INTRODUCTION — von Willebrand disease (VWD) is the most common inherited bleeding disorder. Management can vary widely depending on the type of VWD, severity and location of bleeding, and need for invasive procedures.

This topic reviews the management of VWD in less serious bleeding situations, including treatment of minor bleeding and minor surgical procedures, the use of DDAVP (1-deamino, 8-D arginine-vasopressin, also called desmopressin) and the DDAVP trial, heavy menstrual bleeding, obstetric considerations, and testing and counseling of family members. Minor bleeding is generally defined as bleeding that causes <2 g/dL decrease in hemoglobin concentration and/or leads to transfusion of <2 units of whole blood or red blood cells and is non-life threatening and located in non-critical areas or organs.

Separate topic reviews discuss the treatment of serious bleeding and major surgery, as well as the clinical presentation, diagnosis, and pathophysiology of VWD, and the diagnosis and management of acquired von Willebrand syndrome (aVWS):

●Treatment of major bleeding and major surgery – (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery".)

●Clinical presentation and diagnosis of VWD – (See "Clinical presentation and diagnosis of von Willebrand disease".)

●Pathophysiology of VWD – (See "Classification and pathophysiology of von Willebrand disease".)

●Evaluation and management of aVWS – (See "Acquired von Willebrand syndrome".)

●Normal von Willebrand factor (VWF) function – (See "Biology and normal function of von Willebrand factor".)

GENERAL PRINCIPLES OF CARE — The following general principles apply to the care of individuals with VWD:

●Planning for elective surgery and treatment of bleeding, including performing a DDAVP trial when the patient is not bleeding and ensuring close consultation among the surgeon, anesthesiologist, hematologist, and other clinicians involved in the patient's care. (See 'Trial of DDAVP' below and 'Minor bleeding and minor surgery' below.)

●Planning and treatment for menstrual blood loss, obstetric considerations, possible iron deficiency in women, and treatment for chronic bleeding and prophylactic use of VWF concentrates. (See 'Obstetric considerations' below and 'Chronic bleeding' below.)

●Counseling about the diagnosis, including the type of VWD, bleeding risk, when to seek medical attention, and implications for counseling and testing of family members. (See "Clinical presentation and diagnosis of von Willebrand disease" and 'Testing and counseling of family members' below.)

TRIAL OF DDAVP

Rationale and indications — A DDAVP (desmopressin) trial is used to determine whether DDAVP can be used in that patient to treat minor bleeding or reduce surgical bleeding with minor procedures. DDAVP is not used without a previous trial that demonstrates its efficacy, except in cases of type 1 VWD when the patient has a VWF level >30 IU/dL and does not have a history of serious bleeding [1,2]. There are several instances in which a DDAVP trial is not recommended due to lack of efficacy, as listed below.

DDAVP promotes the release of endogenous von Willebrand factor (VWF) from endothelial storage sites; thus, it is most effective in individuals with sufficient baseline VWF levels to benefit from modest increases (threefold to fivefold over their baseline).

DDAVP also has the advantages of avoiding exposure of the individual to foreign plasma proteins, and it also causes a temporary increase in ultra-high molecular weight VWF multimers in the circulation. These are the most hemostatically active VWF multimers. DDAVP additionally promotes release of stored factor VIII, which is important in clot formation. The mechanism by which DDAVP increases release of endogenous VWF is unclear. The effect cannot be reproduced by direct exposure of cultured endothelial cells to DDAVP [3].

A trial of DDAVP is carried out following diagnosis in a patient when the person is not bleeding and not acutely ill; the trial of DDAVP should be done shortly after the time of diagnosis to assess the response prior to its actual need. The goal is to determine the effectiveness of DDAVP in the future should it be needed for minor surgery or non-life-threatening bleeding. (See 'Minor bleeding and minor surgery' below.)

We recommend a trial of DDAVP in most patients age ≥2 years who have type 1 VWD and many who have type 2 VWD. General experience has shown that patients with type 1 VWD are more likely to benefit from DDAVP than those with type 2 VWD.

We do not perform a DDAVP trial in the following patients (see 'DDAVP indications and contraindications' below):

●Children <2 years of age, in whom DDAVP can cause serious side effects and is not recommended for use in this age group.

●Type 3 VWD patients (absent VWF), who lack endogenous stores of VWF and do not have a response. Severe type 1 and type 2 patients often do not respond to DDAVP with adequate levels of VWF and factor VIII; the decision of whether to perform a trial in these patients should be made individually.

●Patients with cardiovascular disease.

Patients with seizure disorders may receive DDAVP with particular care due to the hyponatremia that may result from DDAVP administration.

Some experts advise against performing a DDAVP trial in individuals with type 2B disease due to the potential risk of precipitating thrombocytopenia [2,4,5]. Others, however, believe individuals with known type 2B disease can undergo a DDAVP trial when at baseline; platelet count pre- and post-DDAVP should be measured as well as VWF and factor VIII levels. If the patient has a response without a significant drop in platelet count (range of <20,000 to 30,000/dL) and the drop is transient, they may benefit from DDAVP during later bleeding episodes.

A DDAVP trial may reveal a shortened half-life of factor VIII, as seen in type 2N, or a shortened half-life of both VWF and factor VIII, as in type 1C, where the VWF-factor VIII complex is cleared rapidly. If the patient is known to have a VWD type with shortened VWF survival, such as type 1C, DDAVP may not be useful, and it is not recommended in the setting of surgery in these patients [5]. A clinical decision should be made about the usefulness of DDAVP depending on the situation.

DDAVP has been widely used during pregnancy and delivery with good effectiveness and safety in appropriate VWD patients [2,5]. DDAVP is not appropriate for serious or life-threatening bleeding because it rarely produces a sufficient increase or duration of VWF, and the increase in VWF may take an hour or more to take effect; these individuals are treated with VWF concentrates.

DDAVP trial procedure — As noted above, a DDAVP (desmopressin) trial is usually performed when an individual is well and not bleeding, to determine whether DDAVP can be used for minor bleeding or minor surgery. Before conducting the trial, it is important to consider possible contraindications, cautions, and potential adverse effects. (See 'DDAVP indications and contraindications' below and 'Cautions with DDAVP' below and 'Adverse effects of DDAVP' below.)

