Cleavage of von Willebrand Factor by Granzyme M Destroys Its Factor VIII Binding Capacity

Von Willebrand factor (VWF) is a pro-hemostatic multimeric plasma protein that promotes platelet aggregation and stabilizes coagulation factor VIII (FVIII) in plasma. The metalloproteinase ADAMTS13 regulates the platelet aggregation function of VWF via proteolysis. Severe deficiency of ADAMTS13 is associated with thrombotic thrombocytopenic purpura, but does not always correlate with its clinical course. Therefore, other proteases could also be important in regulating VWF activity. In the present study, we demonstrate that VWF is cleaved by the cytotoxic lymphocyte granule component granzyme M (GrM). GrM cleaved both denaturated and soluble plasma-derived VWF after Leu at position 276 in the D3 domain. GrM is unique in that it did not affect the multimeric size and pro-hemostatic platelet aggregation ability of VWF, but instead destroyed the binding of VWF to FVIII in vitro. In meningococcal sepsis patients, we found increased plasma GrM levels that positively correlated with an increased plasma VWF/FVIII ratio in vivo. We conclude that, next to its intracellular role in triggering apoptosis, GrM also exists extracellularly in plasma where it could play a physiological role in controlling blood coagulation by determining plasma FVIII levels via proteolytic processing of its carrier VWF

Comparison of the ICare (R) rebound tonometer with the Goldmann applanation tonometer by experienced and inexperienced tonometrists

© 2008 The Royal College of OphthalmologistsPurpose To assess the agreement between ICare® rebound tonometer and Goldmann applanation tonometer in the hands of experienced and inexperienced tonometrists. Patients and methods Two tonometrists, experienced with both Goldmann applanation tonometry (GAT) and ICare® Tonometry (ICT) measured intraocular pressure (IOP), in a masked fashion, in 100 patients. In another series of 58 patients, ICT was performed by an inexperienced tonometrist and GAT by an experienced tonometrist. Results In approximately 80% of patients, the difference in IOP between GAT and ICT was 2 mmHg in group 1 and 3 mmHg in group 2. The 95% limits of agreement were - 4.0–4.4 mmHg in group 1 and - 6.0–5.0 mmHg in group 2. Conclusion ICT compares reasonably with GAT, in both experienced and inexperienced hands. Its ease of use, portability, and sterility make it an attractive tonometer. Its degree of accuracy in inexperienced hands would make it a useful instrument for health care workers with limited ophthalmic experienceL M Abraham, N C R Epasinghe, D Selva and R Casso