Prevention by methylprednisolone of disseminated intravascular coagulation induced by sustained infusion of endotoxin in rats

An experimental model of disseminated intravascular coagulation (DIC) could be induced by a sustained infusion of 100 mg/kg of endotoxin for 4 h. Using this experimental model of DIC, the preventive effect of methylprednisolone against DIC was examined. Rats were injected with methylprednisolone at 0.1, 1.0, 10.0 or 30.0 mg/kg i.p., and thereafter infused continuously with 100 mg/kg/4 h of endotoxin. When compared with rats given no methylprednisolone, the significant prevention was noted in parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the formation of fibrin thrombi in the glomeruli, in rats pretreated with 1.0, 10.0 or 30.0 mg/kg of methylprednisolone.     

Prednisolone inhibits endotoxin-induced disseminated intravascular coagulation and improves mortality in rats: importance of inflammatory cytokine suppression.

In order to determine whether prednisolone has a protective effect against the development of disseminated intravascular coagulation (DIC), we measured the effect of prednisolone on changes in hemostatic parameters and plasma levels of inflammatory cytokines in endotoxin-treated rats. Decreases in platelet count and fibrinogen levels, prolongation of prothrombin time, and increases in the plasma fibrin degradation products and levels of thrombin-antithrombin III (TAT) complex following the administration of endotoxin, all of which are associated with DIC, were significantly suppressed by the administration of prednisolone. Heparin administration significantly suppressed changes in all these parameters except for the decrease in platelet count. The combination of prednisolone and heparin was more effective than either treatment alone. In order to determine whether these effects of prednisolone are correlated with the suppression of inflammatory cytokine production, we examined the relationship between changes in plasma levels of cytokine, the hemostatic parameters listed above, and mortality using a number of intervention regimens designed to alter events of the experimentally induced DIC. Changes in hemostatic parameters associated with DIC following 30 mg/kg per 4 h of endotoxin infusion were significantly suppressed by treatment with 1 mg/kg prednisolone 30 min before beginning endotoxin infusion, followed by administration of 250 U/kg heparin 2 h after the start of endotoxin infusion (prednisolone-endotoxin-heparin regimen). The heparin and prednisolone were administrated subcutaneously. The administration of prednisolone and heparin in the reverse order (i.e. heparin first and prednisolone second: heparin-endotoxin-prednisolone regimen) also suppressed changes in hemostatic parameters, albeit to a smaller degree. Cytokine production was also significantly suppressed by the first treatment, but was not affected by the regimen in which heparin was administered first. Administration of prednisolone alone or heparin alone 30 min before endotoxin significantly reduced the number of renal glomeruli with fibrin thrombi. Plasma levels of creatinine and alanine transferase were reduced only by prednisolone. Increased plasma levels of interleukin-1beta, tissue necrosis factor-alpha and interleukin-6 were suppressed by prednisolone but not by heparin, and there were significant correlations between plasma levels of TAT and cytokines. Prednisolone was more effective than heparin in reducing mortality at 24 h after 100 mg/kg over 4 h of endotoxin infusion (four of 20 versus 15 of 20 deaths for prednisolone and heparin, respectively). These findings suggest that prednisolone inhibits the development of endotoxin-induced DIC and reduces mortality by a different mechanism than heparin, possibly through suppressing the production of inflammatory cytokines. Prednisolone may be efficacious in preventing DIC and multiple organ dysfunction caused by endotoxin.     

Prognostic value of platelet indices as determined by ADVIA 120 in patients suspected of having disseminated intravascular coagulation