The trial is conducted as follows:

●For an intravenous DDAVP trial, a dose of 0.3 mcg/kg (maximum 20 mcg), is given in 50 mL of saline over 20 to 30 minutes [5]. Blood samples for a complete blood count (CBC), platelet count, VWF activity, and factor VIII activity are obtained before DDAVP administration, at one hour after the infusion, and at approximately four hours after the infusion. These time points are used to assess the increase in levels of VWF activity and factor VIII activity and the duration of the effect and to ensure that DDAVP does not cause thrombocytopenia in that individual.

Blood samples for a CBC and platelet count, VWF activity (measured in international units [IU]/dL, which is equivalent to percent activity), and factor VIII activity should be obtained just before the DDAVP is administered and at approximately one hour and four hours after administration.

●If intranasal use is planned, the intranasal formulation should be used for the trial. In this case, DDAVP is administered using one puff in each nostril for individuals weighing ≥50 kg (total dose 2 puffs, 300 mcg) or one puff only in individuals weighing <50 kg (total dose 150 mcg). Blood samples for testing are obtained as above except that the first sample after administration should be taken at two hours; the rise in VWF and factor VIII levels are less than expected for the intravenous dose, but should rise to >30 IU/dL for confirmation of an adequate response.

The formulation of DDAVP for use in VWD and other bleeding disorders (concentration 1.5 mg/mL) is much greater than the formulation for enuresis, which has a lower DDAVP concentration (0.1 mg/mL), and care should be taken to use the correct formulation.

An effective response to DDAVP at one or two hours after an intravenous infusion or intranasal dose is a VWF activity of at least 30 IU/dL and ideally at least 50 IU/dL. The increase usually represents a three- to fivefold increase over the individual's baseline. The increase in VWF levels using intranasal administration is expected to be less than the intravenous, but to be effective should still reach at least 30 IU/dL. Once an adequate response is documented in a trial, DDAVP can be used for subsequent bleeding episodes or invasive procedures without further trials.

There are several measures of VWF activity (VWF:RCo, VWF:GPIbR, VWF:GPIbM, and VWF:Ab); these are discussed in more detail separately. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'VWF functional assays (VWF:Act)'.)

The DDAVP trial in VWD should not be confused with the DDAVP stimulation test used to evaluate for Cushing syndrome (excess adrenocorticotropic hormone [ACTH]).

MINOR BLEEDING AND MINOR SURGERY

Overview (minor bleeding and minor surgery) — The major options for increasing von Willebrand factor (VWF) levels to treat bleeding and provide surgical prophylaxis are DDAVP (desmopressin) and VWF concentrates. Other treatment includes inhibitors of fibrinolysis to stabilize the clot and topical therapies that aid in clot formation (table 1).

Minor bleeding and minor surgery (bleeding that causes <2 g/dL decrease in hemoglobin concentration and/or leads to transfusion of <2 units of whole blood or red blood cells and is located in non-critical areas or organs) often can be treated with DDAVP rather than VWF concentrates in type 1 patients, provided the individual has demonstrated an adequate response in a DDAVP trial. (See 'Trial of DDAVP' above.)

An antifibrinolytic agent such as tranexamic acid is frequently added. In type 1 patients with a baseline VWF level of >30 IU/DL, the 2021 VWD treatment guidelines suggest the use of tranexamic acid alone [2,5]; we concur with this judgment, always considering the seriousness of the clinical setting and past bleeding.

Minor bleeding generally applies to epistaxis; cutaneous, oral, and some gastrointestinal bleeding; hematuria; tooth extraction; and surgery such as tonsillectomy, appendectomy, and others. Elective procedures should not be performed until the individual has the diagnosis of VWD confirmed (and the type defined) or excluded. (See 'Newborn' below.)

Benefits of using DDAVP include decreased exposure of the individual to foreign proteins in the factor concentrates and release of the most hemostatically active VWF monomers. (See 'Trial of DDAVP' above.)

For those who do not have an adequate response to DDAVP, VWF concentrates are given. Ideally, patients should have nearby access to a facility where monitoring of VWF levels and factor VIII can be done and a rapid switch to VWF concentrates can be made if needed.

The following summarizes key management principles:

●DDAVP (desmopressin) is effective in the majority of type 1 VWD patients with minor bleeding or for minor procedures. DDAVP is not used in children <2 years of age (due to concern about serious side effects) or in any VWD type 3 patients (due to lack of response); moderate (and severe) type 2 patients may not have an adequate response, and it is used with particular caution in type 2B VWD patients because of possible thrombocytopenia induced by DDAVP in these individuals. (See 'DDAVP' below.)

●The patient should generally have a trial of DDAVP prior to its use to be certain that they will have an adequate response. (See 'Trial of DDAVP' above.)

●Patients with type 3 and severe types 1 and 2 VWD never/seldom have an adequate response to DDAVP and usually require VWF concentrates. (See 'VWF concentrates for minor bleeding' below.)

●VWF concentrates should be available for use in patients whose bleeding is not controlled by DDAVP, those who do not have an adequate response, and/or those who require prolonged treatment (more than three to five days). (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates'.)

●Attention should be paid to the other conditions and medications that might aggravate bleeding, including agents that affect platelet function. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Overview of approach'.)

●Other therapies such as antifibrinolytic agents or topical agents may be appropriate, either alone or in addition to DDAVP, for selected clinical scenarios such as mucosal bleeding or surgery in the oropharynx or urogenital tract, heavy menstrual bleeding, and epistaxis. Input from the patient and their primary clinician about which agents have been effective in the past may be especially helpful. (See 'Other therapies' below and 'Excessive menstrual bleeding' below.)

DDAVP

DDAVP indications and contraindications — DDAVP is appropriate for treating minor bleeding or for minor surgical procedures in individuals >2 years of age with VWD (typically mild to moderate type 1 and some type 2) and who have previously demonstrated an adequate response in a DDAVP trial. (See 'Trial of DDAVP' above.)

A response is typically considered to have occurred if there is an increase in VWF activity and factor VIII activity to at least >30 international unit (IU)/dL (ideally >50 IU/dL) that persists for more than four to six hours.

DDAVP is not used in the following:

●Children <2 years, due to serious side effects in this age group

●Individuals with type 3 VWD, due to lack of response

●Individuals with lack of response in a DDAVP trial

●Individuals with cardiovascular disease, due to an increased risk of thrombosis

Great care should be taken if administering DDAVP to individuals with a seizure disorder due to the potential risk of hyponatremia.

