risk of transmitting disease.289
VWF concentrates are dosed primarily on the basis of labeled VWF:RCo units and secondarily on the basis of labeled FVIII units. A dosing trial with pharmacokinetic laboratory monitoring should be considered before major surgery for selected patients with type 3 VWD or AVWS who are at risk for poor VWF recovery because of inhibitors. Use of VWF concentrates to prevent or control bleeding has been clinically efficacious, as shown on Table 13. The ultimate goal of surgical prophylaxis is to achieve a therapeutic level of 100 IU/dL VWF:RCo and, at least for the first 3 days of treatment, a nadir of 50 IU/dL VWF:RCo, as well as similar targets for FVIII.251,253-256,290 Successful surgical hemostasis was reported with the use of continuous infusion after initial bolus infusion at rates of 1-2 U/kg/hr VWF:RCo.252
Replacement therapy, using a VWF concentrate, is indicated for significant bleeding events or major surgery in patients who have types 2 and 3 VWD as well as in patients who have type 1 VWD and are unresponsive to DDAVP or require a protracted duration of therapy, or where DDAVP is contraindicated (see above). The dose and duration of therapy are dependent on the hemostatic challenge and expected duration required for hemostasis and wound healing. Major surgery requires hemostasis for 7-14 days,247,251-256 whereas minor surgeries can be treated adequately in 1-5 days.243,244,247,256 Certain procedures can be managed adequately by using a single infusion of 20-40 U/kg VWF:RCo before the procedure. Table 14 lists examples of major and minor surgical procedures. Table 15 lists initial dosing recommendations for use of VWF replacement therapy to prevent or treat bleeding. These recommendations are based on published results (see Table 13) as well as consensus expert opinion. The adequacy of courses of VWF replacement usually should be confirmed by laboratory assessment of VWF:RCo and FVIII levels, although monitoring of single infusions for treatment of outpatients may not be necessary. Duration of VWF elevation after replacement therapy is highly variable in the surgical setting. Thromboembolic events have been reported in patients who have VWD and are in situations of high thrombotic risk and receiving VWF:RCo/FVIII complex replacement therapy, especially in the setting of known risk factors for thrombosis.280-282 In all patients who have VWD and are receiving VWF concentrate, attention should be given to avoid exceeding maximal recommended levels of VWF:RCo and FVIII activities (see Recommendation VII.D, below), perform proper thrombotic-risk assessment, and institute appropriate preventive strategies. Recombinant VWF has been prepared and evaluated in animal models292 but is not available for use in humans.
Human platelets contain 10-15 percent of total blood VWF and platelet transfusions have been used successfully to treat bleeding in VWD patients.293,294 Platelet transfusion therapy should be considered as an adjunctive source of VWF, especially in patients with type 3 or platelet low VWD and platelet-type VWD, to control bleeding that is non- or poorly responsive to replacement therapy with VWF concentrate.
Table 13. Efficacy of VWF Replacement Concentrate for Surgery and Major Bleeding Events*
* For additional detail and information, see Evidence Table 12.
Table 14. Suggested Durations of VWF Replacement for Different Types of Surgical Procedures
*Individual cases may need longer or shorter
duration depending on the severity of VWD and the type of procedure.
Table 15. Initial Dosing Recommendations for VWF Concentrate Replacement for Prevention or Management of Bleeding
*Loading dose is in VWF:RCo IU/dL.
Other Therapies for VWD
Antifibrinolytics. The antifibrinolytic drugs aminocaproic acid and tranexamic acid are agents that inhibit the conversion of plasminogen to plasmin, inhibiting fibrinolysis and thereby helping to stabilize clots that have formed. Studies in hemophilia and in prostatectomy provided the basis for initial trials of antifibrinolytic agents in VWD.295 The drugs can be used orally or intravenously to treat mild mucocutaneous bleeding in patients who have VWD. In patients who have mild to moderate VWD, tranexamic acid given topically in the oral cavity ("swish and swallow or spit") every 6 hours has been used for prophylaxis in dental surgery, in combination with applied pressure, other topical agents, and suturing of surgical sites.242 The evidence for the effectiveness of local application of these agents is based on clinical case series,296 but this route of administration is not currently approved by the U.S. Food and Drug Administration (FDA). When DDAVP and/or VWF/FVIII concentrates are indicated, the use of antifibrinolytic agents as adjuncts to DDAVP or VWF concentrates has been helpful in controlling bleeding, such as in the oral cavity36,221,223,232,242,246-248 and in the gastrointestinal and genitourinary tracts.
