Comparative Analysis and Classification of von Willebrand Factor/Factor VIII Concentrates: Impact on Treatment of Patients with von Willebrand Disease

Abstract

von Willebrand disease (vWD) is a bleeding disorder that results from defects in the quality or quantity of von Willebrand factor (vWF), a glycoprotein essential for normal thrombus formation. vWF circulates in plasma as multimers in sizes ranging up to 20,000 kd. The high molecular weight vWF (HMWvWF) multimers are most essential for primary hemostasis, whereas the lower molecular weight multimers are less functionally active. For many patients, the treatment of choice is factor replacement with a vWF/FVIII concentrate, preferably one with a high content of HMWvWF multimers. Given that the commercially available vWF/FVIII concentrates seem to differ substantially in their biochemical properties as well as in their clinical efficacy, we did a comparative study with 12 vWF/FVIII concentrates to investigate content and activities of FVIII and vWF, as well as the content of HMWvWF multimers. The content of HMWvWF multimers varied considerably among the 12 concentrates. The specific vWF activities, as assessed by ristocetin cofactor activity (vWF:RCo) and collagen-binding activity (vWF:CB), correlated well with the HMWvWF content of the products. Of the products tested, Haemate P/Humate-P had the highest content of HMWvWF multimers (with a multimer pattern closest to that of normal human plasma), the highest specific vWF activities, and the highest values of vWF:RCo and vWF:CB per unit of FVIII:coagulant (C). The goal of bleeding prophylaxis and treatment in type 2, severe type 1, and type 3 vWD patients is to normalize vWF activities (vWF:RCo and vWF:CB) and FVIII:C preferentially by vWF/FVIII concentrates containing the high vWF multimers and a high vWF:RCo/FVIII ratio to achieve normal primary and secondary hemostasis. Based on the present study of a comparative analysis of currently available vWF/FVIII concentrates, a classification of vWF/FVIII products is proposed.

Increased von Willebrand factor antigen and high molecular weight multimers in sickle cell disease associated with nocturnal hypoxemia

“…Our novel clinical data, taken together with previously published experimental evidence, suggest a possible pathophysiological role for vWF: i.e. the increased presence of the more functionally active HMW-vWF multimers [5] with potential pro-coagulant and pro-adhesive effects. They thus provide a basis for further examination of hypoxemia-driven vWF-mediated pathophysiology in SCD.…”

“…In vitro studies have shown that hypoxia is a strong agonist for endothelial release of von Willebrand factor (vWF) [3] including ultra large vWF (ULvWF) multimers [4]. vWF is a large multimeric glycoprotein critical for normal platelet function in primary hemostasis, its high molecular weight (HMW-vWF) multimers being the most hemostatically active subunits [5]. Sparse information is available regarding the relationship between vWF and clinical hypoxemia.…”

Hemostatic efficacy, safety, and pharmacokinetics of a recombinant von Willebrand factor in severe von Willebrand disease

“…14,15 Plasma-derived VWF/FVIII products also vary in composition depending on the source plasma and the manufacturing process. [16][17][18][19] This variability could lead to excessive FVIII levels in VWD patients, with inherent risk of venous thromboembolism. Furthermore, these concentrates show variable deficiency of ultralarge multimers (ULM) of VWF due to proteolysis.…”

“…18 Plasmaderived VWF concentrates variably lack ULM due to in vivo exposure to plasma ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13) and proteolytic cleavage by granulocyte elastases. [16][17][18][19] In contrast to VWF concentrates derived from plasma, rVWF has no exposure to the human protease ADAMTS13 during the production process and therefore contains intact HMWM and ULM. 22 The presence of ULM and the higher purity also contribute to a greater specific activity of rVWF measured as VWF:ristocetin cofactor activity (VWF:RCo) relative to VWF:antigen (VWF:Ag).…”

von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy

“…All but one of these products represent plasma-derived VWF-FVIII concentrates with various VWF:FVIII ratios and multimer profiles that show minor differences. 51 In the studies that have been published relating to the clinical efficacy and safety of these products, they all appear to provide satisfactory hemostasis and are not accompanied by serious adverse events. The use of VWF concentrates with very low FVIII content should be accompanied by the coinfusion of recombinant FVIII to enhance the treatment of acute bleeding episodes and to optimize surgical hemostasis.…”