vON WILLEBRAND’s DISEASE SHANNA BADJE, SRNA MAYO CLINIC HEALTH SYSTEM FRANCISCAN HEALTHCARE SCHOOL OF ANESTHESIA AUGUST 1, 2017

oBJECTIVES Review pathophysiology of von Willebrand’s Disease, including the subtypes Examine therapeutic management, as well as treatment of perioperative bleeding associated with von Willebrand’s disease Discuss the operative concerns and anesthetic considerations for von Willebrand’s Disease

What is von Willebrand’s disease? The most common inherited coagulopathy Prevalence ranges from 1 in 100 to 3 in 100,000 individuals A deficiency of von Willebrand factor von Willebrand factor deficiency may be acquired, often termed von Willebrand Syndrome

Von Willebrand factor vWF is synthesized by the endothelium and platelets, and serves two roles: an adhesion protein for platelets to the injured vessel wall circulates in the plasma to create a complex bound to factor VIII and provides protection for factor VIII against inactivation and clearance -First, vWF acts as a bridge between platelet receptors and exposed collagen in disrupted endothelium. -Platelet binding to exposed collagen in disrupted endothelium initially occurs via a glycoprotein (GP) Ib-vWF and collagen interaction and is followed by firmer adhesion of the platelet to the collagen molecule via a GP IIb/IIIa-vWF and collagen interaction. vWF enables platelets to create a primary plug in disrupted endothelium and to commence the hemostatic process at the site of vessel injury. vWF also acts as a bridge between platelet receptors, specifically between GP IIb/IIIa receptors, to allow platelet aggregation. -vWF deficiency directly limits effective binding of platelets to injured vascular endothelium and to other platelets

Von Willebrand’s disease Subtypes Abbreviations: RIPA = ristocetin-induced platelet aggregation; vWD = von Willebrand disease; vWF = von Willebrand factor; ↓ = decrease; ↑ = increase; ↓↓ = marked decrease. -Type 1: is the most common type and represents a quantitative defect in plasma vwf levels. Clinical severity is quite variable, but generally correlates with the plasma levels of vwf and factor viii. Vwf/factor viii is at about 5-30% of normal levels -Type 2: is characterized by a qualitative defect in plasma vwf. This can involve a reduction in the number of larger vwf multimers or variable changes in vwf antigen and factor viii binding. The absence of larger multimers results in a disproportionate decrease in vwf activity -Type 3: is characterized by the virtual absence of circulating vwf antigen and very low levels of both vwf activity and factor viii (3-10% of normal). These patients experience severe bleeding similar to that of hemophilia (spontaneous hemorrhage)

Clinical Presentation Broad range of bleeding severity If moderate to severe vWD, individual tends to bleed abnormally in childhood or young adulthood Symptoms include easy bruising, epistaxis, and bleeding from mucous membranes Menorrhagia and life-threatening GI bleeding may occur

Diagnosis Not reliable with PT/PTT or bleeding times alone Lab tests to include with bleeding times: vWF antigen and activity Factor VIII activity Series of assays to determine classification of vWD Ristocetin-induced platelet aggregation assay vWF multimer studies The diagnosis of vWD is complex. Will often see normal platelet count and normal PT. The PTT may be prolonged depending on association of concurrent factor VIII levels.

treatment Treatment goals are to increase activity of vWF and factor VIII to 50%-100% of normal before major surgery or 30%-50% before minor surgery The main treatment options are: Desmopressin (DDAVP) Synthetic analogue of the antidiuretic hormone vasopressin Recombinant von Willebrand factor (rVWF) Indicated for on-demand treatment of minor or major hemorrhage in adults with vWD von Willebrand factor/factor VIII (vWF/FVIII) concentrates (Humate P) Used for treatment of bleeds and for surgical prophylaxis when DDAVP is ineffective or contraindicated Treatment of vWD depends on the type of vWD that is diagnosed.

