Von Willebrand DiseaseVon Willebrand Disease

Douglas Montgomery MDDouglas Montgomery MD

7/10/2008 7/10/2008

What is VWDWhat is VWD

Most common inherited bleeding disorder Most common inherited bleeding disorder affecting ~ 1% of the populationaffecting ~ 1% of the population

Inherited VWD is caused by genetic Inherited VWD is caused by genetic mutations that lead to decreased mutations that lead to decreased production OR impaired function of Von production OR impaired function of Von Willebrand Factor (VWF)Willebrand Factor (VWF)

Acquired VWD is most commonly Acquired VWD is most commonly associated with immunoproliferative associated with immunoproliferative cancer and Autoimmune Dz ( SLE)cancer and Autoimmune Dz ( SLE)

How does VWF promote How does VWF promote clottingclotting

VWF is a large molecule which VWF is a large molecule which usually circulates in the blood in the usually circulates in the blood in the form of a “Multimer” composed of form of a “Multimer” composed of two basic subunits.two basic subunits.

These large Multimers have two main These large Multimers have two main binding sites. One site binds to binding sites. One site binds to injured epithelium and the other site injured epithelium and the other site binds to platelets.binds to platelets.

How does VWF promote How does VWF promote clottingclotting

These VWF multimers form an adhesive bridge These VWF multimers form an adhesive bridge between platelets and injured vascular epitheliumbetween platelets and injured vascular epithelium

They also form a bridge between adjacent They also form a bridge between adjacent platelets allowing them to bind together and platelets allowing them to bind together and effectively form a platelet plug at sites of effectively form a platelet plug at sites of endothelial injuryendothelial injury

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

Inherited VWD is classified into Inherited VWD is classified into Three typesThree types

Type I is the most common form accounting for ~ Type I is the most common form accounting for ~ 70% of all patients with VWD. Caused by a variety 70% of all patients with VWD. Caused by a variety of mutations which all result in a quantitative of mutations which all result in a quantitative deficiency of VWF. AD inheritancedeficiency of VWF. AD inheritance

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

Type II has 4 subtypesType II has 4 subtypes Type IIA ~ 15 % of all VWD thereby making it the Type IIA ~ 15 % of all VWD thereby making it the

second most common presentation for VWD. AD second most common presentation for VWD. AD Mutations result in a decrease in only large and Mutations result in a decrease in only large and intermediate size VWF multimers causing intermediate size VWF multimers causing decreased function of VWFdecreased function of VWF

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

Type IIM~ Rare AD mutation that results in Type IIM~ Rare AD mutation that results in reduced binding to plateletsreduced binding to platelets

Type IIN~ Rare AR mutation causing decreased Type IIN~ Rare AR mutation causing decreased binding to Factor VIII resulting in Low factor VIIIbinding to Factor VIII resulting in Low factor VIII

Inherited VWD is classified into Inherited VWD is classified into Three typesThree types

Type III is extremely rare Type III is extremely rare (~1/1,000,000). AR inheritance that (~1/1,000,000). AR inheritance that results in extremely low VWF levels.results in extremely low VWF levels.

This is the most severe form of VWD This is the most severe form of VWD due to very low VWF levels resulting due to very low VWF levels resulting in decreased platelet aggregation in decreased platelet aggregation AND low Factor VIII levelsAND low Factor VIII levels

Pathophysiology and Clinical Pathophysiology and Clinical PresentationPresentation

Bleeding Sx occur when an absolute decrease in amount or Bleeding Sx occur when an absolute decrease in amount or function of VWF occurs. These abnormalities result in function of VWF occurs. These abnormalities result in decreased platelet plug formation during the primary decreased platelet plug formation during the primary haemostatic response.haemostatic response.

