TREATMENT OF VON WILLEBRANDS DISEASE

DR SANA BUSHRA

Introduction
Inherited bleeding disorder First described by Finnish paediatrician Erik von willebrand in 1926 There is quantitative deficiency or dysfunction of von Willebrand factor Essential for platelet plug formation

Classification
Three main phenotypes Type 1 autosomal dominant accounts for 60 to 80% cases and has mild to moderate quantitative deficiency of von Willebrand factor Type 2 ,10 to 30%of cases has qualitative abnormality of vWF with sub types 2A,2B,2M,2N Type 3 is autosomal recessive 1 to 5% cases with very low or undetectable levels

Laboratory Diagnosis
Four simple tests a) bleeding time b) levels of factor Vlll c) von Willebrand factor antigen d) ristocetin cofactor activity Activated partial thromboplastin time and prothrombin time do not rule von Willebrands disease and bleeding time is neither specific nor sensitive

General principles of management

Main stay of treatment replacement of deficient protein at the time of spontaneous bleeding or before invasive procedures Prophylaxis is given in type 3 patients who have recurrent hemorrhages in joints or gastrointestinal bleeding

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Mainstay of therapy are desmopressin , which induces secretion of autologous factorVlll and von Willebrand factor into plasma Plasma concentrates Adjuvant therapy Fibrinolysis inhibitors Platelet concentrates Oral estrogen progestogen preparations

Desmopressin
Desmopressin is a synthetic derivative of antidiuretic hormone Increases vWF through cyclic adenosine mononphosphate signaling and mediates secretion from Weibel-Palade bodies in endothelial cells into plasma Has low cost and unlimited availability

Dosage
Dose is 0.3ug per kg by continuous intravenous infusion for 30 minutes Factor Vlll and vWF levels increase by three to five times within 30 to 60 minutes Also available for subcutaneous injection 0.3ug/kg Nasal inhalation 150ug in children Oral administration not recommended

Clinical efficacy
Test dose should be given by same dose to determine individual pattern of response Patients with type 1 vWF are more responsive to desmopressin Contraindicated in type 2B because of occurrence of transient thromocytopenia Type 3 patients do not have a response to desmopressin

Adverse effects
Tachycardia Headache Facial flushing Hyponatremia Seizures due to water intoxication

Allogeneic replacement therapy

Fresh frozen plasma contains both factorVlll and von Willebrand factor Volume over load may occur due to large amounts that are needed to attain hemotasis Humate-p and Alphanate are commercial concentrates Products containing highly purified factor Vlll that are obtained by recombinant DNA technique or from plasma should not be used because they lack von Willebrand factor

Average recommended dosages of factor Vlll and von Willebrand factor

Type of hemorrhage Major surgery Minor surgery Dental extraction Spontaneous bleeding episode Delivery and puerperium Dose (IU/kg) 50 40 30 25 40 Frequency of infusions daily Daily or every other day Single dose daily Daily before delivery and in the postpartum period

Antifibrinolytic Amino acids

Epistaxis and menorrhagia are sustained in part by rich fibrinolytic activity of mucosal tracts. Local fibrinolytic activity in the buccal mucosa and gums also compromises hemostasis during dental extractions Aminocaproic acid 50 to 60mg/kg every 4 to 6 hours Tranexamic acid 10 to 15 mg/kg every 8 to 12 hours

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Antifibrinolytic amino acids are contraindicated in patients with gross hematuria because clots that donot lyse may cause ureteral obstruction

Reproductive health
Menorrhagia is a frequent symptom in women with von Willebrand s disease Fertility is not impaired In women with type 3 disease oral estrogen progestogen preparations have a success rate as high as 88% These drugs render the endometrium less susceptible to bleeding

Management of delivery
In women with type 1 disease factor Vlll and von Willebrand factor levels tend to rise spontaneously throughout pregnancy and often reach normal levels at term Risk of bleeding is minimal when plasma factor Vlll levels are at least 30 to 40% of normal levels If levels are lower it is necessary to administer desmopressin or concentrates at the time of delivery and for three to four days thereafter

Alloantibodies
Alloantibodies develop in 10 to 15 % of patients with type 3 disease who have received multiple transfusions Concentrates having von Willebrand factor are contraindicated in such cases as life threatening anaphylactic reactions can occur Recombinant factor Vlll may be used

Summary of recommended treatment according to phenotypes

Type 1 2A Treatment of choice desmopressin Factor Vlll-von Willebrand factor concentrates

2B
2M 2N 3 in patients without alloanibodies In patients with alloantibodies

Factor Vlll-von Willebrand factor concentrates

Factor Vlll- von Willebrand factor concentrates Factor Vlll-von Willebrand factor concentrates Factor Vlll von Willebrand factor concentrates Recombinant factor Vlll

Acquired Von Willebrand syndrome

Rare in association with lymphoproliferative and autoimmune diseases, essential thrombocythemia, cancer and valvular heart disease Treatment is removal of underlying cause

Take home message

Desmopressin and plasma concentrates are effective in controlling bleeding in most cases It is hoped that von Willebrand factor that is produced by recombinant DNA techniques will soon undergo clinical trials and become available for replacement therapy

Thank you