Treatment for Type 1 DDAVP is the treatment of choice Releases endogenous vWF and FVIII into the plasma Rapid increase in circulating levels of vWF, factor VIII and RCoF activity Maximal rise of vWF and FVIII observed in 30-60 min Will see 2-4 fold increase for vWF and 3-6 fold increase for FVIII Maintained for at least 6 hours Given IV or intranasally IV: 0.3 mcg/kg in 50 ml saline over 20 min Nasal spray: 300 mcg May repeat does after 12 hours and every 24 hours up to 3 doses due to tachyphylaxis Monitor for fluid retention and hyponatremia RCoF (ristocetin cofactor) activity

Treatment for type 2 Response to DDAVP are variable vWF concentrates recommended if not responsive to DDAVP (Type 2M and 2N) Many with Type 2A have response to DDAVP Rapid loss of vWF , FVIII and RCoF activity occurs as the high- molecular weight multimers are degraded Return to baseline levels 4 hours post transfusion DDAVP is contraindicated in patients with Type 2B due to thrombocytopenia and possible thrombotic complications

Treatment for Type 3 DDAVP has no effect on patients with Type 3 due to the complete deficiency of vWF Treatment of choice are rVWF (with or without FVIII) or vWF-containing FVIII concentrates 20-30 IU/kg every 12 h to keep vWF levels 50%-100% or to control clinical bleeding; levels should be maintained 3- 10 days for major surgery Alloantibody formation occurs in 10-15% of patients with Type 3 At increased risk for life-threatening anaphylactic reactions to vWF-FVIII preparations

Other treatments Antifibrinolytic drugs to treat mild mucotaneous bleeding Aminocaproic acid 50 mg/kg (maximum 5 g/dose) 4 times daily Tranexamic acid 25 mg/kg 3 times daily Topical agents (fibrin sealants) Adjunctive therapy for dental surgery or surface wound bleeding that is not responsive to drugs or concentrates Platelet transfusion ***Cryoprecipitate and FFP not recommended due to potential transmission of viral disease Antifibrinolytics used orally or IV eg, fibrin glue, Gelfoam®, or thrombin-soaked Surgicel Plts to control bleeding that is refractory to other therapies (type 3) Also with FFP, large infusion volumes are usually required

Management of anesthesia… Depends on the type and severity of the disease, along with the urgency and location of the surgical procedure

Preop assessment/goals History: Onset, duration, severity Easy bruising, gum bleeding, heavy periods Subtype if known Physical Exam Ecchymoses, petechiae Lab Tests/Imaging CBC, electrolytes (Na+), BUN, Cr, PT/PTT Type & screen vWF/FVIII, ristocetin cofactor assay if diagnosis unsure Consults Hematology Optimization Premed, transfusion

considerations Potential for excessive bleeding Potential for side effects of desmopressin therapy Avoid IM or PR routes Avoid antiplatelet drugs ICU/stepdown bed

VWF in pregnancy During pregnancy, vWF level increases (two to three times above baseline) in most patients with non-Type 3 vWD If vWF is normal, may proceed with L&D as normal Patients with Type 2 disease may experience hemorrhagic problems Type 2B patients experience thrombocytopenia due to the increased plasma levels Monitoring for excessive bleeding recommended during first week post partum  DDAVP can be administered to patients with vWD in active labor who are known to have a positive response to this therapy. vWF replacement therapy can be given to patients who are still bleeding following DDAVP administration. Patients who are known nonresponders to DDAVP should be treated with vWF and factor VIII concentrates. Lysine analogue antifibrinolytic agents (eg, ε-aminocaproic acid and tranexamic acid) have been successfully used as both adjuncts and monotherapy in some patients with vWD-related hemorrhage.80

References Avery IV EG, Klick JC. The Patient With Anemia and Coagulation Disorders. In: Longnecker DE, Mackey SC, Newman MF, Sandberg WS, Zapol WM. eds. Anesthesiology, 3e New York, NY: McGraw- Hill. http://accessanesthesiology.mhmedical.com/content.aspx?bookid =2152&sectionid=164218385. Accessed July 23, 2017. Pollak, E. von Willebrand Disease Treatment & Management: Approach Considerations, Type I von Willebrand disease, Type 2 von Willebrand disease. [online] Emedicine.medscape.com. Available at: http://emedicine.medscape.com/article/206996-treatment#showall. Accessed 23 Jul. 2017. Thomas K. Bleeding Disorders. In: Hall JB, Schmidt GA, Kress JP. eds. Principles of Critical Care, 4e New York, NY: McGraw-Hill; 2014. http://accessanesthesiology.mhmedical.com/content.aspx?booki d=1340&sectionid=80036628. Accessed July 23, 2017.