Mutations in the VWF gene cause von Willebrand disease.1

 

After an injury, clots protect the body by sealing off damaged blood vessels and preventing further blood loss. Von Willebrand factor acts as a glue to hold blood clots together and prevents the breakdown of other blood clotting proteins. If von Willebrand factor does not function normally or too little of the protein is available, blood clots cannot form properly. Abnormally slow blood clotting causes the prolonged bleeding episodes seen in von Willebrand disease.

The three types of von Willebrand disease are based upon the amount of von Willebrand factor that is produced. Mutations in the VWF gene that reduce the amount of von Willebrand factor cause type 1 von Willebrand disease. People with type 1 have varying amounts of von Willebrand factor in their bloodstream. Some people with a mild case of type 1 never experience a prolonged bleeding episode. Mutations that disrupt the function of von Willebrand factor cause the four subtypes of type 2 von Willebrand disease. People with type 2 von Willebrand disease have bleeding episodes of varying severity depending on the extent of von Willebrand factor dysfunction, but the bleeding episodes are typically similar to those seen in type 1. Mutations that result in an abnormally short, nonfunctional von Willebrand factor generally cause type 3 von Willebrand disease. Because there is no functional protein, people with type 3 von Willebrand disease usually have severe bleeding episodes.

VWF gene on chromosome 12p13

 An apparent association between hereditary hemorrhagic telangiectasia (HHT) and VWD has been reported in several families.

The causative genes in HHT were identified and are located on chromosomes 9q33–34, and 12q13, distinct from the VWF gene on chromosome 12p13. However, because inheriting VWD is likely to increase the severity of bleeding from HHT, the diagnosis is more likely to be made in patients inheriting both defects.272

 

 

 

Pathology

Defect in platelet adhesion

Pathophysiology

VWF serves two roles:

(1) as the major adhesion molecule that tethers the platelet to the exposed subendothelium; and

(2) as the binding protein for factor VIII (FVIII), resulting in significant prolongation of the FVIII half-life in circulation.

The platelet-adhesive function of VWF is critically dependent on the presence of large VWF multimers, whereas FVIII binding is not.

[Most of the symptoms of VWD are “platelet-like” except in more severe VWD when the FVIII is low enough to produce symptoms similar to those found in FVIII deficiency (hemophilia A).]

 

Content 11

VWD is the most common inherited bleeding disorder.

Estimates from laboratory data suggest a prevalence of approximately 1%, but data based on symptomatic individuals suggest that it is closer to 0.1% of the population.

 

 

 

 

Content 3

Content 13

A 4-year-old boy is seen by his pediatrician for a marked bruising tendency of the arms and legs. His mother says that the bruising often appeared without any apparent trauma. The mother also reports that there was no bleeding at the time of circumcision or in association with separation of the umbilical cord. At 3 years of age the patient had an episode of epistaxis that required transfusion of one unit of blood. There is a history of bleeding on the maternal side of the family. The patient's mother and maternal grandmother and great-grandmother had experienced episodes of abnormal bleeding with recurrent epistaxis and menorrhagia.

Summary: A 4-year-old boy has marked bruising without apparent trauma and a history of epistaxis. There is a history of abnormal bleeding in the patient's mother and maternal grandmother and great-grandmother.

Questions

What types of coagulation abnormalities usually result in bruising and epistaxis?

Answer (Click)

What are possible diagnoses in this patient?

Answer (Click)

What laboratory studies would you use to evaluate this patient?

Answer (Click)

Clinical Correlation

The strong family history of abnormal bleeding suggests an inherited condition. Since female family members are affected, hemophilias, which are X-linked, can be excluded. In addition, the type of bleeding experienced by this patient is more in keeping with an abnormality of platelet function. This would include inherited abnormalities in the number of platelets (quantitative abnormalities), abnormalities in the function of platelets (qualitative abnormalities), and abnormalities in the adhesion of platelets to endothelial surfaces (von Willebrand disease).

 

Von Willebrand Disease (vWD) is characterized by which of the following abnormalities?

The correct answer is B.

 

Von Willebrand Disease (vWD) is caused by a defect or deficiency in von Willebrand factor (vWF) causing impaired platelet aggregation and adhesion but normal platelet number. Note that vWD can also cause a prolonged activated partial thromboplastin time (aPTT) due to a decrease in factor VII in the intrinsic pathway. Decreased platelet number results in thrombocytopenia while vWD is characterized by normal platelet number but impaired platelet function. An elevated INR reflects a defect in the extrinsic pathway. Often, women with vWD have a history of heavy menstrual periods (menorrhagia) or bleeding in between periods (metrorrhagia).

References: Yawn B, Nichols WL, Rick ME. Diagnosis and management of von Willebrand disease: guidelines for primary care. Am Fam Physician. 2009;80(11):1261-1268. Pubmed ID: 19961139.

Neutze D, Roque J. Clinical Evaluation of Bleeding and Bruising in Primary Care. Am Fam Physician. 2016;93(4):279-286. Pubmed ID: 26926815.

 


 

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