von Willebrand factor: evidence for variable clearance in vivo according to Y/C1584 phenotype and ABO blood group.

BACKGROUND: The plasma von Willebrand factor (VWF) level (VWF:Ag) is known to correlate with the VWF Y/C1584 variation and with ABO blood group. The ratio of the VWF propeptide (VWFpp) to VWF:Ag and the ratio of coagulation factor VIII (FVIII:C) to VWF:Ag have previously been used as indicators of VWF clearance and/or secretion. OBJECTIVES AND METHODS: To investigate the mechanism underlying the relationship between VWF phenotype and VWF:Ag, the VWFpp/VWF:Ag ratio and FVIII:C/VWF:Ag ratio were determined for plasmas of phenotype Y/C1584, Y/Y1584, blood group O and blood group A (n = 50 for each set). The blood group O plasmas comprised two sets of 25 with low and high mean VWF levels (Low-O and High-O), respectively; similarly for group A (Low-A and High-A). RESULTS AND CONCLUSIONS: The VWFpp/VWF:Ag ratio was greater than 1 (unity) for Y/C1584 plasmas and significantly higher than for Y/Y1584 plasmas; however, the FVIII:C/VWF:Ag ratio was near unity for both and was not significantly different. These results are consistent with increased clearance for Y/C1584 VWF. Similarly, the VWFpp/VWF:Ag ratio and FVIII:C/VWF:Ag ratio in combination were consistent with increased VWF clearance in blood group O compared with blood group A, and in Low-O and Low-A, respectively, compared with High-O and High-A. The data indicate that in vivo C1584 and blood group O are associated with increased VWF clearance, and that clearance contributes to differing VWF level within a given blood group.

Measurement of global haemostasis in severe haemophilia A following factor VIII infusion.

Patients with haemophilia requires different amounts of FVIII to prevent and treat bleeds. We hypothesise that this is because FVIII has variable effects on individual patients' global haemostasis. Twelve patients with severe haemophilia A were infused with 50 IU/kg FVIII and thrombin generation in platelet rich (PRP) and platelet poor plasma (PPP) and velocity of changing clot elasticity were measured preinfusion and at nine subsequent time points over 72 h. Despite a close correlation between median FVIII and median initial rate of thrombin generation (R(2) 0.94), endogenous thrombin potential (ETP; R(2) 0.94) and peak thrombin (R(2) 0.91) in PPP, there was wide inter-patient variability at each time point. There was, however, a highly predictable intra-patient relationship between FVIII level and thrombin generation. Inter-patient variability was due to both differences in FVIII levels and the variable effect FVIII had on an individuals' thrombin generation. The utility of PRP was limited because, at low-FVIII levels, only rate of thrombin generation was measurable. At low-FVIII concentrations, the rate of thrombin generation in PPP was the most useful test whilst at higher levels ETP and peak thrombin could also be used.