Antithrombotic potential of the contact activation pathway.

Abstract

PURPOSE OF REVIEW:

This report examines the mechanism(s) by which each protein of the contact activation system - factor XII (FXII), high-molecular-weight kininogen, and prekallikrein - influences thrombosis risk.

RECENT FINDINGS:

FXII generates thrombin through contact activation via interaction with artificial surfaces as on medical instruments such as indwelling catheters, mechanical valves, stents, and ventricular assist devices. Inhibition of FXIIa-mediated contact activation prevents thrombosis under contact activation circumstances without affecting hemostasis. Current studies suggest that high-molecular-weight kininogen deficiency parallels that of FXII and inhibits contact activation. Prekallikrein inhibition contributes to thrombosis prevention by contact activation inhibition in the nylon monofilament model of transient middle cerebral artery occlusion. However, in arterial thrombosis models where reactive oxygen species are generated, prekallikrein deficiency results in downregulation of vessel wall tissue factor generation with reduced thrombin generation. Exploiting this latter prekallikrein pathway for thrombosis risk reduction provides a general, overall reduced tissue factor, antithrombotic pathway without risk for bleeding.

SUMMARY:

These investigations indicate that the proteins of the contact activation and kallikrein/kinin systems influence thrombosis risk by several mechanisms and understanding of these pathway provides insight into several novel targets to prevent thrombosis without increase in bleeding risk.

• Authors: Alvin H Schmaier
• Journal: Current opinion in hematology (Curr Opin Hematol) Vol. 23 Issue 5 Pg. 445-52 (09 2016) ISSN: 1531-7048 [Electronic] United States
• PMID: 27380557 (Publication Type: Journal Article, Review, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural)

Chemical References

• Biomarkers
• Kininogen, High-Molecular-Weight
• Factor XII
• Prekallikrein

Topics

• Animals
• Biomarkers
• Blood Coagulation
• Enzyme Activation
• Factor XII (antagonists & inhibitors, genetics, metabolism)
• Humans
• Kininogen, High-Molecular-Weight (genetics, metabolism)
• Leukocytes (metabolism)
• Prekallikrein (genetics, metabolism)
• Protein Binding
• Signal Transduction
• Thrombosis (blood, genetics, metabolism, prevention & control)