The usual adult dose of aminocaproic acid is 4-5 g as a loading dose orally or intravenously (1 hour before invasive procedures), and then 1 g per hour, intravenously or orally, or 4-6 g every 4-6 hours orally, until bleeding is controlled, or for 5-7 days postoperatively.215 Total daily dose of aminocaproic acid is limited to 24 g per 24 hours to minimize potential side effects. Weight-based dosing is required in children and can also be used in adults (50-60 mg/kg).215,296 Lower doses (25 mg/kg) may be effective and can be used when gastrointestinal side effects interfere with therapy. Tranexamic acid is given intravenously at a dose of 10 mg/kg every 8 hours.215 The oral form is not currently available in the United States, and use of the intravenous form as an oral rinse ("swish and swallow" approach) is not an FDA-approved indication. The package insert for each drug should be consulted for more detailed guidance and for a full list of risks and contraindications. Both drugs can cause nausea and vomiting; less frequent but serious side effects include thrombotic complications. Both drugs are excreted renally, and dose adjustment or avoidance is advisable when significant renal insufficiency is present. Disseminated intravascular coagulation (DIC) and/or bleeding from the renal parenchyma or upper urinary tract are relative contraindications to antifibrinolytic agents. Renovascular thrombi have followed use of fibrinolytic agents in patients with DIC and have caused renal failure. Patients have also experienced urinary tract obstruction with upper urinary tract bleeding related to large clots in the renal pelvis or lower urinary tract. Changes in color vision during therapy with tranexamic acid require cessation of the drug and ophthalmologic examination.
Topical agents. Topical bovine thrombin (Thrombin-JMI) is marketed in the United States as an aid to hemostasis for topical therapy of accessible minor bleeding from capillaries and small venules. Fibrin sealant (Tisseel VH®, consisting of human thrombin, fibrinogen concentrate, and bovine aprotinin) is indicated as an adjunct to hemostasis in certain surgical situations, but it is not effective for the treatment of massive and brisk arterial bleeding. Fibrin sealants have been used with good results as adjunctive therapy for dental surgery in persons who have hemophilia or VWD.242,297 Topical collagen sponges are also approved for control of bleeding wounds.298 Other topical agents approved for limited indications include Coseal®, Bioglue®, and Quickclot®; however, no reports of their use in treating VWD could be found. Quickclot®, containing the mineral zeolite, was approved recently for use with compression dressings for control of external traumatic bleeding in the prehospital setting (e.g., battlefield). The added benefit of topical agents—when used with single or combination therapies including antifibrinolytic drugs, DDAVP, and VWF/FVIII concentrate—is unproven. The topical use of plasma-derived bovine or human proteins imparts a theoretical risk of disease transmission and of potential allergic and other immune reactions. The use of fibrin sealants in addition to drugs and/or concentrates may be viewed as optional adjunctive therapy for dental surgery and for cases in which surface wound bleeding continues despite combined therapy with drugs and concentrates. The safety of these topical agents in therapy for VWD remains to be demonstrated.
