Marked difference in pathophysiology between tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats

OBJECTIVE: Tissue factor and lipopolysaccharide frequently have been used to induce disseminated intravascular coagulation in experimental animal models. Although the pathophysiology of disseminated intravascular coagulation may differ according to the agents used to induce it, these previous models have not distinguished between the use of different disseminated intravascular coagulation-inducing agents. In this study, we attempted to evaluate the characteristic features of these agents in two types of disseminated intravascular coagulation models, with special reference to selected hemostatic parameters and pathologic findings in the kidney. DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Twenty-seven male Wistar rats, age 6-7 wks, weighing 160-170 g. INTERVENTIONS: Three groups of animals were studied: a control group (n = 8) receiving physiologic saline, a tissue factor-treated group (n = 11) receiving tissue factor 3.75 units/kg, and a lipopolysaccharide-treated group (n = 8) receiving lipopolysaccharide 30 mg/kg; each group sustained infusion for 4 hrs via the tail vein. MEASUREMENTS AND MAIN RESULTS: The degree of hemostatic activation in both types of experimental disseminated intravascular coagulation was identical, based on the results of thrombin-antithrombin III complex levels. Markedly elevated D-dimer concentrations were observed without organ dysfunction or fibrin deposition in the kidney on administration of tissue factor, whereas markedly elevated plasminogen activator inhibitor activity, decreased antithrombin III activity, severe organ failure, and marked fibrin deposition in the kidney were observed for lipopolysaccharide administration. CONCLUSION: Because pathophysiology differed remarkably between the tissue factor- and lipopolysaccharide-induced disseminated intravascular coagulation models in rats, we recommend that they be assessed carefully as distinct entities to determine implications of their experimental and clinical use.     

急性白血病与弥散性血管内凝血

目的分析急性白血病（AL）患者弥散性血管内凝血（DIC）的发生情况，凝血功能改变及其临床意义。方法对67例AL患者、25例AL完全缓解（CR）患者、20例健康体检者进行凝血常规、D-二聚体等检测。结果根据ISTH修订标准，15例AL患者合并DIC，发生率为22．4％，AML与ALL的DIC发生率AML-M3之间无统计学差异（P〉0．05），AML-M3与non-AML-M3的DIC的发生率之间有统计学差异（P〈0．05）。DIC组PT、APTT、TT较对照组、CR组及non-DIC组均明显延长（P〈0．01），而FIB则降低（P〈0．05）。结论AL尤其AML-M3患者容易合并DIC，观察患者凝血功能改变以及出血表现可有助于尽早发现DIC并指导临床预防及治疗，从而有利于改善AL合并DIC患者的临床预后。     

妊娠期高血压疾病与弥散性血管内凝血

妊娠期高血压疾病是妊娠期特有的疾病，也是产科常见的、严重威胁母儿安全的并发症。我国发病率为9．4％，国外报道为7％-12％。近年来的研究表明，妊娠期高血压疾病的发生与血管内皮细胞损伤及血管细胞因子的合成及障碍有关。其病理基础是全身小动脉痉挛，造成微小血管狭窄，血管壁渗透性增加。血液浓缩。此外，妊娠期高血压疾病患者的凝血因子活性多数增高，凝血功能亢进。上述病理生理变化，形成了妊娠期高血压疾病患者易发生弥散性血管内凝血（disseminated intravascular coagulation，DIC）的病理基础。     

实验性弥散性血管内凝血大鼠淋巴循环的变化

目的 探讨实验性弥散性血管内凝血（DIC）大鼠淋巴循环的变化。方法 32只雄性Wistar大鼠按随机数字表法分为DIC组（n=16）和假手术组（n=16），每组中8只动物用于肠系膜淋巴微循环观察，另8只进行淋巴动力学检测。颈静脉注射高分子右旋糖酐（dextran 500）制备Wistar大鼠实验性DIC模型，通过淋巴学方法，观察DIC时大鼠淋巴循环的变化。结果DIC时，肠系膜微淋巴管（ML）收缩性、肠淋巴流量、淋巴细胞输出量明显降低，淋巴液中有少量单核细胞，并且淋巴液黏度较高。经生理盐水治疗后，ML收缩性、肠淋巴流量、淋巴细胞输出量均显著升高，淋巴液中有大量单核细胞出现，与假手术组比较差异均有显著性（P均〈0．05），且淋巴液黏度明显低于DIC组（P〈0．05）。结论 Wistar大鼠实验性DIC时，淋巴循环障碍表现为ML收缩性降低、淋巴循环转运功能障碍和淋巴液黏度增高。     

