Histidine-rich glycoprotein attenuates catheter thrombosis.

Factor (F) XII knockdown attenuates catheter thrombosis in rabbits. Because histidine-rich glycoprotein (HRG) modulates FXIIa activity, we hypothesized that HRG depletion would promote catheter thrombosis. To test this, rabbits were given antisense oligonucleotides (ASOs) against HRG, FXII, or a control ASO or saline. The activated partial thromboplastin time (aPTT), prothrombin time (PT), and catheter-induced thrombin generation were determined in blood collected before and after treatment. Compared with the controls, the HRG- and FXII-directed ASOs reduced hepatic mRNA and plasma levels of HRG and FXII, respectively, by over 90%. Whereas HRG knockdown shortened the aPTT by 2.5-fold, FXII knockdown prolonged it by 4-fold; neither ASOs affected the PT. Catheter segments shortened the lag time and increased peak thrombin in plasma from control rabbits; effects significantly enhanced and attenuated in plasma from rabbits given the HRG- and FXII-directed ASOs, respectively. Catheters were then inserted into the right external jugular vein of the rabbits and the time for catheter occlusion was determined. The catheter occlusion times with the control ASO or saline were 62 ± 8 and 60 ± 11 min, respectively. The occlusion time was significantly reduced to 34 ± 9 min with HRG knockdown and significantly prolonged to 128 ± 19 min with FXII knockdown. HRG levels are decreased with sepsis or cancer and such patients are prone to catheter thrombosis. Because HRG modulates catheter thrombosis, our findings suggest that HRG supplementation may prevent this problem.