Re-evaluation of mouse tissue factor pathway inhibitor and comparison of mouse and human tissue factor pathway inhibitor physiology

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 alpha and beta in man, and alpha, beta and gamma 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) TFPI alpha is a soluble form and TFP beta is glycosyl phosphatidyl inositol (GPI) membrane anchored; (iii) the predominant circulating form of TFPI in plasma is lipoprotein-associated; (iv) low levels of TFPI alpha circulate in plasma and increase following heparin treatment; and (v) TFPI alpha is the isoform in platelets. They differ in that: (i) mouse TFPI circulates at a similar to 20-fold higher concentration; (ii) mouse lines with isolated isoform deletions show this circulating mouse TFPI is derived from TFPI gamma; (iii) sequences homologous to the mouse TFPI gamma 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 alpha and beta in human plasma and alpha and gamma in mouse plasma. Conclusion: To dissect the pathophysiological roles of human TFPI alpha and TFPI beta, studies in TFPI gamma null mice, expressing only alpha and beta, only alpha or only beta should better reflect the human situation.