1. Von Willebrand Disease
Gerald A Soff, MD

2. Case 1
• 18 year old woman, presents with easy bruising,
including all 4 extremities, heavy menses, prolonged
bleeding after wisdom teeth extractions.
• PT: 13”
• aPTT: 38” (NL 24- 36”)
• Factor VIII: 45%
• Factor IX: 105%
• Factor XI: 110%
• Ristocetin Cofactor: 48%
• vWF Antigen: 52%

3. Case 2
• 32 year old woman, presents with 2nd trimester pregnancy. She has
had excessive bleeding after arthroscopy, and a history of a brother
who died from bleeding at 12 years of age after an appendectomy.
No history of excessive bruising.
• PT: 13”
• aPTT: 58” (NL 24- 36”)
• Factor VIII: 3%
• Factor IX: 105%
• Factor XI: 110%
• Ristocetin Cofactor: 105%
• vWF Antigen: 110%

4. Case 3
• 55 year old woman, hematology consult for hemorrhage after
hysterectomy for cervical cancer.
• She has had life-long severe bleeding, with minimal trauma.
• At age 13, with first menses, she had massive hemorrhage, and had
“radioactive cobalt” implants in her ovaries to stop bleeding.
• She had a brother who dies of hemorrhage at age 2 years.
• PT: 13”
• aPTT: 52” (NL 24- 36”)
• Factor VIII: <5%
• Factor IX: 105%
• Factor XI: 110%
• Ristocetin Cofactor: <10%
• vWF Antigen: <10%

5. All Three Cases Have “von
Willebrand Disease”
Case 1: Type I

6. All Three Cases Have “von
Willebrand Disease”
• Case 1: Type I
• Case 2: vWD Normandy

7. All Three Cases Have “von
Willebrand Disease”
Case 1: Type I
Case 2: vWD Normandy
Case 3: Type III

8. Von Willebrand’s Disease
 Definition; An autosomally inherited hemorrhagic
disorder
– Defective platelet adhesion
– Reduced Factor VIII levels
– A mucocutaneous pattern of bleeding
 First described by the Finnish physician Erik von
Willebrand in 1926
 Many members of a large family from the Aland Islands in
the Gulf of Bothnia had a bleeding disorder with a distinct
inherited pattern.

9. von Willebrand Disease (VWD):
Overview
 Common inherited bleeding disorder
 Characterized by deficiency of von Willebrand factor (VWF)
 Variable clinical manifestations
 A group of disorders, (Different types).
– Ewenstein B. Annu Rev Med. 1997;48:525-542;
– Hambleton J. Curr Opin Hematol. 2001;8:306-311;
– Murray E, Lillicrap D. Transfus Med Rev. 1996;10:93-110.

10. VWD Prevalence
• Von Willebrand disease (VWD) is the most common
congenital bleeding disorder.
• It is estimated to occur at a frequency of 1-3%, but is
symptomatic in only about one in 10,000.
• Caused by mutations in von Willebrand factor (VWF).
• The gene for von Willebrand Factor is located on
chromosome 12, and the disease is inherited in an
autosomal manner.

11. Von Willebrand Factor
• vWF is a large adhesive glycoprotein that is present in
the circulation as a heterogeneous population of
disulfide-linked multimers of 250,000 molecular weight
subunit, ranging from a dimer (Mr about 500,000) to a
polymer of about 80 subunits (Mr about 20 x 106 ).
• Human vWF is synthesized as preprovWF (Mr
approximately 350,000) comprising a 22-residue signal
sequence, a 741-residue propeptide, and a 2050-residue
polypeptide that represents the basic subunit of the
mature protein

12. Von Willebrand Factor
• A glycoprotein consisting of disulfide-linked high molecular
weight multimeric FVIII proteins (multimers), and is
synthesized in megakaryocytes and endothelial cells, and
stored in platelets and endothelial cells.
• Von Willebrand factor serves as a carrier protein for FVIII
and promotes platelet aggregation after vessel injury.