Recent technological advances have made it possible to record a variety of platelet indices using automated hematology analyzers. Disseminated intravascular coagulation (DIC) is associated with the dramatic hemostasis activation, with evidence of fibrin formation and platelet consumption. We investigated the prognostic significance of platelet indices as measured by ADVIA in 222 patients suspected of having DIC. The presence of overt DIC was defined using the scoring system of the International Society of Thrombosis and Haemostasis Subcommittee. Twenty-eight day hospital mortality was used as a clinical prognosis parameter. Median platelet count and platelet-crit (PCT) levels markedly decreased in nonsurvivors, whereas mean platelet volume (MPV), platelet component distribution width (PCDW) and platelet dry mass distribution width (PMDW) were significantly increased in nonsurvivors. In terms of ROC analysis, which was conducted to predict 28-day mortality, areas under the receiver operating characteristic curve (AUC) were; 0.73 platelet count, 0.72 for PCT, 0.69 for PCDW, 0.65 for PMDW and 0.61 for MPV. The odds ratio of a reduced platelet count for the relative risk of 28-day mortality was 5.249 (95% CI: 2.399-11.486), and the odds ratio for PCDW was 3.240 and for PMDW 3.262. Among these indices, platelet count, PCDW and PMDW were found to be more predictive of 28-day hospital mortality. Our results suggest that these indices may provide prognostic information on hospital mortality in the patients suspected of having DIC.     

Disturbances of blood coagulation associated with Salmonella typhi infections

Disturbances of blood coagulation were studied in 32 consecutive patients with typhoid fever on their admission to hospital. Estimations of prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degradation products (FDPs), factors VII, VIII and XII, alpha I antitrypsin, plasminogen, CI esterase inhibitor, and platelet counts were performed as well as liver function tests and blood counts. Five patients had laboratory evidence of disseminated intravascular coagulation (DIC) and two had a generalised bleeding disorder which in the other three was inapparent. The platelet count in the group as a whole was low (P less than 0.05) and the FDPs in most cases were mildly elevated. The pre-kallikrein values were depressed in three of the five with DIC, whereas factor XII was not reduced. These results indicate that bleeding disorders in typhoid fever are uncommon. The depression of pre-kallikrein indicates that the DIC is probably triggered by activation of the intrinsic coagulation pathway. Most patients had lymphopenia and monocytopenia but only two had neutropenia.     

6,7-Dihydroxy-3-phenylcoumarin inhibits thromboplastin induced disseminated intravascular coagulation

6,7-Dihydroxy-3-phenylcoumarin (DHPC) was tested to determine whether it had any effect on vitamin K inhibition, by investigating the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen level and platelet count. The anticoagulant and antithrombotic effects of DHPC were compared with those of warfarin by conducting a 4 h acute trial on thromboplastin-induced disseminated intravascular coagulation (DIC), investigating various haemostatic and antioxidant system parameters and performing a haemogram. Of most significance was that in the 5-d DHPC trial on healthy controls, PT, APTT, fibrinogen, platelet count remained within normal levels. In the 4-h DIC trial, both DHPC (0.025 mg/kg, i.v.) and warfarin (0.25 mg/kg, i.v.) significantly inhibited DIC, by reducing the PT, APTT, and fibrin degradation products and increasing fibrinogen levels and platelet count. In the DIC drug groups, lipid peroxidation significantly increased only in the warfarin group and glutathione significantly increased only in the DHPC group. However leucocyte count was significantly higher in the DHPC than the warfarin group. Further investigation is required for why DHPC is effective on the parameters investigated, at doses one-tenth of those of warfarin.     

Clinical evaluation of acute and chronic pulmonary thromboembolism using intravascular ultrasound and angioscopy

Pulmonary artery thrombi and parietal lesions were observed in 13 patients (mean age 58 +/- 18 years) with acute pulmonary thromboembolism (n = 4) and chronic pulmonary thromboembolism (n = 9) using intravascular ultrasound and angioscopy at the time of right heart catheterization. Patients with acute pulmonary thromboembolism without underlying disease mainly had non-echogenic intraluminal mass, and good pulsatile vessel without intimal thickening. Angioscopy directly showed red thrombi with white fibrin coating, and no parietal lesions. Patients with chronic pulmonary thromboembolism could be classified into 3 groups: 1) Poor extensibility of the vessel wall and intimal thickening with non-echogenic thrombi on intravascular ultrasound, and relatively fresh parietal thrombi consisting of a mixture of red blood cell and fibrin, and spider web-like fibrin net on angioscopy (6 patients). 2) Crescent parietal thrombi and wall irregularity on intravascular ultrasound, and probably organized thrombi with a mixture of red and white surface on angioscopy (one patient). 3) Marked and echogenic intimal thickening and poor extensibility on intravascular ultrasound, and intimal surface irregularities and yellowish changes on angioscopy (one patient). All patients suffering acute deterioration in the chronic phase belonged to groups 1) or 2). Intravascular ultrasound and angioscopy are useful for characterizing the thrombi and related pulmonary artery lesions in patients with pulmonary thromboembolism. The pulmonary artery intima and thrombus differ between acute and chronic pulmonary thromboembolism.     

