# Von Willebrand Disease

## Introduction

Von Willebrand disease (VWD) stands as the most common inherited bleeding disorder in humans, with a prevalence estimated at approximately 1% of the general population based on laboratory screening studies, though the prevalence of clinically symptomatic VWD is considerably lower at roughly 0.01%. The disease results from quantitative or qualitative defects in von Willebrand factor (VWF), a large multimeric glycoprotein that serves two indispensable roles in hemostasis: mediating platelet adhesion to sites of vascular injury under conditions of high shear stress and serving as the carrier protein that stabilizes coagulation factor VIII in the circulation. VWD is classified into quantitative deficiencies, encompassing type 1 (partial deficiency) and type 3 (complete or near-complete absence), and qualitative defects grouped under the type 2 designation, which includes subtypes 2A, 2B, 2M, and 2N. Accurate diagnosis requires the careful integration of a standardized clinical bleeding assessment, a panel of VWF-specific laboratory assays, and in many cases, multimer analysis and genetic testing to arrive at a precise subtype classification that directly informs treatment decisions.

## VWF Biology

### Structure and Function

The VWF gene is located on chromosome 12p13.3, spanning approximately 178 kilobases and containing 52 exons. A partial pseudogene residing on chromosome 22 shares high sequence homology with exons 23 through 34 of the functional VWF gene, a feature that significantly complicates molecular diagnostic testing and must be accounted for in primer design for genetic analysis. VWF is synthesized exclusively in two cell types: endothelial cells, where it is stored in specialized secretory organelles known as Weibel-Palade bodies, and megakaryocytes, where it is packaged within platelet alpha granules. The biosynthesis of VWF is a complex, multi-step process. Pro-VWF monomers first dimerize through C-terminal disulfide bonds in the endoplasmic reticulum, and these dimers subsequently multimerize through N-terminal disulfide bonds in the Golgi apparatus, generating the enormous multimeric structures that are characteristic of mature VWF.

The largest of these structures, termed ultra-large VWF (ULVWF) multimers, are the most hemostatically active forms. Upon secretion from endothelial Weibel-Palade bodies, ULVWF multimers unfurl into long strings that are anchored to the endothelial surface and are subsequently cleaved by the metalloprotease ADAMTS13 at the Tyr1605-Met1606 bond within the A2 domain. This proteolytic processing regulates VWF multimer size and prevents pathological platelet aggregation, as occurs in thrombotic thrombocytopenic purpura when ADAMTS13 activity is deficient.

VWF fulfills two critical hemostatic functions. First, it mediates platelet adhesion to sites of vascular injury. When the subendothelial matrix is exposed following vessel damage, the A3 domain of VWF binds to exposed collagen fibrils, and the A1 domain engages the platelet glycoprotein Ib/IX/V receptor complex. This VWF-mediated platelet adhesion is particularly critical under conditions of high shear stress, such as those found in arterioles and the microvasculature, where direct platelet-collagen interaction is insufficient to initiate hemostasis. Second, VWF serves as the essential carrier protein for factor VIII through its D'D3 domain. This non-covalent interaction protects factor VIII from premature proteolytic degradation in the circulation and extends its half-life from approximately 2 hours (in the absence of VWF) to approximately 12 hours. This carrier function explains why patients with severe VWF deficiency also exhibit markedly reduced factor VIII levels.

### VWF Clearance

The clearance of VWF from the circulation is primarily hepatic, mediated by several receptor systems including low-density lipoprotein receptor-related protein 1 (LRP1), the asialoglycoprotein receptor (ASGPR), and CLEC4M (a C-type lectin receptor). ABO blood group has a clinically significant influence on VWF levels: individuals with blood type O have approximately 25% lower VWF levels compared to those with non-O blood types, a phenomenon attributable to increased VWF clearance rather than decreased synthesis. This ABO effect has important implications for diagnostic thresholds and must be considered when interpreting VWF levels, particularly in patients whose values fall in the borderline range. Enhanced clearance is the hallmark of VWD type 1C, also known as the Vicenza variant, which is characterized by a markedly shortened VWF half-life. Patients with this subtype demonstrate a brisk initial response to desmopressin (DDAVP) but a very short duration of response due to accelerated clearance of the released VWF.

