The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: Substantial reduction in mortality and morbidity
The suprapharmacologic dosing of antithrombin concentrate for Staphylococcus aureus-induced disseminated intravascular coagulation in guinea pigs: Substantial reduction in mortality and morbidity
复制标题
DOI：
10.1182/blood.v89.12.4393
复制
发表时间：
1997-06-15
期刊：
影响因子：
20.3
通讯作者：
Szymanski, LM
中科院分区：
文献类型：
--
作者：
Kessler, CM;Tang, ZC;Szymanski, LM
为了评价抗凝血酶(AT)浓缩物对弥散性血管内凝血(DIG)的发病率、死亡率和实验室结果的影响，建立了革兰氏阳性败血症的动物模型。从DIC患者(DIC-SA)和非DIC患者(Non-DIC-SA)的血培养中分离出金黄色葡萄球菌(SA)，建立豚鼠DIC模型。非DIC-SA动物和注入无菌生理盐水的动物作为对照。在注射SA后30分钟或24小时内给予不同剂量的AT。通过凝血酶原时间、活化部分凝血活酶时间、纤维蛋白原、纤维蛋白原-纤维蛋白降解产物和AT活性的变化在4小时内确认DIC。临床出血也很明显。未经治疗的DIC-SA动物在24小时内死亡率为36%，72小时后死亡率高达75%。在DIC-SA输注30分钟后，任何剂量的AT在125到1000 IU/kg之间的干预与100%的存活率(在250 IU/kg组中P<0.05)以及AT活性和纤维蛋白原浓度的持续增加(P<0.05)相关。与未治疗的DIC-SA相比，AT联合低分子肝素(LMWH)或单独应用LMWH时，DIC-SA的死亡率略有下降，但并不显著。在所有DIC-SA动物的死前和尸检中观察到大出血，但在接受AT的动物中相当少(在250、500和1000IU/kg组中P<或等于.001)。相比之下，接受低分子肝素单独治疗或联合AT治疗的患者出现出血，并出现病理性DIGH。未处理的DIC-SA组、125IU/kg AT和LMWH单独处理组的豚鼠均可检测到终末器官纤维蛋白的形成。在DIC-SA输注后30分钟给药，剂量在250到1000 IU/kg之间，可阻止末端器官中纤维蛋白的形成(250和1000 IU/kg组P<或等于.001)。在DIC后24小时给药，SA-SA不能逆转DIC的组织病理学证据，但有利于影响存活率，在1000IU/kg AT组达到统计学意义(P<或等于0.025)。综上所述，在这个豚鼠模型中，血管上剂量的AT浓缩剂显著降低了发病率和死亡率，改善了由DIC-SA引起的实验室指标的不良变化，并且与不良的出血并发症无关。这些发现为研究AT疗法在DIC-SA患者中的应用提供了依据。(C)1997年由美国血液病学会主办。
An animal model of gram-positive septicemia was developed to evaluate the effects of antithrombin (AT) concentrates on morbidity, mortality, and laboratory consequences of disseminated intravascular coagulation (DIG). DIC was induced in guinea pigs by infusing Staphylococcus aureus (SA) isolated from blood cultures of patients with DIC (DIC-SA) or without DIC (non-DIC-SA). The non-DIC-SA animals and animals infused with sterile saline served as controls. Varying doses of AT were administered either 30 minutes or 24 hours after infusion of SA. DIC was confirmed within 4 hours by changes in prothrombin time, activated partial thromboplastin time, fibrinogen, fibrinogen-fibrin degradation products, and AT activity. Clinical bleeding was also evident. Mortality of untreated DIC-SA animals was 36% within 24 hours and up to 75% by 72 hours. Intervention with any dose of AT between 125 and 1,000 IU/kg 30 minutes after DIC-SA infusion was associated with 100% survival (P less than or equal to.05 in the 250 IU/kg group) and sustained increases in AT activity and fibrinogen concentrations (P less than or equal to.05). When AT was administered in combination with low molecular weight heparin (LMWH) or if LMWH was adminstered alone, mortality from DIC-SA was slightly, but not significantly reduced compared with untreated DIC-SA. Gross hemorrhage was observed premortem and at autopsy in all of the DIC-SA animals but in substantially fewer animals that received AT (P less than or equal to.001 in the 250, 500, and 1,000 IU/kg groups). In contrast, groups treated with LMWH, alone or with AT, experienced hemorrhage and appeared to develop pathologic DIG. Fibrin formation in end-organs was detected in all guinea pigs in the untreated DIC-SA group and in the groups treated with 125 IU/kg AT and LMWH alone. AT doses between 250 and 1,000 IU/kg administered 30 minutes after DIC-SA infusion prevented fibrin formation in end-organs (P less than or equal to.001 in the 250 and 1,000 IU/kg groups). AT administered 24 hours after DIC-SA could not reverse pre-existing histopathologic evidence of DIC but favorably affected survival, which reached statistical significance in the 1,000 IU/kg AT group (P less than or equal to.025). In summary, suprapharmacologic doses of AT concentrate significantly decreased morbidity and mortality and ameliorated adverse changes in laboratory measures induced by DIC-SA in this guinea pig model and were not associated with untoward hemorrhagic complications. These findings provide justification for studying the use of AT therapy in patients with DIC-SA. (C) 1997 by The American Society of Hematology.