Therefore many of the patients present with Sx similar to Therefore many of the patients present with Sx similar to those seen with platelet disorders:those seen with platelet disorders:

Easy bruising, Skin bleeding, and prolonged bleeding form Easy bruising, Skin bleeding, and prolonged bleeding form the Gums/GI tract/Uterusthe Gums/GI tract/Uterus

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

Clinical Clinical characteristic characteristic

Platelet defect Platelet defect Clotting factor Clotting factor deficiency deficiency

Site of bleeding Site of bleeding Skin, mucous Skin, mucous membranes membranes (gingivae, nares, GI (gingivae, nares, GI and genitourinary and genitourinary tracts) tracts)

Deep in soft tissues Deep in soft tissues (joints, muscles) (joints, muscles)

Bleeding after Bleeding after minor cuts minor cuts

Yes Yes Not usually Not usually

Petechiae Petechiae Present Present Absent Absent

Ecchymoses Ecchymoses Small, superficial Small, superficial Large, palpable Large, palpable

Hemarthroses, Hemarthroses, muscle hematomas muscle hematomas

Rare Rare Common Common

Bleeding after Bleeding after surgery surgery

Immediate, mild Immediate, mild Delayed, severe Delayed, severe

Clinical Presentation for Clinical Presentation for Type III and Type IIN Type III and Type IIN

Symptoms are generally severe and Symptoms are generally severe and present at an early age with bleeding present at an early age with bleeding @ circumcision, when deciduous @ circumcision, when deciduous teeth erupt, or when learning to walk teeth erupt, or when learning to walk and crawl.and crawl.

Soft tissue , joint, and GU bleeding Soft tissue , joint, and GU bleeding are the rule are the rule in additionin addition to easy to easy bruising, skin bleeding, and GI bruising, skin bleeding, and GI bleeding.bleeding.

Clinical Presentation / DiagnosisClinical Presentation / Diagnosis

Difficult Dx due to most patients Difficult Dx due to most patients having mild form of Type I.having mild form of Type I.

Lack of bleeding challengesLack of bleeding challenges ( ie invasive ( ie invasive dental procedures ,T&A ,trauma to mucous membranes)dental procedures ,T&A ,trauma to mucous membranes)

Difficult to assign importance of Difficult to assign importance of minor excessive bleedingminor excessive bleeding ( ie heavy ( ie heavy menstrual bleeding )menstrual bleeding )

Difficult to assign importance of ASA Difficult to assign importance of ASA or NSAID causing excessive bleedingor NSAID causing excessive bleeding

Clinical Presentation / DiagnosisClinical Presentation / Diagnosis

Most patients with Type I or Type II have Most patients with Type I or Type II have mild to moderate bleeding abnormalities.mild to moderate bleeding abnormalities.

Classic history includes frequent nose Classic history includes frequent nose bleeds as a child , lifelong easy bruising , bleeds as a child , lifelong easy bruising , and bleeding with invasive dental and bleeding with invasive dental procedures or tooth extractionsprocedures or tooth extractions

Exacerbation of bleeding with ASA or Exacerbation of bleeding with ASA or NSAID useNSAID use

Many females may be asymptomatic until Many females may be asymptomatic until their first mensestheir first menses

Difficult Diagnosis And Difficult to Difficult Diagnosis And Difficult to Asses Response to treatmentAsses Response to treatment

Wide variety of mutations result in a Wide variety of mutations result in a wide variety of clinical scenarioswide variety of clinical scenarios

No single lab test can asses all No single lab test can asses all aspects of VWDaspects of VWD

VWD affects are: Quantitative or VWD affects are: Quantitative or Qualitative or mediated through Qualitative or mediated through platelet VWF or mediated through platelet VWF or mediated through Factor VIII or a combo of theseFactor VIII or a combo of these

Some Lab test for VWFSome Lab test for VWF

Plasma VWF antigen level (VWF:Ag)Plasma VWF antigen level (VWF:Ag) Plasma VWFPlasma VWF activity activity (ristocetin Cofactor activity)(ristocetin Cofactor activity)

Factor VIII ActivityFactor VIII Activity Platelet function analyzer assayPlatelet function analyzer assay VWF Multimer Gel ElectrophoresisVWF Multimer Gel Electrophoresis Ristocetin induced platelet aggregationRistocetin induced platelet aggregation Bleeding timeBleeding time

What do the test MeasureWhat do the test Measure

VWF Ag : VWF Ag : Immunological assay ( ELISA) Quantitative test Immunological assay ( ELISA) Quantitative test only No assessment of function (Type I decreased)only No assessment of function (Type I decreased)