## Classification

### Type 1 VWD (70-80% of VWD)

Type 1 VWD represents a partial quantitative deficiency of VWF and accounts for the vast majority of VWD cases. It is defined by VWF levels between 15 and 50 IU/dL, though some expert panels define definite VWD as VWF levels below 30 IU/dL, with values between 30 and 50 IU/dL designated as "low VWF," a clinically meaningful but distinct entity. The inheritance pattern is autosomal dominant with variable penetrance, meaning that not all individuals carrying a causative mutation will manifest clinically significant bleeding. The multimer pattern in type 1 VWD is normal, with all multimer sizes present in proportionally reduced amounts, and VWF:Ag, VWF:RCo (ristocetin cofactor activity), and FVIII levels are all reduced in a concordant fashion.

The genetic basis of type 1 VWD is heterogeneous. Mutations distributed throughout the VWF gene can affect synthesis, intracellular transport, secretion, or clearance of VWF, and in a substantial proportion of cases, no identifiable VWF mutation is found, suggesting polygenic or epigenetic influences. The type 1C subtype, also called the Vicenza or accelerated clearance variant, deserves particular attention. It is identified by a markedly elevated VWF propeptide-to-VWF antigen ratio (greater than 3), reflecting normal VWF production but rapid clearance from the circulation. This distinction is clinically important because patients with type 1C show a shortened response to DDAVP, with VWF levels declining to baseline much more rapidly than in typical type 1 VWD.

### Type 2 VWD (20-25% of VWD)

Type 2 VWD encompasses the qualitative defects of VWF, in which the protein is dysfunctional despite being present in variable quantities. There are four recognized subtypes, each with distinct pathophysiologic mechanisms, laboratory profiles, and therapeutic implications.

#### Type 2A

Type 2A VWD is characterized by decreased platelet-dependent VWF function resulting from the selective loss of high-molecular-weight (HMW) multimers, which are the most hemostatically active VWF forms. Most causative mutations are inherited in an autosomal dominant pattern. The loss of HMW multimers can occur through two distinct mechanisms: impaired intracellular multimer assembly in the endoplasmic reticulum or Golgi apparatus, or increased susceptibility of secreted VWF to cleavage by ADAMTS13 in the circulation. Multimer analysis is the key diagnostic tool, revealing the absence of both HMW and intermediate-weight multimers, with relative preservation of the smaller multimeric forms. The VWF:RCo/VWF:Ag ratio is characteristically low (below 0.7), reflecting the disproportionate loss of functional activity relative to antigen levels.

#### Type 2B

Type 2B VWD results from gain-of-function mutations in the A1 domain of VWF that increase its affinity for the platelet GPIb receptor. This heightened affinity leads to spontaneous binding of VWF to platelets in the circulation, with consequent consumption of both HMW multimers and platelets. The disorder is inherited in an autosomal dominant fashion, with the most commonly identified mutations being R1306W and V1316M. Patients typically present with mild to moderate thrombocytopenia, which may worsen during physiologic stress, pregnancy, surgery, or infection due to increased VWF secretion under these conditions. The hallmark diagnostic finding is enhanced ristocetin-induced platelet aggregation (RIPA) at low-dose ristocetin (0.5 to 0.7 mg/mL), a concentration that does not induce aggregation in normal plasma. It is essential to distinguish type 2B VWD from platelet-type (pseudo) VWD, which is caused by a gain-of-function mutation in the platelet GPIb receptor rather than in VWF itself. This distinction is made through mixing studies using combinations of patient and normal platelets with patient and normal plasma.

#### Type 2M

Type 2M VWD is defined by decreased platelet-dependent VWF function with a preserved, normal multimer pattern. Like type 2A, the VWF:RCo/VWF:Ag ratio is below 0.7, but in contrast to type 2A, all multimer sizes including HMW forms are present. The causative mutations typically reside in the A1 domain and impair VWF binding to the platelet GPIb receptor without disrupting the multimer assembly or stability. This subtype is less common than type 2A and is sometimes diagnostically challenging because the multimer analysis is normal.