Other Issues in Medical Management
All persons who have significant bleeding symptoms related to VWD are likely to require human blood product administration and should receive immunizations for hepatitis A and B as recommended for individuals with hemophilia.299 Persons who have VWD should be counseled to avoid aspirin, other NSAIDs, and other platelet-inhibiting drugs.300-302
In an international registry of 189 cases of AVWS, DDAVP produced clinical and laboratory improvement in one-third of cases, although this effect was often short lived.117 If FVIII activity and the PTT were abnormal, a good DDAVP response was less common than in hereditary VWD and was often brief. In the international registry series, most patients who had AVWS also received VWF/FVIII concentrates; the extent and duration of response was varied. Therefore, VWF:RCo and FVIII levels must be measured pre- and postinfusion of DDAVP or VWF/FVIII concentrates in patients who have AVWS to determine the extent and duration of response and to guide subsequent dosage and dosing intervals.117,157
In patients who had a previous inadequate response to DDAVP and VWF/FVIII concentrates, intravenous immunoglobulin G (IGIV; 1 g/kg daily for 2 days) given alone was effective in controlling bleeding and raising VWF:RCo activity for 3 weeks in all eight patients who had excessive bleeding and an IgG-monoclonal gammopathy of uncertain significance (MGUS).303 In the international registry series, one-third of the 63 patients treated with high-dose IGIV had a good response.117 The underlying diagnoses of the responders were lymphoproliferative disorders (including MGUS), solid tumors, and autoimmune diseases. An anti-VWF antibody could be demonstrated in vitro in about two thirds of those responders. High dose IGIV therapy in the setting of AVWS is an off-label use but should be considered when DDAVP and VWF/FVIII concentrate therapy fail to control bleeding symptoms adequately.304-306 Some patients who have immune-mediated AVWS have responded to plasmapheresis, corticosteroids, and immunosuppressive agents.117 Because many patients in the international registry series received multiple therapeutic modalities, the independent contribution of each therapy to clinical improvement was unclear.
When all other therapeutic modalities fail to control bleeding adequately, the infusion of recombinant FVIIa may be considered, but this agent should be used with caution. Little experience has been reported for its use in treating VWD. A recent report described acute myocardial infarction immediately after the second dose of 90 microgram/kilogram in a 50 year old man who had hereditary type 2A VWD, gastrointestinal bleeding, and several risk factors for, but no history of, coronary artery disease.307
Cardiac Valvular Diseases. Congenital or acquired heart disease has been associated with AVWS.117,119,308 Elevated shear stress around a stenotic valve or septal defect may promote the proteolysis and depletion of high-molecular-weight VWF multimers.134 Patients who had associated aortic stenosis or other cardiac valvular disorders infrequently responded to any of the therapies described above.117,122 After surgical correction of the cardiac defect, the multimer pattern has improved at least transiently in most patients studied.119,122,308 Administration of VWF/FVIII concentrate immediately preoperatively should be considered for patients who demonstrate transient improvement in VWF activity with a test dose.
Angiodysplasia. Bleeding from gastrointestinal angiodysplasia has been reported in persons who have AVWS309 as well as in persons who have various types of congenital VWD. For example, bleeding from angiodysplasia is a classic presentation of AVWS associated with aortic stenosis122,310 and is often resistant to medical therapy, requiring surgical correction of the valve defect to ameliorate bleeding symptoms. In the absence of a correctable underlying etiology of angiodysplasia and bleeding associated with AVWS or congenital VWD, management of the condition can be challenging, as no single treatment modality is successful in all cases.311
Thrombocytosis. Thrombocytosis, especially in persons who have essential thrombocythemia, is associated with a relative reduction in the proportion of high-molecular-weight multimers.125 Although the relation of this abnormality to bleeding is inconsistent, treatment is aimed at reduction of the platelet count.
