The findings indicate that HABP2, although primarily localized in the plasma, is upregulated in the lung endothelium with LPS-induced ALI and in cultured human pulmonary ECs. The enzymatic activity of HABP2 is differentially regulated by HA, with HMW-HA inhibiting HABP2 protease activity and LMW-HA binding to the PABD of HABP2 and stimulating activity. Activated HABP2 induces protease-activated receptor signaling in ECs, which leads to activation of the actin regulatory molecules RhoA and ROCK and endothelial barrier disruption. The barrier-disruptive role of HABP2 is further confirmed by vascular silencing of HABP2 expression, which attenuated the vascular leakiness observed in LPS- and ventilator-induced lung injury.

Title:
Hyaluronic Acid Binding Protein 2 Is a Novel Regulator of Vascular Integrity

Authors and Source:
Mambetsariev N et al. Arterioscler Thromb Vasc Biol. 2009 Dec 30. [Epub ahead of print]

The authors compared FSAP activation in the presence of apoptotic vs. non-apoptotic cells. FSAP in plasma was found to be activated upon incubation with apoptotic cells as evidenced by appearance of two-chain FSAP on western blots. No FSAP activation was observed upon incubation of plasma with living cells. FSAP activation by apoptotic cells was also indicated by complex formation of FSAP with C1Inh and AP, whereas no such complexes could be detected after incubation with living cells.

Moreover, the authors asked, whether a similar mechanism can also be expected in vivo and they analysed plasmas from cases of sepsis, during which the formation of apoptotic cells is a hallmark-They found elevated levels of FSAP/C1Inh complexes in plasma of baboons with lethal sepsis and in plasmas from 8 out of 16 patients suffering from severe sepsis.

In conclusion the authors demonstrate that FSAP is activated upon contact with apoptotic cells and forms complexes with C1Inh and AP. They sugest, that determination of complexes between FSAP and C1Inh or AP in plasma is  a tool to study FSAP activation in vivo.

Title:
Factor VII-activating protease is activated in sepsis

Authors and Source:
S Zeerleder, I Bulder, F Stephan, M de Kruif, J Hoogerwerf, T van der Poll, L Aarden
ISTH 2009: PP-TH-153  

pro-uPA was found to be cleaved much more efficiently and at lower concentrations than FVII, indicating a preference of FSAP for the fibrinolytic system. Purified FSAP -MI activated FVII much less effficient than FSAP-wt. This was confirmed with FSAP from plasma of 5 individuals homozygous for the FSAP -MI allele. Pro-uPA was only weakly processed by FSAP from homozygous Marburg I carriers.

However, the central finding was on Factor VIII (FVIII) processing: FSAP-wt caused inactivation of FVIII, whereas FSAP-MI caused activation.

The authors conclude that the hypothesis of a haemostatic imbalance and increased athero-thrombotic risk in Marburg I-carriers due to reduced uPA but unchanged FVII activation capacity needs a revision and should take into consideration circulating FVIII levels.

Title:
The Marburg I polymorphism (G534E) of Factor VII activating protease (FSAP) prevents FVII activation, but contributes to thromboembolic risk due to FVIII activation.

Authors and Source:
M Etscheid, L Muhl, D Pons, KT Preissner, W Ruf, W Jukema, SM Kanse
Poster presentation ISTH 2009: OC-TH-110  

The authors analysed the association of 290 common SNPs of 51 thrombosis and inflammation genes with VTE. Genetic variants of 4 genes encoding i) FXIII subunit A, ii) Factor VII-activating protease (FSAP/HABP2), iii) protease activated receptor-1, and iv) the urokinase receptor showed the strongest evidence for association with VTE.

A variant allele of FXIII subunit A was associated with 1.66-fold increased risk of VTE. Alleles of HABP2 (rs6585234 and rs3862019), protease activated receptor-1 (rs253061 and rs153311), and Urokinase-receptor (rs344782) were each associated with lower risk of VTE.

The HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen.