Tissue factor pathway inhibitor response does not correlate with tissue factor-induced disseminated intravascular coagulation and multiple organ dysfunction syndrome in trauma patients

OBJECTIVE: To determine the precise relationship between tissue factor and tissue factor pathway inhibitor (TFPI) after trauma, as well as to test the hypothesis that low TFPI levels are not sufficient to prevent tissue factor-dependent intravascular coagulation, leading to multiple organ dysfunction syndrome (MODS). DESIGN: Prospective, observational cohort study. SETTING: Emergency room and intensive care unit in a university hospital. PATIENTS: Thirty-three trauma patients, 18 with disseminated intravascular coagulation (DIC) and 15 without DIC were studied. Ten normal, healthy volunteers served as control subjects. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Antigen concentration of tissue factor and TFPI, and global parameters of coagulation and fibrinolysis were measured on the day of admission, and on days 1-4 after admission. The number of systemic inflammatory response syndrome (SIRS) criteria that patients met and the DIC score were determined, simultaneously. The results of these measurements, incidence of MODS, and outcome were compared between the DIC patients and those without DIC. In the DIC patients, significantly higher tissue factor levels (p =.0049) and lower platelet counts (p =.0016) were found compared with the non-DIC patients and control subjects. However, the TFPI values remained at normal levels during the study period. No correlation was found between the peak levels of tissue factor and TFPI. The mean duration of SIRS and the maximum number of the SIRS criteria being met by the patients in the DIC group were statistically longer and higher than those in the non-DIC patients. The incidence of MODS and the number of the dysfunctioning organs were higher in the DIC patients compared with those in the non-DIC patients, and the DIC patients had a poor outcome. CONCLUSIONS: We systematically elucidated the relationship between tissue factor and TFPI in post-trauma patients. Highly activated tissue factor-dependent coagulation pathway is not sufficiently prevented by the normal TFPI levels in patients with DIC. The DIC associated with thrombotic and inflammatory responses causes MODS, and leads to poor outcome in post-trauma patients.     

产科弥散性血管内凝血19例诊断分析

产科弥散性血管内凝血(DIC)病情凶险,进展迅速,直接威胁母婴生命,早期诊断是其治疗的关键。本研究旨在对我院7年来收治的19例产科DIC进行回顾分析,以探讨产科DIC的诊断及其相关问题。本研究中所有病例诊断均符合全国第六届血栓与止血会议制订的DIC诊断标准[1]。     

Coagulation inhibitors in sepsis and disseminated intravascular coagulation

Sepsis is a syndrome that is increasing in frequency and continues to be associated with an unacceptably high mortality. DIC is an important and common sequel of sepsis, is implicated in the development of multiple organ failure, and has been shown repeatedly to connote a poor prognosis. Increasing understanding of the pathogenesis of DIC has suggested several novel therapies designed to correct deficiencies in inhibitors of coagulation. To date, small randomized, controlled studies of antithrombin III concentrates in sepsis and DIC have shown a trend to increased survival, but have not achieved statistical significance. Currently, a large randomized controlled trial of antithrombin III in sepsis is being conducted. Until more data are available, important questions remain as to its proper place in the treatment of sepsis, septic shock, and DIC. Similarly, therapy with protein C and tissue factor-pathway inhibitor has been beneficial in animal models of sepsis and DIC. The results of controlled clinical trials in humans are eagerly awaited.     

Fibrinolysis and disseminated intravascular coagulation in open heart sergery

Fibrinolysis and disseminated intravascular coagulation (DIC) have been implicated as the cause or contributing mechanisms for hemorrhage during and after cardiopulmonary bypass. Even when unassociated with hemorrhage, both processes have been thought to be common occurences during open heart surgery. In order to measure the degree to which these mechanisms occur, fibrin split products (FSP) were measured simultaneously in blood and chest tube drainage of open heart surgical patients. In addition, serial measurements of platelets and fibrinogen were also measured in the blood of these patients. It is concluded that fibrinolysis invariably occurs to a high degree in the chest postoperatively but with few systemic manifestations and that fibrinolysis and/or DIC are rare causes of a hemorrhagic diathesis after cardiopulmonary bypass.     

