Extravascular Binding of Coagulation Factor IX Gives Hemostasis a Boost

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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 (rFIXK5A) while the exchange to arginine (rFIXK5R) conveyed increased interactions compared with recombinant wild-type FIX (rFIXWT).[2] Using pharmacokinetic (PK) analysis in hemophilia B mice in vivo, Machado et al[3] demonstrate in this issue that the elimination of rFIXK5A is considerably slower than that of rFIXWT or rFIXK5R. The accelerated elimination of rFIXK5R and rFIXWT from the vascular compartment was attributed to a speedy redistribution into the extravascular compartment where rFIXK5R produced a prolonged positivity for FIX antigen. Increased deposition of rFIXK5R in the extracellular matrix correlated with reduced bleeding of hemophilia B mice for up to 7 days. In contrast, the rFIXK5A, which has essentially the same PK profile as rFIXK5R and rFIXWT 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

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