#### Type 2N (Normandy)

Type 2N VWD, named after the Normandy region of France where it was first described, results from mutations in the D'D3 domain of VWF that impair its ability to bind and stabilize factor VIII. The inheritance is autosomal recessive, requiring either homozygosity or compound heterozygosity for causative mutations. The characteristic laboratory finding is a disproportionately low FVIII level (typically 5 to 40 IU/dL) relative to VWF antigen and activity levels, which are normal or only mildly reduced. This laboratory profile closely mimics mild hemophilia A, and indeed, type 2N VWD is one of the most important diagnoses to consider in females who present with an apparent hemophilia A phenotype or in males whose family history suggests autosomal rather than X-linked inheritance. The definitive diagnostic test is the VWF:FVIII binding assay, which directly measures the capacity of the patient's VWF to bind factor VIII in vitro.

| Type | Frequency | Inheritance | Defect | VWF:Ag | VWF:RCo | RCo/Ag Ratio | FVIII | Multimers | RIPA (Low-Dose) | DDAVP Response |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 70-80% | AD | Partial quantitative deficiency | Low | Low | >0.7 | Low | Normal (all sizes reduced) | Normal | Usually effective |
| 2A | Variable | AD | Loss of HMW multimers | Low-normal | Low | <0.7 | Low-normal | Absent HMW + intermediate | Normal | Variable |
| 2B | Variable | AD | Increased GPIb affinity | Low-normal | Low | <0.7 | Low-normal | Absent HMW only | Enhanced | CONTRAINDICATED |
| 2M | Uncommon | AD | Decreased platelet binding, normal multimers | Low-normal | Low | <0.7 | Low-normal | Normal | Normal | Variable |
| 2N | Uncommon | AR | Impaired FVIII binding | Normal | Normal | >0.7 | Very low (5-40) | Normal | Normal | Short-lived |
| 3 | <5% | AR | Complete VWF absence | <5 IU/dL | <5 IU/dL | N/A | Very low (1-10) | Absent | Absent | Ineffective |

### Type 3 VWD (<5% of VWD)

Type 3 VWD represents the most severe form of the disease, characterized by the complete or near-complete absence of VWF, with VWF antigen levels below 5 IU/dL. It is inherited in an autosomal recessive pattern and is caused by homozygous or compound heterozygous null mutations in the VWF gene. The bleeding phenotype is severe, combining the mucocutaneous hemorrhage characteristic of VWF deficiency with deep tissue and joint bleeding resembling hemophilia, the latter driven by the markedly reduced factor VIII levels (typically 1 to 10 IU/dL) that result from loss of the VWF carrier function. A clinically important complication specific to type 3 VWD is the development of alloantibodies against VWF, which occurs in approximately 5 to 10% of type 3 patients following exposure to VWF-containing replacement products. These antibodies not only render VWF replacement ineffective but also carry the risk of severe anaphylactic reactions upon subsequent VWF exposure.

<image>A comprehensive classification diagram of von Willebrand disease showing all types and subtypes. Arrange as a table or grid with columns for: Type (1, 2A, 2B, 2M, 2N, 3), Inheritance pattern, VWF:Ag level, VWF:RCo level, VWF:RCo/Ag ratio, FVIII level, multimer pattern (show as a schematic gel electrophoresis pattern with HMW, intermediate, and LMW bands for each type), RIPA at low-dose ristocetin, and key distinguishing features. For the multimer patterns, show: Type 1 (proportionally reduced all sizes), Type 2A (loss of HMW and intermediate), Type 2B (loss of HMW only), Type 2M (normal pattern), Type 2N (normal pattern), Type 3 (absent). Include a molecular diagram showing VWF domains (D'D3, A1, A2, A3, C-domains) with annotations showing which domain is affected in each subtype. Medical laboratory education style with clear, detailed tables.</image>

## Diagnosis

### Clinical Assessment

The clinical evaluation of a patient with suspected VWD begins with a thorough standardized bleeding history. The International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT) provides a validated, quantitative framework for scoring bleeding symptoms across multiple categories. A score of 4 or greater in adults, or 3 or greater in children, is considered clinically significant and warrants further laboratory investigation. The predominant bleeding pattern in VWD is mucocutaneous, reflecting the primary role of VWF in platelet-dependent primary hemostasis. Common presenting symptoms include recurrent epistaxis, menorrhagia (often the most common presenting complaint in women), easy bruising, gingival bleeding, prolonged bleeding after dental procedures, and excessive hemorrhage following surgery or trauma. A family history of bleeding, typically following an autosomal dominant pattern, provides additional diagnostic support for most VWD types.