VWF activity : VWF activity : Ristocetin cofactor activity :quantitate Ristocetin cofactor activity :quantitate platelet agglutination after addition of ristocetin and VWF OR platelet agglutination after addition of ristocetin and VWF OR Collagen binding activity: quantitate binding of VWF to Collagen binding activity: quantitate binding of VWF to collagen coated platelets (decreased in all except TypeIIN)collagen coated platelets (decreased in all except TypeIIN)

VWF Electrophoresis : VWF Electrophoresis : Size distribution of VWF Size distribution of VWF Multimers (Type IIA decreased large and intrmd multimer)Multimers (Type IIA decreased large and intrmd multimer)

Risocetin induced platelet Risocetin induced platelet aggregation :aggregation :Measures the ability of the pt VWF to bind Measures the ability of the pt VWF to bind

to platelets after the addition of ristocetinto platelets after the addition of ristocetin ((Type IIB Type IIB

Increased plt agIncreased plt ag))

Variables that influence Variables that influence TREATMENTTREATMENT

Most important is an accurate and Most important is an accurate and complete diagnosis of VWD Typecomplete diagnosis of VWD Type

Patients past history of bleeding with Patients past history of bleeding with various challenges (various challenges (location and severity)location and severity)

Previous response to treatmentPrevious response to treatment Determine a Proactive plan for Determine a Proactive plan for

surgical procedures or delivery surgical procedures or delivery

6 medical treatments6 medical treatments

Desmopressin Desmopressin (dDAVP)(dDAVP)

VWF replacement VWF replacement (Humate P or as a last (Humate P or as a last resort Cryoprecipitate)resort Cryoprecipitate)

Antifibrinolytic therapyAntifibrinolytic therapy ( Epsilon ( Epsilon aminocaproic acid ie EACA or Tranexamic acid )aminocaproic acid ie EACA or Tranexamic acid )

Topical Agents Topical Agents (Avitene or Fibrin sealant )(Avitene or Fibrin sealant )

Recombinant Factor VIIA Recombinant Factor VIIA (emergent use)(emergent use)

Adjuvant Platelet transfusionAdjuvant Platelet transfusion

TRIAL OF DDAVPTRIAL OF DDAVP

Trial of dDAVP is recommended for all Trial of dDAVP is recommended for all patients with type I and Most type II patients with type I and Most type II patients patients (caution with type IIB as thrombocytopenia MAY (caution with type IIB as thrombocytopenia MAY worsen and aggravate bleeding)worsen and aggravate bleeding)

Effective Response for most patients is Effective Response for most patients is validated with an increase in VWF activity validated with an increase in VWF activity to at least 30IU/dL and optimally to to at least 30IU/dL and optimally to 50IU/dL50IU/dL

Once adequate response is documented Once adequate response is documented dDAVP can be utilized for surgery or dDAVP can be utilized for surgery or vaginal deliveryvaginal delivery

dDAVPdDAVP

Synthetic analogue of antidiuretic Synthetic analogue of antidiuretic hormone that increases VWF and Factor hormone that increases VWF and Factor VIII levels.VIII levels.

Side Effects include : Vasodilatation Side Effects include : Vasodilatation resulting in facial flushing, headache, and resulting in facial flushing, headache, and sometimes hypotension and nausea.sometimes hypotension and nausea.

Tachyphylaxis occurs after repeated dosesTachyphylaxis occurs after repeated doses WATER RETENTION WITH HYPONATREMIA WATER RETENTION WITH HYPONATREMIA

AND SEIZURES exacerbated by AND SEIZURES exacerbated by NSAIDS/ASANSAIDS/ASA

dDAVPdDAVP In general 0.3 micrograms /Kg ( max 20 In general 0.3 micrograms /Kg ( max 20

Mcg) IV infused over 30 minutes with VWF Mcg) IV infused over 30 minutes with VWF and Factor VIII levels increasing within 30-and Factor VIII levels increasing within 30-60 minutes after the infusion and 60 minutes after the infusion and remaining increased for 6-12 hours.remaining increased for 6-12 hours.