The role of granulocytes in the activation of intravascular coagulation and the precipitation of soluble fibrin by endotoxin

This study examines the role of neutrophils (PMN) in the pathogenesis of endotoxin-induced microclot formation. It is intended to clarify whether granulocytes are involved in endotoxin-induced activation of intravascular coagulation (generation of soluble fibrin) and/or in endotoxin-induced precipitation of soluble fibrin. Precipitation of soluble fibrin was achieved by injection of endotoxin into ancrod- infused rabbits with circulating soluble fibrin (first model). Activation of intravascular coagulation was elicited by two intravenous injections of endotoxin into rabbits (second model). Seventy-two and ninety-six hours after injection of nitrogen mustard, leukopenic rabbits had PMN counts between 0 and 50 cells per mul. Neutropenia did not prevent the occurrence of glomerular microclots after infusion of ancrod and injection of endotoxin (first model). Neutropenia influenced neither the decrease in mean fibrinogen concentrations nor the drop in mean platelet counts after ancrod and endotoxin administration. In contrast to the first model, neutropenia prevented the occurrence of glomerular microclots and of circulating soluble fibrin after two injections of endotoxin (second model). It did not, however, protect rabbits from the decrease in mean platelet counts after endotoxin administration. These data indicate that granulocytes are involved in endotoxin-induced activation of intravascular coagulation and the production of soluble fibrin but are not essential to endotoxin-induced precipitation of soluble fibrin.     

Aggravation of endotoxin-induced disseminated intravascular coagulation and cytokine activation in heterozygous protein-C-deficient mice

In the pathogenesis of sepsis and disseminated intravascular coagulation (DIC), dysfunctional anticoagulant pathways are important. The function of the protein C system in DIC is impaired because of low levels of protein C and down-regulation of thrombomodulin. The administration of (activated) protein C results in an improved outcome in experimental and clinical studies of DIC. It is unknown whether congenital deficiencies in the protein C system are associated with more severe DIC. The aim of the present study was to investigate the effect of a heterozygous deficiency of protein C on experimental DIC in mice. Mice with single-allele targeted disruption of the protein C gene (PC+/-) mice and wild-type littermates (PC+/+) were injected with Escherichia coli endotoxin (50 mg/kg) intraperitoneally. PC+/-mice had more severe DIC, as evidenced by a greater decrease in fibrinogen level and a larger drop in platelet count. Histologic examination showed more fibrin deposition in lungs, kidneys, and liver in mice with a heterozygous deficiency of protein C. Interestingly, PC+/- mice had significantly higher levels of proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, indicating an interaction between the protein C system and the inflammatory response. Survival was lower at 12 and 24 hours after endotoxin in the PC+/- mice. These results confirm the important role of the protein C system in the coagulative-inflammatory response on endotoxemia and may suggest that congenital deficiencies in the protein C system are associated with more severe DIC and adverse outcome in sepsis.     

Disseminated intravascular coagulation in sepsis.

Disseminated intravascular coagulation (DIC) has been considered a rather rare syndrome characterized by severe bleeding. In fact, both of these beliefs are wrong. Bleeding is fairly rare in DIC. The clotting parameters are usually normal unless the DIC is fulminating. It is usually thought that fibrinogen may be low or absent in DIC. However, afibrinogenemia is rare. Fibrinogen is usually high in DIC because of the high rate of fibrinogen manufacture by the liver in response to stress. DIC is very common and most cases are never diagnosed. This is because it has been hard to find fibrin thrombi in autopsy cases and because acute severe bleeding is uncommon. The reason fibrin thrombi are rare may be because they have been lysed by endogenous fibrinolytic enzymes before the autopsy. The appearance of endogenous fibrinolytic response could be a defense mechanism to lyse the microclots of DIC. In fact, this response is often successful. This defense can be aided by the administration of plasminogen activators that will lyse the clots. Heparin has been used for the treatment of DIC but has proved useless and is, in fact, dangerous. This is because heparin will not dissolve clots and may actually promote platelet agglutination. Administration of plasminogen activators will actually prevent bleeding diathesis.     

