TREATMENT OF VON WILLEBRANDS DISEASE

TREATMENT OF VON WILLEBRANDS DISEASEThe New England Journal of MedicineIntroductionInherited bleeding disorderFirst described by Finnish paediatrician Erik von willebrand in 1926There is quantitative deficiency or dysfunction of von Willebrand diseaseEssential for platelet plug formation

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

Laboratory DiagnosisFour simple testsa) bleeding timeb) levels of factor Vlllc) von Willebrand factor antigend) ristocetin cofactor activityActivated partial thromboplastin time and prothrombin time do not rule von Willebrands disease and bleeding time is neither specific nor sensitive

General principles of managementMain stay of treatment replacement of deficient protein at the time of spontaneous bleeding or before invasive proceduresProphylaxis is given in type 3 patients who have recurrent hemorrhages in joints or gastrointestinal bleeding

continuedMainstay of therapy are desmopressin , which induces secretion of autologous factorVlll and von Willebrand factor into plasmaPlasma concentrates Adjuvant therapyFibrinolysis inhibitorsPlatelet concentratesOral estrogen progestogen preparationsDesmopressinDesmopressin is a synthetic derivative of antidiuretic hormoneIncreases vWF through cyclic adenosine mononphosphate signaling and mediates secretion from Weibel-Palade bodies in endothelial cells into plasmaHas low cost and unlimited availabilityDosageDose is 0.3ug per kg by continuous intravenous infusion for 30 minutesFactor Vlll and vWF levels increase by three to five times within 30 to 60 minutesAlso available for subcutaneous injection 0.3ug/kgNasal inhalation 150ug in childrenOral administration not recommended

Clinical efficacyTest dose should be given by same dose to determine individual pattern of responsePatients with type 1 vWF are more responsive to desmopressinContraindicated in type 2B because of occurrence of transient thromocytopeniaType 3 patients do not have a response to desmopressinAdverse effectsTachycardiaHeadacheFacial flushingHyponatremiaSeizures due to water intoxicationAllogeneic replacement therapyFresh frozen plasma contains both factorVlll and von Willebrand factorVolume over load may occur due to large amounts that are needed to attain hemotasisHumate-p and Alphanate are commercial concentratesProducts containing highly purified factor Vlll that are obtained by recombinant DNA technique or from plasma should not be used because they lack von Willebrand factorAverage recommended dosages of factor Vlll and von Willebrand factorType of hemorrhageDose (IU/kg)Frequency of infusionsMajor surgery50dailyMinor surgery40Daily or every other dayDental extraction30Single doseSpontaneous bleeding episode25dailyDelivery and puerperium40Daily before delivery and in the postpartum periodAntifibrinolytic Amino acidsEpistaxis 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 extractionsAminocaproic acid 50 to 60mg/kg every 4 to 6 hoursTranexamic acid 10 to 15 mg/kg every 8 to 12 hours

continuedAntifibrinolytic amino acids are contraindicated in patients with gross hematuria because clots that donot lyse may cause ureteral obstructionReproductive healthMenorrhagia is a frequent symptom in women with von Willebrand s diseaseFertility is not impairedIn 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 bleedingManagement of deliveryIn women with type 1 disease factor Vlll and von Willebrand factor levels tend to rise spontaneously throughout pregnancy and often reach normal levels at termRisk of bleeding is minimal when plasma factor Vlll levels are at least 30 to 40% of normal levelsIf levels are lower it is necessary to administer desmopressin or concentrates at the time of delivery and for three to four days thereafterAlloantibodiesAlloantibodies develop in 10 to 15 % of patients with type 3 disease who have received multiple transfusionsConcentrates having von Willebrand factor are contraindicated in such cases as life threatening anaphylactic reactions can occur Recombinant factor Vlll may be usedSummary of recommended treatment according to phenotypesType Treatment of choice1desmopressin2AFactor Vlll-von Willebrand factor concentrates2BFactor Vlll-von Willebrand factor concentrates2MFactor Vlll- von Willebrand factor concentrates2NFactor Vlll-von Willebrand factor concentrates3 in patients without alloanibodiesFactor Vlll von Willebrand factor concentratesIn patients with alloantibodiesRecombinant factor VlllAcquired Von Willebrand syndromeRare in association with lymphoproliferative and autoimmune diseases, essential thrombocythemia, cancer and valvular heart diseaseTreatment is removal of underlying causeTake home messageDesmopressin and plasma concentrates are effective in controlling bleeding in most casesIt is hoped that von Willebrand factor that is produced by recombinant DNA techniques will soon undergo clinical trials and become available for replacement therapy