Von Willebrand Disease

Etiology

Von Willebrand disease (VWD) can be inherited or acquired.[4][5]

Inherited phenotypic forms of Von Willebrand disease are:

• Type 1: This is an autosomal dominant disease (AD, incomplete penetrance approximately 60%) and is caused by a partial quantitative deficiency of von Willebrand factor.
• Type 2: This is an autosomal dominant disease caused by several qualitative defects in von Willebrand factor. It has four subtypes (2A-AD or AR, 2B-AD, 2N-AR, 2M-AD). 2A is the most common variant.
• Type 3: This is an autosomal recessive disease (AR) and is caused by a complete quantitative defect. The von Willebrand factor levels are not detectable, and the severe bleeding disorder characterizes this variant.

The VWF gene is highly polymorphic, and this polymorphism leads to a big variation in the normal spectrum of von Willebrand levels function. Subsequently, there is a spectrum of presentations and disease severity.

Acquired von Willebrand disease occurs when secondary (acquired) processes lead to a functional impairment of von Willebrand factor, either by decreasing its available quantity or interfering with the physiological hemostasis pathway. The most commonly associated conditions are lung cancer, Wilm's tumor, gastric cancer, MGUS, multiple myeloma, chronic lymphocytic leukemia, hairy cell leukemia, myeloproliferative neoplasms (MPN), plasma cell dyscrasias, lymphomas, systemic lupus erythematosus (SLE), Felty syndrome, autoimmune hemolytic anemia, or other autoimmune disorders, metabolic disorders (hypothyroidism), drug side effects, and states of high-vascular flow such as AS, VSD, VAD (ventricular assist devices), extracorporeal membrane oxygenation (ECMO), or metallic cardiac valves. The von Willebrand factor is a large multimeric glycoprotein, and it is susceptible to the shear stress associated with high flow states.

The autoimmune spectrum can be quite varied as von Willebrand factor occurs as a multimer, and this heterogeneity means that certain multimer sizes may escape the immune-mediated antibody response. The mechanism in malignancy includes the formation of non-specific antibodies that bind the von Willebrand factor forming an immune complex and hence increase clearance by the reticular endothelial system. The other mechanism is the absorption of the von Willebrand factor on the surface of malignant cells, such as the case in multiple myeloma or solid tumors or proteolysis of von Willebrand factor multimers as is usually seen in MPN.

Epidemiology

Von Willebrand disease is estimated to affect approximately 1% of the unselected population, but clinically significant disease prevalence is estimated to be about 125 per million, with severe disease affecting up to five per million.

There is an equal distribution between males and females. Acquired von Willebrand disease prevalence is unknown but may represent 1% to 5% of all von Willebrand disease. Its prevalence is higher in certain groups. For example, it has been reported in up to 20% of malignancies and up to 100% of certain high flow states such as extracorporeal membrane oxygenation (ECMO) and metallic cardiac valves.[6]

Pathophysiology

Von Willebrand factor is a multimer formed from a basic dimer subunit. It is produced in megakaryocytes and endothelial cells. The size of the multimer determines the physiological hemostatic effect. Bigger multimers are more active and even prothrombic. They are cleaved by circulating proteases into smaller units. These larger multimers are stored in cytoplasmic granules and released in response to a trigger such as thrombin, fibrin, and histamine.

Larger multimers have more available sites for binding to platelets and endothelium. Von Willebrand factor increases factor VIII half-life by preventing its degradation. Regarding the subtypes, type I is characterized by a mild decrease in von Willebrand factor antigen (Ag), von Willebrand factor activity, and VIII:C. 

Of note, von Willebrand factor levels of less than 30% are required for a diagnosis of Von Willebrand disease. Conversely, type III  is characterized by a significant decrease in the parameters above.

• A qualitative decrease with specific variations characterizes type II disease: 
• Type 2A: variable decrease in von Willebrand factor Ag and VIII:C with a significant decrease in von Willebrand factor activity and absence of large and intermediate size multimers. 
• Type 2B: variable decrease in von Willebrand factor Ag and VIII:C and a significant decrease in von Willebrand factor activity and absence of large multimers. However, most importantly, this type is hypersensitive to ristocetin-induced platelet aggregation (RIPA).
• Type M: vWF activity is decreased relative to Ag and multimers are present. 
• Type N: this is characterized variably by a decrease in vWF Ag and activity but is distinguished from the other types by the significant decrease in VIII: C, albeit usually more than 5%. This specific subtype can be confused with hemophilia A.

History and Physical

Low von Willebrand factor is quite common in the general population, but not all patients have clinically significant bleeding issues. Therefore, a significant proportion of the patient population goes undiagnosed. Most cases are diagnosed formally after investigating significant bleeding problems such as recurrent and excessive bruising, prolonged bleeding from minor skin trauma, and prolonged bleeding from mucosal surfaces (epistaxis, dental extractions, menstruation).

