Von Willebrand Disease Douglas Montgomery MD 7/10/2008
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)
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.
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
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
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
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
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
Clinical Platelet defect Clotting factorcharacteristic deficiencySite of bleeding Skin, mucous Deep in soft tissues membranes (joints, muscles) (gingivae, nares, GI and genitourinary tracts)Bleeding after Yes Not usuallyminor cutsPetechiae Present AbsentEcchymoses Small, superficial Large, palpableHemarthroses, Rare Commonmuscle hematomasBleeding after Immediate, mild Delayed, severesurgery
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.
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
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
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
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
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)
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
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
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
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
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
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 patients clinical condition and laboratory work. If using preoperatively, administer 2 hours before surgery.
VWF replacement therapy fordDAVP 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
Unresponsive Refractory Bleeding Recombinant Factor VIIa which may “bypass” the need for factor VIII and also binds to activated platelets Consider a platelet transfusion
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??
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
HAPPY TO CONSULT H ematology A nesthesiology P erinatology P ediatrics Y es There is a Proactive Plan