DDAVP administration and dosing — DDAVP (desmopressin) is generally not used without a previous trial in a patient to evaluate efficacy. (See 'Trial of DDAVP' above.)

For those with a demonstrated response, DDAVP can be administered by several routes (intravenous or subcutaneous injection or intranasal spray) (table 2). The subcutaneous preparation is not approved for use in the United States, though it has been used successfully in Europe and in a small number of patients in the United States [6,7]. Any route can be used as long as the individual has previously demonstrated a response during a prior DDAVP trial. If someone has a good response to an intranasal DDAVP trial, the intravenous route would be expected to work, although it would be ideal to confirm this with a VWF activity measurement. The intranasal route can be complicated by absorption and the timing is less precise for peak levels. (See 'Trial of DDAVP' above.)

The intranasal formulation of DDAVP (Stimate) was voluntarily recalled in mid-2020 due to packaging issues that affected potency. It is predicted to be available again in the second half of 2023. The intravenous and subcutaneous forms of DDAVP were not affected by the recall; subcutaneous DDAVP is not approved for use in the United States.

The table summarizes the dosing and adverse effects of DDAVP (table 2). Important aspects of administration and dosing include the following:

●Goal of therapy – The goal is an increase in VWF and factor VIII activities to at least >30 IU/dL (ideally >50 IU/dL), which persists for more than four to six hours and controls bleeding; this is usual in most cases of minor bleeding or minor procedures.

●Intravenous dosing – Intravenous dosing is usually used with the onset of minor bleeding or approximately one hour prior to minor procedures and when intravenous access is already available for other reasons. Intravenous infusion yields the most reliable increases in VWF in those patients who respond to it.

The intravenous DDAVP dose is 0.3 mcg/kg (maximum 20 mcg), diluted in 50 mL of normal saline and infused over 20 to 30 minutes [8]. The dose maximum of 20 mcg is commonly used in the United States due to concerns about increasing toxicity (especially hyponatremia) and diminishing efficacy at higher doses.

A three- to fivefold increase in baseline levels of VWF activity and factor VIII activity is expected at approximately 30 to 60 minutes after the infusion, with levels higher than baseline persisting for 8 to 12 hours [9]. The half-life of the released VWF will correspond to the particular half-life of the patient's own VWF protein [10-12].

A repeat dose may be given at 8 to 12 hours if clinically indicated. Subsequent doses are usually switched to once-daily doses for one to three or occasionally up to five days [13,14]. Patients should be monitored for hyponatremia when more than three to four doses are given, particularly if intravenous fluids are used. (See 'Adverse effects of DDAVP' below.)

●Subcutaneous dosing – Local practices vary regarding the use of the subcutaneous route; consultation with the local hemostasis expert is advised. Subcutaneous DDAVP preparations are not approved for use for VWD in the United States, but subcutaneous use is approved in various countries (Canada, countries in Europe), using the same dosing as the intravenous route. Peak levels are slightly lower and occur later than with intravenous administration, but other kinetic parameters are similar [15].

●Intranasal dosing – Intranasal administration of DDAVP has become a favored choice for many patients who have less serious bleeding that does not require a hospital visit (eg, heavy menstrual bleeding) or those who need treatment prior to a planned minor invasive procedure such as dental work or skin biopsy. The VWF and factor VIII responses may not peak until after approximately one and a half to two hours rather than at 30 to 60 minutes as seen after intravenous administration, and the peak level of VWF reached is similar to a lower intravenous dose of 0.2 mcg/kg [16]. The intranasal route allows therapy to be administered at home in a timely manner for minor bleeding.

The intranasal DDAVP dose is 150 mcg (one puff) for individuals weighing <50 kg and 300 mcg (2 puffs, one puff into each nostril) for individuals weighing ≥50 kg [8].

Patients and parents should be instructed to make sure to use the DDAVP formulation for bleeding disorders, which has a concentration of 150 mcg/spray, not the formulation for enuresis, which has a much lower concentration (eg, 1 to 10 mcg/spray); the lower dose formulation is not sufficient for VWD treatment.

DDAVP can be given for three to five days. Beyond this period of time it is generally no longer effective due to depletion of VWF stores, resulting in tachyphylaxis [17]. Also, serious hyponatremia can occur with longer duration therapy, and fluid restriction (1 liter/day) may be necessary [18].

Once a DDAVP trial has shown efficacy, the DDAVP response is usually monitored clinically (assessment for ongoing bleeding). If clinically relevant bleeding occurs after DDAVP, VWF and factor VIII levels should be measured, and administration of a VWF concentrate and/or factor VIII may be required.

Monitoring of serum sodium concentration is appropriate for hospitalized individuals, as well as those receiving more than three doses of DDAVP and/or those receiving intravenous fluids. (See 'Adverse effects of DDAVP' below.)

Cautions with DDAVP — DDAVP is not appropriate for treating major or life-threatening bleeding in individuals with VWD because it rarely produces a sufficient increase or duration in VWF (or factor VIII) activity. These individuals are treated with VWF concentrates. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates'.)

DDAVP is seldom used in children under the age of two years and is not recommended in this age group due to risks of hyponatremia and seizures. (See 'Adverse effects of DDAVP' below.)

DDAVP is effective for only short-term use, since tachyphylaxis develops within a few days. Thus, additional therapies may be required if bleeding is prolonged for more than a few days. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates' and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Other therapies'.)

DDAVP should be used cautiously in a patient at risk of thrombotic complications such as cardiovascular or cerebrovascular disease and in conjunction with antifibrinolytic agents. (See 'Antifibrinolytic agents' below.)

Adverse effects of DDAVP — Adverse effects of DDAVP include the following [19]:

●Hyponatremia

●Flushing (due to vasodilation)

●Headache (may be reduced by slowing the infusion rate)

●Nausea

●Hypotension (mild) or hypertension

●Tingling or weakness (may be related to hyponatremia)

●Potential for thrombosis (rare); for this reason DDAVP is not recommended in patients who have concomitant cardiovascular disease

Hyponatremia is due to the antidiuretic hormone activity of DDAVP. It can be severe enough to cause seizures or even death if measures are not taken to monitor for and mitigate it [20]. This includes close monitoring and limiting of free water intake, both oral and intravenous.

A retrospective review of 107 children and adolescents with bleeding disorders who were treated with DDAVP perioperatively reported that 11 (10 percent) developed a serum sodium <130 mEq/L [21]. One two-year-old child developed seizures. Another study that used a fluid restriction protocol in children treated with DDAVP found that using two-thirds maintenance fluids was an effective strategy for reducing the risk of severe hyponatremia [22].

