The factor VIII/von Willebrand factor complex: basic and clinical issues

Factor VIIII (FVIII) and von Willebrand factor (VWF) are two distinct but related glycoproteins that circulate in plasma as a tightly bound complex (FVIII/VWF). Their deficiencies or structural defects are responsible for the most common inherited bleeding disorders, namely hemophilia A (HA) and von Willebrand's disease (VWD). The VWF has a dual role in hemostasis: first it promotes platelet adhesion to thrombogenic surfaces as well as platelet-to-platelet cohesion during thrombus formation; second, it is the carrier for FVIII in plasma. FVIII acts as a co-factor to accelerate the activation of factor X by activated factor IX in the coagulation cascade. After many years of investigations, the molecular mechanisms of FVIII/VWF interactions are now well known and recent biochemical investigations have confirmed that VWF is a key partner for FVIII, playing significant roles in FVIII function, its production and its stabilization, in its conformation and immunogenicity. FVIII and VWF are both present in most plasma-derived FVIII/VWF concentrates used in clinical practice. FVIII/VWF concentrates can be classified into three main categories according to the degree of their purification. Intermediate-high purity plasma-derived concentrates containing FVIII/VWF currently in use since 1987 carry a low risk of transmitting blood-borne infections. Concentrate safety depends on the interaction of two factors: the decrease of viral plasma load and the increase of viral inactivation. These FVIII/VWF concentrates are currently used in type 3 VWD and in type 1 or 2 VWD patients who are unresponsive to desmopressin (DDAVP). More recently the presence of the physiologic FVIII/VWF complex has been considered to play an important role also in replacement therapy for patients with HA. The correct use of FVIII/VWF concentrates in VWD and HA have been reported in several national and international guidelines.