Attempt to administer 1-2 hours before Attempt to administer 1-2 hours before delivery. General recommendation is to delivery. General recommendation is to achieve a factor VIII level at or above 50% achieve a factor VIII level at or above 50% for C/Sfor C/S

Repeat doses Q 12-24 hours for 2-4 dosesRepeat doses Q 12-24 hours for 2-4 doses Water intake should be decreased monitor Water intake should be decreased monitor

I/O closely. Check Serum Na q 12I/O closely. Check Serum Na q 12

Nasal Spray dDAVPNasal Spray dDAVP

Hemophilia A and mild-to-moderate von Hemophilia A and mild-to-moderate von Willebrand disease (type 1):Willebrand disease (type 1):

    Intranasal (using high concentration Intranasal (using high concentration spray [1.5 mg/mL]): <50 kg: 150 mcg (1 spray [1.5 mg/mL]): <50 kg: 150 mcg (1 spray); >50 kg: 300 mcg (1 spray each spray); >50 kg: 300 mcg (1 spray each nostril); repeat use is determined by the nostril); repeat use is determined by the patient's clinical condition and laboratory patient's clinical condition and laboratory work. If using preoperatively, administer 2 work. If using preoperatively, administer 2 hours before surgery.hours before surgery.

VWF replacement therapy for VWF replacement therapy for dDAVP REFRACTORY PATIENTSdDAVP REFRACTORY PATIENTS

Recommended as primary therapy for patients Recommended as primary therapy for patients with Type III VWDwith Type III VWD

Recommended as secondary Tx if dDAVP has Recommended as secondary Tx if dDAVP has failed or prolonged Tx required, or bleeding is failed or prolonged Tx required, or bleeding is severe.severe.

Infuse 20-30 IU/kg of ristocetin cofactor Infuse 20-30 IU/kg of ristocetin cofactor activity(labeled on replacement)activity(labeled on replacement)

Goal is to achieve VWF/Factor VIII @50-100% Goal is to achieve VWF/Factor VIII @50-100% activity level. Keep below 200% due to risk of activity level. Keep below 200% due to risk of thrombosis. Check levels dailythrombosis. Check levels daily

Cryprecipitate has high risk of viral transmissionCryprecipitate has high risk of viral transmission

Unresponsive Refractory BleedingUnresponsive Refractory Bleeding

Recombinant Factor VIIa which may Recombinant Factor VIIa which may “bypass” the need for factor VIII and “bypass” the need for factor VIII and also binds to activated plateletsalso binds to activated platelets

Consider a platelet transfusionConsider a platelet transfusion

Other TricksOther Tricks

Topical FloSeal or AviteneTopical FloSeal or Avitene Both are used primarily for nasal or Both are used primarily for nasal or

oral bleedingoral bleeding Possible utility @ time of C/S for Possible utility @ time of C/S for

peritoneal edged bleeding? Or apply peritoneal edged bleeding? Or apply to suture line?? As a temporizing to suture line?? As a temporizing measure until definitive Tx can be measure until definitive Tx can be started??started??

Summary OB ManagementSummary OB Management Determine appropriate Tx well before deliveryDetermine appropriate Tx well before delivery dDAVP or Factor VIII replacement strategy and dDAVP or Factor VIII replacement strategy and

dosage schedule on the chartdosage schedule on the chart C/S only indicated for OB reasonsC/S only indicated for OB reasons C/S OK with VFW activity and Factor VIII activity C/S OK with VFW activity and Factor VIII activity

of at least 50IU/dL before delivery and maintained of at least 50IU/dL before delivery and maintained for 3-5 days after deliveryfor 3-5 days after delivery

Regional anesthesia may be OK if VWF and Factor Regional anesthesia may be OK if VWF and Factor VIII levels are maintained > 50IU/dLVIII levels are maintained > 50IU/dL

Circumcision delayed until baby boy’s w/u is Circumcision delayed until baby boy’s w/u is completed to r/o or confirm VWDcompleted to r/o or confirm VWD

Late PPH up to 3 weeks after delivery is likelyLate PPH up to 3 weeks after delivery is likely

HAPPY TO CONSULTHAPPY TO CONSULT H ematologyH ematology A nesthesiologyA nesthesiology P erinatologyP erinatology P ediatricsP ediatrics Y es There is a Proactive Plan Y es There is a Proactive Plan