History and Disease Characteristics

Originally described by Erik von Willebrand in the Aland Islands, Finland, von Willebrand disease (vWD) is the most common inherited bleeding disorder with autosomal dominant transmission.1 vWD is caused by a deficiency or dysfunction of the von Willebrand factor (vWF) protein. Because of a complete lack, decreased amount, or dysfunction of this protein, defective interaction between platelets and the walls of blood vessels disrupts primary hemostasis, resulting in increased bleeding.2

The vWF protein is a large, multimeric glycoprotein with normal circulating plasma concentrations of approximately 10 mg/mL. It is typically produced and stored in the Weibel-Palade bodies of endothelial cells, alpha granules of platelets, and subendothelial connective tissue.1 Various stimuli cause the release of vWF protein from these storage sites. vWF plays a primary role in hemostasis, binding platelets to regions of vascular injury. In addition, vWF is responsible for binding and stabilization of the procoagulant protein factor VIII.2 If factor VIII is unbound in the plasma, it rapidly deteriorates. When vWF is exposed in endothelial tissue during injury to a blood vessel, it binds to collagen to repair the damaged tissue. It also uncoils and slows the movement of platelets such that coagulation occurs.1 

Types of Von Willebrand Disease 

vWD is classified as type 1 (partial quantitative vWF deficiency), type 2 (qualitative vWF deficiency), or type 3 (total vWF deficiency). Type 2 is further subdivided into 4 variants according to the qualitative characteristics of the dysfunctional vWF protein. These are labeled 2A, 2B, 2N, and 2M. Each variant corresponds to distinct molecular mechanisms with related clinical characteristics, and treatment recommendations exist for each variant.2

Etiology

vWD can be inherited or acquired. All 3 types listed above are hereditary forms of vWD. Children inherit type 1 or type 2 vWD from either parent. For type 3, a child must inherit the mutant gene from both parents. vWD can be acquired when a genetic mutation occurs during the lifetime of an individual and is usually observed in patients with autoantibodies.1 

Symptoms

Type 1 vWD, the most prevalent  type, is characterized by mucocutaneous bleeding that is mild in comparison with the mild to moderate mucocutaneous bleeding found in types 2A, 2B, and 2M. Type 2N is characterized by symptoms similar to those of hemophilia A, which include excessive bleeding, especially postoperatively. Individuals with type 3 vWD present with severe internal and joint bleeding, but this type is much rarer than the other types. Individuals with acquired vWD typically demonstrate mild to moderate bleeding similar to that seen in subtypes 2A, 2B, and 2M.1

The most common signs of vWD include the following2:

  • easy bruising
  • nosebleeds
  • hematomas
  • prolonged bleeding following superficial injuries
  • gum bleeding
  • excessive menstrual bleeding.

Epidemiology

 vWD is estimated to affect 1 in every 100 to 10,000 people.3 Because predominantly minor bleeding occurs in type 1 and type 2 vWD, it is suspected that these types are underdiagnosed because many affected individuals may not come to medical attention.3 Type 1 vWD accounts for 60% to 80% of all cases. Type 2 accounts for 20% to 30% of cases. Lastly, patients with type 3 account for fewer than 5% of all cases. Acquired vWD is most often found in individuals older than 40 years of age with no prior history of bleeding.1 

Diagnosis

A personal and family history of bleeding raises the possibility of vWD. Screening tests measure plasma concentrations of vWF antigen (vWF:Ag), ristocetin cofactor (RCoF) activity, the prothrombin time (PT), factor VIII coagulant activity, and the activated partial thromboplastin time (aPTT) to confirm a diagnosis of vWD.4 

Differentiation into a specific subtype of vWD (1, 2A, 2B, 2M, 2N, or 3) requires specialized laboratory analysis of the following: vWF multimers, factor VIII protein binding, vWF propeptide antigen, vWF collagen-binding activity, and low-dose ristocetin-induced platelet agglutination.4 

Early diagnosis is more common in patients with type 3 vWD because of severe bleeding beginning in infancy . An early diagnosis of type 1 or type 2 vWD is less likely because bleeding is usually mild.1 Another interesting factor that may complicate or delay the diagnosis of type 1 or type 2 vWD is that vWF levels vary depending on degree  of physiologic stress; levels of estrogen, vasopressin, and growth hormones; and adrenergic stimulation. Pregnancy, operative procedures, acute infections, and strenuous exercise may temporarily elevate vWF levels. Therefore,  vWF levels may normalize in patients with vWD at any moment in time, so repeated diagnostic testing is necessary to obtain an accurate vWD diagnosis.4  

Treatment

Nontransfusional and transfusional compounds are the 2 main categories of medication used to treat vWD. 

