The Marburg I polymorphism of factor VII activating protease is associated with low proteolytic and low pro-coagulant activity.
BACKGROUND
Factor VII activating protease (FSAP) is a plasma protease with FVII and pro-urokinase (pro-uPA) activating properties. A single nucleotide polymorphism (SNP) (Marburg I, MI) in the FSAP gene (HABP-2) leads to a low activity of the MI-FSAP towards pro-uPA, but supposedly not towards FVII and is described as a risk factor for athero-thrombosis and liver fibrosis. Recently we found, however, that FVII is an extremely poor substrate of FSAP and identified tissue factor pathway inhibitor (TFPI) as a novel substrate for FSAP. This prompted us to re-investigate the proteolytic activity profile of FSAP and to re-define its role in haemostasis.


METHODS
Using purified protein and genotyped plasma samples, we systematically compared the activities of wild type (WT) and MI-FSAP towards natural plasma substrates. The influence of FSAP on coagulation was studied in prothrombin time assays.


RESULTS
FSAP from homozygous MI-carriers has a general low proteolytic activity making this variant a natural "knock-down". In human plasma WT-FSAP, but not MI-FSAP, accelerated the extrinsic coagulation by inactivation of TFPI. The diminished ability of MI-FSAP to cleave TFPI is reflected by a positive correlation between the FSAP enzymatic activity and cleaved TFPI in the circulation.


CONCLUSIONS
Most likely TFPI cleavage by WT-FSAP occurs in vivo and contributes to an elevated level of endogenous FVIIa. This may explain why MI-FSAP is not a clear indicator for deep vein thrombosis in population studies. The loss of the pro-fibrinolytic protective function of FSAP in carriers of the MI-SNP may account for the association of the MI-SNP with atherosclerosis and thromboembolic complications.
Department of Hematology/Transfusion Medicine, Paul Ehrlich Institute, Langen, Germany. michael.etscheid@pei.de
M
M
Etscheid
L
L
Muhl
D
D
Pons
J W
JW
Jukema
H
H
König
S M
SM
Kanse
D001777:Blood Coagulation / Q000235:genetics / Q000502:physiology*; D015331:Cohort Studies; D015942:Factor VIIa / Q000378:metabolism; D005838:Genotype; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D059748:Proteolysis; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000097:blood* / Q000235:genetics*
C433550:HABP2 protein, human; D012697:Serine Endopeptidases; D015942:Factor VIIa