Coagulation factors and the protein C system as determinants of thrombin generation in a normal population.
BACKGROUND
Thrombin generation is a powerful tool to probe overall plasma coagulability.


OBJECTIVE
To determine which plasma factors influence the various parameters of the thrombin generation curve, for example lag time, peak height and endogenous thrombin potential (ETP), under different experimental conditions.


METHODS
Plasma levels of coagulation factors and inhibitors, as well as thrombin generation at 1 pm tissue factor (TF) +/- thrombomodulin (TM) and at 13.6 pm TF +/- activated protein C (APC), were determined in plasma from 140 healthy individuals. Data were analysed by multiple regression models.


RESULTS
Thrombin generation increased with age and was higher in females than in males. Under all conditions, the lag time was mainly dependent on the levels of free tissue factor pathway inhibitor (TFPI), free protein S (PS), factor VII (FVII), FIX and fibrinogen. The major determinants of thrombin generation (ETP and peak height) at 1 pm TF were fibrinogen, FXII (despite inhibition of contact activation), free TFPI and antithrombin (AT), both in the absence and in the presence of TM. Thrombin generation in the presence of TM was also dependent on protein C levels. At 13.6 pm TF, thrombin generation was determined by prothrombin, AT, fibrinogen, free TFPI and FV levels in the absence of APC, and by free TFPI, free PS and FX levels in the presence of APC.


CONCLUSIONS
The lag time, ETP and peak height of thrombin generation depend on the levels of multiple coagulation factors and inhibitors. The specific assay determinants vary with the experimental conditions.
Dielis
A W J H
AW
Department of Internal Medicine, Laboratory for Clinical Thrombosis and Haemostasis, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands. a.dielis@bioch.unimaas.nl
Castoldi
E
E
Spronk
H M H
HM
van Oerle
R
R
Hamulyák
K
K
Ten Cate
H
H
Rosing
J
J
D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D019774:Blood Coagulation Factor Inhibitors / Q000032:analysis; D001779:Blood Coagulation Factors / Q000032:analysis*; D005260:Female; D006801:Humans; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D011486:Protein C; D012044:Regression Analysis; D012737:Sex Factors; D013917:Thrombin / Q000096:biosynthesis*
D019774:Blood Coagulation Factor Inhibitors; D001779:Blood Coagulation Factors; D011486:Protein C; D013917:Thrombin