Thrombocytopenia in septicemia: the role of disseminated intravascular coagulation

The mechanism of isolated thrombocytopenia in septicemia is unknown, but compensated disseminated intravascular coagulation (DIC) has been suggested as a possible cause. To investigate this possibility, platelet counts and sensitive assays for in vivo thrombin and plasmin generation, including fibrinogen gel chromatography and fibrinopeptide A (FPA) assays, were obtained on 31 septicemic patients. Fifteen of 17 patients with gram-negative septicemia and 8 of 14 patients with gram- positive septicemia had thrombocytopenia. Platelet survival studied demonstrated a decreased platelet survival. In 11 of 12 patients with severe thrombocytopenia (platelet count less than 50,000mul), there was laboratory evidence of intravascular coagulation. In contrast, there was little evidence of intravascular coagulation in 8 of 11 patients with moderate thrombocytopenia (platelet counts 50,000 to less than 150,000/mul) or in 7 of 8 patients with normal platelet counts. This report indicates that while DIC accompanies thrombocytopenia in many patients with severe thrombocytopenia, there is frequently little evidence for intravascular coagulation in patients with moderate thrombocytopenia. It is apparent that factors other than intravascular thrombin must play a role in producing the thrombocytopenia of septicemia.     

Measurement of thrombus precursor protein in septic patients with disseminated intravascular coagulation and liver disease

BACKGROUND AND OBJECTIVES: Disseminated intravascular coagulation (DIC) is a syndrome characterized by systemic intravascular activation of coagulation leading to the widespread deposition of fibrin in the circulation. Therefore, the determination of soluble fibrin is crucial for the diagnosis of DIC. Thrombus precursor protein (TpP) levels can be determined as a measure of soluble polymers, which are the immediate precursors of insoluble fibrin. In this study, the potential diagnostic usefulness of this TpP test was investigated in septic patients with DIC and liver diseases. DESIGN AND METHODS: TpP analysis was performed on 155 plasma samples from 95 septic patients, including 72 patients without liver disease and 23 patients with liver diseases, and on 42 plasma samples from normal healthy subjects. The study population was subdivided according to three phases of DIC described as compensated, decompensated and full-blown DIC. Plasma TpP level was determined using a new assay, the TpPTM (American Biogenetic Sciences, USA), which is based on an ELISA method. RESULTS. Septic patients with decompensated (16.1 9.1 mg/mL) or full- blown (20.9 12.4 mg/mL) phases of DIC had significantly higher TpP levels than those with the compensated (5.6 6.2 mg/mL) phase of DIC or healthy controls (2.9 1.6 mg/mL). In septic patients with liver disease, a significant difference was found between the TpP levels of patients with full- blown DIC (21.6 10.6 mg/mL) and those of patients with the decompensated phase (13.4 6.5 mg/mL). Plasma TpP levels correlated significantly with other DIC parameters including platelet count, fibrinogen, antithrombin and TAT, and correlated weakly with D-dimer. INTERPRETATION AND CONCLUSIONS: Our findings indicate that septic patients who developed decompensated or full-blown DIC or organ dysfunction have significantly higher plasma levels of TpP, and suggest the potential usefulness of the TpP assay as an aid to the diagnosis of DIC in cases of sepsis and liver disease complicated by sepsis.     

