The results of studies with cultured endothelial cells have shown that most von Willebrand factor (vWF) synthesized is directly secreted (constitutive pathway) and consists of both mature vWF, its precursor molecule pro-vWF, and the cleaved vWF prosequence. Only fully processed, functionally mature vWF is stored within the cell, together with the propeptide, and leaves the cell only on stimulation (regulated secretion). Both in resting and stimulated cultured endothelial cells, the stoichiometry of the released propeptide to the released mature vWF is essentially equimolar. In the present study, we have measured the molar ratio of propeptide to mature vWF in vivo, both under resting conditions and conditions that reflect activation of the endothelium. To this end, we devised a method that allows the measurement of the propeptide (vW antigen II) on a quantitative, is, molar basis, using purified recombinant propeptide as a standard. Our results show that the molar concentration of the propeptide in normal plasma is about one tenth of the concentration of mature vWF (expressed as half-dimer concentration). This ratio is approximately 1:1 in the medium of cultured endothelial cells. On administration in healthy subjects of either 1-deamino-8-D-arginine vasopressin or endotoxin, both agents being known to elicit an intravascular increase of vWF, the molar ratio of propeptide to mature vWF increased fourfold to fivefold. The propeptide concentration returned to baseline values after about 6 to 7 hours of injection of each stimulus, whereas the increase of mature vWF was much more sustained. Because the respective half-lives of mature vWF and its propeptide clearly differ, measurement of the concentration of these proteins could provide a means to assess the extent of activation of the endothelium under physiological and pathophysiological conditions.
The efficacy and safety of thrombopoietin-receptor agonists (TRAs) in elderly patients with primary immune thrombocytopenia (ITP) is uncertain. In 384 ITP patients treated with TRAs when aged ≥60 years, we investigated TRAs response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROT). After 3 months, 82.5% and 74.3% of eltrombopag and romiplostim-treated patients achieved a response, respectively (p=0.09); 66.7% maintained the response (median follow-up: 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; while no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. During TRA, 34 major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, and were associated with thrombosis history (SHR: 2.04, p=0.05) and platelet count <20x109/L at TRA start (SHR: 1.69, p=0.04), respectively. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but one during persisting TRA treatment (incidence rate: 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRA; 53 (13.8%) patients maintained SROT, which was associated with TRA discontinuation in complete response (p<0.001). Very old age (≥75, 41.1%) was associated with more frequent TRAs start in persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in elderly ITP patients, with no fatal haemorrhages and with SROT in a significant portion of patients; in patients with thrombosis history caution is warranted and a careful risk/benefit balance should be carried out.
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