弥散性血管内凝血患者全血细胞组织因子活性改变的意义

目的 应用脂多糖(LPS,内毒素)刺激全血细胞组织因子(TF)的表达及促凝活性(TF-PCA)增强程度.观察弥散性血管内凝血(DIC)时TF-PCA的改变及在诊断DIC中的意义.方法 病例资料来源:华中科技大学同济医学院附属协和医院2005年1月至2007年1月住院急性粒细胞白血病患者,正常对照组(A组)38例,疾病组中相关凝血检查lF常病例(B组)8例,1～2项凝血检查异常组(C组)21例,疑似DIC组(D组,凝血检查3项或以上,但未达到DIC诊断标准者)12例,符合DIC诊断病例(E组)23例.采用用LPS刺激的全血复钙时间检测全血细胞TF活性(Tssue Factor Clotting Time,TiFaCr),即在抗凝全血中加入或不加IPS于370℃温育一定时间,然后复钙检查全血凝固时间,根据全血凝固时间缩短的程度(△s)来判断TF-PCA的强弱.应用SPSS 13.0软件进行成LSD-t检验及双变量相关性处理,以P<0.05为差异具有统计学意义.结果 对受检病例进行回顾性、描述性分析显示DIC、疑似DIC患者TF-PCA分别是(95.2±68.6)、(85.8±16.9)As与正常组(30.4±25.1)△s比较差异具有统计学意义(P<0.01),TF mRNA检测、TF-PCA抑制实验结果 提示TiFaCT.测定TF-PCA有较高的敏感性和特异性.结论 DIC和疑似DIC患者在LPS刺激后TF-PCA明显增强,TiFaCT 对于DIC的诊断及预后评价有重要临床参考价值.     

The pathogenesis and management of disseminated intravascular coagulation

The pathologic and progressive generation of thrombin in human blood can result in the development of disseminated intravascular coagulation (DIC), a syndrome associated with many underlying conditions and manifested as microvascular thrombosis, tissue hypoxia, and organ damage. DIC can be either acute or chronic, with acute DIC resulting from generation of a large amount of thrombin in a brief time period and chronic (compensated) DIC developing as a result of exposure of the coagulation system to small amounts of tissue factor leading to increased but nonacute levels of thrombin generation. DIC can also be considered a thrombohemorrhagic syndrome. Acute DIC at first manifests in a hypercoagulable state and leads to thrombosis, but can be followed by the development of a so-called hypocoagulable phase caused by depletion of clotting factors. This depletion can sometimes lead to bleeding. Bleeding is less common in chronic DIC, as coagulation factors and platelets are more likely to be able to be replenished in the majority of patients. Diagnosis of DIC can sometimes be difficult, depending upon the stage and presentation of the syndrome. During the thrombotic phase of DIC, many common laboratory parameters remain normal, with the important exception of an early drop in circulating platelets. DIC is easier to diagnose when the patient is bleeding, as abnormalities can normally be detected in global coagulation tests and factor assays. Therapy involves identification and treatment of the underlying condition, if possible. In the interim, measures to control bleeding can be administered, if necessary, and may include supportive care with blood products, antithrombin, heparin, and other agents.     

Trauma, sepsis, and disseminated intravascular coagulation

Disseminated intravascular coagulation (DIC) was first observed clinically in a case of sepsis following severe trauma. It was postulated that the observed clotting defect and bleeding were due to the using up of clotting factors in an episode of intravascular clotting. It was also postulated that the multiple organ failure observed was due to obstruction of the microcirculation of the organs by microclots. Evidence for this process was worked out in many animal studies. It was then postulated that if these microclots could be lysed before organ necrosis was produced, organ failure could be prevented. This prevention was shown to be possible in animals. It was then tried in humans using plasminogen activators, and the approach was found to be effective. Using a low dose of plasminogen activator over a 24-hour period caused no changes in the coagulation profile or bleeding.     

Heparin treatment in thrombin-induced disseminated intravascular coagulation in the baboon

BACKGROUND AND METHODS: We postulated that low-dose heparin (10 IU/kg.hr) administered as a continuous iv infusion may prevent or ameliorate the induction of thrombin-induced disseminated intravascular coagulation in baboons under general anesthesia. In a nonrandomized experiment lasting 8 hrs, animals were divided into three groups: 11 received thrombin only (group A); ten were pretreated with heparin before thrombin administration (group B); and 15 received heparin 2 hrs after disseminated intravascular coagulation was induced with thrombin (group C). All animals were monitored hemodynamically and coagulation tests were performed hourly. Tests included the following: one-stage prothrombin ratio; activated partial thromboplastin time; fibrinogen and fibrin degradation products; thrombin time; plasma fibrinogen level; antithrombin III and activated clotting time. After the acute phase of the experiment, the animals were observed for 6 days and a postmortem examination was performed on a survivor of each group. RESULTS: Six (55%) group A animals died within 6 days, while there were no deaths in group B and one animal (7%) died in group C. In group C, the administration of heparin could not normalize the clotting profile, but the mortality rate was significantly less than in group A. The prophylactic administration of heparin in group B prevented the induction of disseminated intravascular coagulation. The postmortem findings were of interest, but no statistically valid conclusions could be made, as only one autopsy was done for each group. However, the results suggest that heparin pretreatment may protect against lung edema and liver necrosis. CONCLUSIONS: The results suggest that heparin, in a dose of 10 IU/kg.hr iv, could possibly be safely used in patients at high risk of developing disseminated intravascular coagulation and in those patients with established disseminated intravascular coagulation.     

Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient

The incidence of sepsis and complications stemming from septicemia has remained constant in recent years despite improved levels of monitoring and care. Disseminated intravascular coagulation (DIC), a syndrome that occurs frequently in septic patients, is associated with increased mortality. Organ dysfunction is also a common sequela that is strongly correlated with DIC. Cytokines released early in the course of sepsis stimulate a procoagulant state that causes development of intravascular fibrin deposition. In a later stage of DIC, bleeding may occur in parallel because of consumption of clotting factors and inhibitors. Therapeutic strategies to attenuate or reverse these conditions have focused on multiple stages of the molecular cascade of events, including preventing cytokine induction, inhibiting coagulation processes, and promoting fibrinolysis. Recent clinical trials have supported the use of antithrombin and activated protein C supplementation in DIC associated with severe sepsis. Studies of other novel therapeutic avenues are still ongoing. Future efforts may be directed at combining 2 or more agents to achieve prompt and successful reversal of DIC. Copyright © 2002 by W.B. Saunders Company     

Modified score for disseminated intravascular coagulation in the critically ill

Objective To assess the value of the diagnosis of overt disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Haemostasis (ISTH) criteria and that of the parameters included in the ISTH score for overt DIC in predicting day 28 mortality in intensive care patients. Also, to assess the value of the components of the score in the diagnosis of overt DIC.Design and setting Retrospective clinical study in a university hospital intensive care unit.Patients and participants 494 consecutive patients admitted in the ICU between January 2002 and October 2003.Measurements and results Clinical and laboratory data, including hemostatic parameters, were collected from computerized databases and patient files. Altogether 19% (95/494) of the patients fulfilled the criteria for overt DIC. Their day 28 mortality rate was higher than that of patients without overt DIC (40% vs. 16%). The lowest platelet count (area under curve, AUC, 0.910), highest plasma D-dimer (AUC 0.846), lowest antithrombin (AUC 0.823), and Owren-type prothrombin time activity (AUC 0.797) discriminated well the patients with and without overt DIC, whereas plasma fibrinogen (AUC 0.690) had poor discriminative power. No patient with the diagnosis of overt DIC had decreased plasma fibrinogen. Day-1 SOFA and APACHE II score, the first CRP measurement, and the lowest antithrombin were independent predictors of day 28 mortality.Conclusions The diagnosis of overt DIC was not an independent predictor of day 28 mortality. In ICU patients plasma antithrombin seems a promising candidate in the panel of indicators for overt DIC whereas the value of plasma fibrinogen is in doubt.     

大鼠弥散性血管内凝血时水通道蛋白1基因表达与肾脏损伤的关系

目的 研究对Wistar大鼠滴注脂多糖(LPS)造成弥散性血管内凝血(DIC)后,肾脏细胞表面水通道蛋白1(AQP1)mRNA表达变化与其损伤的关系.方法 清洁级,雄性Wistar大鼠50只随机分为5组(每组10只):对照组(经鼠尾静脉持续4 h滴注10 mL生理盐水后直接取血及组织);DIC组:滴注LPS(30 mg/kg,溶于10mL生理盐水持续4 h鼠尾静脉滴注)后4 h,6 h,8 h,10 h组,在滴注LPS后4 h,6 h,8 h及10 h取血及组织.检测各组血小板(PLT)计数、凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、纤维蛋白原(FIB)、D-二聚体(D-D);各组.肾、肺组织苏木苏.伊红(HE)染色,观察肾、肺组织中微血栓形成情况及病理变化(结合血液学指标与病理变化判断DIC病程),提取各组大鼠肾组织总RNA,RT-PCR检测AQP1 mRNA水平的表达.采用SNK-q方法对结果进行统计学分析.结果 各实验组PLT计数、PT、APTT、FIB及D-D与对照组相比,差异具有统计学意义(P<0.01);滴注LPS后4 h的AOP1 mRNA表达较对照组下调(P<0.01),6 h达最低;滴注LPS后6 h肾小管细胞浊肿,8h肾小管细胞变性坏死.结论 肾脏AQP1 mRNA表达下调先于肾小管细胞的损伤,表明AQP1参与了大鼠DIC时肾小管细胞的损伤.