Von Willebrand disease pathophysiology

Von Willebrand disease Microchapters
Home
Patient Information
Overview
Historical Perspective
Classification
Pathophysiology
Causes
Differentiating Von Willebrand disease from other Diseases
Epidemiology and Demographics
Risk Factors
Screening
Natural History, Complications and Prognosis
Diagnosis
Diagnostic Study of Choice
History and Symptoms
Physical Examination
Laboratory Findings
Electrocardiogram
Chest X Ray
CT
MRI
Ultrasound
Other Imaging Findings
Other Diagnostic Studies
Treatment
Medical Therapy
Surgery
Primary Prevention
Secondary Prevention
Cost-Effectiveness of Therapy
Future or Investigational Therapies
Case Studies
Case #1
Von Willebrand disease pathophysiology On the Web
Most recent articles
Most cited articles
Review articles
CME Programs
Powerpoint slides
Images
American Roentgen Ray Society Images of Von Willebrand disease pathophysiology All Images X-rays Echo & Ultrasound CT Images MRI
Ongoing Trials at Clinical Trials.gov
US National Guidelines Clearinghouse
NICE Guidance
FDA on Von Willebrand disease pathophysiology
on Von Willebrand disease pathophysiology
Von Willebrand disease pathophysiology in the news
Blogs on Von Willebrand disease pathophysiology
Directions to Hospitals Treating Von Willebrand disease
Risk calculators and risk factors for Von Willebrand disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Pathophysiology

In healthy individuals, VWF circulates as high-molecular-weight multimers carrying factor VIII. Some persons have mildly reduced VWF levels, which may contribute to a bleeding phenotype but are not necessarily caused by defects in the VWF gene. Persons with low VWF levels and a bleeding tendency are classified as having low VWF, rather than von Willebrand’s disease (VWD). There is a partial deficiency of functionally normal VWF in type 1 VWD and a complete deficiency in type 3 disease. This deficiency can result from a reduction in protein synthesis, which is often caused by null alleles (large gene deletions, stop codons, frame-shift mutations, or splice-site mutations) but may also be due to mutations in the promotor regions. Homozygosity or compound heterozygosity for these defects results in type 3 VWD. Some heterozygous carriers have mild symptoms and receive a diagnosis of type 1 disease. However, most cases of type 1 VWD are caused by heterozygous missense mutations that exert a dominant-negative effect because the mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a abnormality of the entire multimer.

Deficiency of vWF shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus.

In more severe cases of type 1 vWD, genetic changes are common within the vWF gene and are highly penetrant. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology in addition to polymorphisms of the vWF gene alone. The individual's ABO blood group can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.

Genetics

Von Willebrand disease types 1 and 2 (except type 2N which is inherited recessively) are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. The diagram below illustrates autosomal dominant inheritance.

von Willebrand disease

von Willebrand disease types I and II are inherited in an autosomal dominant pattern.

• The vWF gene is located on chromosome twelve (12p13.2).
• It has 52 exons spanning 178kbp. *
• VWD Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.

Associated conditions

Acquired conditions associated with Von Willebrand disease include the following:

Heart-related conditions

• Mitral valve prolapse
• Ventricular assist device
• Ventricular septal defect
• Aortic stenosis

Malignant diseases

• Monoclonal gammopathy of undetermined significance

• Leukemia example chronic myeloid leukemia and chronic lymphocytic leukemia
• Wilms tumor
• Waldenström macroglobulinemia
• Essential thrombocythemia
• Multiple myeloma
• Non-Hodgkin lymphoma
• Polycythemia vera

Drugs and other agents

• Valproic acid
• Ciprofloxacin
• Griseofulvin

Autoimmune disorders

• Systemic lupus erythematosus

Other disorders

• Hypothyroidism
• Uremia
• Hemoglobinopathies
• Angiodysplasia