Authors and Source:
Reiner AP, Lange LA, Smith NL, Zakai NA, Cushman M, Folsom AR. J Thromb Haemost. 2009 Sep;7(9):1499-1505

Title:
Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study.

Women were analysed that took oral contraceptives with different estrogen and progestin dosage. Marburg I variant, FSAP antigen and FSAP activity was measured at the start and after 6 cycles of OC. Marburg I was found to be present in 49 (8.4%) of the women, in all three treatment groups (P=0.44). Marburg I was associated with significantly reduced levels of FSAP (P<0.001). OC use increased the median plasma concentration of FSAP antigen by 25% and FSAP activity by 58% (P<0.001). The relative increase in FSAP activity was significantly higher in women carrying the wild type genotype (63%) than in women carrying the Marburg I variant (50%) (P=0.01). The increase in FSAP was independent of the estrogen dosage and progestin (P>0.1).

In conclusion, OCs increased FSAP in plasma independent of the estrogen dosage and the progestin component but with less significance in women carrying Marburg I genotype than in women with the wild type genotype.

Authors and Source
JJ Sidelmann, SO Skouby, C Kluft, U Winkler, F Vitzthum, H Schwarz, J Jespersen
Poster presentation ISTH 2009: OC-MO-090  

Titel
The effect of monophasic oral contraceptive regimens on factor VII-activating protease – a randomized multicentre study

Along these lines Parahuleva and colleagues examined the relation between plasma concentration of FSAP and pro-inflammatory activation of macrophages and the signalling pathways induced by FSAP.

FSAP treatment induced IkappaB-dependent NF-kappaB activation in freshly isolated human monocytes. FSAP also induced the phosphorylation and proteolytic degradation of the inhibitor IkappaBα. Moreover, the phosphorylation of p65, which is known to contribute to the enhancement of DNA-binding activity of NF-kappaB, was induced by  FSAP.

Expression of NF-kappaB, ICAM, IL-6, and tissue factor, all of which under the control of NF-kB, was increased by FSAP.

The authors conclude that FSAP may play a novel role in atherosclerosis by enhancing the inflammatory response of human monocytes/macrophages via NF-kappaB activation.

Authors and Source:
M. Parahuleva, R. Maj, A. Staubitz, H. Hoelscherman, H. Tillmanns, A. Erdogan, S. Kanse.
Poster presentation ISTH 2009: OC-WE-128  

Title:
Factor VII activating protease (FSAP) – inflammation and coagulation cross-talk in patients with coronary artery disease

Author and Source:
Muhl et al. FEBS Lett. 2009 Jun 18;583(12):1994-1998.

Title:
Structure – function analysis of FSAP: Sequence determinants for heparin binding and cellular functions

Comment:
The anti-FSAP antibodies used for these studies are available from American Diagnostica.

Based on these activities a role of FSAP in the hemostatic system has been suggested.

Authors and Source:
Römisch et al., Blood Coagul Fibrinolysis. 1999 Dec;10(8):471-479
Title:
A protease isolated from human plasma activating factor VII independent of tissue factor.

Authors and Source:
Römisch et al., Haemostasis. 1999;29(5):292-299
Title:
The FVII activating protease cleaves single-chain plasminogen activators

Authors and Source:
Etscheid et al., Biol Chem. 2000 Dec;381(12):1223-1231
Title:
Activation of proPHBSP, the zymogen of a plasma hyaluronan binding serine protease, by an intermolecular autocatalytic mechanism

Authors and Source:
Kannemeier et al., J Biochem. 2001 Jul;268(13):3789-3796
Title:
Factor VII and single-chain plasminogen activator-activating protease: activation and autoactivation of the proenzyme

When FSAP was purified from such plasmas it displayed reduced pro-uPA activating activity, while Factor VII activating activity was normal.

In 1 % of the plasmas reduced activity levels as well as reduced antigen levels were found.

Authors and Source:
Roemisch et al., Bloood Coagul. Fibrinolysis 2001 July;12(5):375-383

Title:
Quantitation of the factor VII- and single-chain plasminogen activator-activating protease in plasmas of healthy subjects