PB0594 - Factor XI localization in human deep venous thrombus and function of activated factor XI on mural thrombus formation under low-shear condition.

Monday, June 26, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Nobuyuki Oguri

Graduate student, Department of Pathology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan

Co-Author(s)

Toshihiro Gi, MD (he/him/his)

Department of Pathology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan
KM

Kazunari Maekawa

Department of Pathology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan
EF

Eiji Furukoji

Department of Radiology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan
HO

Hoshimi Okawa

Tsukuba Research Institute
ONO Pharmaceutical Co., Ltd
Tsukuba, Ibaraki, Japan
SK

Sho Kouyama

Minase Research Institute
ONO Pharmaceutical Co., Ltd
Osaka, Osaka, Japan
TS

Tatefumi Sakae

Department of Radiology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan
MA

Minako Azuma

Department of Radiology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan
YA

Yujiro Asada

Department of Pathology
Miyazaki Medical Association Hospital
Miyazaki, Miyazaki, Japan
Atsushi Yamashita, MD, PhD

Professor, Department of Pathology, Faculty of Medicine
University of Miyazaki
Miyazaki, Miyazaki, Japan

Background: Anticoagulants targeting coagulation factor XI (FXI)/ activated FXI (FXIa) are under development. However, it remains unclear whether FXI is present in human deep venous thrombus (DVT) and why FXI/FXIa inhibition does not result in excess bleeding.

Aims: To investigate the localization of FXI in human DVT and function of FXIa on mural thrombus formation under low shear condition.

Methods: We examined pathological findings of human aspirated DVT (n=15) on time-dependent change; fresh component, cell lytic change, and organizing reaction. Localization of FXI in the DVT was evaluated with immunohistochemistry and immunofluorescence. Rabbit ex vivo bloods after oral administration of FXIa inhibitor (ONO-16000586, 50 mg/kg) and activated factor X (FXa) inhibitor (rivaroxaban, 15 mg/kg,) and human peripheral blood were perfused on a flow chamber under a shear rate of 70/S.

Results: All venous thrombi were composed of more than two components on time-dependent change; fresh component, cell lytic change, or organizing reaction. Immunohistochemically, FXI was localized in all DVT. Double immunofluorescence revealed a close distribution of FXI with fibrin but not with von Willebrand factor or glycophorin A, an erythrocyte marker. Immunopositive areas for FXI, fibrin, glycoprotein IIb/IIIa and glycophorin A in CD34-negative non-endothelialized areas were larger than those in CD34-positive endothelialized areas (organizing area). The FXIa and FXa inhibitors, which comparably inhibited rabbit venous thrombus formation, did not affect platelet covering area under low shear condition. The FXIa or FXa inhibitor mildly or strongly inhibited fibrin formation after perfusion, respectively. FXIa inhibitor reduced human FXIa activation and production of prothrombin fragment 1+2 during perfusion under low-shear rate.

Conclusion(s): The thrombus composition suggests multistep thrombus formation in human DVT. The FXI localization may provide rationale of FXI/FXIa inhibition for prevention of human DVT. Preserved fibrin formation under FXIa inhibition may be associated with a minor hemostatic role of FXI.