Extravascular Binding of Coagulation Factor IX Gives Hemostasis a Boost

Hemophilia B is caused by a hereditary deficit of functional coagulation factor IX (FIX), which in its severe manifestation can be associated with spontaneous, debilitating bleeding episodes. Treatment of patients with severe hemophilia B has dramatically improved with the advent of extended half-life FIX concentrates. However, since these products are geared toward prolonged residence inside the vasculature, questions have been raised about the role of the extravascular compartment as a reservoir of FIX. Distribution of FIX into the extravascular compartment, which has been estimated to account for as much as 75% of total FIX, depends on specific residues in the γ-carboxyglutamic (Gla) domain of FIX.[1] Consequently, interactions of FIX with endothelial cells and the extravascular compartment were significantly reduced after exchanging residue 5 of the FXI Gla domain from lysine to alanine (rFIX_K5A) while the exchange to arginine (rFIX_K5R) conveyed increased interactions compared with recombinant wild-type FIX (rFIX_WT).[2] Using pharmacokinetic (PK) analysis in hemophilia B mice in vivo, Machado et al[3] demonstrate in this issue that the elimination of rFIX_K5A is considerably slower than that of rFIX_WT or rFIX_K5R. The accelerated elimination of rFIX_K5R and rFIX_WT from the vascular compartment was attributed to a speedy redistribution into the extravascular compartment where rFIX_K5R produced a prolonged positivity for FIX antigen. Increased deposition of rFIX_K5R in the extracellular matrix correlated with reduced bleeding of hemophilia B mice for up to 7 days. In contrast, the rFIX_K5A, which has essentially the same PK profile as rFIX_K5R and rFIX_WT in vitro, induced clotting in hemophilia B mice in vivo efficiently during early time points but efficacy began to fade after 24 hours when the activity of intravascular FIX was at or below the detection limit. Together, Machado et al demonstrate with their meticulous work that manipulating the interactions of FIX with endothelial cells and the connective tissue has important implications for the function of FIX and subsequent clotting. Open questions remain with regard to delineating the extravascular clotting activity of FIX and the underlying mechanism.

Publication History

Received: 28 February 2023

Accepted: 28 March 2023

Accepted Manuscript online:
03 April 2023

Article published online:
24 May 2023

• References

• 1 Feng D, Stafford KA, Broze GJ, Stafford DW. Evidence of clinically significant extravascular stores of factor IX. J Thromb Haemost 2013; 11 (12) 2176-2178
• 2 Cheung WF, Hamaguchi N, Smith KJ, Stafford DW. The binding of human factor IX to endothelial cells is mediated by residues 3-11. J Biol Chem 1992; 267 (29) 20529-20531
• 3 Machado SK, Peil H, Kraushaar T. et al. Modulation of Extravascular binding of recombinant factor IX impacts duration of efficacy in mouse models. Thromb Haemost 2023; 123 (08) 751-762