Plasma Kallikrein Contributes to Coagulation in the Absence of Factor XI by Activating Factor IX.

Abstract

OBJECTIVES:

FXIa (factor XIa) induces clot formation, and human congenital FXI deficiency protects against venous thromboembolism and stroke. In contrast, the role of FXI in hemostasis is rather small, especially compared with FIX deficiency. Little is known about the cause of the difference in phenotypes associated with FIX deficiency and FXI deficiency. We speculated that activation of FIX via the intrinsic coagulation is not solely dependent on FXI(a; activated FXI) and aimed at identifying an FXI-independent FIX activation pathway. Approach and Results: We observed that ellagic acid and long-chain polyphosphates activated the coagulation system in FXI-deficient plasma, as could be demonstrated by measurement of thrombin generation, FIXa-AT (antithrombin), and FXa-AT complex levels, suggesting an FXI bypass route of FIX activation. Addition of a specific PKa (plasma kallikrein) inhibitor to FXI-deficient plasma decreased thrombin generation, prolonged activated partial thromboplastin time, and diminished FIXa-AT and FXa-AT complex formation, indicating that PKa plays a role in the FXI bypass route of FIX activation. In addition, FIXa-AT complex formation was significantly increased in F11-/- mice treated with ellagic acid or long-chain polyphosphates compared with controls and this increase was significantly reduced by inhibition of PKa.

CONCLUSIONS:

We demonstrated that activation of FXII leads to thrombin generation via FIX activation by PKa in the absence of FXI. These findings may, in part, explain the different phenotypes associated with FIX and FXI deficiencies.

• Authors: Mayken Visser, René van Oerle, Hugo Ten Cate, Volker Laux, Nigel Mackman, Stefan Heitmeier, Henri M H Spronk
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 40 Issue 1 Pg. 103-111 (01 2020) ISSN: 1524-4636 [Electronic] United States
• PMID: 31766871 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Factor IX
• Factor XI
• Plasma Kallikrein
• Thrombin

Topics

• Animals
• Blood Coagulation (physiology)
• Disease Models, Animal
• Factor IX (metabolism)
• Factor XI (metabolism)
• Factor XI Deficiency (blood, complications)
• Female
• Male
• Mice
• Mice, Inbred C57BL
• Plasma Kallikrein (metabolism)
• Thrombin (metabolism)
• Thrombosis (blood, etiology)