1. Von Willebrand Disease
PHM Fall 2018
Instructor: Ms. Maya Latif
Coordinator: Dr. J. Henderson
Von Willebrand Disease
By Marzyeh Azimi, Braiden Cutmore, Lok Kan Lee, Negin Sadeghlo
Phm142,
Fall 2018

2. What is Von Willebrand Disease
•A genetic bleeding disorder mediated by reduced quantity or quality of von Willebrand factor (vWF)
Genetic – Caused by mutation to a gene which encodes vWF, autosomal dominant, Different mutations result in different types of VWD
Bleeding disorder, like hemophilia, most common, gums and skin, nosebleeds and bruising, excessive bleeding after cuts surgeries, dental, menorrhagia and hemmorage after childbirth in women.
Internal bleeding
vWF –

3. Pathway & Genetics
Glycoprotein that circulates in the plasma and its role in primary hemostasis is to carry/ stabilize factor VIII and to act as a link between platelets and vascular subendothelial structures
Produced and stored in megakaryocytes and endothelial cells:
Processed in ER and Golgi apparatus for further processing and maturation
Consist of 3 A, 3 B, 2 C, and 4 D domains; each domain has unique functional properties. specific domains bind to receptors on platelets as well different types of collagens

4. Pathway & Genetics
The vWF gene encodes a protein with numerous copies of homologous motifs consisting of 3 A, 3 B, 2 C, and 4 D motifs.
The motifs encode for protein domains that provide the various function
Mutations are present in the vWF gene that cause either qualitative or quantitative defects in the factor: missense mutations and large deletions, promoter, and frameshift nonsense mutations

5. Types of Von Willebrand Disease
•Type 1 (most common): Not enough vWF in bloodstream, but the vWF works correctly
•Type 2 (second most common, four subtypes): Defect in vWF structure
A: The incorrect vWF size prevents platelet plug formation B: The incorrect vWF size causes vWF to attach to platelets, and the immune system destroys the resulting structures (leads to a lack of both platelets and vWF) N: The mutated vWF structure causes vWF to not protect factor VIII, which prevents fibrin clot formation M: The mutated vWF structure cannot attach to platelets
•Type 3 (rare): No vWF in blood; most severe type of Von Willebrand disease

6. Diagnosis •Family history: Pattern of inheritance
•Laboratory screening tests:
•Complete blood count, clotting tests such as prothrombin time (PT) & partial thromboplastin time (APTT)
•Homeostasis factor assays: *MUST DO*
•von Willebrand factor antigen (vWF:Ag)
•Functional FVIII assay
•von Willebrand factor activity (ristocetin cofactor or collagen binding),
•Binding of FVIII by vWF
Must use the family history and laboratory studies, including coagulation studies à can be confused with hemophila A in patients who present with extremely low levels of vWF
The CBC might be normal, but could also show a microcytic anemia (if the individual is iron deficient) or a low platelet count (thrombocytopenia),
The aPTT is often normal, but may be prolonged when the factor VIII (FVIII) level is reduced to below 30–40 IU/dL (normal range is approximately 50–150 IU/dL)
The prothrombin time (PT) is normal in VWD
vWF:Ag: Quantity of VWF protein (antigen) in the plasma
Functional FVIII assay which determines the activity of FVIII in the coagulation cascade
The ristocetin cofactor activity assay determines the ability of VWF to agglutinate platelets, initiated by the antibiotic ristocetin
Collagen binding: This test determines the ability of VWF to bind to collagen (a sub-endothelial matrix component). It is used in some centers to help identify functional VWF discordance (i.e., to help distinguish types 1 and 2 VWD)
vWD:RIPA Ability of VWF to aggregate platelets at 2–3 concentrations of ristocetin.
SDS-agarose electrophoresis is used to determine the complement of VWF oligomers in the plasma
More recent diagnostic tools include molecular diagnostic testing used to detect and classify mutations associated with this condition.
Rule out hemophilia A

7. Treatment 1) Desmopressin acetate (DDAVP) *First Line*
•Synthetic hormone
•Stimulates production of more vWF and FVIII
•For type 1 and some type 2 subtypes of vWD
2) Clotting factor-containing concentrates
•vWF or FVIII
•Type 1-3 vWD
•Non-responsive to DDAVP
•Patients that cannot be treated with DDAVP
It is important to note that the use of cryoprecipitate as a treatment is strictly historical as the amount of vWF in cryoprecipitate is not regulated.
von Willebrand factor deficiency + factor VIII replacement
FVIII is prefered ovre vWF
Antifibrolytic drugs can also be used in conjunction with DDAVP and replacement therapy, but this type of therapy is usually used to stop bleeding after minor surgery, injury, or tooth extraction. Treatments for women with this condition who suffer from heavy menstrual bleeding may include using a combination of oral contraceptives, which can cause an increase in production of von Willebrand factor and factor VIII, and aminocaproic acid or tranexamic acid, which are antifibrinolytic drugs that can decrease bleeding by decelerating the breakdown of clots. With proper diagnosis and appropriate treatment, persons affected with von Willebrand disease can manage the disease and live active and productive lives.20,21

8. Individuals with von Willebrand disease can live normal and productive lives with correct diagnosis and treatment

9. Summary Von Willebrand disease is a genetic bleeding disorder
Von Willebrand factor (vWF) is a protein involved in blood clotting process through stabilizing factor VIII, and it acts as a “gummy” link between platelets, collagens and endothelial structures
There are 3 main types of Von Willebrand disease (type 1, 2A/B/M/N, 3), with type 1 being the most common, and type 3 being the most rare but most severe
Type 1 and 3 Von Willebrand disease is associated with abnormal concentrations of vWF in the body
Type 2 Von Willebrand disease is associated with structural changes of vWF, which prevents blood clotting from occurring properly
vWF gene codes for different domains of the vWF protein and depending on the type of mutation that occurs in the exons of the gene, qualitative or quantitative defects can be manifested which results in different types of vWF disease
Diagnosis of vWD includes determining the pattern of inheritance, blood screening, and homeostasis factor assays.
Treatments for vWD include desmopressin acetate and clotting -actor containing concentrates.

10. References
Cardenas EB, Tatum OL. Von Willebrand Disease: Elucidating the Clinical Picture Through the Use of Molecular Methods. Laboratory Medicine Dec 1;39(12):743-8.
James, PD, & Goodeve AC. von Willebrand Disease. Genetics in Medicine : Official Journal of the American College of Medical Genetics (5), /GIM.0b013e
Phillips S, Lazarchick J, Bergmann S. Type 3 Von Willebrand Disease: A Case Report of a Rare Entity. Blood [Internet]. 2016;128(22):4988. Available from:
Sadler JE. Von Willebrand disease type 1: a diagnosis in search of a disease. Blood [Internet] ;101(6):2089–93. Available from:
Tosetto A, Castaman G. How I treat type 2 variant forms of von Willebrand disease. Blood [Internet] Apr;125(6):907–14. Available from: