Histidine-rich glycoprotein attenuates catheter thrombosis

Abstract

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.

Histidine-Rich Glycoprotein Modulates the Toxic Effects of High-Dose Polyphosphate in Mice

“…25 Second, HRG binds FXIIa (activated FXII) and attenuates its capacity to promote autoactivation and to activate FXI. [25][26][27] The relative importance of these 2 mechanisms is uncertain.…”

Histidine-rich glycoprotein: antithrombosis without bleeding

“…In this issue of Blood Advances , Malik et al have shown that plasma concentrations of histidine-rich glycoprotein (HRG) modulate factor XIIa (FXIIa) activity and, in turn, catheter thrombosis. 1 This observation suggests that high concentrations of HRG may reduce contact activation and, thus, thrombosis. These studies may be the first step toward characterizing and translating a target that reduces thrombosis risk without affecting hemostasis.…”

“…This background set the stage for the investigations of this article. 1 In these studies, Malik et al questioned whether HRG depletion would promote catheter thrombosis. It is generally agreed that FXII is the major promoter of catheter thrombosis because its knockdown attenuates it.…”