Kerschen E, Hernandez I, Zogg M, Maas M, Weiler H
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA.
J Thromb Haemost. 2015 Jun;13(6):1073-80. doi: 10.1111/jth.12876. Epub 2015 Mar 31.
The high allelic frequency of the prothrombotic Leiden polymorphism in human blood coagulation factor V (FV) has been speculated to reflect positive selection during evolution. Heterozygous Leiden carriers enrolled in the placebo arm of the PROWESS sepsis trial and heterozygous Leiden mice challenged with endotoxin both showed reduced mortality, whereas homozygous Leiden mice were not protected from lethal endotoxemia. Follow-up analyses of clinical outcomes and of mouse models of infection with various pathogens remained inconclusive.
To establish whether activated protein C resistance of FV Leiden modifies the outcome of bacterial infection in murine sepsis models.
Homozygous and heterozygous FV Leiden mice were subjected to gram-positive (S. aureus) or gram-negative (Y. pestis; E. coli) septic peritonitis or polymicrobial, focal septic peritonitis induced by cecal ligation and puncture. The effect of FV Leiden on 7-day survival and bacterial dissemination was assessed. Outcomes were compared with the sepsis survival of mice with genetically impaired hemostasis (hemophilia A, thrombocytopenia, thrombin receptor PAR4 [protease activated receptor 4] deficiency, endothelial protein C receptor [ProcR/EPCR] deficiency).
Heterozygous, but not homozygous, Leiden mice were protected from lethal infection with highly virulent S. aureus and Y. pestis strains. FV Leiden did not affect the outcome of sepsis induced by cecal ligation and puncture, staphylokinase-deficient S. aureus, Pla-deficient Y. pestis, or E. coli. Thrombocytopenia, deficiency of PAR1 or PAR4 did not affect S. aureus sepsis survival, whereas hemophilia A increased mortality. ProcR deficiency selectively abolished the survival advantage of heterozygous Leiden mice.
In mice, heterozygous FV Leiden carriers are protected from sepsis mortality after infection with clinically relevant human bacterial pathogens.
据推测，人类凝血因子V（FV）中促血栓形成的莱顿多态性的高等位基因频率反映了进化过程中的正选择。参加PROWESS脓毒症试验安慰剂组的杂合子莱顿携带者和接受内毒素攻击的杂合子莱顿小鼠均显示死亡率降低，而纯合子莱顿小鼠并未免受致命性内毒素血症的影响。对各种病原体感染的临床结局和小鼠模型的后续分析尚无定论。
确定FV莱顿的活化蛋白C抵抗是否会改变小鼠脓毒症模型中细菌感染的结局。
将纯合子和杂合子FV莱顿小鼠置于革兰氏阳性（金黄色葡萄球菌）或革兰氏阴性（鼠疫耶尔森菌；大肠杆菌）感染性腹膜炎，或由盲肠结扎和穿刺诱导的多微生物局灶性感染性腹膜炎中。评估FV莱顿对7天生存率和细菌播散的影响。将结果与遗传性止血功能受损（甲型血友病、血小板减少症、凝血酶受体PAR4[蛋白酶激活受体4]缺乏症、内皮蛋白C受体[ProcR/EPCR]缺乏症）小鼠的脓毒症生存率进行比较。
杂合子而非纯合子莱顿小鼠免受高毒力金黄色葡萄球菌和鼠疫耶尔森菌菌株的致命感染。FV莱顿不影响盲肠结扎和穿刺、缺乏葡萄激酶的金黄色葡萄球菌、缺乏Pla的鼠疫耶尔森菌或大肠杆菌诱导的脓毒症结局。血小板减少症、PAR1或PAR4缺乏不影响金黄色葡萄球菌脓毒症的生存率，而甲型血友病会增加死亡率。ProcR缺乏选择性地消除了杂合子莱顿小鼠的生存优势。
在小鼠中，杂合子FV莱顿携带者在感染临床相关的人类细菌病原体后可免受脓毒症死亡的影响。
