an older lecture but very useful.

1. Von Willebrand Disease
Douglas Montgomery MD
7/10/2008

2. What is VWD
 Most common inherited bleeding disorder
affecting ~ 1% of the population
 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 Dz ( SLE)

3. How does VWF 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.

5. 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
 VWF additionally functions as a carrier for factor
VIII AND 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

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

9. 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 only large
and intermediate size VWF multimers causing
decreased function of VWF
 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
clearance of platelet aggregates
 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

10. Inherited VWD is classified into
Three types
 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
AND low Factor VIII levels

11. 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
haemostatic response.
 Therefore many of the patients present with Sx similar to
those seen with platelet disorders:
 Easy bruising, Skin bleeding, and prolonged bleeding form
the Gums/GI tract/Uterus
 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

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

13. 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.

14. Clinical Presentation / Diagnosis
 Difficult Dx due to most patients
having mild form of Type I.
 Lack of bleeding challenges ( ie invasive
dental procedures ,T&A ,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

15. 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

16. Difficult Diagnosis And Difficult to
Asses Response to treatment
 Wide variety of mutations result in a
wide variety of clinical scenarios
 No single lab test can asses 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

17. Some Lab test for VWF
 Plasma VWF antigen level (VWF:Ag)
 Plasma VWF activity (ristocetin Cofactor activity)
 Factor VIII Activity
 Platelet function analyzer assay
 VWF Multimer Gel Electrophoresis
 Ristocetin induced platelet aggregation
 Bleeding time

18. What do the test 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 TypeIIN)
 VWF Electrophoresis : Size distribution of VWF
Multimers (Type IIA decreased large and intrmd 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)

19. Variables that influence
TREATMENT
 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

20. 6 medical treatments
 Desmopressin (dDAVP)
 VWF replacement (Humate P or as a last
resort Cryoprecipitate)
 Antifibrinolytic therapy ( Epsilon
aminocaproic acid ie EACA or Tranexamic acid )
 Topical Agents (Avitene or Fibrin sealant )
 Recombinant Factor VIIA (emergent use)
 Adjuvant Platelet transfusion

21. TRIAL OF DDAVP
 Trial of dDAVP is recommended for all
patients with type I and Most type II
patients (caution with type IIB as thrombocytopenia
MAY worsen and aggravate bleeding)
 Effective Response for most patients is
validated with an increase in VWF activity
to at least 30IU/dL and optimally to 50IU/
dL
 Once adequate response is documented
dDAVP can be utilized for surgery or
vaginal delivery

22. dDAVP
 Synthetic analogue of antidiuretic
hormone that increases VWF and Factor
VIII levels.
 Side Effects include : Vasodilatation
resulting in facial flushing, headache, and
sometimes hypotension and nausea.
 Tachyphylaxis occurs after repeated doses
 WATER RETENTION WITH HYPONATREMIA
AND SEIZURES exacerbated by
NSAIDS/ASA

23. dDAVP
 In general 0.3 micrograms /Kg ( max 20
Mcg) IV infused over 30 minutes with VWF
and Factor VIII levels increasing within
30-60 minutes after the infusion and
remaining increased for 6-12 hours.
 Attempt to administer 1-2 hours before
delivery. General recommendation is to
achieve a factor VIII level at or above
50% for C/S
 Repeat doses Q 12-24 hours for 2-4 doses
 Water intake should be decreased monitor
I/O closely. Check Serum Na q 12

24. Nasal Spray dDAVP
 Hemophilia A and mild-to-moderate von
Willebrand disease (type 1):

Intranasal (using high concentration
spray [1.5 mg/mL]): <50 kg: 150 mcg (1
spray); >50 kg: 300 mcg (1 spray each
nostril); repeat use is determined by the
patient's clinical condition and laboratory
work. If using preoperatively, administer 2
hours before surgery.

25. VWF replacement therapy for
dDAVP REFRACTORY PATIENTS
 Recommended as primary therapy for patients
with Type III VWD
 Recommended as secondary Tx if dDAVP has
failed or prolonged Tx required, or bleeding is
severe.
 Infuse 20-30 IU/kg of ristocetin cofactor
activity(labeled on replacement)
 Goal is to achieve VWF/Factor VIII @50-100%
activity level. Keep below 200% due to risk of
thrombosis. Check levels daily
 Cryprecipitate has high risk of viral transmission

26. Unresponsive Refractory Bleeding
 Recombinant Factor VIIa which may
“bypass” the need for factor VIII and
also binds to activated platelets
 Consider a platelet transfusion

28. Other Tricks
 Topical FloSeal or Avitene
 Both are used primarily for nasal or
oral bleeding
 Possible utility @ time of C/S for
peritoneal edged bleeding? Or apply
to suture line?? As a temporizing
measure until definitive Tx can be
started??

29. Summary OB Management
 Determine appropriate Tx well before delivery
 dDAVP or Factor VIII replacement strategy and
dosage schedule on the chart
 C/S only indicated for OB reasons
 C/S OK with VFW activity and Factor VIII activity
of at least 50IU/dL before delivery and
maintained for 3-5 days after delivery
 Regional anesthesia may be OK if VWF and Factor
VIII levels are maintained > 50IU/dL
 Circumcision delayed until baby boy’s w/u is
completed to r/o or confirm VWD
 Late PPH up to 3 weeks after delivery is likely

30. HAPPY TO CONSULT
 H ematology
 A nesthesiology
 P erinatology
 P ediatrics
 Y es There is a Proactive Plan