The physical examination can often be normal. Sometimes evidence of bleeding/bruising (petechiae, hematomas) may be noted.

In the case of a qualitative defect, von Willebrand disease may mimic hemophilia and predominantly present with bleeding into soft tissues, joints, and hematuria rather than mucocutaneous bleeding. Sometimes, type 2N von Willebrand disease is misdiagnosed as hemophilia.

Evaluation

Patients with a clinical history consistent with von Willebrand disease are investigated further with the following labs:

• Complete blood count (CBC): Platelet levels tend to be normal
• Coagulation profile: aPTT may be prolonged, as there would be increased factor VIII degradation in von Willebrand disease. PT should be normal.
• Von Willebrand factor antigen: von Willebrand factor protein levels are measured. This is a test for a quantitative defect.
• Von Willebrand factor activity: This is a qualitative analysis for von Willebrand factor physiological function. This is tested through Ristocetin cofactor activity (vWF:RCo) and collagen binding activity (vWF:CB). Normal Ristocetin cofactor activity levels are above 50 IU/dL. Levels below 30 are diagnostic for von Willebrand disease.
• Factor VIII Activity: Decreased von Willebrand factor leads to increased degradation of factor VIII.
• Von Willebrand factor activity/antigen ratio: This helps identify cases with a significant qualitative deficit. A low ratio should raise suspicion for type 2 von Willebrand disease; however, absolute normal values have yet to be determined.

Patients with von Willebrand disease activity/antigen levels between 30 and 50 should be designated as “low-von Willebrand factor” and be considered for treatment in high bleeding risk scenarios.

Treatment / Management

Stable patients with type 1, some type 2 (except type 2B), and acquired von Willebrand disease patients are given a trial of desmopressin (DDAVP), which is a synthetic analog of vasopressin to check for a response. This is usually performed when patients are not actively bleeding.[7][8][9]

Type 1 usually shows a good response to the DDAVP trial. Type 2A shows a variable and transient response which is often clinically adequate. Type 2M and Type 2N usually show a poor or minimal response. Type 3 von Willebrand disease does not respond to Desmopressin as there is a complete lack of von Willebrand factor. A successful trial sees von Willebrand factor activity levels of at least 30 IU/dL (ideally 50 IU/dL). Desmopressin causes von Willebrand factor release from endothelial cells. DDVAP can be administered subcutaneously, intravenously, and via intranasal spray. It leads to increased von Willebrand factor and factor VIII levels, with response persisting for up to 12 hours. It is useful for minor bleeding episodes (including epistaxis and menses) and elective minimally invasive surgical procedures.

Von Willebrand factor replacement can be considered in patients with type 3 von Willebrand disease or severe variants of type 1 and two that do not demonstrate a sufficient DDAVP response in serious bleeding scenarios. There are many different preparations available, including factor VIII concentrates that also include von Willebrand factor. Von Willebrand factor replacement therapy often is used in serious bleeding scenarios such as trauma or major surgery. Usually, it is administered as a short course. Examples of intermediate-purity vWF concentrates include single factor formulations like alphanate and others that contain both vWF and FVIII. Patients with von Willebrand disease type III need the products mentioned above for episodes of bleeding or surgery. Conversely, for mild type I and type II A disease (or minor procedures in this category), DDAVP might suffice. However, other scenarios might require von Willebrand and FVIII factors mentioned previously.

Tranexamic acid can also be used as an anti-fibrinolytic agent. It prevents the breakdown of fibrin clots. It is useful in case of mucosal bleeding.[10](B3)

Differential Diagnosis

• Factor X deficiency
• Factor XI deficiency
• Hemophilia A
• Hemophilia B
• Bernard-Soulier syndrome
• Platelet function defects
• Antiplatelet drug ingestion
• Fibrinolytic defects  

Prognosis

For the majority of patients, vWD is a mild, manageable bleeding disorder. Clinically severe hemorrhage is usually only seen with trauma or invasive procedures.

Complications

Alloantibody formation can occur in 10 to 15% of patients with type 3 disease. This means that the potential for this complication requires appropriate management as these patients have an increased risk for life-threatening anaphylactic reactions to vWF-FVIII preparations. During pregnancy, vWF levels increase in most women with types 1 and 2 vWD; labor and delivery are typically normal. However, patients with type 2B disease may experience hemorrhagic problems. Women with vWD whose vWF does not rise to normal levels during pregnancy require assessment with a specialist and interprofessional team management.

Some of the less common but more serious include GI bleeding, hematomas, and hemarthrosis, potentially leading to progressive joint damage and degeneration. In these cases, VWD limit the range of motion of an affected joint.