Evaluation of plasma tissue plasminogen activator (I-PA) levels in patients with liver diseases

Previous studies have demonstrated that plasma tissue plasminogen activator (t-PA) level was elevated in patients with liver disease. In this study, t-PA antigen levels were investigated in patients with acute hepatitis (AH; N = 12), chronic hepatitis (CH; N = 8), compensated liver cirrhosis (CLC; N = 40), decompensated liver cirrhosis (DLC; N = 23) and hepatocellular carcinoma (HCC; N = 35). The increased t-PA levels (higher than 14 ng/ml) were found in 33% (4/12) of AH on the early hospital days, 25% (2/8) of CH, 45% (18/40) of CLC and 91% (21/23) of DLC, and 60% (21/35) of Hcc cases. In patient with LC, the correlations between t-PA levels and serum total bilirubin (T.Bill) and hepatic synthetic functions were investigated. The results were that the t-PA levels correlated positively with T. Bil and negatively with liver synthetic functions such as albumin, protein C and choline-esterase, indicating that t-PA increased almost in proportion to the deterioration of hepatic function. Serial determination of t-PA in patients with HCC treated by transcatheter arterial embolization (TAE) revealed that TAE failed to normalize the t-PA levels. In one case of HCC complicated with disseminated intravascular coagulation (DIC), t-PA showed a marked increase at acute phase of DIC and subsequent decrease after the successful treatment for DIC by gabexate mesilate (FOY) infusion. These results suggest that increased t-PA in liver disease is due mainly to deterioration of hepatic function, and that secondary fibrinolytic state, such as DIC, is also a contributing factor.     

Thrombin vs. plasmin generation in disseminated intravascular coagulation associated with various underlying disorders.

In order to assess the thrombin and plasmin generation in vivo in disseminated intravascular coagulation (DIC), plasma levels of thrombin-antithrombin III (ATIII) complex (TAT) and plasmin-alpha 2-antiplasmin (a2AP) complex (PAP) were measured together with standard coagulation and fibrinolytic parameters in 80 patients with DIC. Both TAT and PAP were markedly elevated in patients with DIC. When plotted by the underlying disease categories, differences in the magnitude of the elevations of these complexes were recognized among groups. Patients with acute promyelocytic leukemia (APL) had the highest PAP, the lowest TAT/PAP ratio, low a2AP, and low fibrinogen, indicating that the most excessive fibrinolysis can occur in APL. Similar profiles, although less marked, were observed in patients with other leukemias and vascular diseases. Patients with sepsis showed the highest TAT/PAP ratio and the lowest PAP with no decrease in a2AP or fibrinogen, demonstrating a relatively impaired fibrinolysis. Patients with cancer had a relatively high TAT and high TAT/PAP ratio. In addition, both TAT and PAP were markedly elevated in patients with shock. From these, it was suggested that, although laboratory manifestations in DIC are extremely variable from patient to patient, underlying disorders are, at least in part, responsible for the observed variations. Recognition of this variable activation of coagulation and fibrinolysis would be helpful for the proper management of patients with DIC.     

Blood coagulation changes in systemic lupus erythematosus

Changes of blood coagulation in 32 cases of SLE were investigated. Abnormalities frequently found were elevation of blood fibrinogen, FDP, V111R: Ag levels, prolonged or shortened KPTT time, and depressed AT-III value. Half of the patients with SLE showed laboratory changes compatible with the diagnostic criteria of DIC, but acute DIC was encountered clinically only in 2 cases hypercoagulation state or hypercoagulation with lower fibrinolysis, however were frequently seen. Lupus anticoagulant were detected in 6 patients and deep vein thrombosis of lower extremity in 1 patient. Examination of blood coagulation in patients with SLE was, therefore, of clinical importance.     

Roles of protein C, protein S, and antithrombin III in acute leukemia

Protein C, protein S, and antithrombin III were measured in 35 patients with acute leukemia (13 with AML and 22 with ALL). Low levels of proteins C and S were present in 15 (42.9%) and 20 (57.1%) patients, respectively, and 6 patients had low levels of antithrombin (ATIII). Seven patients also had DIC at presentation. There were no significant differences in the levels of protein C, protein S, and ATIII in patients with or without DIC. Twenty patients were available for re-evaluation at the end of induction therapy. The low levels of protein C and ATIII found at diagnosis had risen to normal levels at the end of the induction therapy, while low =levels of protein S remained in 75% of the patients. One patient with low protein C at presentation developed myocardial infarction on day 15, and another patient died of progressive neuropathy. No other thrombotic manifestations were seen. Whether the low protein C, protein S, or antithrombin levels predispose patients with acute leukemia to thrombosis in the absence of DIC is not known.     