### Laboratory Testing

The initial diagnostic panel for VWD consists of three essential assays: VWF antigen (VWF:Ag), which measures the total quantity of VWF protein regardless of function; VWF ristocetin cofactor activity (VWF:RCo) or the newer VWF:GPIbM assay, which measures the ability of VWF to bind the platelet GPIb receptor; and factor VIII activity. The VWF:GPIbM assay uses a gain-of-function GPIb mutant that binds VWF without requiring ristocetin and has shown superior reproducibility compared to the traditional VWF:RCo assay, particularly at low VWF levels.

Confirmatory and subtyping studies build upon the initial panel. The VWF:RCo/VWF:Ag ratio is a critical discriminating parameter: a ratio below 0.7 suggests a qualitative defect (type 2A, 2B, or 2M) rather than a simple quantitative reduction. VWF multimer analysis, performed by agarose gel electrophoresis, is essential for distinguishing among the type 2 subtypes and confirming type 1 VWD. Low-dose RIPA testing is the diagnostic hallmark of type 2B VWD. The VWF collagen binding assay (VWF:CB) provides an additional functional assessment that is particularly sensitive to HMW multimer deficiency. The VWF:FVIII binding assay is the definitive test for type 2N VWD.

Diagnostic thresholds require careful interpretation. A VWF:Ag or VWF:RCo level below 30 IU/dL is considered diagnostic of definite VWD. Values between 30 and 50 IU/dL fall into the category of "low VWF," which may not meet formal criteria for VWD but can be associated with clinically significant bleeding, particularly in the context of hemostatic challenges such as surgery or trauma. Because VWF is an acute-phase reactant, its levels fluctuate in response to stress, inflammation, estrogen exposure, pregnancy, and aging. A single normal result therefore does not exclude VWD, and repeat testing is often necessary when clinical suspicion remains high. Blood type O must be factored into interpretation, as these individuals have constitutively lower VWF levels.

### Specialized Testing

A formal DDAVP trial is an essential component of the VWD evaluation for patients in whom DDAVP may be used therapeutically. The protocol involves measuring VWF:Ag, VWF:RCo, and FVIII activity at baseline and then at 1 hour and 4 hours after intravenous administration of DDAVP at 0.3 mcg/kg. An adequate response is defined as greater than a twofold rise in VWF levels with a sustained response at the 4-hour time point. Patients who demonstrate a brisk initial rise but rapid decline to baseline should be suspected of having the type 1C (accelerated clearance) variant. The DDAVP trial must be performed and documented before relying on DDAVP for clinical prophylaxis or treatment, as individual responses are highly variable and cannot be predicted from the VWD subtype alone.

Genetic testing is increasingly incorporated into the diagnostic evaluation of VWD, particularly for types 2B, 2N, and 3, where phenotypic testing may be ambiguous or where confirmation of the specific mutation has implications for genetic counseling and family cascade testing. However, for the majority of type 1 VWD cases, phenotypic testing remains the primary diagnostic approach.

## Treatment

### Desmopressin (DDAVP)

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) is a synthetic analogue of antidiuretic hormone that stimulates the release of VWF and factor VIII from endothelial Weibel-Palade body stores via V2 receptor activation. It can be administered by the intravenous route at a dose of 0.3 mcg/kg diluted in 50 mL of normal saline and infused over 30 minutes, or intranasally using the high-concentration formulation (Stimate) at 150 mcg for patients weighing less than 50 kg or 300 mcg for those above 50 kg. The standard intranasal formulation used for diabetes insipidus (DDAVP nasal spray) delivers an inadequate dose for hemostatic purposes and must not be substituted for Stimate.

Following DDAVP administration, VWF and factor VIII levels typically rise two- to fivefold above baseline within 30 to 60 minutes, with the hemostatic effect lasting 6 to 12 hours. DDAVP is effective in the majority of patients with type 1 VWD and may provide a useful response in some patients with type 2A and type 2N disease. It is contraindicated in type 2B VWD, where the release of additional abnormal VWF with heightened GPIb affinity can precipitate worsening thrombocytopenia and potentially dangerous platelet aggregation. It is also ineffective in type 3 VWD, as these patients lack VWF stores to release. Response in type 2A is variable and must be assessed on an individual basis.

Tachyphylaxis is a well-recognized limitation of DDAVP, with diminishing VWF release observed after more than two to three doses administered within a 48-hour period due to depletion of endothelial stores. Side effects include facial flushing, headache, tachycardia, and, most importantly, hyponatremia resulting from the antidiuretic effect. Free water intake should be restricted for 24 hours following administration, and DDAVP should be avoided in children under 2 years of age due to the heightened risk of hyponatremic seizures.

