What are the Different Types of von Willebrand Disease?

Patient Presentation
An 8-year-old male comes to the hematology clinic for his specialty care for von Willebrand Disease.
The past medical history reveals that he was diagnosed with Type 1 von Willebrand Disease as a toddler after abnormal bruising and prolonged bleeding was noted by his family.
The family history has some family members who have heavy menstrual bleeding but no other problems.
The review of systems shows that he has had no significant joint or other bleeding since his last visit. He has desmopressin to be taken at home which has been used twice in the past 6 months after a bike fall and after falling off playground equipment.
The pertinent physical exam shows him to be growing well. He has minor bruising on his legs and arms. There are no problems with his joints.
He is to follow-up in another 6 months.

Bleeding can be caused by problems of platelets, coagulation proteins or the blood vessels. Once the blood vessels are disrupted, platelets are exposed to connective tissue and collagen which causes the platelets to release granules that help other platelets to aggregate to the area. Tissue factors and platelet granules cause circulating prothrombin to converted to thrombin. Thrombin interacts with fibrinogen to form fibrin monomers. Factor VIII causes the fibrin monomers to polymerize. The fibrin polymers and aggregated platelets then form the primary plug that along with blood vessel contraction stops the bleeding.

vonWillebrand Disease was first described in 1926 by Erick Adolph vonWillebrand. (Hemophilia A is the common name for the deficiency in Factor VIII. Hemophilia B is a common name for the deficiency of IX). von Willebrand Factor (vWF) is a multimeric protein which is a carrier for Factor VIII and prevents Factor VIII degredation. vWF also stabilizes the bonds between platelets and endothelial cells. vWF is synthesized and stored in platelets and endothelial cells. VWF is a dimer which binds together to make up multimers of low, intermediate and high molecular weights. The low molecular weight multimers are the Factor VIII carriers. High molecular weight multimers have more sites for platelet binding and therefore are important for normal platelet function.

Many people with von Willebrand Disease are asymptomatic with <3% of the US population affected. The gene is found on chromosome 12p. Acquired forms of vWD can be found also. Menorrhagia is often the only symptom women may have. People are usually diagnosed because of menorrhagia, epistaxis, easy/increased bleeding or bruising, postoperative bleeding, or family history. Physical examination may be normal or have increased bruising or mucosal bleeding.

Screening tests include CBC, template bleeding time, prothrombin time (PT) and activated partical thromboplastin time (aPTT). Generally a normal CBC, normal to prolonged template bleeding time, and aPTT with a normal prothrombin time are seen. Specific tests such as vWF level, Factor VIII activity, Ristocetin activity (i.e. vWF activity), vWF antigen and subtype determination may also be needed or desired. Treatment may include Desmopressin (DDAVP), Factor VIII and Aminocaproic acid (Amicar).

Learning Point
It has 3 main types:

    Type 1 (70-80% of patients)

    • Problem: A quantitative defect with decreased amounts of vWF. The vWF is correctly formed.
    • Genetics: Autosomal dominant with variable penetrance
    • Clinical symptoms: Generally mild
    • Laboratory: May vary in same patient at different times. Generally decreased vWF activity, vWF antigen, and Factor VIII are seen.

    Type 2 (15-20%)

    • Problem: Qualitative defects of the vWF molecule which is present but is made or processed incorrectly
    • Genetics: Autosomal dominant or autosomal recessive
    • Clinical symptoms: Moderate

    Type 2A (most common Type 2 subtype)

    • Problem: There is an increased amount of vWF multimers. The total amount of vWF is decreased.
    • Genetics: Autsomal dominant
    • Laboratory: Normal to decreased Factor VIII and vWF and decreased ristocetin cofactor activity are seen. vWF subtype analysis reveals multimeric abnormalities and decreased amount of intermediate and high molecular weight multimer complexes.

    Type 2B

    • Problem: The vWF molecules are too big and bind platelets too much resulting in an intermittant thrombocytopenia
    • Genetics: Autosomal dominant
    • Laboratory: There are variable amounts of Factor VIII and vWF, and special ristocetin testing shows clumping of normal platelets. Platelet count can fall more during prengnacy, surgical procedures and with taking DDAVP.

    Type 2M

    • Problem: decreased vWF binding to platelets that is not due to a decrease of high molecular weight multimers
    • Laboratory: There is decreased vWF activity. There is also normal vWF antigen, Factor VIII, and subtype analysis

    Type 2 Normandy

    • Problem: vWF doesn’t bind to Factor VIII very well and therefore Factor VIII levels are low
    • Genetics: Autosomal recessive
    • Clinical Symptoms: should be considered when incomplete response to treatment is seen
    • Laboratory: Low Factor VIII levels are seen along with normal vWF antigen and ristocetin cofactor activity.

    Type 3 (rarest)

    • Problem: A quantative and qualitative defect with decreased amounts of vWF and Factor VIII, that also don’t attach to platelets and endothelial cells well.
    • Genetics: Autosomal recessive
    • Clinical symptoms: Most severe symptoms, lack of secondary transfusion response and response to DDAVP
    • Laboratory: Decreased vWF and Factor VIII are seen. vWF multimeric analysis shows variable results.

Questions for Further Discussion
1. What common reasons cause bleeding because of other coagulation pathway protein problems?
2. What is the most common cause of bleeding?

Related Cases

To Learn More
To view pediatric review articles on this topic from the past year check PubMed.

Information prescriptions for patients can be found at Pediatric Common Questions, Quick Answers for this topic: Hemophilia.

Geil, JD. Von Willebrand Disease. eMedicine.
Available from the Internet at http://www.emedicine.com/ped/topic2419.htm (rev. 8/19/2004, cited1/3/2005).

Rudolph CD, et.al. Rudolph’s Pediatrics. 21st edit. McGraw-Hill, New York, NY. 2003:1573.

Woodhead JC. Pediatric Clerkship Guide. Mosby. St. Louis MO, 2003:170-179.

Donna M. D’Alessandro, MD
Associate Professor of Pediatrics, Children’s Hospital of Iowa

January 24, 2005