Factors and inhibitors of blood coagulation and fibrinolysis in acute nonlymphoblastic leukaemia

Factors of coagulation and fibrinolysis have been evaluated in 15 patients with untreated acute nonlymphoblastic leukaemia (ANLL). 10 patients had major bleeding (MB) and 6 had laboratory signs of DIC. 5 patients went into complete remission (CR). Antithrombin III (AT III) was decreased in 7 patients, antiplasmin (AP) in 9, fibronectin (FN) in 6 and factor XIII in 4/12. The ratio between factor VIIIR:Ag and factor VIII:C was over 2.0 in 11 patients, and high values were especially seen in patients with MB and patients with DIC. Spontaneous proteolytic activity, measured with S-2288 was increased in 3 patients who all had MB, and none of whom achieved CR. 2 patients with promyelocytic leukaemia (M3) had low fibrinogen and AP, high FDP and normal AT III, speaking for primary fibrinolysis, which in addition to proteolytic enzymes in the blast cells are important contributing factors regarding MB in ANLL.     

Elevated TFPI in malignant disease: relation to cancer type and hypercoagulation

We have previously reported high levels of the coagulation inhibitor TFPI in the blood of patients with gastrointestinal cancer. TFPI is not an acute-phase reactant, but high levels have also been reported in patients with septicaemia and disseminated intravascular coagulation (DIC). To study its relationship with other types of malignancy, TFPI activity was first determined in plasma samples from 214 patients with various malignancies. In a second cohort of 83 patients, total and free TFPI antigen, protein C, antithrombin, fibrin monomer and D-dimer were also measured. Elevated TFPI activity and antigens were found in about half of the patients with solid tumours. In contrast, elevated TFPI was rare in haematological malignancies (12%). In the 18 patients with acute nonlymphocytic leukaemia (ANLL), elevated free TFPI was found only in patients who also had DIC. No correlation was found between TFPI levels and fibrin monomer or D-dimer levels. Only four out of 20 patients with solid tumours had normal levels of fibrin monomer and D-dimer, yet three out of these four had elevated TFPI. In conclusion, elevated TFPI in ANLL is related to the coexistence of DIC. In solid tumour disease increased TFPI may reduce protective fibrin formation, but the pathogenic mechanism is as yet unknown.     

Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies.

STUDY OBJECTIVE: Our aim was to document the following in patients with septic shock and disseminated intravascular coagulation (DIC): (1) the influence of DIC in the mortality rate and the occurrence of organ failure; (2) the comparative prognostic value of initial antithrombin III (ATIII), protein C (PC), and protein S (PS) levels; and (3) the compared pattern of sequential ATIII, PC, and PS levels according to clinical outcome. DESIGN: Demographic data, criteria of severity, mortality in ICU, frequency of organ failure, hemodynamic and oxygenation parameters, and laboratory findings were compared in patients with septic shock according to the occurrence of DIC. Initial and sequential levels of ATIII (activity), PC (antigen and activity), PS (total and free), and C4b binding protein (C4bBP) were compared according to the outcome in patients with DIC. PATIENTS: Sixty patients with septic shock were studied. Forty-four entered the group DIC+; 16 entered the group DIC-. RESULTS: Simplified acute physiologic score (SAPS), frequency of acquired organ failure, blood lactate, and transaminase values were significantly higher in the group DIC+. The mortality rate reached 77 percent in group DIC+ vs 32 percent in DIC- (p less than 0.001). In patients with DIC, a fatal outcome was associated with higher bilirubin and transaminase levels, lower PaO2/FIo2 ratio, Vo2, Do2 and O2 extraction. In the group DIC+, all patients but two had severe deficiencies in ATIII and PC levels. Significant correlations were found between initial ATIII and PC levels, PC and free PS levels, and free PS and C4bBP levels. Initial ATIII levels had the best prognostic value for prediction of subsequent death. Serial measurements were consistent with a prolonged ATIII and PC deficiency with significantly different levels between survivors and nonsurvivors. CONCLUSIONS: DIC is a strong predictor of death and multiple organ failure in patients with septic shock. Sequential ATIII, PC, and PS measurements were consistent with prolonged consumption or inhibition that might account for a sustained procoagulant state and inhibition of fibrinolysis. The initial ATIII level was the best laboratory predictor of death in these patients.     

Activation and complexation of protein C and cleavage and decrease of protein S in plasma of patients with intravascular coagulation

Activated protein C (APC) is inhibited by two major plasma inhibitors (PCIs). To find evidence for in vivo complexation of APC, immunoblotting studies were performed on plasmas of 85 patients with suspected disseminated intravascular coagulation (DIC). Samples from 62 of these patients contained 5% to 35% of protein C antigen in APC:inhibitor complexes, indicating that protein C activation and inhibition had occurred. In 24 normal plasmas, no detectable APC:PCI complexes were observed (less than 5%). Patients with higher levels of complexes had more abnormal coagulation test data for DIC. The major band of APC complexes detected by anti-protein C antibodies did not react with antibodies to the heparin-dependent protein C inhibitor (PCI- 1) previously described. Rather, APC was complexed with another recently described plasma protein C inhibitor, PCI-2. Immunoblotting studies for protein S, the cofactor for APC, revealed that the majority of the DIC patient plasmas contained a higher than normal proportion of protein S in cleaved form, suggesting that protein S may have been proteolytically inactivated. Protein S total antigen levels were also found to be low in DIC patients, excluding those with malignancy. These studies support the hypothesis that the protein C pathway is activated during DIC.     