Nontransfusional Compounds

Desmopressin

Desmopressin (DDAVP), a non-replacement drug treatment, is the gold standard treatment for individuals with type 1 vWD. It can be administered intravenously, intranasally, or subcutaneously. Desmopressin works by releasing stored vWF, usually increasing levels of circulating vWF and factor VIII protein within 30 to 60 minutes. The mechanism of action of desmopressin is ineffective in individuals with type 3 vWD because vWF protein is completely lacking.5,6 

Clinicians have observed the varying responses to desmopressin in patients type 2 vWD.5 The response of patients with Type 2A is similar to that of patients with type 1 vWD: an increase in the level of circulating vWF within 30 to 60 minutes of administration. However, this therapeutic effect is short-lived, and vWF levels usually return to baseline after 4 hours. Desmopressin may be contraindicated in patients with type 2B vWD because of the risk for thrombotic complications and thrombocytopenia. Patients who have type 2M or type 2N vWD rarely obtain any beneficial effect from treatment with desmopressin.7 

Common side effects of desmopressin include fluid retention and hyponatremia. Weight-based fluid restriction and monitoring of sodium intake are recommended for those receiving desmopressin.6 Minor side effects include facial flushing, gastrointestinal upset, transient hypertension or hypotension, and headache.1

Recombinant vWF

The Food and Drug Administration approved recombinant vWF (Vonvendi®) in 2015 for the treatment of adults with vWD experiencing minor or major hemorrhage.8 A phase 3 trial proved the safety and efficacy of recombinant vWF; excellent control was achieved in 119 of 122 minor bleeds, 59 of 61 moderate bleeds, and 6 of 7 major bleeds. Only one infusion was required to treat 81.8% of bleeds successfully. No thrombotic events or severe allergic reactions developed in the patients in this trial.8,9 

vWF/Factor VIII Concentrates

Humate-P® and Alphanate SD/HT® are replacement therapies that use plasma-derived concentrates to replace the levels of vWF and factor VIII. These 2 treatments differ in the ratio of vWF to factor VIII. Humate-P and Alphanate SD/HT are administered intravenously. Humate-P is indicated for patients requiring prolonged treatment, those with any of the type 2 variants, those with severe type 3, and those with type 1 who cannot tolerate desmopressin. Common side effects include rash, edema, chest tightness, pruritus, and urticaria.1

Antifibrinolytic Drugs 

Antifibrinolytic drugs such as aminocaproic acid and tranexamic acid are used when patients with vWD are experiencing active bleeding. Their mechanism of action is to inhibit fibrinolysis and stabilize clot formation. The adult dose of aminocaproic acid is administered orally or intravenously, and tranexamic acid is administered intravenously at a dose of 10 mg/kg every 8 hours. Both are given to treat mild mucocutaneous bleeding. They are also administered prophylactically to patients with vWD 1 hour before an invasive procedure to control bleeding. Side effects include emesis, nausea, and rarely thrombotic complications.1 

Topical Agents

Topical bovine thrombin (Thrombin-JMI) is used to control minor bleeding from capillaries and small venules. Fibrin sealant (Tisseel VH®) is another topical agent applied during surgical procedures, in particular dental surgeries.1 

Transfusional Compounds

Patients with tType 3 vWD may require platelet transfusions to control severe bleeding that does not respond to other treatments. It is recommended that blood transfusions be used as a last resort to treat vWD because of the potential transmission of viral diseases.10 

References

  1. Bharati KP, Prashanth UR. Von Willebrand disease: an overview.  Indian J Pharm Sci. 2011;73(1):7-16. doi:10.4103/0250-474X.89751
  2. Pollak ES. von Willebrand disease. Practice essentials. Medscape. Updated March 11, 2021. Accessed July 25, 2021.
  3. Von Willebrand disease. Frequency. MedlinePlus Genetics. Updated August 18, 2020. Accessed July 25, 2021.
  4. Pollak ES. von Willebrand disease workup. Medscape.  Updated March 11, 2021. Accessed July 25, 2021.
  5. Pollak ES. von Willebrand disease medication. Medscape.  Updated March 11, 2021. Accessed July 25, 2021.
  6. Pollak ES. von Willebrand Disease treatment & management. Type 1 von Willebrand disease. Medscape.  Updated March 11, 2021. Accessed July 25, 2021.
  7. Pollak ES. von Willebrand Disease treatment & management. Type 2 von Willebrand disease. Medscape.  Updated March 11, 2021. Accessed July 25, 2021.
  8. Pollak ES. von Willebrand Disease treatment & management. Approach considerations. Medscape.  Updated March 11, 2021. Accessed July 25, 2021.
  9. Gill JC, Castaman G, Windyga J, et al. Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease. Blood. 2015;126(17):2038-2046. doi:10.1182/blood-2015-02-629873
  10. Pollak ES. When is platelet transfusion indicated for the treatment of von Willebrand disease? Medscape. Updated December 30,2019. Accessed July 25, 2021.

Reviewed by Debjyoti Talukdar, MD, on 8/10/2021.

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