### VWF-Containing Factor Concentrates

For patients who do not respond adequately to DDAVP, who have VWD subtypes in which DDAVP is contraindicated or ineffective, or who require major surgical prophylaxis, VWF-containing factor concentrates are the mainstay of therapy. Humate-P is a plasma-derived product containing both VWF and factor VIII in a VWF:RCo to FVIII ratio of approximately 2.4:1. It is the most extensively studied and widely used concentrate for VWD and serves as the standard for surgical prophylaxis and treatment of significant bleeding. Dosing is guided by VWF:RCo units, with a typical loading dose of 40 to 60 IU/kg followed by maintenance doses of 20 to 40 IU/kg every 8 to 12 hours. For major surgery, perioperative targets include VWF:RCo levels above 100% with maintenance above 50% for 7 to 14 days. Alphanate is an alternative plasma-derived product with a lower VWF:RCo to FVIII ratio.

Vonvendi (vonicog alfa) is the first recombinant VWF product, produced without accompanying factor VIII. Because there is no endogenous FVIII stabilization immediately upon infusion, recombinant factor VIII must be co-administered with the initial dose. Subsequent doses may not require FVIII supplementation because the infused recombinant VWF stabilizes endogenous FVIII. Advantages of Vonvendi include standardized manufacturing, absence of pathogen transmission risk, and a consistent multimer profile that includes ULVWF multimers, providing potentially superior hemostatic potency.

### Antifibrinolytics

Antifibrinolytic agents are a critical adjunctive therapy in VWD management, particularly for mucosal bleeding where the fibrinolytic activity of mucosal surfaces can undermine clot stability. Tranexamic acid, a lysine analogue that competitively inhibits plasminogen activation, is administered at 1 to 1.3 g orally three times daily or 10 mg/kg intravenously. Aminocaproic acid, at 50 to 60 mg/kg orally every 6 hours, serves as an alternative. These agents can be used as monotherapy for minor mucosal bleeding episodes such as epistaxis, gingival bleeding, or mild menorrhagia, or as adjuncts to DDAVP or VWF concentrate for more significant hemostatic challenges including dental procedures. Antifibrinolytics are contraindicated in the setting of hematuria because inhibition of fibrinolysis within the urinary tract can lead to obstructive clot formation in the ureters or renal pelvis.

### Hormonal Therapy for Menorrhagia

Menorrhagia is the presenting symptom of VWD in approximately 60% of affected women, making it a critically important clinical manifestation that should prompt VWD screening in all adolescents and women with heavy menstrual bleeding. Combined oral contraceptives serve a dual purpose, both raising endogenous VWF and FVIII levels through estrogen-mediated stimulation and reducing endometrial bleeding through hormonal regulation of the menstrual cycle. The levonorgestrel-releasing intrauterine device is an effective option for reducing endometrial bleeding without systemic hormonal effects. Tranexamic acid, administered cyclically during menstruation, is effective for heavy menstrual bleeding and can be combined with hormonal therapy for optimal control.

## VWD in Pregnancy

Pregnancy presents unique challenges in the management of VWD. VWF and factor VIII levels rise progressively during pregnancy, typically reaching two- to threefold elevation by the third trimester due to estrogen-driven increases in synthesis. In many women with type 1 and some with type 2 VWD, these physiologic increases may normalize VWF levels by the time of delivery. However, patients with type 3 VWD and those with severe type 2 variants will not achieve adequate hemostatic levels and require VWF concentrate supplementation for delivery.

Hemostatic targets for delivery include VWF:RCo above 50 IU/dL for vaginal delivery and above 100 IU/dL for cesarean section. A critical consideration is the rapid decline in VWF levels that occurs after delivery, as the estrogen-driven stimulus to VWF production abruptly diminishes. Postpartum hemorrhage risk remains elevated, and prophylactic VWF replacement or antifibrinolytic therapy should be maintained for at least 3 to 5 days after vaginal delivery and longer following cesarean section. Neuraxial anesthesia, including epidural placement, is generally considered safe when VWF:RCo and factor VIII levels are both confirmed to be above 50 IU/dL at the time of the procedure.

