TY - JOUR
T1 - Deletion of tissue factor pathway inhibitor isoform beta or gamma, but not alpha, improves clotting in hemophilic mice
AU - Eldem, Irem
AU - Antunes-Heck, Lilian
AU - Subramanian, Renumathi
AU - Lasky, Nina M.
AU - Ashworth, Katrina
AU - Di Paola, Jorge
AU - Girard, Thomas J.
N1 - Publisher Copyright:
© 2024 The Authors
PY - 2024/10
Y1 - 2024/10
N2 - Background: Tissue factor pathway inhibitor (TFPI) regulates tissue factor–triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane–anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein–associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein–associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks. Objectives: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice. Methods: Engineered TFPI isoform–specific, hemophilic (factor VIII-null) mice were evaluated for clotting. Results: Mice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001). Conclusion: In hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα.
AB - Background: Tissue factor pathway inhibitor (TFPI) regulates tissue factor–triggered coagulation. Humans and mice express transcripts encoding for multidistributed (endothelial, platelet, and plasma) 3-Kunitz domain TFPIα and endothelial membrane–anchored 2-Kunitz TFPIβ. Mice express a third transcript, γ, that encodes plasma lipoprotein–associated 2-Kunitz TFPI. In humans, proteolysis of α and/or β produces plasma lipoprotein–associated 2-Kunitz TFPI at lower levels. In clinical trials, monoclonal antibodies that target all TFPI isoforms extend coagulation and correct bleeding in hemophilic patients but with some thrombosis risks. Objectives: To determine the impact of TFPI isoform-specific deletions on promoting clotting in hemophilic mice. Methods: Engineered TFPI isoform–specific, hemophilic (factor VIII-null) mice were evaluated for clotting. Results: Mice expressing any single TFPI isoform were healthy. Thrombin generation assays identified TFPIγ as the dominant anticoagulation isoform in mouse plasma. Hemostasis was assessed by serial bleeding times from a tail vein laceration. Repeatedly, after a clot forms, it was manually disrupted; the number of clots/disruptions occurring over a 15-minute period were reported. C57BL/6 and hemophilic mice clot on average 25.6 vs 5.4 times, respectively. On a hemophilia background, TFPIβ or TFPIγ-specific deletion improved clotting to 14.6 and 15.2 times, respectively (P < .0001). TFPIα-specific deletion was without impact, clotting 5.1 times. Heterozygous deletion of TFPIβ was effective, clotting 11.8 times (P < .0001). Heterozygous deletion of TFPIα or TFPIγ alone was ineffective, clotting 3.0 and 6.1 times, respectively, but heterozygous TFPIαγ deletion improved clotting to 11.2 times (P < .001). Conclusion: In hemophilic mice, endothelial TFPIβ and plasma γ-derived 2-Kunitz TFPI individually contribute more to bleeding than total TFPIα.
KW - TFPI isoforms
KW - hemophilic mice
KW - hemostasis
UR - http://www.scopus.com/inward/record.url?scp=85198154225&partnerID=8YFLogxK
U2 - 10.1016/j.jtha.2024.06.006
DO - 10.1016/j.jtha.2024.06.006
M3 - Article
C2 - 38925489
AN - SCOPUS:85198154225
SN - 1538-7933
VL - 22
SP - 2681
EP - 2691
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 10
ER -