von Willebrand factor/factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery.

BACKGROUND: While plasma-derived concentrates containing large amounts of von Willebrand factor (VWF) are effective in treating von Willebrand disease (VWD), optimal dosing remains to be fully characterized. OBJECTIVES: To determine the feasibility of dosing Haemate P VWF/factor VIII (FVIII) concentrate based on pharmacokinetics (PK) in the management of surgical subjects with VWD. METHODS: VWD subjects scheduled for elective surgery were enrolled in a prospective multicenter open-label cohort study. A pre-operative loading dose of VWF/FVIII concentrate based upon prior individual subject PK analysis was administered followed by postoperative therapeutic/maintenance infusions. RESULTS: Twenty-eight subjects with types 1, 2A or 3 VWD and one with type 2 M were enrolled. Median in vivo recovery of VWF ristocetin cofactor (VWF:RCo) was 1.9 IU dL(-1) (IU kg(-1))(-1) with an interquartile range (IQR) of 1.6-2.5 IU dL(-1) (IU kg(-1))(-1). Median response, half-life and clearance were 74.0% (IQR, 55.5-100%), 15.6 h (IQR, 9.0-28.4 h) and 3.26 mL kg(-1) h(-1) (IQR, 2.29-5.21 mL kg(-1) h(-1)), respectively. A PK-guided median VWF:RCo loading dose of 62.4 IU kg(-1) (IQR, 50.1-87.0 IU kg(-1)) was administered. Postoperative mean trough VWF:RCo levels of 62-73 IU dL(-1) were sufficient to prevent bleeding. Investigators rated hemostasis excellent or good in 96.3% of subjects on the day of surgery and 100% on the next day and on day 14. A subject with multiple risk factors developed pulmonary embolism, which resolved without sequelae. CONCLUSIONS: Haemate P provided effective and safe hemostasis in VWD subjects undergoing elective surgery. Selection of Haemate P loading dose on the basis of VWF PK proved feasible.

Importance of MHC class 1 alpha2 and alpha3 domains in the recognition of self and non-self MHC molecules.

The importance of the species of different domains of class I MHC molecules in peripheral T cell recognition and positive and negative selection was evaluated in a single system. In transgenic mice expressing AAD (containing the alpha1+alpha2 domains of HLA-A2.1 and the alpha3 domain of H-2Dd), the CTL response to influenza peptide M1(58-66) in the context of the alpha1+alpha2 domains of HLA-A2.1 was as strong as the influenza-specific H-2Db-restricted response. However, this strong response was only discernible if the target cell MHC molecule also contained a murine alpha3 domain. In contrast, the response in HLA-A2.1 transgenic mice was about 30-fold weaker, and these CTL were indifferent to the origin of the target molecule alpha3 domain. Further analysis suggested that the major impact of the murine alpha3 domain of the transgene product was to enhance positive selection of a low affinity population of AAD-restricted T cells, presumably through species-specific interaction with CD8. Surprisingly, the response to non-self human class I MHC determinants was not augmented in AAD mice, indicating that the T cells selected are narrowly focused on AAD-related structures. Further analysis indicated that the alphal+alpha2 domains as well as the alpha3 domain influenced the magnitude of the response to non-self human class I MHC determinants, and this effect was mapped to alpha2. We suggest that the alpha2 domains of murine class I molecules contain conserved structural elements that augment the avidity of T cell-class I interactions, and this is particularly important in the recognition of non-self MHC molecules.