Department of Medicine, Corporal Michael J. Crescenz VAMC, 3900 Woodland Avenue, Philadelphia, PA, 19104, USA.
Department of Biology, University of Pennsylvania, Philadelphia, PA, 19104, USA.
J Med Case Rep. 2023 Apr 13;17(1):161. doi: 10.1186/s13256-023-03833-0.
The clotting or hemostasis system is a meticulously regulated set of enzymatic reactions that occur in the blood and culminate in formation of a fibrin clot. The precisely calibrated signaling system that prevents or initiates clotting originates with the activated Factor Seven (FVIIa) complexed with tissue factor (TF) formed in the endothelium. Here we describe a rare inherited mutation in the FVII gene which is associated with pathological clotting.
The 52-year-old patient, with European, Cherokee and African American origins, FS was identified as having low FVII (10%) prior to elective surgery for an umbilical hernia. He was given low doses of NovoSeven (therapeutic Factor VIIa) and had no unusual bleeding or clotting during the surgery. In fact, during his entire clinical course he had no unprovoked bleeding. Bleeding instances occurred with hemostatic stresses such as gastritis, kidney calculus, orthopedic surgery, or tooth extraction, and these were handled without factor replacement. On the other hand, FS sustained two unprovoked and life-threatening instances of pulmonary emboli, although he was not treated with NovoSeven at any time close to the events. Since 2020, he has been placed on a DOAC (Direct Oral Anticoagulant, producing Factor Xa inhibition) and has sustained no further clots.
POSSIBLE MECHANISM OF (UNAUTHORIZED) FVII ACTIVATION: FS has a congenitally mutated FVII/FVIIa gene, which carries a R315W missense mutation in one allele and a mutated start codon (ATG to ACG) in the other allele, thus rendering the patient effectively homozygous for the missense FVII. Structure based comparisons with known crystal structures of TF-VIIa indicate that the patient's missense mutation is predicted to induce a conformational shift of the C170's loop due to crowding of the bulky tryptophan to a distorted "out" position (Fig. 1). This mobile loop likely forms new interactions with activation loop 3, stabilizing a more active conformation of the FVII and FVIIa protein. The mutant form of FVIIa may be better able to interact with TF, displaying a modified serine protease active site with enhanced activity for downstream substrates such as Factor X.
Factor VII can be considered the gatekeeper of the coagulation system. Here we describe an inherited mutation in which the gatekeeper function is altered. Instead of the expected bleeding manifestations resulting from a clotting factor deficiency, the patient FS suffered clotting episodes. The efficacy of the DOAC in treating and preventing clots in this unusual situation is due to its target site of inhibition (anti-Xa), which lies downstream of the site of action of FVIIa/TF.
凝血或止血系统是一个在血液中发生的酶促反应的精密调节集合，最终导致纤维蛋白凝块的形成。防止或启动凝血的精确校准信号系统起源于激活的因子 VIIa（FVIIa）与内皮细胞中形成的组织因子（TF）形成的复合物。在这里，我们描述了一种罕见的 FVII 基因突变，该突变与病理性凝血有关。
这位 52 岁的患者，有欧洲、切罗基和非裔美国人血统，FS 在接受脐疝择期手术前被发现 FVII 水平较低（10%）。他接受了低剂量的诺维诺瓦（治疗性 FVIIa），手术过程中没有出现异常出血或凝血。事实上，在他整个临床过程中，他没有无故出血。出血事件发生在胃炎症、肾结石、骨科手术或拔牙等止血应激情况下，这些情况下没有进行因子替代治疗。另一方面，FS 发生了两次未经诱发的、危及生命的肺栓塞事件，尽管他在任何接近事件的时间都没有接受诺维诺瓦治疗。自 2020 年以来，他一直在服用直接口服抗凝剂（DOAC），并且没有再发生血栓。
（未经授权的）FVII 激活的可能机制：FS 有一种先天性突变的 FVII/FVIIa 基因，其中一个等位基因携带 R315W 错义突变，另一个等位基因携带突变的起始密码子（ATG 到 ACG），因此患者实际上是错义 FVII 的纯合子。基于结构的与已知 TF-VIIa 晶体结构的比较表明，患者的错义突变预计会导致 C170 环的构象移位，因为大体积的色氨酸拥挤到扭曲的“外”位置（图 1）。这个移动的环可能与激活环 3 形成新的相互作用，稳定 FVII 和 FVIIa 蛋白的更活跃构象。FVIIa 的突变形式可能能够更好地与 TF 相互作用，显示出改良的丝氨酸蛋白酶活性位点，对下游底物（如因子 X）具有增强的活性。
因子 VII 可以被认为是凝血系统的守门员。在这里，我们描述了一种遗传突变，其中守门员功能发生了改变。与预期的由于凝血因子缺乏导致的出血表现相反，患者 FS 发生了血栓形成事件。在这种不寻常的情况下，DOAC 在治疗和预防血栓形成方面的疗效归因于其抑制的靶位（抗-Xa），该靶位位于 FVIIa/TF 作用部位的下游。
