Hermans P W, Hibberd M L, Booy R, Daramola O, Hazelzet J A, de Groot R, Levin M
Department of Paediatrics, Sophia Children's Hospital, Erasmus University Rotterdam, The Netherlands.
Lancet. 1999 Aug 14;354(9178):556-60. doi: 10.1016/s0140-6736(99)02220-5.
Intravascular coagulation with infarction of skin, digits, and limbs is a characteristic feature of meningococcal sepsis. Children with meningococcal sepsis have higher than normal concentrations of plasminogen activator inhibitor 1 (PAI-1) in plasma. Combined with the widespread venous thrombosis, this finding suggests an impairment of fibrinolysis. A common functional insertion/deletion (4G/5G) polymorphism exists in the promoter region of the PAI-1 gene. We tested the hypothesis that children with the 4G/4G genotype produce higher concentrations of PAI-1, develop more severe coagulopathy, and are at greater risk of death during meningococcal sepsis.
The relation between meningococcal disease outcome, PAI-1 concentration, and PAI-1 genotype was investigated in 175 children with meningococcal disease (37 from Rotterdam, the Netherlands, and 138 from London, UK) and 226 controls (137 from Rotterdam, 89 from London). PAI-1 concentrations in plasma were measured by ELISA, and the 4G/5G PAI-1 polymorphism was detected by PCR and hybridisation.
Concentrations of PAI-1 on admission correlated with presentation (sepsis or meningitis) and outcome. The median PAI-1 concentration in children who died was substantially higher than that in survivors (2448 [IQR 1115-3191] vs 370 [146-914] ng/mL; p<0.0001). Patients with the 4G/4G genotype had significantly higher PAI-1 concentrations than those with the 4G/5G or 5G/5G genotype (1051 [550-2440] vs 436 [198-1225] ng/mL; p=0.03), and had an increased risk of death (relative risk 2.0 [1.0-3.8] for the two cohorts combined, and 4.8 [1.8-13] for the London cohort).
A genetic predisposition to produce high concentrations of PAI-1 is associated with poor outcome of meningococcal sepsis. This finding suggests that impaired fibrinolysis is an important factor in the pathophysiology of meningococcal sepsis.
血管内凝血伴皮肤、手指和肢体梗死是脑膜炎球菌败血症的特征性表现。患脑膜炎球菌败血症的儿童血浆中纤溶酶原激活物抑制剂1（PAI-1）浓度高于正常水平。结合广泛存在的静脉血栓形成，这一发现提示纤溶功能受损。PAI-1基因启动子区域存在常见的功能性插入/缺失（4G/5G）多态性。我们检验了以下假设：4G/4G基因型的儿童产生更高浓度的PAI-1，发生更严重的凝血病，并且在患脑膜炎球菌败血症期间死亡风险更高。
在175例患脑膜炎球菌病的儿童（37例来自荷兰鹿特丹，138例来自英国伦敦）和226例对照者（137例来自鹿特丹，89例来自伦敦）中研究脑膜炎球菌病结局、PAI-1浓度和PAI-1基因型之间的关系。采用酶联免疫吸附测定法（ELISA）测量血浆中PAI-1浓度，通过聚合酶链反应（PCR）和杂交检测4G/5G PAI-1多态性。
入院时PAI-1浓度与临床表现（败血症或脑膜炎）及结局相关。死亡儿童的PAI-1浓度中位数显著高于存活者（2448[四分位间距1115 - 3191]对370[146 - 914] ng/mL；p<0.0001）。4G/4G基因型患者的PAI-1浓度显著高于4G/5G或5G/5G基因型患者（1051[550 - 2440]对436[198 - 1225] ng/mL；p = 0.03），且死亡风险增加（两个队列合并后的相对风险为2.0[1.0 - 3.8]，伦敦队列中为4.8[1.8 - 13]）。
产生高浓度PAI-1的遗传易感性与脑膜炎球菌败血症的不良结局相关。这一发现提示纤溶功能受损是脑膜炎球菌败血症病理生理学中的一个重要因素。
