The document describes 3 cases of von Willebrand disease (VWD), with Case 1 having Type I VWD characterized by a partial deficiency of von Willebrand factor (vWF), Case 2 having Type 2N VWD or Normandy VWD characterized by a qualitative defect with normal levels of vWF, and Case 3 having the most severe Type III VWD characterized by a complete deficiency of vWF. VWD is an inherited bleeding disorder caused by defects in vWF that leads to reduced platelet adhesion and coagulation Factor VIII levels. The classification and treatment of the different VWD types is outlined based on the level and functional abnormalities of vWF

1. Von Willebrand Disease
Gerald A Soff MD

2. Case 1
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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
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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
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55 year old woman. Hematology consulted 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 died 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”
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Case 1: Type I

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

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

8. Von Willebrand’s “Disease”
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Definition; An autosomally inherited hemorrhagic
disorder
– Defective platelet adhesion
– Reduced Factor VIII levels
– A mucocutaneous pattern of bleeding
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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.

10. von Willebrand Disease (VWD):
Overview
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Characterized by deficiency/dysprotein of von
Willebrand factor (VWF)
Variable clinical manifestations
A group of disorders, (Different types).
It is estimated to occur at a frequency of 1-3%, but
is symptomatic in only about one in 10,000.
– 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;10:93110.

11. Von Willebrand Factor
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A heterogeneous population of disulfide-linked
multimers:
– Basic unit is dimer of 250,000 Dalton subunits
– vWF Molecules in circulation range from a single dimer
(Mr about 500,000) to a polymer of about 80 subunits
(Mr about 20 x 106 ).
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Synthesized in megakaryocytes and endothelial
cells, and stored in platelets and endothelial cells.

12. Von Willebrand Factor
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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. Cellular Biosynthesis
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Endoplasmic reticulum:
– VWF dimer is disulfide-bonded at the C-terminus.
– The signal peptide is then cleaved.
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Golgi:
– Carbohydrate.
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Post-Golgi:
– N-linked multimerization by self-association of the von
Willebrand
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Weibel-Palade bodies: Storage granules in endothelium.
Regulated secretion of fully multimerized VWF and selfassociated vWF dimmers.
Megakaryocytes/Platelets -granule

15. Structural Organization of Weibel-Palade bodies of
Endothelial Cells:
Tomogram sections and images showing VWF tubules.
Berriman J A et al.
PNAS 2009;
106:17407-17412

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

17. ADAMTS13 Processing of “UltraLarge” Molecular Weight vWF

18. 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.

20. Von Willebrand Disease: Overview of
Common Types
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Decrease in vWF function (Ristocetin cofactor)
and antigen.
– Abnormal bleeding time or platelet function screen.
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Decrease in FVIII coagulant activity
(FVIII:C),
– activated partial thromboplastin time (APTT) may
be high-normal or elevated.

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

23. 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
(FVIIIR:Ag)
VWF antigen/ the detection and quantitation of VWF by
immunoassay.
vWF R:Co
Ristocetin cofactor; A measure of VWF function using the
antibiotic ristocetin, which induces VWF binding to platelets.
vWF
Multimers
The multiple molecular forms of VWF.
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

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

25. 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
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26. Multimer Structure of vWF
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Image by Marlies Ledford. In
Hoffman’s Hematology, 5th Edition
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Type 1; Decrease in all
multimer sizes
Type 2; Decrease in large
multimers
Type 3; Absence of VWF

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

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

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

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

31. VWD: Type 2A
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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

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

33. VWD: Type 2N
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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

34. VWD: Type 2M
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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.

35. VWD: Type 3
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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
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–
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Mucosal bleeds are common
May experience joint bleeds similar to hemophilia
Inhibitors to VWF may develop following
replacement therapy.

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

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

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

39. Ristocetin-Induced Platelet
Agglutination

40. Binding of von WiIlebrand factor (VWF) to
formalin-fixed platelets

41. Effects of ABO Blood Group on
vWF Levels
ABO Type
N
Mean (%)
O
A
B
AB
456
240
196
109
74.8
105.9
116.9
123.3
Mean +/- 2 SD
(%)
(35.6-157.0)
(48.0-233.9)
(56.8-241.0)
(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.

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

43. Treatment of vWD

44. Treatment of vWD
DDAVP
 F VIII Concentrate with intact vWF
multimers
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– Humate P ®
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Antifibrinolytic, Adjuvant therapies.
– Amicar ®

45. DDAVP
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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, and 2M
Ineffective in type 3
Can worsen Type 2B (Thrombocytopenia).
Best to test dose in non-emergent setting.
(cont)

46. DDAVP
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0.3 ug/kg IV daily for 1-2 doses
– (Stimate® by nasal spray, 100 ug/spray. 10%
bioavailability)
– Good for mild bleeds or prophylactic therapy
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Side effects include
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Flushing
Hyponatremia, seizures
Headache
Abdominal cramps
Alteration in blood pressure
Tachyphylaxis may occur if dosed too frequently

47. DDAVP: Indications
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Generally used as treatment for
spontaneous or trauma-induced injuries in
patients with mild to moderate VWD
Frequently used to treat
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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
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Major bleeds
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Maintain VWF:RCo  50%
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Loading dose of 40-60 IU/kg body weight
Then, 40-50 IU/kg every 8-12 hours for 3 days
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. Acquired VWD
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Extremely rare
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Causes
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Fewer than 100 well-documented cases
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.

50. Pseudo-VWD
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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