Intravascular coagulation associated with the adult respiratory distress syndrome

In seven of 30 consecutive patients with the adult respiratory distress syndrome, disseminated intravascular coagulation (DIC) developed. Increasing respiratory dysfunction characterized by decreased effective static compliance and increased hypoxemia coincided with the development of DIC. Patients in whom DIC developed were characterized by a high incidence of bleeding, gangrene of the extremities, renal dysfunction, mortality and autopsy evidence of fibrin microthrombi in the lungs, kidney and skin.In 12 of 23 patients who did not meet the criteria for DIC, the platelet count decreased by at least 50 per cent of the initial values at some time during their illness. Fibrin microthrombi were found in the lungs in the majority of the patients subjected to autopsy. These data support the concept that deposition of platelets on damaged pulmonary capillary endothelium may be more common in the adult respiratory distress syndrome than the DIC syndrome.     

Coagulation abnormalities in rheumatoid disease

Forty-one patients with rheumatoid arthritis, including 6 with acute vasculitis, 13 with chronic vasculitis, and 22 without vasculitis, were studied for evidence of intravascular coagulation and fibrinolysis (ICF). The mean plasma fibrinogen levels were elevated in all groups. The fibrinogen, platelet count, and fibrin split products were usually elevated in acute vasculitis. Fewer patients on corticosteroids had abnormal coagulation tests. Active plasmin was detected in 12 patients primarily with chronic vasculitis. Plasminogen activator activity was not diminished in vascular endothelium of normal appearing skin of those patients with or without vasculitis. None of the patients demonstrated decompensated intravascular coagulation and fibrinolysis. The results suggest over-compensated ICF occurring in rheumatoid arthritis, but rheumatoid patients with vasculitis cannot be clearly distinguished from those without vasculitis on the basis of the usual tests performed for coagulation and fibrinolysis abnormalities.     

A case of heparin-induced thrombocytopenia with sepsis and congestive heart failure--first autopsy report on Japan--.

An 84-year-old man was referred to the emergency department with severe dyspnea. Based on his physical findings, electrocardiogram, X-ray and echocardiographic findings, congestive heart failure was suspected and drip infusion of prophylactic heparin against intracardiac thrombosis was commenced together with dopamine, nitroglycerin and furosemide. Diuresis occurred and the pulmonary congestion ameliorated remarkably. Starting on the 20th hospital day, the platelet count was gradually reduced (from 256,000 to 55,000 /microl) and the fibrin degradation product concentration rose (27.6 microg/ml). However, prothrombin time was not prolonged (89%), the concentration of antithrombin III was low -normal (69%) and the fibrinogen concentration was high (650 mg/dl). Thus, heparin-induced thrombocytopenia (HIT), rather than disseminated intravascular coagulation (DIC), was suspected. Heparin was withdrawn on the 24th hospital day and replaced by nafamostat mesilate after which the platelet count was restored to 100,000 /microl. Enzyme-linked immunosorbent assay for HIT antibodies was positive. Unfortunately, the patient died from uncontrolled sepsis on the 29th hospital day. At autopsy, platelet-rich thrombi were found in the small pulmonary arteries and intestinal arteries. No evidence of DIC, such as fibrin-rich thrombosis, was observed. This is the first autopsy report of HIT in Japan.     

Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy

Disseminated intravascular coagulation (DIC) is caused by a variety of underlying disorders, and criteria for diagnosis are not well defined. However, the most helpful are a low platelet count, positive plasma protamine test, and fibrinogen and fibrin degradation product levels viewed in the context of the patient's underlying disease. The cornerstone of therapy is prompt treatment of the underlying disease and elimination of the trigger mechanism. Additional treatment must be individualized, and generalizations are difficult to make. However, if the patient has low hemostatic factors and is actively bleeding or requires an invasive procedure, then replacement with the appropriate hemostatic factors should be tried. Heparin is indicated in patients with purpura fulminans and venous thromboembolism, but there is little evidence that heparin reverses organ dysfunction associated with DIC. In addition, heparin is also probably indicated in patients with retained dead fetus and hypofibrinogenemia prior to induction of labor, excessive bleeding associated with a giant hemangioma, and neoplastic disease, particularly promyelocytic leukemia. Although the use of heparin in acute forms of DIC remains controversial, the majority of studies suggest that it is not helpful. The role of antithrombin III (AT-III) concentrates is unknown, but they theoretically may be helpful when DIC is associated with very low AT-III levels, as is seen in liver disease.     