13. Von Willebrand Factor
•Adapted from Ginsburg D, Bowie EJW: Molecular genetics of von Willebrand disease.
Blood 79:2507, 1992.
• In Hoffman’s Hematology, 5th Edition

14. The sites of cellular biosynthesis
 Endoplasmic reticulum:
– VWF dimer that is disulfide-bonded at the C-terminus.
– The signal peptide is then cleaved.
 Golgi:
– Carbohydrate.
 Post-Golgi:
– N-linked multimerization by self-association of the von
Willebrand
 Weibel-Palade bodies: Storage granules termed.
 Regulated secretion of fully multimerized VWF and self-
associated vWF dimmers.
 A regulated pathway also is assumed to occur in
megakaryocytes in which the secretory granule is the
platelet -granule, a source of in vivo VWF release

15. Multimer Structure of vWF
• Type 1; Decease in all
multimer sizes
• Type 2; Decrease in
large multimers
• Type 3; Absence of
VWF
Image by Marlies Ledford. In
Hoffman’s Hematology, 5th Edition

16. Weibel-Palade Bodies of Endothelial
Cells
A B
A. Immunofluorescence staining of a human umbilical vein endothelial cell.
VWF is present in the perinuclear region, where it is synthesized and in the Weibel-
Palade bodies (arrowhead) throughout the cytoplasm. Bar = 10 μm.
B. Electron micrograph of Weibel-Palade bodies of the same origin. Bar = 0.5 μm. VWF,
von Willebrand factor.

17. The Von Willebrand Factor Receptor
(GPIb-V-IX Complex)
• Glycoprotein Ib/V/IX is a complex of the products of four genes.
• Deficiency of any results in loss of the receptor.

19. Von Willebrand Disease:
Overview
 Mutations in von Willebrand factor result in deficient or defective
von Willebrand factor antigen and von Willebrand factor activity
(Ristocetin cofactor).
 These are usually accompanied by a decrease in FVIII
coagulant activity (FVIII:C), because normal expression of
FVIII:C in the circulation is dependent on FVIII:C complexing
with its carrier protein, von Willebrand factor.
 The coagulation screening tests typically associated with the
defects in von Willebrand factor and FVIII:C include a prolonged
activated partial thromboplastin time (APTT) and a long bleeding
time.

20. Symptoms of vWD; Mucocutaneous
Bleeding
• Easy bruising
• Epistaxis
• Postoperative or Posttraumatic bleeding
• Mucosal Bleeding
– Gastrointestinal
– Genitourinary tracts.
• Menorrhagia.
• Rare for hemarthrosis, deep bleeds.

21. Definitions
VWD Autosomally inherited bleeding disorder with a reduced amount or
function of VWF.
VWF The glycoprotein that is abnormal or present in reduced amounts
in patients with VWD.
vWF:Ag VWF antigen/ the detection and quantitation of VWF by
(FVIIIR:Ag) immunoassay.
vWF R:Co Ristocetin cofactor; A measure of VWF function using the
antibiotic ristocetin, which induces VWF binding to platelets.
vWF The multiple molecular forms of VWF.
Multimers
vWF Subunits The intact or degraded subunits of VWF multimers, identified
after the complete reduction of VWF disulfide bonds.
F VIII (Anti-hemophilia Factor). VWF serves as a FVIII carrier protein
FVIIIC:Ag Factor VIII coagulant antigen

22. VWD Mutations
(From Nichols WC, Ginsburg D: von Willebrand disease. Medicine 76:1, 1997.)
In Hoffman’s Hematology, 5th Edition

23. Classifications of VWD:
Major Types
Type 1; Partial Quantitative Defect
Type 2; Qualitative Defect. Loss of large
molecular weight multimers
Type 3; Complete Deficiency of VWF

24. Multimer Structure of vWF
• Type 1; Decease in all
multimer sizes
• Type 2; Decrease in
large multimers
• Type 3; Absence of
VWF
Image by Marlies Ledford. In
Hoffman’s Hematology, 5th Edition

