Brüggemann Lois W, Schoenmakers Saskia H H F, Groot Angelique P, Reitsma Pieter H, Spek C Arnold
Laboratory for Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Crit Care Med. 2006 Aug;34(8):2201-6. doi: 10.1097/01.CCM.0000228918.30931.E8.
The factor V Leiden (FVL) mutation (Arg506Glu) results in the production of an FV protein that when activated is relatively resistant to inactivation by activated protein C and thereby leads to predisposition to thrombosis. The rather high prevalence of the FVL mutation in the general population prompted speculation about a potential survival benefit for individuals carrying the FVL allele. Indeed, both clinical and experimental animal data suggest that a heterozygous FVL genotype might protect against the lethal consequences of sepsis. We sought to confirm the survival advantage of heterozygous FVL mice in septic disease.
Controlled animal experiment.
Academic research laboratory.
Wild-type, heterozygous, and homozygous FVL mice subjected to 1 x 10 live bacteria as model for septic peritonitis.
None.
The intraperitoneal injection of E. coli led to growth and dissemination of bacteria and provoked an inflammatory response as evident from elevated cytokine levels (interleukin-6, interleukin-10, and tumor necrosis factor-alpha), induced thrombin-antithrombin complex levels, increased granulocyte influx into the peritoneal cavity, liver necrosis, and adhesion of leukocytes to the vessel wall, resulting in approximately 50% mortality after 72 hrs. The FVL genotype had no significant effect on bacterial outgrowth, markers of inflammation (i.e., tumor necrosis factor-alpha levels of 152 [96.2-200], 152 [99.7-1745], and 110 [99.7-177] pg/mL in peritoneal lavage fluid at t = 20 hrs for wild-type, heterozygous, and homozygous FVL mice, respectively), thrombin generation (i.e., thrombin-antithrombin complex levels of 19.9 [9.31-37.4], 10.4 [6.55-15.8], and 12.6 [8.24-29.0] ng/mL in peritoneal lavage fluid at t = 6 hrs for wild-type, heterozygous, and homozygous FVL mice, respectively), and/or survival (50%, 36%, and 50% for wild-type, heterozygous, and homozygous FVL mice, respectively).
The FVL allele has no beneficial effect in mouse septic peritonitis, and the general protective effect of FVL in sepsis needs further investigation.
因子V莱顿（FVL）突变（Arg506Glu）导致FV蛋白的产生，该蛋白被激活后对活化蛋白C的灭活具有相对抗性，从而导致易患血栓形成。FVL突变在普通人群中的较高患病率引发了关于携带FVL等位基因的个体可能具有生存益处的猜测。事实上，临床和实验动物数据均表明，杂合FVL基因型可能预防败血症的致命后果。我们试图证实杂合FVL小鼠在脓毒症疾病中的生存优势。
对照动物实验。
学术研究实验室。
野生型、杂合型和纯合型FVL小鼠，以腹腔注射1×10⁸活细菌作为脓毒性腹膜炎模型。
无。
腹腔注射大肠杆菌导致细菌生长和播散，并引发炎症反应，表现为细胞因子水平（白细胞介素-6、白细胞介素-10和肿瘤坏死因子-α）升高、凝血酶 - 抗凝血酶复合物水平升高、粒细胞流入腹腔增加、肝坏死以及白细胞黏附于血管壁，72小时后死亡率约为50%。FVL基因型对细菌生长、炎症标志物（即t = 20小时时，野生型、杂合型和纯合型FVL小鼠腹腔灌洗液中肿瘤坏死因子-α水平分别为152 [96.2 - 200]、152 [99.7 - 1745]和110 [99.7 - 177] pg/mL）、凝血酶生成（即t = 6小时时，野生型、杂合型和纯合型FVL小鼠腹腔灌洗液中凝血酶 - 抗凝血酶复合物水平分别为19.9 [9.31 - 37.4]、10.4 [6.55 - 15.8]和12.6 [8.24 - 29.0] ng/mL）和/或生存率（野生型、杂合型和纯合型FVL小鼠分别为50%、36%和50%）均无显著影响。
FVL等位基因在小鼠脓毒性腹膜炎中无有益作用，FVL在败血症中的总体保护作用需要进一步研究。
