Importance of Pharmacokinetics in the Treatment of von Willebrand Disease

Abstract

von Willebrand disease (vWD) and haemophilia A are the most frequent bleeding disorders in the general population, occurring in 66-100 people per million worldwide. 1 vWD is caused by both qualitative and quantitative defects in von Willebrand factor (vWF) resulting in a dual defect in haemostasis, i.e. the abnormal platelet adhesion due to reduced and/or dysfunctional vWF (primary haemostasis) and the abnormal coagulation due to low levels of factor VIII (FVIII) (secondary haemostasis).vWF serves as a bridge between platelets and subendothelium and is essential for the cohesion of platelets. Thus, vWF has a primary function in the formation of thrombi in blood coagulation. In addition, vWF binds to circulating FVIII and acts as a chaperone, protecting FVIII from proteolytic degradation. In the absence of or after a decrease in vWF, the half-life of FVIII in the circulation is reduced significantly. 2 However, the absence of vWF does not affect FVIII synthesis. Classification of von Willebrand DiseaseSince vWD is caused by both qualitative and quantitative mutations in vWF, the disease is classified according to the degree of qualitative and quantitative involvement (see Table 1). 3 Patients with type 1 vWD present with a decrease in the production of vWF and most remain mildly symptomatic. Type 2 vWD is the result of a vWF-dependent platelet function. 4,5 Type 3 vWD is the least common subtype and results from absent or profound reductions in plasma vWF and the absence of vWF in platelets and endothelial cells. In general, type 3 vWD is diagnosed in the first year of life due to severe and sometimes life-threatening bleeds. Managing von Willebrand DiseaseThe treatment options for vWD are dependent on the subtype of the disease.The main goal of treatment is to normalise the levels of both vWF and FVIII to achieve haemostasis. 6 Demopressin (DDAVP) is the gold standard for the treatment of type 1 vWD. DDAVP induces the release of endogenous vWF and helps to correct vWF/FVIII levels in the majority of these patients.However, DDAVP is not effective in type 3 vWD or in severe forms of types 1 and 2 vWD. Also, DDAVP is not recommended in patients with type 2A vWD because any increase in vWF is dysfunctional. 7 In patients with type 2B vWD, DDAVP can induce transient thrombocytopenia, thus it is generally contraindicated. 8 In patients in whom DDAVP either is not effective or is contraindicated, the current treatment option of choice is transfusional therapy with virally inactivated plasma-derived FVIII/vWF concentrates. Since the 1980s, plasma-derived FVIII/vWF concentrates have been used successfully to treat types 3 and 2B vWD patients and types 1 and 2 patients who are unresponsive to DDAVP. 9 Currently, recombinant-concentratecontaining vWF is unavailable, and the majority of products are intermediatepurity plasma-derived FVIII concentrates containing vWF. Approved in 1981, Haemate P has become the most widely used concentrate in vWD. 9 Haemate P has demonstrated a good safety record in clinical practice. [10][11...