25. Classification of von Willebrand
Disease
Type Description
1 Partial quantitative deficiency of VWF
2 Qualitative deficiency of VWF
Decreased platelet-dependent VWF function with
2A selective deficiency of high-molecular-weight multimers
2B Increased affinity for platelet GPIb
Decreased platelet-dependent VWF function with high-
2M molecular-weight multimers present
2N Markedly decreased binding of factor VIII to VWF
3 Complete deficiency of VWF

26. VWD Types
VWD VIII VWF:Ag R:Co Multimers
Type
1 Low Low Low Nl in Plasma &
Platelets
2A Low or Nl Low or Nl Decreased Absent large
relative to Ag and medium
2B Low or Nl Low or Nl Increased at Low Absent large
Concentrations and medium
2N Moderate to Nl Nl Normal
Severe decrease
3 Moderate to Absent Absent None or Trace
severe decrease (or trace)

27. VWD: Type 1
• Most common form
– Approximately 75%-80% of VWD
patients
– Generally mild to moderate
• Characterized by
– Proportionately reduced levels of FVIII,
VWF:RCo, and VWF:Ag
– Functionally and structurally normal
VWF

28. VWD: Type 2 Variants
• Approximately 15%-21% of
patients with VWD
• Qualitative VWF abnormality
• Most common variants are 2A, 2B,
2M, 2N

29. VWD: Type 2A
Absence of large and intermediate-
sized
VWF multimers
10%-12% of all VWD patients
Mutations result in either
– Increased proteolysis or
– Decreased cellular processing and
release

30. VWD: Type 2B
• Increased VWF affinity for platelet
GPlb and secondary clearance of
large-sized multimers
• 3%-5% of all VWD patients
• Thrombocytopenia may be present.

31. VWD: Type 2N
• Also called VWD Normandy and autosomal
hemophilia
• 1%-2% of all VWD patients
• Mutation in region of FVIII binding
• Autosomal recessive inheritance
• Compound heterozygotes with type 1 VWD or
true homozygotes are those that are clinically
affected
• Sometimes misdiagnosed as mild hemophilia

32. VWD: Type 2M
• Characterized by decreased
binding to platelet GPIb
• 1%-2% of all VWD patients
• Abnormal multimers, but not
associated with selective loss of
large molecular weight forms.

33. VWD: Type 3
• 1%-3% of all VWD patients
• Characterized by virtually no detectable VWF:Ag
and markedly decreased FVIII:C (< 5 U/dL)
• Patients suffer from severe, spontaneous bleeds
– Mucosal bleeds are common
– May experience joint bleeds similar to
hemophilia
• Inhibitors to VWF may develop following
replacement therapy.

34. Approach to the Assessment of vWD
 Bleeding history
– Family History
 Complete blood cell count
 vWD profile testing
– vWF:Ag
– vWF:RCo
– fVIII:C
 ABO Blood Type

35. Diagnosing VWD:
Initial Evaluation
 Detailed personal and family history is key
 Screening laboratory values are often normal
– Platelet count
– Prothrombin time (PT)
– Activated partial thromboplastin time (aPTT)
 Bleeding time (BT) is an insensitive screening tool for
type 1 disease
 Hambleton J. Curr Opin Hematol. 2001;8:306-311.

36. Laboratory Diagnosis
• vWF activity (Ristocetin Cofactor)
• vWF antigen
• factor VIII activity
• vWF multimeric analysis
• ABO Blood Type
• Bleeding time (PFA 100)

37. Ristocetin-Induced Platelet
Agglutination

38. Figure 14-8. Binding of von WiIlebrand factor
(VWF) to formalin-fixed platelets

39. Effects of ABO Blood Group on
vWF Levels
ABO Type N Mean (%) Mean +/- 2 SD
(%)
O 456 74.8 (35.6-157.0)
A 240 105.9 (48.0-233.9)
B 196 116.9 (56.8-241.0)
AB 109 123.3 (63.8-238.2)
Gill JC, Endres-Brooks J, Bauer PJ, et al: The effect of ABO blood group
on the diagnosis of von Willebrand disease. Blood 1987; 69:1691.

