Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 May;27(3):332-339.
doi: 10.1111/hae.14300. Epub 2021 Mar 29.

The Function of extravascular coagulation factor IX in haemostasis

David M Mann  1 , Katherine A Stafford  2 , Man-Chiu Poon  3 , Davide Matino  4 , Darrel W Stafford  5
Affiliations
Review

The Function of extravascular coagulation factor IX in haemostasis

David M Mann et al. Haemophilia. 2021 May.

Abstract

Introduction: The majority of clotting factor IX (FIX) resides extravascularly, in the subendothelial basement membrane, where it is important for haemostasis.

Aim: We summarize preclinical studies demonstrating extravascular FIX and its role in haemostasis and discuss clinical observations supporting this. We compare the in vivo binding of BeneFIX® and the extended half-life FIX, Alprolix® , to extravascular type IV collagen (Col4).

Methods: Three mouse models of haemophilia were used: the FIX knockout as the CRM- model and two knock-in mice, representing a CRM+ model of a commonly occurring patient mutation (FIXR333Q ) or a mutation that binds poorly to Col4 (FIXK5A ). The murine saphenous vein bleeding model was used to assess haemostatic competency. Clinical publications were reviewed for relevance to extravascular FIX.

Results: CRM status affects recovery and prophylactic efficacy. Prophylactic protection decreases ~5X faster in CRM+ animals. Extravascular haemostasis can explain unexpected breakthrough bleeding in patients treated with some EHL-FIX therapeutics. In mice, both Alprolix® and BeneFIX® bind Col4 with similar affinities (Kd~20-40 nM) and show dose-dependent recoveries. As expected, the concentration of binding sites in the mouse calculated for Alprolix® (574 nM) was greater than for BeneFIX® (405 nM), due to Alprolix® binding to both Col4 and the endothelial cell neonatal Fc receptor.

Conclusion: Preclinical and clinical results support the interpretation that FIX plays a role in haemostasis from its extravascular location. We believe that knowing the CRM status of haemophilia B patients is important for optimizing prophylactic dosing with less trial and error, thereby decreasing clinical morbidity.

Keywords: CRM status; coagulation factor IX; collagen IV; extravascular factor IX; haemophilia.

PubMed Disclaimer

References

REFERENCES

    1. White GC 2nd, Rosendaal F, Aledort LM, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost. 2001;85:560.
    1. Malec LM, Croteau SE, Callaghan MU, Sidonio RF Jr. Spontaneous bleeding and poor bleeding response with extended half-life factor IX products: a survey of select US haemophilia treatment centres. Haemophilia. 2020;26(3):https://doi.org/10.1111/hae.13943
    1. Kleiboer B, Nielsen B, Ma AD, Abajas Y, Monroe DM, Key NS. Excessive breakthrough bleeding in haemophilia B patients on factor IX-albumin fusion protein prophylactic therapy: a single centre case series. Haemophilia. 2020;26(1): https://doi.org/10.1111/hae.13896
    1. Stern DM, Drillings M, Nossel HL, Hurlet-Jensen A, LaGamma KS, Owen J. Binding of factors IX and IXa to cultured vascular endothelial cells. Proc Natl Acad Sci USA. 1983;80:4119-4123.
    1. Heimark RL, Schwartz SM. Binding of coagulation factors IX and X to the endothelial cell surface. Biochem Biophys Res Commun. 1983;111:723-731.

LinkOut - more resources