Use of nonsteroidal antiinflammatory drugs (NSAIDs) can further exacerbate hyponatremia. These agents generally are not used by individuals with VWD, but their inadvertent use should especially be avoided in the setting of DDAVP therapy [23].

A causal association between DDAVP and thrombosis has not been demonstrated, and some individuals with independent risk factors for thrombosis have been treated with DDAVP without thrombotic consequences [24,25]. Nevertheless, common sense dictates caution with the use of DDAVP in patients with known coronary or cerebral arterial vascular disease.

Evidence of efficacy — The efficacy of DDAVP in raising VWF levels and preventing or reducing serious bleeding has been established primarily from observational studies and clinical experience. The efficacy varies with the type and severity of VWD (table 3), as DDAVP causes release of only the patient's pre-formed VWF from sites of synthesis, and if a patient has a qualitative defect, the abnormal VWF will also be released by DDAVP. Since DDAVP typically raises the plasma VWF activity by approximately three- to fivefold, individuals with a baseline VWF activity above 10 percent are most likely to have a good to excellent response, with an increase in plasma VWF activity to >50 IU/dL (>50 percent) [26].

●Type 1 disease – Numerous observational studies in individuals with type 1 VWF and VWF activity above 10 percent have demonstrated good hemostasis when bleeding is treated with DDAVP [26-28]. Inadequate response to DDAVP has been noted in individuals with severe type 1 disease or in those with absent stores of VWF in platelets (rare, referred to as "platelet-low VWD") [27,29]. Platelet VWF (a surrogate marker for endothelial cell VWF) is not generally evaluated, and a DDAVP trial will identify individuals who do not benefit from DDAVP. (See 'Trial of DDAVP' above.)

●Type 2 disease – Good to excellent responses to DDAVP are less frequent in individuals with type 2 disease, but responses do occur in type 2 patients, especially those with mild disease [11,26,27,30-32]. DDAVP testing will help determine whether a specific patient is likely to benefit. (See 'Trial of DDAVP' above.)

Special attention should be paid to individuals with type 2B disease (table 3) because the dysfunctional VWF in these individuals causes increased binding to platelets and can cause thrombocytopenia (via sequestration and increased clearance of platelets); this effect may be magnified after administration of DDAVP. However, some type 2B individuals have demonstrated a good response with inconsequential or no thrombocytopenia and no thrombotic complications [33-35]. (See "Classification and pathophysiology of von Willebrand disease", section on 'Type 2B'.)

●Type 3 disease – Individuals with type 3 disease have absent VWF, including no VWF in storage granules, and thus these individuals are not expected to have a response to DDAVP [8].

VWF concentrates for minor bleeding — VWF concentrates (table 1) are appropriate for treating minor bleeding or surgery if DDAVP cannot be used (eg, due to negative DDAVP trial) and/or if DDAVP fails to control bleeding sufficiently or if prolonged therapy (eg, more than three to five days) is needed.

●The initial dose for minor bleeding is 40 to 50 international units/kg intravenously, which is expected to raise the plasma VWF activity to ≥50 IU/dL.

●Subsequent doses of approximately half the initial dose are given every 12 to 48 hours to maintain VWF activity levels of >30 IU/dL, with measurement of plasma VWF activity. Patients with rapid clearance may require higher and/or more frequent doses.

Information about different VWF concentrates (plasma-derived and recombinant), dosing, monitoring, duration of therapy, and adverse effects is presented separately. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates'.)

Other therapies

Antifibrinolytic agents — Antifibrinolytic agents (epsilon aminocaproic acid [EACA; Amicar] and tranexamic acid [TXA; Cyklokapron, Lysteda]) promote stability of the hemostatic plug by reducing fibrinolysis. They are especially effective in areas with naturally high fibrinolytic activity such as the nose, oropharynx, or urogenital tract. These agents are contraindicated in the presence of upper urinary tract bleeding, since clots may lead to ureteral obstruction [36].  

We sometimes use an antifibrinolytic agent alone (without a VWF concentrate or DDAVP) to decrease bleeding in individuals with mild bleeding; this is particularly useful with heavy menstrual bleeding, postpartum bleeding, epistaxis, and for selected dental, gynecologic, and other minor procedures [13,14,37]. We add an antifibrinolytic agent to VWF concentrate or DDAVP when bleeding occurs in an area with high antifibrinolytic activity or when DDAVP alone is only partially effective.

Antifibrinolytic agents can be given orally or intravenously, with the route determined by the clinical situation (eg, orally for an outpatient, intravenously for an inpatient who cannot take medications by mouth). Typical schedules are presented in the table (table 1).

●EACA (epsilon aminocaproic acid) – The usual oral dose in patients with VWD is 25 to 50 mg/kg per dose every six hours (maximum single dose 5 grams). Intravenous use is uncommon and not defined in congenital bleeding disorders.

●TXA (tranexamic acid) – The usual oral dose is 25 mg/kg per dose orally every six to eight hours. The usual intravenous dose is 10 mg/kg every eight hours.

Dosing must be adjusted for renal insufficiency.

The duration of therapy is generally in the range of three to seven days.

Prolonged use of an antifibrinolytic agent carries a risk of thrombosis, particularly in patients who have an underlying hypercoagulable state [38].

Topical therapies — Topical agents are most often used for nasal or oral bleeding.

Supports such as Gelfoam or Surgicel can be soaked in topical thrombin and applied to local areas of bleeding [39]. It is recommended that human thrombin be used for this purpose. If human thrombin is not available, bovine thrombin can be used, although exposures to large amounts of topical bovine thrombin carry a risk of antibody formation against the bovine factor V in the preparation that can cross-react with human factor V and cause bleeding [40]. (See "Acquired inhibitors of coagulation", section on 'Thrombin (factor IIa) inhibitors'.)

Other available topical agents that may be used include micronized collagen (Avitene), which is available in strips for packing, and fibrin sealant (using human thrombin) [39]. (See "Fibrin sealants".)

Estrogens — We do not use estrogen replacement therapy for VWD, but individuals who have other reasons for this therapy may benefit (due to the estrogen-induced increase in VWF synthesis) [41,42]. (See "Menopausal hormone therapy: Benefits and risks" and "Biology and normal function of von Willebrand factor", section on 'Synthesis'.)