Hypothyroidism. In contrast to the above syndromes, AVWS that occurs in hypothyroidism is caused by decreased synthesis, and the VWF multimer patterns are normal.312,313 A minority of patients who have hypothyroidism have VWF levels below normal, and not all who have low VWF levels have bleeding symptoms. The decrease in VWF is corrected by thyroid hormone replacement.127,313
Menorrhagia is often the primary bleeding symptom in women who have VWD.85,314,315 Menorrhagia, however, may be a sign of a gynecological disorder rather than VWD.316 Therefore, a full gynecological evaluation is required before therapy is initiated.316
Medical therapies that have been described to control menorrhagia in women who have VWD include combined oral contraceptives, tranexamic acid, DDAVP, and, most recently, the levonorgestrel-releasing intrauterine system (Table 16). Data regarding the effectiveness of these therapies are limited. The only published randomized clinical trial of DDAVP for menorrhagia was small and failed to demonstrate efficacy compared to placebo.317 The available data show no evidence that DDAVP is more effective than other therapies used to treat menorrhagia.318 Depending on the woman's age, underlying gynecologic condition, and reproductive plans, any of the therapies demonstrated to be effective for the treatment of menorrhagia in women without VWD may be suitable, with the exception of NSAIDs, which decrease platelet function and systemic hemostasis.319 In one retrospective review of 36 adolescent girls with VWD and menorrhagia, treatment using oral contraceptive pills (OCPs) or intranasal DDAVP were equally efficacious.320
Table 16. Effectiveness of Medical Therapy for Menorrhagia in Women Who Have VWD
In the adolescent or adult female who does not desire pregnancy, but may desire future childbearing, the first choice of therapy should be combined oral contraceptives. Combined oral contraceptives contain a synthetic estrogen (ethinyl estradiol) and a progestin.328 The progestin prevents ovulation, and the synthetic estrogen prevents breakthrough bleeding.329 A majority of studies have found that combined oral contraceptives increase fibrinogen, prothrombin, factor VII, FVIII, and/or VWF330-332 and, consequently, promote hemostasis. It is not known whether the increase in coagulation factors associated with combined oral contraceptives contributes to the clinical response, but combined oral contraceptives do reduce menstrual blood loss333 and increase hemoglobin concentrations in women who have anemia.334-336 Combined oral contraceptives, used by tens of millions of women for prolonged periods of time, have been proven to be safe for long-term use337 except in women with thrombophilia.329 Although no formal studies of the effects of the contraceptive patch on hemostasis have been performed, the patch likely has effects similar to those of combined oral contraceptives.338
For a woman who has VWD and would otherwise be a suitable candidate for an intrauterine device, the second choice of therapy should be the levonorgestrel-releasing intrauterine system. The levonorgestrel-releasing intrauterine system is a progestin-impregnated intrauterine device that is believed to reduce menstrual blood loss by opposing estrogen induced growth of the endometrium or lining of the uterus.339
Women who do not respond to hormonal therapy and are being considered for treatment with DDAVP or VWF concentrate should be referred to a hemophilia treatment center or to a hematologist who has expertise in hemostasis. Treatments specific for VWD (such as DDAVP or VWF concentrate), or antifibrinolytic therapy, although they have not been proven to be effective for menorrhagia, may be tried.
In addition to medical therapies, surgical therapies have been used to treat menorrhagia in women who have VWD. Dilation and curettage (D & C), while occasionally necessary to diagnose intrauterine pathology, is not effective in controlling heavy menstrual bleeding.323 In two cases reported by Greer et al.323 and two cases reported by Kadir et al.,340 D & C resulted in further blood loss.
