Abstract

Evaluation of the anticoagulant activity of C1 esterase inhibitor in human and mouse plasma.

F. Philip Giorgino,¹ Steven P. Grover,² Nigel Mackman²

1. Nova Southeastern University Dr. Kiran C. Patel College of Allopathic Medicine (NSU MD).
2. Division of Hematology, Department of Medicine, UNC Blood Research Center, University of North Carolina at Chapel Hill.

 

INTRODUCTION

Venous thromboembolism (VTE) is a leading cause of morbidity and mortality resulting from inappropriate activation of coagulation. C1 esterase inhibitor (C1INH) inhibits proteases in the intrinsic coagulation pathway. Patients with a congenital deficiency in C1INH, which causes hereditary angioedema (HAE), have elevated markers of activation of coagulation. The effects of exogenous C1INH addition and congenital C1INH deficiency on plasma-based coagulation were investigated.

 

METHODS

Coagulation was investigated in 1) normal human plasma (NHP) with added human C1INH, 2) plasma from HAE patients, 3) and plasma from C1INH-deficient mice. We measured activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin generation (TG) using calibrated automated thrombography, and levels of thrombin-antithrombin (TAT) complex and D-dimer.

 

OUTCOMES

Exogenous C1INH significantly prolonged aPTT (p<0.0001), but not PT in NHP. Exogenous C1INH significantly decreased intrinsic (p<0.0001) but not extrinsic pathway-initiated thrombin generation in NHP in a dose-dependent manner. Plasma from HAE patients had significantly higher TG (p<0.05) than healthy controls. This suggests that endogenous C1INH has an anticoagulant function and that a reduction of C1INH in HAE patients is associated with increased baseline coagulation. C1INH-deficient mice had significantly higher plasma levels of TAT complexes (p<0.0001) and D-dimer (p<0.01) compared to wild type controls, which is similar to the pattern reported in HAE patients.

 

DISCUSSION

C1INH selectively inhibits the intrinsic coagulation pathway. Deficiency of endogenous C1INH increases intrinsic pathway-initiated TG in plasma. C1INH deficiency in mice increases baseline plasma markers of coagulation activation.