Combined oral contraceptives are commonly used for heavy menstrual bleeding in VWD if the patient does not want to become pregnant; there are no objective studies to show their efficacy. (See 'Excessive menstrual bleeding' below.)

CHRONIC BLEEDING

VWF prophylaxis for chronic bleeding — For individuals with severe, recurrent bleeding (eg, recurrent gastrointestinal bleeding, epistaxis, joint bleeding similar to hemophilia), chronic VWF administration can be used prophylactically, similar to that in individuals with hemophilia receiving routine prophylaxis with factor VIII or factor IX. This is consistent with recommendations in a comprehensive 2021 guideline on VWD treatment [5].

Although this severity of bleeding is uncommon, several retrospective studies have demonstrated that regular prophylaxis can provide dramatic reductions in chronic bleeding of various types (epistaxis, oral or GI bleeding, joint bleeding, heavy menstrual bleeding) and can reduce hospitalizations [43-47].

The approach using chronic VWF administration is most likely to be appropriate in individuals with one or more of the following:

●Frequent or chronic bleeding that recurs, usually in the same site, despite appropriate on-demand (intermittent) therapy

●Bleeding that interferes with daily activities, school attendance, or work

●Bleeding that adversely affects quality of life

An antifibrinolytic agent may also be given, particularly if the bleeding is in a site of high fibrinolytic activity (eg, epistaxis). (See 'Antifibrinolytic agents' above.)

An international group was organized to determine how to administer long-term replacement VWF to severely affected patients (eg, chronic epistaxis, gastrointestinal bleeding, menstrual bleeding, or joint bleeding) using a prophylactic schedule. Their initial study indicated that in 10 patients using an escalating dose frequency that began with a once weekly schedule of 50 international units/kg and escalated to three times per week if necessary, the bleeding rate had decreased significantly (mean annualized bleeding rate decreased from 25 to 6.1) [46]. Due to difficulty in enrolling the number of patients needed, an update of this study was not able to recommend optimal doses for prophylaxis, as different bleeding sites may require different frequency and doses.

An open-label randomized trial involving 19 individuals showed that prophylactic treatment was associated with a decrease in bleeding compared with on-demand treatment given at the time of bleeding [48].

A study involving 2790 VWD patients followed over 22 years showed that individuals with VWD had twice as many hospitalizations and outpatient visits as matched controls; in a subgroup of the VWD patients, prophylactic therapy decreased hospitalizations by half [47].

A disadvantage of prophylactic therapy is the possible development of an inhibitor (alloantibody to infused VWF and/or factor VIII). In one report, an individual developed an inhibitor to VWF and factor VIII and was changed to prophylaxis with a bypassing agent [27]. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Adverse effects (VWF concentrates)'.)

Information about choice of VWF concentrate formulation and monitoring is presented separately. (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates'.)

Excessive menstrual bleeding — Excessive menstrual bleeding (also called abnormal uterine bleeding [AUB] or heavy menstrual bleeding [HMB]) is common in women with VWD. (See "Clinical presentation and diagnosis of von Willebrand disease", section on 'Heavy menstrual bleeding'.)

A series of questions (table 4) can be helpful to assess the degree of blood loss before therapy is started. Interpretation of the replies and other pertinent questions are discussed in more detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis".)

Once it is determined that medical therapy is appropriate (eg, that the woman does not have an anatomic reason for bleeding such as a polyp, endometritis, tumor, or endocrine abnormality such as thyroid disease or hyperprolactinemia), and the woman is not pregnant, the following options can be discussed with the patient and an approach selected based on bleeding severity and patient preferences:

●Hormonal contraception (combined oral contraceptives or a levonorgestrel-releasing intrauterine device) may be used if pregnancy is not desired [49]. This may also be helpful for controlling painful menstruation, as nonsteroidal antiinflammatory drugs (NSAIDs) are generally avoided in VWD. (See "Hormonal contraception for suppression of menstruation".)

●For those who prefer to avoid oral contraceptives (eg, desire to become pregnant or to avoid a daily pill), DDAVP and antifibrinolytic agents are both options. Typically, one of these therapies is selected, and if it is ineffective, the other is tried.

•An antifibrinolytic agent may be used, usually for days one to five of menses. (See 'Antifibrinolytic agents' above.)

•Intranasal DDAVP has been used by women with VWD at the onset of menses to control excessive menstrual bleeding [50-52]. It is typically taken once daily on days one to three of menses.

In a cross-over study of 116 women, tranexamic acid was more effective in lowering menstrual blood loss than DDAVP [52].

●If bleeding is more severe and/or is not adequately reduced with the measures listed above, a brief course of von Willebrand factor (VWF) concentrate replacement therapy can be started at the onset of menstrual bleeding; the optimal dose and duration are under study. Recombinant VWF may be useful because of its longer half-life [53].

●Endometrial ablation is a minimally invasive office procedure performed by hysteroscopy that can be used to surgically destroy the endometrium using a surgical instrument, radiofrequency, heat, or cryotherapy. This is only appropriate for women who do not wish to become pregnant in the future, and it does not cause cessation of menses. Several studies, including a 2009 meta-analysis of endometrial ablation in women with bleeding disorders, found the procedure to be safe and effective and comparable to a levonorgestrel-releasing intrauterine device in reducing blood loss [54-56]. Indications, contraindications, and potential complications are discussed separately. (See "Overview of endometrial ablation".)

Supporting evidence for these different therapies comes from observational studies. Various studies have described good efficacy of intranasal DDAVP in reducing blood loss from heavy menstrual bleeding, reduced need to seek medical attention, and reduced the number of days lost from work or school [50-52]. One prospective crossover study using tranexamic acid and intranasal DDAVP showed that both agents were effective, but tranexamic acid was superior to DDAVP in reducing bleeding in this setting [52].

Additional details of the initial evaluation and other treatments are presented separately. (See "Abnormal uterine bleeding: Management in premenopausal patients".)

Chronic GI bleeding — Recurrent gastrointestinal (GI) bleeding occurs in individuals with VWD, particularly in more severe VWD, and may be treated with VWF concentrates as needed (ie, on demand) or with prophylactic VWF concentrate infusions, similar to other types of bleeding (see 'VWF prophylaxis for chronic bleeding' above). In addition to VWF concentrates, it is important to give treatment specific to the cause of bleeding, which may include a proton pump inhibitor in peptic ulcer disease.

