Pathogenesis , clinical presentation & lab tests

1. Von Willebrand Disease

2. Historical Aspects
 First described by Finnish Physician –
Erik Von Willibrand in 1926
 Many members of a large family from
the Aland islands in the Gulf of Bothnia
had a bleeding disorder with distinct
inherited pattern

4. What is VWD
 Most common inherited bleeding disorder
affecting ~ 1% of the population
 Characterised by :
- Defective platelet adhesion
- Reduced factor VIII levels
- A mucocutaneous pattern of bleeding
 Autosomal dominant – most common
bleeding disorder in women

5.  Inherited VWD is caused by genetic
mutations that lead to decreased
production or impaired function of Von
Willebrand Factor (VWF)
 Acquired VWD is most commonly
associated with immunoproliferative
cancer and Autoimmune disease ( SLE)

6. How doesVWF promote
clotting
 VWF is a large molecule which usually
circulates in the blood in the form of a
“Multimer” composed of two basic subunits.
 These large Multimers have two main binding
sites.
 One site binds to injured epithelium and the
other site binds to platelets.

10. How does VWF promote
clotting
 These VWF multimers form an adhesive bridge
between platelets and injured vascular
epithelium
 They also form a bridge between adjacent
platelets allowing them to bind together and
effectively form a platelet plug at sites of
endothelial injury

11.  VWF additionally functions as a carrier for
factor VIIIc & it also protects factor VIII
from being rapidly broken down thereby
extending its half life.
 Therefore VWF is also extremely important
in normal Fibrin clot formation

13. Inherited VWD is classified into
Three types
 Type I is the most common form accounting for
~ 70% of all patients with VWD
 AD inheritance
 Caused by a variety of mutations which all
result in a quantitative deficiency of VWF

14.  Type II has 4 subtypes which in total account
for ~ 25% of all patients with VWD.
 Caused by a variety of different mutations
which in general adversely affect the
function of VWF not the amount.
 Type II is sub classified into 4 subtypes of
which the majority manifest AD inheritance

15. Type II has 4 subtypes
 Type IIA ~ 15 % of all VWD thereby making it
the second most common presentation for
VWD.
 AD Mutations result in a decrease in high-
molecular-weight multimers causing
decreased function of VWF & in-efficient
binding to platelets

16.  Type IIB ~ 5% of all VWD.
 AD inherited mutations resulting in an
overactive platelet binding site (GP1b) that
may result in thrombocytopenia mediated via
increased consumption & clearance of platelet
aggregates

17.  Type IIM~ Rare AD mutation that results in
reduced binding to platelets
 Type IIN~ Rare AR mutation causing
decreased binding to Factor VIII resulting in
low factor VIII

18.  Type III is extremely rare(~1/1,000,000).
 AR inheritance that results in extremely low
VWF levels.
 This is the most severe form of VWD due to
very low VWF levels resulting in decreased
platelet aggregation & low Factor VIII levels

20. Pathophysiology and Clinical
Presentation
 Bleeding Sx occur when an absolute decrease in amount
or function of VWF occurs.
 These abnormalities result in decreased platelet plug
formation during the primary hemostatic response
 Therefore many of the patients present with Sx similar
to those seen with platelet disorders:
 Easy bruising, Skin bleeding, and prolonged bleeding
from the Gums/GI tract/Uterus

21.  The exception to this presentation is seen with Type
IIN and Type III (most severe form) VWD patients
who have low Factor VIII levels and present with soft
tissue, joint , and GU bleeding which are classic for
hemophilia.
 These Sx and the low factor VIII levels may result in a
misdiagnosis of Hemophilia A

22. Delayed, severe
Immediate, mild
Common
Rare
Hemarthroses,
muscle hematomas
Bleeding after
surgery
Large, palpable
Small, superficial
Ecchymoses
Absent
Present
Petechiae
Not usually
Bleeding after
minor cuts
Skin, mucous
membranes
(gingivae, nares, GI
and genitourinary
tracts)
Yes
Site of bleeding
Clotting factor
deficiency
Deep in soft tissues
(joints, muscles)
Platelet defect
Clinical
characteristic

23. Clinical Presentation for
Type III and Type IIN
 Symptoms are generally severe and present
at an early age with bleeding @ circumcision,
when deciduous teeth erupt, or when learning
to walk and crawl.
 Soft tissue ,joint, and GU bleeding are the rule
in addition to easy bruising, skin bleeding, and
GI bleeding

24. Clinical Presentation / Diagnosis
 Difficult Dx due to most patients having mild
form of Type I
 Lack of bleeding challenges ( ie invasive dental
procedures ,trauma to mucous membranes)
 Difficult to assign importance of minor
excessive bleeding ( ie heavy menstrual
bleeding )
 Difficult to assign importance of ASA or NSAID
causing excessive bleeding

25. Clinical Presentation / Diagnosis
 Most patients with Type I or Type II have
mild to moderate bleeding abnormalities.
 Classic history includes frequent nose bleeds
as a child , lifelong easy bruising , and
bleeding with invasive dental procedures or
tooth extractions
 Exacerbation of bleeding with ASA or NSAID
use
 Many females may be asymptomatic until their
first menses

26. Difficult Diagnosis And Difficult to
Assess Response to treatment
 Wide variety of mutations result in a wide
variety of clinical scenarios
 No single lab test can assess all aspects of
VWD
 VWD affects are: Quantitative or Qualitative
or mediated through platelet VWF or
mediated through Factor VIII or a combo of
these

27. Lab tests for VWF
 Plasma VWF antigen level (VWF:Ag)
 Plasma VWF activity (ristocetin Cofactor activity)
 VWF:RCo/VWF:Ag ratio
 Factor VIII levels
 Platelet function analyzer assay
 VWF Multimer Gel Electrophoresis
 Ristocetin induced platelet aggregation
 Bleeding time , APTT

28. What do the tests Measure
 VWF Ag : Immunological assay ( ELISA)
Quantitative test only. No assessment of
function (Type I decreased)
 VWF activity : Ristocetin cofactor activity
:quantitate platelet agglutination after addition
of ristocetin and VWF OR Collagen binding
activity: quantitate binding of VWF to collagen
coated platelets (decreased in all except Type
IIN)

29.  VWF:RCo/VWF:Ag ratio – the ratio
between antigen and activity levels , which
can help distinguish type I from type II VWD
 Factor VIII levels : VWF is required to
maintain FVIII in circulation

30.  VWF Electrophoresis : Size distribution of
VWF Multimers (Type IIA decreased large and
intermediate multimer)
 Risocetin induced platelet aggregation:
Measures the ability of the pt VWF to bind to
platelets after the addition of ristocetin (Type
IIB Increased plt ag)

31. Variables that influence Rx
 Most important is an accurate and
complete diagnosis of VWD Type
 Patients past history of bleeding with various
challenges (location and severity)
 Previous response to treatment Determine a
Proactive plan for surgical procedures or
delivery

32. 6 medical treatments
 Desmopressin (dDAVP) – releases VWF from
endothelial stotage sites
 VWF replacement (or as a last resort
Cryoprecipitate)
 Antifibrinolytic therapy ( Epsilonaminocaproic
acid ie EACA or Tranexamic acid )
 Topical Agents (Avitene or Fibrin sealant )
 Recombinant Factor VIIA (emergent use)
 Adjuvant Platelet transfusion

33. Thank You