40. Modifying Conditions
• Conditions associated with higher VWF levels
– Age
– Acute and chronic inflammation
– Diabetes
– Malignancy
– Pregnancy or oral contraceptive use
– Stress; exercise
– Hyperthyroidism
• Conditions associated with reduced VWF levels
– Hypothyroidism
– O Blood type

41. Treatment of vWD

42. Treatment of vWD
 DDAVP; 0.3 ug/kg IV daily for 1-2 doses
– (Stimate by nasal spray, 100 ug/spray. 10%
bioavailability)
– Good for mild or prophylactic therapy
– Can worsen Type 2B (Thrombocytopenia) and no good
for type 3
– Best to test dose in nonemergent setting.
 Humate P (F VIII Concentrate with large multimers)
– Minor bleed; 15-20 Un/kg IV, and repeat q 24 as
needed.
– Major bleeds; 40-50 U/Kg, then 20-30 U/kg q 12 hr.
– (Dose based on R:Co activity, 0.5 R:Co/1.0 FVIII
Units)

43. Treatment: Mild VWD
• Specific therapies include
– DDAVP (synthetic derivative of
vasopressin)
• Parenteral (IV or SQ)
• Intranasal (high concentrations)
– Plasma-derived FVIII products containing
high concentrations of VWF
• Humate-P (FDA approved), Alphanate, Koate
• DO NOT use cryoprecipiate

44. Treatment: VWD
• Adjuvant therapies
– Antifibrinolytics
• Amicar, cyklocapron
– Fibrin glue
– PO or parenteral estrogen

45. DDAVP
• A synthetic version of vasopressin
• Increases plasma VWF concentrations
by stimulating its release from
intracellular stores in endothelial cells
• Treatment of choice for type 1
• Variable response in types 2A, 2B, and
2M
• Ineffective in type 3
(cont)

46. DDAVP
• Side effects include
– Flushing
– Hyponatremia, seizures
– Headache
– Abdominal cramps
– Alteration in blood pressure
• Tachyphylaxis may occur if dosed too
frequently

47. DDAVP: Indications
 Generally used as treatment for spontaneous or
trauma-induced injuries in patients with mild to
moderate VWD
 Frequently used to treat
– Mucosal bleeding
– Menorrhagia
– Minor surgical procedures after documenting
patient response
 Contraindicated in individuals with known
hypersensitivity or significant side effects

48. Humate-P: VWF:RCo Dosing
 Major bleeds
– Loading dose of 40-60 IU/kg body weight
– Then, 40-50 IU/kg every 8-12 hours for 3 days
– Maintain VWF:RCo 50%
– Then, 40-50 IU/kg body weight daily 7 days
 Minor bleeds in moderate to severe patients
(eg, menorrhagia, epistaxis)
– 40-50 IU/kg body weight
– 1 or 2 doses

49. Humate-P: VWF:RCo Dosing
• Major bleeds in moderate to severe patients
(eg, CNS trauma, hemarthroses)
– Loading dose of 50-75 IU/kg body weight
– Then, 40-60 IU/kg body weight every
8-12 hours for 3 days
• Maintain VWF:RCo 50%
– Then, 40-60 IU/kg body weight daily 7 days

50. Acquired VWD
• Extremely rare
– Fewer than 100 well-documented cases
• Causes
– Circulating inhibitors
– Absorption
– Proteolysis
– Others
• Underlying autoimmune disorder or malignancy is common
• Treatment must target the underlying disorder as well as acute
symptoms of bleeding
• VWF concentrates are often required and sometimes less
effective; successful use of rFVIIa has been reported

51. Pseudo-VWD
• Rare disorder characterized by an intrinsic
platelet defect with increased affinity of
GPIb/IX for VWF
• Increased aggregation on RIPA as with
subtype 2B
• Distinction that the patient has a platelet
disorder as opposed to VWD is determined
by additional testing