In addition to the usual causes of GI bleeding such as peptic ulcers, individuals with VWD have a high prevalence of angiodysplasia in the GI tract. This is thought to be due to the role of VWF in angiogenesis; the angiodysplastic lesions are hypothesized to develop due to alterations in the gastrointestinal vasculature that arise in the absence of normal VWF levels [57]. (See "Biology and normal function of von Willebrand factor", section on 'Other functions of VWF' and "Acquired von Willebrand syndrome", section on 'Consequences of reduced VWF'.)

Individuals with VWD who have GI bleeding should be evaluated for GI angiodysplasia if other causes for the bleeding are not found. Angiodysplastic lesions are commonly associated with more severe types of VWD and often cause recurrent bleeding [58]. Patients who have recurrent GI bleeding due to angiodysplasia may benefit from treatment with lenalidomide, an antiangiogenic agent, in addition to VWF concentrate prophylaxis [59]. This decision is individualized and should be discussed with an expert in bleeding disorders. (See "Overview of angiogenesis inhibitors", section on 'Immunomodulatory drugs (IMiDs)'.)

Screening for iron deficiency — It may be prudent to evaluate women with heavy menstrual bleeding or individuals with other chronic bleeding (epistaxis, GI bleeding) for iron deficiency anemia or iron deficiency without anemia so they can be treated with iron replacement therapy if needed. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

OBSTETRIC CONSIDERATIONS — Several scenarios related to pregnancy and delivery require special consideration.

Reproductive counseling — Reproductive counseling and genetic testing may be appropriate for any individual considering childbearing; however, genetic testing is rarely used, except for individuals with type 3 VWD and some with severe type 2 VWD. It is useful to obtain a personal and family bleeding history from that individual to determine the risk of VWD and to educate the individual about the likelihood of having an affected child and the likely severity. Both potential parents should be interviewed. (See "Genetic counseling: Family history interpretation and risk assessment".)

VWD is typically an autosomal dominant condition (table 3). Affected individuals inherit a pathogenic variant in the VWF gene from one parent, and they have a 50 percent chance of transmitting the variant to their children.

A person who inherits an abnormal VWF gene from both parents has a type 3 VWD (very severe decrease in or absence of von Willebrand factor [VWF]); type 3 is considered autosomal recessive and may be either homozygous or compound heterozygous. The offspring of a homozygote or compound heterozygote for disease-causing VWF variants will receive one of the abnormal genes, which may or may not be symptomatic in that offspring.

Prenatal testing — Families with type 3 VWD may choose to have prenatal diagnosis using chorionic villus sampling [60]. The method used for molecular testing depends on the specific gene variant in the family, and it is important that maternal DNA be distinguished from fetal DNA. (See "Chorionic villus sampling".)

Pregnancy — Pregnancy is generally well-tolerated in women with VWD, and the majority do not require additional treatment during the pregnancy. Since VWF levels typically rise two- to threefold over baseline during the second and third trimesters of pregnancy (see "Clinical presentation and diagnosis of von Willebrand disease", section on 'Changes with aging and pregnancy'), many patients with VWD reach normal levels of both VWF and factor VIII at term [61]. However, the increase may not be as large in individuals with more severe VWD and thrombocytopenia may worsen in type 2B VWD [61-63].

In a large database review from 2007 that described outcomes of more than 4000 pregnancies and deliveries in women with VWD, there was no increase in adverse fetal outcomes compared with controls [64]. However, the risks of antepartum and postpartum bleeding were increased (odds ratios [ORs] 10.2 and 1.5, respectively) and transfusions were used more frequently (OR 4.7; 95% CI 3.2-7.0). There were five deaths (0.12 percent), which is 10-fold greater than expected based on the non-VWD population.

Major principles of management preceding and during pregnancy include the following:

●The obstetrician and the woman's primary clinician (and a hematologist with expertise in the management of VWD) should evaluate the woman and review her clinical history prior to the pregnancy or as early as possible after pregnancy is established. The main goals are to determine her baseline VWF activity and factor VIII activity and to discuss a plan for treatment of bleeding or any procedures if needed. They should continue to monitor her throughout the pregnancy and delivery. We measure VWF and factor VIII activity levels and platelet count during the second and third trimesters (in the third trimester, during the 34^th week if possible).

●Anesthesia consultation should be obtained prior to the onset of labor to discuss options for regional anesthesia or analgesia. A VWF activity level of 50 international units/dL or higher is considered adequate for regional anesthesia, although some experts recommend that patients with type 2 VWD and type 3 VWD should avoid neuraxial anesthesia [65]. The 2021 VWD guidelines include a target range of 50 to 150 IU/dL for neuraxial anesthesia [5]. (See 'Delivery and postpartum care' below.)

●Procedures such as amniocentesis and chorionic villus sampling are generally safe if levels of VWF and factor VIII activity are maintained at 50 international units (IU)/dL or higher and routine hemostatic testing (prothrombin time [PT], activated partial thromboplastin time [aPTT], platelet count) is otherwise normal [66].

●For those who require treatment for bleeding during pregnancy, we use an antifibrinolytic agent and/or VWF concentrate to raise the VWF activity to ≥50 IU/dL, depending on the degree of bleeding or hemostatic challenge.

●Previously, DDAVP was not used during pregnancy until just prior to delivery due to a theoretical possibility that DDAVP could initiate uterine contractions [62,67]. However, more experience has indicated that DDAVP may be used in pregnant women for prophylaxis before invasive procedures [5,68,69]. (See 'Delivery and postpartum care' below.)

Delivery and postpartum care — For delivery, the patient should be hospitalized in a center where VWF and factor VIII levels can be monitored and VWF and factor VIII replacement products can be administered if necessary. Knowledge of the woman's type of VWD, baseline activities of factor VIII and VWF, current and prior responses to DDAVP, and past bleeding episodes is useful for guiding peripartum therapy [70-72].

●Anesthesia – Neuraxial anesthesia may be considered when VWF and factor VIII levels are maintained above 50 IU/dL (and are continued at that level for at least six hours after anesthesia), although some experts recommend avoidance of neuraxial anesthesia in type 2 and type 3 patients [65,73].