## Acquired Von Willebrand Syndrome (AVWS)

Acquired von Willebrand syndrome refers to VWF deficiency arising in patients without a prior history of inherited VWD. It is an important diagnostic consideration in any patient who presents with new-onset mucocutaneous bleeding, particularly in the absence of a personal or family bleeding history. The most common underlying associations include lymphoproliferative disorders, particularly monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma, and chronic lymphocytic leukemia, in which the monoclonal protein may bind VWF and accelerate its clearance or inhibit its function. Myeloproliferative neoplasms, especially essential thrombocythemia with extreme thrombocytosis, can cause AVWS through adsorption of VWF onto the excess platelet mass. Aortic stenosis is a particularly well-recognized cause through the mechanism of Heyde syndrome, in which the high shear stress across the stenotic valve causes mechanical unfolding and accelerated ADAMTS13-mediated cleavage of HMW multimers. A similar mechanism occurs in patients with left ventricular assist devices (LVADs). Other associations include hypothyroidism and autoimmune disorders.

Diagnosis rests on the identification of reduced VWF levels in a patient without a family history of bleeding, in conjunction with evidence of an underlying causative condition. The VWF propeptide-to-VWF antigen ratio can help distinguish AVWS from inherited type 1 VWD, as it is typically elevated in AVWS due to increased clearance with normal production. Treatment focuses on addressing the underlying disorder when possible. DDAVP may provide a transient response but is often short-lived. VWF concentrate can be used for acute hemostatic needs. Intravenous immunoglobulin (IVIG) may transiently raise VWF levels when an autoimmune mechanism is operative, though the effect is temporary and repeated infusions are often needed. In Heyde syndrome, aortic valve replacement corrects the hemodynamic abnormality and resolves the AVWS.

<image>A diagnostic and treatment algorithm for von Willebrand disease. Start with "Clinical suspicion of VWD (mucocutaneous bleeding, positive BAT score, family history)." First step: initial panel (VWF:Ag, VWF:RCo or GPIbM, FVIII, CBC). If VWF:Ag <30 IU/dL: definite VWD → proceed to subtyping. If 30-50 IU/dL: "low VWF" → repeat testing, consider clinical significance. Subtyping branch: check VWF:RCo/Ag ratio and multimer analysis. If ratio >0.7 with proportionally reduced multimers → Type 1 (DDAVP trial). If ratio <0.7 with loss of HMW multimers → Type 2A (confirm with multimer gel). If ratio <0.7 with enhanced RIPA at low-dose ristocetin → Type 2B (DDAVP contraindicated). If ratio <0.7 with normal multimers → Type 2M. If low FVIII with normal VWF → check VWF:FVIIIB → Type 2N. If VWF <5 IU/dL → Type 3. Treatment boxes for each type: Type 1 → DDAVP + TXA; Type 2A → DDAVP trial or VWF concentrate; Type 2B → VWF concentrate only; Type 2N → VWF/FVIII concentrate; Type 3 → VWF/FVIII concentrate. Clinical algorithm style with diagnostic tests and treatment decisions.</image>

## Key Clinical Pearls

- VWF levels are influenced by ABO blood type (type O ~25% lower), stress, inflammation, estrogen, and age; a single normal result does not exclude VWD - repeat testing is often necessary
- Type 2B VWD is one of the few inherited causes of thrombocytopenia + bleeding; DDAVP is contraindicated (can worsen thrombocytopenia)
- Type 2N VWD mimics mild hemophilia A; suspect it in females with isolated low FVIII or males with autosomal pattern of inheritance; VWF:FVIII binding assay is diagnostic
- Always perform a DDAVP trial before relying on DDAVP for prophylaxis; response is variable and must be documented for each patient
- Menorrhagia is the most common presenting symptom of VWD in women; screen for VWD in all adolescents and women with heavy menstrual bleeding
- Acquired VWD should be suspected in patients with new-onset mucocutaneous bleeding and no family history; look for underlying MGUS, lymphoproliferative disease, aortic stenosis, or MPN

## References
1. Leebeek FWG, Eikenboom JCJ. Von Willebrand's Disease. N Engl J Med. 2016;375(21):2067-2080.
2. James AH, et al. ASH ISTH NHF WFH 2021 guidelines on the diagnosis of von Willebrand disease. Blood Adv. 2021;5(1):280-300.
3. Connell NT, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021;5(1):301-325.
4. Castaman G, et al. Von Willebrand disease in the year 2020: an update. Haematologica. 2020;105(9):2199-2207.
5. Tiede A, et al. How I treat the acquired von Willebrand syndrome. Blood. 2011;117(25):6777-6785.