Guidelines for the Evaluation of Intravenous Desmopressin and von Willebrand Factor/Factor VIII Concentrate in the Treatment and Prophylaxis of Bleedings in von Willebrand Disease Types 1, 2, and 3

Abstract

The current standard for the diagnosis and management of patients with congenital von Willebrand disease (vWD) includes bleeding times (BTs), PFA-100 closure time (PFA-CT), factor (F) VIII:coagulant activity (C), vWF:antigen (Ag), vWF:ristocetin cofactor activity (RCo), a sensitive vWF:collagen-binding activity (CB), ristocetin-induced platelet aggregation (RIPA), analysis of vWF multimers in low- and high-resolution agarose gels, and the response to desmopressin. Guidelines and recommendations for prophylaxis and treatment of bleedings in vWD patients with vWF/FVIII concentrates should be derived from analysis of the content of these concentrates and from pharmacokinetic studies in different types of vWD patients with severe type 1, 2, or 3 vWD. The vWF/FVIII concentrates should be characterized by labeling with FVIII:C, vWF:RCo, vWF:CB, and vWF multimeric pattern, which will determine their predicted efficacy and safety in prospective management studies. Because the bleeding tendency is moderate in type 2 and severe in type 3 vWD, and because the FVIII:C levels are subnormal in type 2 and very low in type 3 vWD patients, new guidelines using vWF:RCo unit dosing for the prophylaxis and treatment of bleeding episodes are proposed. Such guidelines should be stratified for the severity of bleeding, the type of surgery (either minor or major), and also for the severity and type of vWD (i.e., either type 2 or 3 vWD).

Dominant von Willebrand Disease Type 2A Groups I and II due to Missense Mutations in the A2 Domain of the von Willebrand Factor Gene: Diagnosis and Management

“…The in vivo responses of VWF parameters to VWF-FVIII concentrates have to be evaluated according to standardized recommendations proposed by the Scientific Standardization Committee of the International Society on Thrombosis and Hemostasis for studies on ex vivo biological effects of virus-inactivated concentrates in VWD patients [20,21,22]. Infusion of FVIII/VWF concentrate using both FVIII:C and VWF:RCo dosing (in IU/kg body weight, BW) for the treatment of spontaneous bleeding or bleeding prophylaxis during surgery has to be evaluated prospectively in every VWD patient for recovery after the first loading dose during daytime, evening, night and at the weekend by the responsible hematologist in the hospital (table 2).…”

“…7, right). This prompted us to adapt the recommendations for VWD patients using VWF:RCo dosing with the compelling need for prospective evaluation studies according to a standardized protocol (table 3) [4, 21, 22]. …”

“…These and other observations prompted us to propose adjusted guidelines using VWF:RCo dosing based on a previously published prospective study [20,21,22] (table 3). Our studies showed that a loading dose of Haemate-P completely corrected both VWF:RCo and VWF:CB levels and strongly prolonged Ivy BT to normal values for ≥12 h in mild and pronounced VWD type 2A, but for ∼6–8 h in severe VWD 2A with absent RIPA.…”

“…We have introduced adjusted recommendations to dose FVIII/VWF concentrates in international units of VWF:RCo per kilogram BW for the acute and prophylactic treatment of bleeding in VWD type 2 and extended it to recessive VWD type 1 and type 3 (table 3) [18]. The adjusted recommendations are to be tailored to the patient regarding the severity of bleeding complications, the severity of VWD, the type of surgery (minor or major) and the type of VWD (type 2 or 3; table 2) [4,20,21,22]. Such recommendations have to be confirmed regarding safety and cost-effectiveness in prospective studies and are to be amended if necessary to improve the management of VWD patients [24, 25].…”

Managing Patients with von Willebrand Disease Type 1, 2 and 3 with Desmopressin and von Willebrand Factor-Factor VIII Concentrate in Surgical Settings

“…DDAVP can be used to treat major bleeds or to prevent bleeding in connection with surgery or other invasive procedures, if VWF:ristocetin cofactor activity (RCo) and FVIII:coagulant activity (C) reach normal levels after DDAVP. If response is lower or the duration is short, a VWF/FVIII concentrate should be considered [8,9,10,11,12,13,14,15,16]. …”