A retrospective review of 106 deliveries among 71 individuals with VWD seen by a high-risk anesthesia consult service reported that neuraxial anesthesia was used in 94 (89 percent) without complications [72]. DDAVP or VWF concentrate was used in 27 (29 percent), more commonly in type 2 than in type 1 disease. There were no adverse anesthetic outcomes. The authors emphasized the importance of antepartum planning and a systematic approach to providing hemostatic therapy prior to neuraxial procedures when needed. We believe that most patients with type 1 and mild-moderate type 2 VWD may receive neuraxial anesthesia, depending on their bleeding histories and the ability to keep their VWF levels at 50 to 100 IU/dL with replacement VWF factor concentrates. More severe type 2 and all type 3 patients should receive alternative anesthesia as needed.

●Delivery – Routine vaginal delivery is appropriate for most individuals; cesarean delivery is reserved for obstetric indications [74]. Regardless of the mode of delivery, it is recommended that levels of VWF and factor VIII be maintained at 50 IU/dL or higher during delivery and for at least three to five days after delivery [66,75-77]. We suggest the use of VWF concentrates and factor VIII concentrates, respectively, in women whose VWF activity and factor VIII activity fall below 50 IU/dL [62,78].

VWF levels start to decline soon after delivery (hours) and return to nonpregnant values within a very short time (approximately one week or earlier) [79]. Many women with VWD who do not require treatment during the pregnancy may have serious bleeding shortly after delivery and during the one to three weeks postpartum and require therapy with DDAVP or a VWF concentrate. Some have bleeding despite VWF therapy [80].

Types of hemostatic therapies are used to reduce bleeding risk in some cases (mostly moderate-to-severe type 1 and types 2 and 3):

●DDAVP – In patients who are known to have an adequate VWF response to DDAVP, we give DDAVP after the beginning of labor or near the time of delivery as can best be estimated. Subsequent doses can be given as needed, at approximately 12-hour intervals for two to four doses. Excessive free water intake should be limited and serum sodium levels measured to avoid hyponatremia. (See 'DDAVP' above.)

●VWF concentrates – If VWF levels are <50 IU/dL and cannot be raised with DDAVP, VWF concentrates are used. (See 'VWF concentrates for minor bleeding' above and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Available products and dosing'.)

●Antifibrinolytic therapy – Administration of tranexamic acid has been shown to be effective in decreasing postpartum blood loss in VWD patients [81-83]. In one study of 34 individuals with VWD, tranexamic acid, given at the onset of labor, had similar efficacy when given alone or in addition to other hemostatic medications [82].

The 2021 VWD guidelines suggest giving tranexamic acid during the postpartum period in all type 1 patients and other VWD patients with low VWF levels [5]. Unless there are other contraindications, we agree with this recommendation. Women can be assured that the medication is safe during breastfeeding [84].

The postpartum period requires extra vigilance since VWF levels decline dramatically postpartum. In a retrospective series of 106 deliveries, there were 11 instances of postpartum hemorrhage, representing approximately 10 percent of the cohort [72]. Of these, eight had cesarean deliveries. Three individuals had received DDAVP, and one received a VWF concentrate prior to delivery. Transfusion was required in 4 percent of deliveries, and hysterectomy was performed in one due to retained placenta.

After delivery, DDAVP may be used (caution is advised because of the increased plasma volume due to the pregnancy) as well as VWF concentrates, antifibrinolytic therapy, and in cases of recalcitrant bleeding, recombinant factor VIIa (rFVIIa). Since rFVIIa is prothrombotic, it should be reserved for extreme circumstances such as life-threatening hemorrhage, and the patient should be monitored carefully.

Continuation of intermittent DDAVP, antifibrinolytic therapy, or VWF replacement therapy may be required for the first two to four weeks after delivery with the choice of therapy individualized based on the site and severity of bleeding. For those who experience postpartum bleeding, the average time of onset is from 11 to 23 days after delivery. (See 'DDAVP' above and 'Antifibrinolytic agents' above and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'VWF concentrates' and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery", section on 'Overview of approach'.)

Newborn — Data regarding bleeding risk in newborns are extremely limited.

Elective surgical procedures on the newborn (eg, circumcision) should be delayed until the infant's VWD and factor VIII status have been determined. (See "Neonatal circumcision: Risks and benefits".)

OTHER ASPECTS OF ROUTINE MEDICAL CARE

Individuals who require antithrombotic therapy — Individuals with VWD may have cardiovascular or venous thromboembolic (VTE) disease that warrants systemic antithrombotic therapy (eg, anticoagulation, antiplatelet agents) [85,86].

Treatment or prophylaxis for thrombosis in individuals with VWD is complicated by their underlying bleeding disorder. All individuals with VWD who have an indication for antithrombotic therapy should be treated in consultation with a hematologist or other expert with experience using anticoagulation in patients with bleeding disorders to weigh the risks and benefits of different therapy options.

Important considerations in decisions regarding treatment include the following:

●Prior bleeding phenotype (the frequency and severity of historical bleeding, responses to past treatment, and von Willebrand factor [VWF] and factor VIII activity levels)

●Indication for antithrombotic therapy

●Properties of available anticoagulants (eg, unfractionated heparin can be rapidly reversed)

For acute VTE, unfractionated heparin is administered cautiously without a loading dose to initiate therapy if the VWF activity level is at least 15 international units (IU)/dL or preferably 30 IU/dL or higher. If bleeding does not occur, an oral anticoagulant usually can be introduced cautiously after two days of heparin therapy. If bleeding occurs, reversal of the anticoagulant is done and VWF replacement therapy with VWF concentrates is given. In some cases, VWF concentrates are given to maintain the VWF level at >30 IU/dL for the duration of the anticoagulant therapy (eg, three times weekly) [85]. The duration of therapy may need to be shortened (eg, four to eight weeks instead of three months), despite the risk of recurrent thrombosis, since the bleeding risk outweighs the thrombotic risk after four to six weeks of anticoagulation in these patients.

For treatment of arterial thrombosis (eg, acute coronary syndrome), the patient should receive VWF concentrates to raise the VWF activity above 30 IU/dL during the evaluation (eg, angiography) and with therapy (eg, stent placement). Once VWF activity levels have been raised above 30 IU/dL, routine anticoagulation appropriate to the procedure can be cautiously administered. Longer-term anticoagulation or antiplatelet therapy without VWF replacement therapy can be given cautiously with close monitoring of the patient's clinical status.

For stroke prophylaxis in individuals with atrial fibrillation, low-dose aspirin can be cautiously administered; since VWD interferes with platelet adhesion, aspirin will add an additional insult to platelets [1,87]. In general, great caution and careful monitoring should be carried out in these patients, and the patients should be selected for reliability and a good understanding of their disease and the risks of anticoagulation. As appropriate, patients with VWD should be a part of the decision-making process after being informed of their risks of thrombosis versus bleeding, taking severity of their VWD and individual bleeding history into account.