Endometrial ablation, on the other hand, reduced menstrual blood loss in seven out of seven women who had VWD.341 Three, however, ultimately required hysterectomy, compared to 12-34 percent of women who did not have VWD who usually require hysterectomy.342-346 Women who have VWD and undergo hysterectomy may be at greater risk of perioperative bleeding complications than other women, and bleeding may occur despite prophylactic therapy.137,315 Hysterectomy carries the risk of bleeding complications, but women who require the operation should not be deprived of its benefits. Because menorrhagia is often the primary bleeding symptom experienced by a woman who has VWD, hysterectomy offers the possibility of the elimination of bleeding symptoms for menorrhagia and significant improvement in quality of life.345,347,348
Hemorrhagic Ovarian Cysts
There are multiple case reports of women who have VWD and have experienced hemorrhagic ovarian cysts.322,323,349-353 Silwer, for example, reported that 9 of 136 (6.8 percent) women who had VWD experienced this problem.137 Ovulation is not normally accompanied by any significant bleeding, but in a woman who has a congenital bleeding disorder such as VWD, the potential exists for bleeding into the peritoneal cavity or bleeding into the residual follicle, resulting in a hemorrhagic ovarian cyst352 or retroperitoneal hematoma.323 Acute treatment of hemorrhagic ovarian cysts with surgical therapy, tranexamic acid, and factor replacement has been reported.323,351,352 Oral contraceptives have been used to prevent recurrences.349,350,352
Few options are available for the management of menorrhagia or recurrent hemorrhagic ovarian cysts in women who have VWD and desire pregnancy. Although data are limited to case reports, DDAVP, antifibrinolytics, or VWF concentrate may be tried.322
Ideally, planning for pregnancy begins before conception. Women who have VWD and are contemplating a pregnancy should be aware that they may be at an increased risk of bleeding complications during pregnancy354 and are definitely at increased risk of postpartum hemorrhage.145 Before conception or during pregnancy, women should be offered the opportunity to speak with a genetic counselor regarding the inheritance of VWD355 and with a pediatric hematologist regarding the evaluation of the infant after delivery.
Women who have type 1, type 2, or type 3 VWD and have FVIII levels <50 IU/dL, VWF:RCo <50 IU/dL, or a history of severe bleeding should be referred for prenatal care and delivery to a center that, in addition to specialists in high-risk obstetrics, has a hemophilia treatment center and/or a hematologist with expertise in hemostasis. Laboratory, pharmacy, and blood bank support is essential. Before any invasive procedure, such as chorionic villus sampling, amniocentesis, or cervical cerclage, women who have VWD should have laboratory assays for FVIII and VWF:RCo in order to receive appropriate prophylaxis.355,356 FVIII and VWF:RCo levels should be obtained in the third trimester of pregnancy to facilitate planning for the delivery.356 Before delivery, all women who have VWD should meet with an anesthesiologist to plan for the possible need for the administration of hemostatic agents, and/or alternatives, if necessary, for regional anesthesia at the time of delivery.355 A pregnant woman carrying a baby at risk for type 3 or severe types 1 or 2 VWD should be referred to a pediatric hematologist to discuss neonatal testing and potential bleeding in the infant.85,354,375
There are limited data on the use of DDAVP for VWD in pregnancy. Mannucci reported using DDAVP for prophylaxis prior to procedures in 31 pregnant women "without mishap,"357 but specific data are not provided. DDAVP, in the lower doses used to treat diabetes insipidus, however, is generally thought to be safe for mother and fetus. In a review of 53 cases of women who were pregnant and used DDAVP, administered in doses of 7.5-100 micrograms a day for diabetes insipidus, no adverse maternal or neonatal effects were attributable to the medication.274 In an in vitro placenta model, DDAVP did not cross the placenta in detectable amounts.274
Tranexamic acid crosses the placenta358 but has been used to treat bleeding during pregnancy in a limited number of cases without adverse fetal effects.359-364 Data regarding aminocaproic acid in pregnancy are limited, but aminocaproic acid was not found to be teratogenic in rabbits.365 In cases of its use during pregnancy, no adverse fetal effects have been reported.366
Miscarriage and Bleeding During Pregnancy
In the general population, miscarriage is common, and 12-13.5 percent of diagnosed pregnancies result in spontaneous abortion.367,368 Although detailed data were not provided, in a study of 182 females who had severe VWD, Lak et al.85 reported that miscarriage was no more frequent than in the general population. Other studies, however, have found a higher incidence of miscarriage among women who have VWD compared to controls145 or compared to the background rate.322,354 Bleeding complications during pregnancy other than miscarriage have been reported.322,323,369-371 Kadir et al.354 found that 33 percent of women who had VWD bled during their first trimester.
Table 17 summarizes nine case series reporting pregnancy outcomes in women who had VWD, including rates of miscarriage, peripartum prophylaxis, postpartum hemorrhage, and perineal hematoma. Prophylaxis included cryoprecipitate, fresh frozen plasma, DDAVP, and factor replacement.
