Department of Hematology/Transfusion Medicine, Paul Ehrlich Institute, Langen, Germany.
Thromb Res. 2012 Dec;130(6):935-41. doi: 10.1016/j.thromres.2012.07.023. Epub 2012 Aug 18.
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.
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.
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.
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.
因子 VII 激活蛋白酶（FSAP）是一种血浆蛋白酶，具有激活因子 VII 和尿激酶原（pro-uPA）的特性。FSAP 基因（HABP-2）中的单核苷酸多态性（SNP）（马堡 I，MI）导致 MI-FSAP 对 pro-uPA 的活性降低，但据称对因子 VII 没有影响，并被描述为动脉血栓形成和肝纤维化的危险因素。然而，最近我们发现，因子 VII 是 FSAP 的极差底物，并确定组织因子途径抑制剂（TFPI）为 FSAP 的新底物。这促使我们重新研究 FSAP 的蛋白水解活性谱，并重新定义其在止血中的作用。
使用纯化蛋白和基因分型血浆样本，我们系统地比较了野生型（WT）和 MI-FSAP 对天然血浆底物的活性。在凝血酶原时间测定中研究了 FSAP 对凝血的影响。
杂合 MI 携带者的 FSAP 具有普遍较低的蛋白水解活性，使这种变体成为天然的“敲低”。在人血浆中，WT-FSAP 而不是 MI-FSAP 加速了外源性凝血，通过灭活 TFPI 实现。MI-FSAP 裂解 TFPI 的能力降低反映在循环中 FSAP 酶活性与裂解 TFPI 之间存在正相关。
WT-FSAP 很可能在体内裂解 TFPI，并导致内源性 FVIIa 水平升高。这可能解释了为什么 MI-FSAP 在人群研究中不是深静脉血栓形成的明确指标。MI-SNP 携带者中 FSAP 的促纤溶保护功能丧失可能解释了 MI-SNP 与动脉粥样硬化和血栓栓塞并发症的关联。