Testing and counseling of family members — First-degree relatives of an individual with documented VWD should have a thorough bleeding history taken and potentially may be tested, particularly those with a bleeding history and/or when the disease in the index patient is moderate or severe.

Preconception testing and counseling is discussed above. (See 'Reproductive counseling' above.)

INVESTIGATIONAL THERAPIES — The following approaches are under investigation [88]:

●Gene therapy or gene editing:

•Gene therapy to express von Willebrand factor (VWF) in endothelial cells. The VWF gene is large and requires gene therapy vectors that can accommodate its size. For some types of VWD (type 2A and 2N), smaller portions of the gene may be used. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Inherited single gene disorders'.)

•Gene editing to allow transcriptional silencing of variant VWF alleles or to directly edit the patient's abnormal VWF gene. (See "Overview of gene therapy, gene editing, and gene silencing", section on 'Gene editing'.)

Autologous endothelial cells treated with gene therapy or gene editing constructs could be transduced or transfected ex vivo and transplanted into the recipient.

●Increasing factor levels – Increasing factor VIII and VWF activity by increasing factor levels might reduce bleeding risk.

•Factor VIII

-BIVV001 is a factor VIII-VWF fusion protein that does not require VWF for stabilization. (See "Gene therapy and other investigational approaches for hemophilia", section on 'VWF fusion for factor VIII'.)

-Emicizumab is a bispecific antibody that mimics factor VIII function. It binds to factors IXa and X simultaneously, bringing these two molecules together and essentially substituting for the scaffold role of factor VIIIa as a cofactor for factor IXa in activating factor X. (See "Hemophilia A and B: Routine management including prophylaxis", section on 'Emicizumab for hemophilia A'.)

•VWF

-Interleukin 11 (IL-11) increases VWF production.

-Nanobodies fused to albumin target VWF and extend its lifespan.

●Increasing VWF half-life – Another approach involves preventing degradation of VWF and prolonging its half-life using antibodies that bind to susceptible sites on VWF and block its destruction by ADAMTS13.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: von Willebrand disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: von Willebrand disease (The Basics)")

●Beyond the Basics topics (see "Patient education: von Willebrand disease (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Education – Risks in von Willebrand disease (VWD), include increased bleeding after trauma and invasive procedures; epistaxis; and excessive menstrual, gastrointestinal, and postpartum bleeding. In severe disease, joint and soft tissue bleeding may occur. We counsel about the diagnosis and type of VWD (table 3), bleeding risk, and when to seek medical attention. (See 'General principles of care' above.)

●Minor bleeding/minor surgery – The main options are DDAVP (desmopressin) and von Willebrand factor (VWF) concentrates (table 1). Antifibrinolytic agents and topical therapies may also be used. (See 'Minor bleeding and minor surgery' above.)

•DDAVP – DDAVP is often sufficient, provided a response was demonstrated in a DDAVP trial. We perform a baseline DDAVP trial in most type 1 and many type 2 patients ≥2 years old. The table summarizes dosing, monitoring, and adverse effects (table 2). VWF and factor VIII activity >30 international units (IU)/dL (>30 percent) control most minor bleeding. (See 'Trial of DDAVP' above.)

•VWF concentrates – (See "von Willebrand disease (VWD): Treatment of major bleeding and major surgery".)

●Heavy menstrual bleeding – Determine the degree of blood loss (table 4) and cause(s), including anatomic and endocrine. Medical therapies include hormonal contraception, antifibrinolytic agents (usually days 1 to 5 of the menstrual period), intranasal DDAVP (first three days of the menstrual period), VWF concentrates, or endometrial ablation. The choice is individualized depending on desire for pregnancy, efficacy, costs, burdens, and adverse effects. (See 'Excessive menstrual bleeding' above.)

●GI bleeding – Angiodysplasia in the gastrointestinal (GI) tract is common and should be evaluated if another bleeding source is not found. Angiodysplasia may be treated with lenalidomide and/or prophylactic VWF. (See 'Chronic GI bleeding' above.)

●Iron deficiency – Individuals with chronic bleeding (epistaxis, GI, or heavy menstrual bleeding) should be evaluated for iron deficiency and treated if necessary. (See "Causes and diagnosis of iron deficiency and iron deficiency anemia in adults" and "Treatment of iron deficiency anemia in adults".)

●Pregnancy – VWF generally increases during pregnancy; additional treatment is rarely required. The obstetrician and hematologist should review the bleeding history, measure baseline VWF and factor VIII, and plan for treatment of bleeding or procedures. VWF and factor VIII should be retested during the second and third trimesters. Anesthesia consultation should be obtained before labor onset. Amniocentesis, chorionic villus sampling, neuraxial anesthesia, and delivery are generally safe if VWF and factor VIII are ≥50 IU/dL, although some experts recommend avoiding neuraxial anesthesia in type 2 and type 3 patients despite levels ≥50 IU/dL. Bleeding is treated with antifibrinolytics and/or VWF concentrates. (See 'Pregnancy' above.)

●Delivery – The patient should be hospitalized in a center where VWF and factor VIII activity levels can be monitored and VWF can be administered. Cesarean delivery is reserved for obstetric indications. VWF starts to decline within hours after delivery, which can lead to serious postpartum bleeding. Regardless of the mode of delivery, VWF and factor VIII should be maintained ≥50 IU/dL during and for ≥3 to 5 days after delivery. Treatment may include DDAVP, VWF concentrates, antifibrinolytic therapy, and for severe recalcitrant bleeding, recombinant factor VIIa (rFVIIa). Late bleeding can occur two to four weeks after delivery. (See 'Delivery and postpartum care' above.)

●Antithrombotic therapy – Antithrombotic therapy can be used if needed (acute coronary syndrome, venous thromboembolism). Close monitoring is required. VWF concentrate may be required during anticoagulation. (See 'Individuals who require antithrombotic therapy' above.)

●First-degree relatives – VWD is autosomal dominant. First-degree relatives should have a thorough bleeding history and may require testing, particularly if they have a bleeding history or when the disease in the index patient is moderate or severe. Preconception counseling and genetic testing may be appropriate. (See 'Testing and counseling of family members' above and 'Reproductive counseling' above.)