Hypercoagulopathy induced by chemotherapy in a patient with lung cancer. A possible role for a factor with thrombosis-inducing activity (TIA).

We treated a patient with lung cancer in whom a hypercoagulopathy was induced acutely by chemotherapy. He received systemic chemotherapy twice and in both instances developed disseminated intravascular coagulopathy (DIC), accompanied by acute decrements of the peripheral platelet count and plasma fibrinogen, an increment of the fibrin degradation products (FDP), and bleeding tendency with the appearance of skin purpura. In each instance, the plasma thrombosis-inducing activity (TIA) appeared one to three days after chemotherapy and subsided subsequently.     

老年肺心病急性加重期血小板参数的变化与高凝状态的研究

目的探讨老年肺心病急性加重期血小板4项分析参数的变化及对机体凝血功能的影响。方法分别测定40例老年肺心病急性加重期病人、37例经治疗后的缓解期病人及35名健康老年人的血小板4项参数值,包括血小板计数(PLT)、平均血小板体积(MPV)、血小板压积(PCT)、血小板分布宽度(PDW)。结果老年肺心病急性加重期病人PLT及PCT显著低于经治疗后的缓解期病人及健康老年人(P<0.01);而MPV,PDW则显著增高(P<0.05)。结论老年肺心病急性加重期可通过多种机制引起血小板参数的变化,进而造成机体高凝状态,是血栓及弥散性血管内凝血(DIC)形成的基础,同时对临床判断肺心病的病情及预后有重要意义。     

Increased plasma-soluble fibrin monomer levels in patients with disseminated intravascular coagulation

Plasma-soluble fibrin monomer (SFM) level in patients with disseminated intravascular coagulation (DIC) was significantly higher than the level in patients with pre-DIC or in non-DIC patients, and the level in patients with pre-DIC was significantly higher than that in non-DIC patients. There was no significant difference in plasma SFM levels among various diseases underlying DIC. Plasma SFM level in patients with good outcome was significantly decreased after treatment for DIC. The sensitivity of fibrin degradation products and platelet number was high for DIC, but not for pre-DIC. The sensitivity of thrombin-antithrombin III complex, plasmin-plasmin inhibitor complex, and SFM was high for both DIC and pre-DIC. The specificity of these markers was also high. Receiver operating characteristic analysis suggests that plasma SFM level could be the most useful marker for the diagnosis of both DIC and pre-DIC. © 1996 Wiley-Liss, Inc.     

International Society on Thrombosis and Haemostasis score for overt disseminated intravascular coagulation predicts organ dysfunction and fatality in sepsis patients.

We evaluated the score for disseminated intravascular coagulation (DIC) recently published by the International Society for Thrombosis and Haemostasis (ISTH) in a well-defined series of sepsis patients. Thirty-two patients suffering from severe sepsis and eight patients with septic shock were evaluated following the ISTH DIC score. Fibrin monomer and D-dimer were chosen as fibrin-related markers (FRM), respectively. DIC scores for nonsurvivors (n = 13) as well as for septic shock patients were higher (P < 0.04) compared with survivors and patients with severe sepsis, respectively. Using fibrin monomer and D-dimer, 30 and 25% of patients suffered from overt DIC. Overt DIC was associated with significantly elevated thrombin-antithrombin complexes and plasminogen activator inhibitor type-1 levels as well as with significantly lower factor VII clotting activity. Patients with overt DIC had a significantly higher risk of death and of developing septic shock. Since more than 95% of the sepsis patients had elevated FRM, the DIC score was strongly dependent on prolongation of the prothrombin time and platelet counts. The ISTH DIC score is useful to identify patients with coagulation activation, predicting fatality and disease severity. It mainly depends on the prolongation of the prothrombin time and platelet counts.     

川芎嗪对慢性肺原性心脏病急性加重期患者血小板活化功能的影响

探讨肺心病患者血小板活化功能的变化及川芎嗪对其影响。方法４６例慢性肺心病急性加重期患者随机分为２组，Ａ组２４例进行常规治疗：Ｂ组２２例在常规治疗基础上予川芭嗪注射液１２０ｍｇ／ｄ静滴，疗程均为１５日。