No large prospective studies correlate VWF:RCo and FVIII levels with the risk of bleeding at the time of childbirth, but the opinion of experts is that VWF:RCo and FVIII levels of 50 IU/dL should be achieved before delivery323 and maintained for at least 3-5 days afterward.9,215,323,354-356 There is no consensus on levels of VWF:RCo and FVIII that are safe for regional anesthesia,372 but if VWF:RCo and FVIII levels are ≥50 IU/dL and the coagulation screen is normal, regional anesthesia may be considered safe.354
DDAVP may be used to raise factor levels in responders, but care must be taken in its administration at the time of childbirth. Women commonly receive 1-2 liters or more of fluid at the time of a vaginal delivery and 2-3 liters or more at the time of cesarean delivery. Fluids containing oxytocin, which also causes fluid retention, combined with DDAVP may result in fluid retention and life-threatening hyponatremia. Chediak and colleagues reported complications of fluid retention in two women who received DDAVP at the time of childbirth. One woman who received three doses 18 hours apart developed severe hyponatremia (sodium level of 108 mEq/L) and experienced grand mal seizures.371
Table 17. Pregnancies in Women Who Have VWD
Cryo, cryoprecipitate; DDAVP,
1-desamino-8-D-arginine vasopressin (desmopressin, a synthetic analog of
vasopressin); FFP, fresh frozen plasma; FVIII, FVIII concentrate; Haemate
P®, European equivalent of Humate-P®; NHS 8Y,
National Health Services (United Kingdom) factor VIII concentrate (8Y); VWD,
von Willebrand disease.
Because NSAIDs, commonly prescribed for pain after childbirth, may decrease platelet function and systemic hemostasis,319 alternative analgesics should be considered.
Postpartum hemorrhage is an anticipated problem among women who have VWD. By the end of gestation, an estimated 10-20 percent of a woman's blood volume, or at least 750 mL/minute, flows through the uterus.373 After delivery of the infant and placenta, the uterus must contract, and the uterine vasculature must constrict to prevent exsanguination.374 Failure of the uterus to contract is the single most important cause of postpartum hemorrhage.374 Nonetheless, women who have VWD are at an increased risk of postpartum hemorrhage compared to controls.137,145,321 Multiple case series document an increased incidence of postpartum hemorrhage in women who have VWD (see Table 17).
Perineal hematoma, a rare complication of vaginal birth, occurs with some frequency in women who have VWD. Greer et al.323 reported one hematoma in 13 vaginal deliveries, and Kadir and colleagues354 reported three hematomas in 49 vaginal deliveries. This is a relatively high frequency compared to a rate of only 2.2/1,000 in a cohort of 26,187 spontaneous or operative vaginal deliveries.378
In women who have VWD, vaginal bleeding is frequently reported to occur more than 2-3 weeks postpartum. The duration of bleeding after delivery in a normal patient is a median of 21-27 days.379-381 However, the VWF levels that are elevated during pregnancy return to baseline within 7-21 days,382,383 predisposing women who have VWD to delayed postpartum hemorrhage. In the absence of a bleeding disorder, delayed or secondary postpartum hemorrhage is rare and occurs following less than 1 percent of deliveries.384,385 In contrast, 20-25 percent of women who had VWD had delayed postpartum hemorrhage, making delayed postpartum hemorrhage 15-20 times more common among these women compared to normal subjects.354,376
Among the published series of cases of women who were pregnant and had VWD (Table 17), multiple cases of postpartum hemorrhage occurred despite prophylaxis. The average time of presentation of postpartum hemorrhage in women who have VWD was estimated to be 15.7 ± 5.2 days after delivery.386 The implication is that women who have VWD may require frequent evaluation—and possibly prophylaxis—for 2 weeks or more postpartum. Weekly contact with these women is recommended during the postpartum period.356
The recommendations are graded according to criteria described in the "Introduction" and in Table 1. Evidence tables are provided for recommendations given a grade of B and having two or more references.