3. 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%
4. 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%
5. Case 3
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%
7. All Three Cases Have “von
Willebrand Disease”
Case 1: Type I
Case 2: Case 2: Type IIN (vWD Normandy)
8. All Three Cases Have “von
Willebrand Disease”
Case 1: Type I
Case 2: Type IIN (vWD Normandy)
Case 3: Type III
In a male, how would you differentiate vWD
Normandy from Hemophilia A?
9. 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.
10.
11. von Willebrand Disease (VWD):
Overview
Characterized by deficiency/dysprotein of von
Willebrand factor (VWF).
Variable clinical manifestations.
Heterogeneous, (Different types).
It is estimated to occur at a frequency of from 1%
to 0.1%, depending on definition (laboratory
findings versus clinical syndrome).
– 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.
12. Von Willebrand Factor
A heterogeneous population of disulfide-linked
multimers:
– Basic unit is dimer of two 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 ).
Synthesized in megakaryocytes and endothelial
cells, and stored in platelets and endothelial cells.
13. Von Willebrand Factor
Von Willebrand factor serves as a carrier protein for
FVIII and promotes platelet adhesion (GP Ib-V-IX )
after vessel injury.
Also contributes to platelet aggregation (GP IIb/IIIa).
14. 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
15. Cellular Biosynthesis
Endoplasmic reticulum.
– VWF dimer 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 in endothelium.
– Regulated secretion of fully multimerized VWF and self-associated vWF
dimmers.
Also present in Megakaryocytes/Platelets -granules.
16. 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
Presence of Von Willebrand
antigen, referred to as “Factor
VIII: Related Antigen
(VIII:RAG)”, was an early test
for endothelial cells,
megakaryocytes, and platelets.
17. Multimer Structure of vWF
Type 1; Decrease in all
multimer sizes
Type 2; Decrease in large
multimers
Type 3; Absence of VWF
(Note, platelet vWF is
“larger” than vWF in
normal plasma)
Image by Marlies Ledford. In
Hoffman’s Hematology, 5th Edition
19. The Von Willebrand Factor Receptor
(GP Ib-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.
21. Von Willebrand Disease: Overview of
Common Types
Decrease in vWF function (Ristocetin cofactor)
and antigen.
– Abnormal platelet function screen.
– Abnormal bleeding time (but test rarely available
for 20+ years).
Decrease in FVIII coagulant activity
(FVIII:C),
– activated partial thromboplastin time (APTT) may
be high-normal or elevated.
22. Symptoms of vWD;
Mucocutaneous Bleeding
Easy bruising
Epistaxis
Postoperative or Post-traumatic bleeding
Mucosal Bleeding
– Gastrointestinal
– Genitourinary tracts.
Menorrhagia.
Rare for hemarthrosis, deep bleeds.
Why does low Factor VIII in vWD not typically
contribute to bleeding tendency?
23.
24. 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
25. VWD Mutations
(From Nichols WC, Ginsburg D: von Willebrand disease. Medicine 76:1, 1997.)
In Hoffman’s Hematology, 5th Edition
26. 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
27. Multimer Structure of vWF
Type 1; Decrease 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
28. Classification of von Willebrand
Disease
Type Description
1 Partial quantitative deficiency of VWF
2 Qualitative deficiency of VWF
2A
Decreased platelet-dependent VWF function with
selective deficiency of high-molecular-weight
multimers
2B Increased affinity for platelet GPIb
2M
Decreased platelet-dependent VWF function with
high-molecular-weight multimers present
2N Markedly decreased binding of factor VIII to VWF
3 Complete deficiency of VWF
29. VWD Types
VWD
Type
VIII VWF:Ag R:Co Multimers
1 Low Low Low Nl in Plasma
& Platelets
2A Low or Nl Low or Nl Decreased
relative to Ag
Absent large
and medium
2B Low or Nl Low or Nl Increased at
Low
Concentrations
Absent large
and medium
2N Moderate to
Severe
decrease
Nl Nl Normal
3 Moderate to
severe
decrease
Absent
(or trace)
Absent None or
Trace
30. VWD: Type 1
Most common form
– Prevalence 1% - 1 in 10,000
– 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
31. VWD: Type 2 Variants
Approximately 15%-21% of patients with VWD
Qualitative VWF abnormality
Most common variants are 2A, 2B, 2M, 2N
33. 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
36. VWD: Type 2B
Gain of platelet-dependent function
Increased VWF affinity for platelet GP lb and
secondary clearance of large-sized multimers
3%-5% of all VWD patients
Thrombocytopenia may be present.
37. Type 2M von Willebrand Disease
Loss of platelet-dependent function
Normal multimers!
– R1205H-Type Vicenza VWD
38. 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 hemophilia A.
– May be differentiated by family history and definitively by
genomic sequencing.
39. VWD: Type 2M
Characterized by decreased binding to platelet
GP Ib
1%-2% of all VWD patients
Abnormal multimers, but not associated with
selective loss of large molecular weight forms.
– May be missed if multimer assay not done in expert
hands.
40. 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.
42. 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!
43. Diagnosing VWD:
Initial Evaluation
Detailed personal and family history of bleeding.
Physical: Mucocutaneous pattern of bleeding.
Screening laboratory values are often normal
– Platelet count
– Prothrombin time (PT)
– Activated partial thromboplastin time (aPTT)
Hambleton J. Curr Opin Hematol. 2001;8:306-311.
45. vWD Associated With Factor VIII
Deficiency.
Why does the clinical manifestations not include
the classic deep and delayed bleeding seen in
Hemophilia A?
47. Binding of von WiIlebrand Factor (VWF) to
Formalin-Fixed platelets
48. 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.
49. 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
51. Treatment of vWD
DDAVP
F VIII Concentrate with intact vWF
multimers
– Humate P ®
Antifibrinolytic, Adjuvant therapies.
– Amicar ®
52. 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, and 2M
Ineffective in type 3
Can worsen Type 2B (Thrombocytopenia).
Best to test dose in non-emergent setting.
53. DDAVP
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
Side effects include
– Flushing
– Hyponatremia, seizures
– Headache
– Abdominal cramps
– Alteration in blood pressure
Tachyphylaxis may occur if dosed too frequently
54. Federici A B et al. Blood 2004;103:2032-2038
Biologic Responses to DDAVP in 26
Patients With Type 1 VWD.
55. Biologic Responses To DDAVP in
15 Patients With Type 2A VWD
Federici A B et al. Blood 2004;103:2032-2038
56. 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.
57. 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
58. 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.
59. Pseudo-VWD
Rare disorder characterized by an intrinsic platelet
defect with increased affinity of GPIb/IX for VWF
Increased aggregation on Ristocetin Induced Platelet
Agglutination, as with subtype 2B
Distinction that the patient has a platelet disorder as
opposed to VWD is determined by additional testing
