Related Experiment Video
Updated: Feb 5, 2026
Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Re-evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway
T J Girard1, K Grunz1, N M Lasky1
1Division of Hematology, Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA.
Abstract:
Essentials Mouse models are often used to define roles of tissue factor pathway inhibitor (TFPI) in man. TFPI isoform-specific KOs reveal unexpected differences between mouse and human TFPI physiology. Mouse plasma contains 20 times more TFPI than man, derived from TFPIγ, a form not found in man. TFPIγ null mice, expressing only TFPI isoforms α and β, may better reflect the human situation. SUMMARY: Background Mouse models can provide insight into the pathophysiology of human thrombosis and hemostasis. Tissue factor pathway inhibitor (TFPI) regulates coagulation through protein S (PS)-enhanced factor (F) Xa inhibition and FXa-dependent inhibition of FVIIa/tissue factor (TF) activity. TFPI is expressed as isoforms α and β in man, and α, β and γ in the mouse. Objective Assess the reliability of extending TFPI-related studies in mice to humans. Method Compare mouse and human TFPI physiology using a variety of methods. Results Mouse TFPI and human TFPI are similar in regard to: (i) the mechanisms for FVIIa/TF and FXa inhibition; (ii) TFPIα is a soluble form and TFPIβ is glycosyl phosphatidyl inositol (GPI) membrane anchored; (iii) the predominant circulating form of TFPI in plasma is lipoprotein-associated; (iv) low levels of TFPIα circulate in plasma and increase following heparin treatment; and (v) TFPIα is the isoform in platelets. They differ in that: (i) mouse TFPI circulates at a ~20-fold higher concentration; (ii) mouse lines with isolated isoform deletions show this circulating mouse TFPI is derived from TFPIγ; (iii) sequences homologous to the mouse TFPIγ exon are present in many species, including man, but in primates are unfavorable for splicing; and (iv) tandem mass spectrometry (MS/MS) detects sequences for TFPI isoforms α and β in human plasma and α and γ in mouse plasma. Conclusion To dissect the pathophysiological roles of human TFPIα and TFPIβ, studies in TFPIγ null mice, expressing only α and β, only α or only β should better reflect the human situation.
Insights
Mouse models for tissue factor pathway inhibitor (TFPI) studies differ from humans. TFPIγ isoform in mice is absent in humans, making TFPIγ null mice better models for human TFPI physiology research.
Area of Science:
- Biochemistry
- Hematology
- Molecular Biology
Background:
- Mouse models are crucial for studying human thrombosis and hemostasis.
- Tissue factor pathway inhibitor (TFPI) regulates coagulation via FXa and FVIIa/TF inhibition.
- TFPI exists as isoforms α and β in humans, and α, β, and γ in mice.
Purpose of the Study:
- To evaluate the accuracy of mouse models for human TFPI research.
- To compare TFPI physiology between mice and humans.
Main Methods:
- Comparative analysis of mouse and human TFPI.
- Utilizing isoform-specific knockout mouse models.
- Employing tandem mass spectrometry (MS/MS) for protein identification.
Main Results:
- Mouse and human TFPI share inhibition mechanisms and isoform characteristics (soluble α, membrane-bound β).
- Mouse plasma has ~20x higher TFPI levels, primarily from the TFPIγ isoform, which is absent in humans.
- TFPIγ exon sequences are unfavorable for splicing in primates, explaining the isoform difference.
Conclusions:
- TFPIγ null mice, expressing only TFPI α and β, offer a more accurate model for human TFPI studies.
- Understanding these species-specific differences is vital for dissecting pathophysiological roles of human TFPI isoforms.
More Related Videos
Related Concept Videos
01:52Eukaryotic Transcription Inhibitors
Eukaryotic transcription inhibitors usually contain two distinct domains, a...
01:20Physiology of Smell and Olfactory Pathway
The olfactory...
01:30Factors Affecting Drug Distribution: Tissue Permeability
Small molecules with a molecular weight below 500 to 600 Daltons can easily pass through the capillary membrane, gaining access to different tissues. Larger...
01:27C4 Pathway and CAM
C4 Pathway
The C4 pathway is used by plants such as...
02:16Transcription Factors
01:23Factors Affecting Drug Distribution: Physiological Barriers
The capillary endothelial barrier allows only smaller molecules below 600 Da (Daltons) to pass through. It also restricts drugs like heparin that are bound to blood components, limiting their movement within the bloodstream.
The...