Elevated levels of cytokines in plasma from patients with disseminated intravascular coagulation

We measured blood concentrations of tumor necrosis factor (TNF), interleukin-1 beta (IL 1-beta), soluble interleukin 2 receptor (s-IL 2r), and interferon alpha (IFN alpha) in 30 patients with disseminated intravascular coagulation (DIC) and compared the results to those of 25 patients without DIC. Plasma levels of TNF, IL 1-beta, and s-IL 2r were higher in patients with DIC than in those without DIC. In one case of acute promyelocytic leukemia, plasma levels of TNF and IL-1 beta increased at the onset of DIC but decreased upon DIC improvement. These findings suggest that activation of the immune system is involved in the development of DIC. However, these concentrations were not markedly increased in patients with leukemia, although blood TNF and s-IL 2 r were markedly elevated in patients with solid cancers. Especially in patients with solid cancers, hyperactivation of the immune system may cause an increase in blood TNF and IL-1 beta and the development of DIC.     

Role of endothelin in disseminated intravascular coagulation.

We examined the changes in plasma levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, in 47 cases of disseminated intravascular coagulation (DIC) to investigate the role of ET-1 in DIC and its relation to multiple organ failure (MOF). A significant elevation of plasma levels of ET-1 was observed in some cases of DIC, especially in patients with sepsis, blastic crisis of chronic myelogenous leukemia, and cancer. However, no such significant elevation was observed in patients with acute promyelocytic leukemia (APL), acute leukemias except for APL, or non-Hodgkin lymphoma. Plasma levels of ET-1 were higher in patients with DIC with MOF than in those without MOF. Although the levels of ET-1 were decreased or remained low with clinical improvement in most DIC patients, the levels were further increased or remained high in patients who showed no improvement in DIC. It is suggested that ET-1 must play an important role in further progression of MOF with the vasoconstriction and microcirculatory disorders.     

Activation of the coagulation cascade in patients with leptospirosis.

BACKGROUND: Disseminated intravascular coagulation (DIC) is common among patients with sepsis. Leptospirosis is an important cause of sepsis in tropical areas, and pulmonary hemorrhage associated with thrombocytopenia is the major cause of death, but the coagulopathy in severe leptospirosis has not been further characterized. The aim of this study was to evaluate coagulation factors and the presence of DIC in patients with leptospirosis in northeast Thailand. METHODS: We measured plasma concentrations of fibrinogen, D-dimer, thrombin-antithrombin III complexes, and prothrombin fragment 1,2 and evaluated the DIC score in 79 patients with culture-confirmed and/or serologically confirmed leptospirosis and in 33 healthy Thai control subjects. RESULTS: The median concentrations of fibrinogen, D-dimer, thrombin-antithrombin III complexes, and prothrombin fragment 1,2 were significantly elevated in a cohort of 79 patients with leptospirosis, compared with healthy control subjects (P相似文献   

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.     

Activation of the coagulation cascade in severe falciparum malaria through the intrinsic pathway

. The mechanisms involved in the activation of the coagulation cascade in severe falciparum malaria were studied in 22 adult patients (19 male, three female) aged 18-45 (mean ± SD 31 ± 11) years. Of these, nine had multiple vital organ dysfunction, and bleeding occurred in four patients, two of whom died. During acute illness the reduction in plasma antithrombin III (AT III) concentrations and elevation in thrombin-AT III complexes were associated with significant reductions in factor XII and prekallikrein activities, and an increase in the C1 inhibitor antigen/activity ratio. Serial plasminogen activity remained within the normal range in all patients while protein C activity was significantly reduced. All patients had markedly elevated plasma polymorphonuclear leucocyte elastase (PMN-elastase) levels with mild depletion of alpha-2 macroglobulin but normal concentrations of alpha-1 antitrypsin. There was no correlation between PMN-elastase concentrations and any of the coagulation parameters or concentrations of proteinase inhibitors. These results suggest that the intrinsic pathway of the clotting cascade is activated in severe malaria. This may cause activation of the complement system and release of bradykinin and PMN-elastase and could contribute to the pathogenesis of severe malaria.     

Mechanism of the therapeutic effect of anisodamine in disseminated intravascular coagulation: study of platelet adhesion and aggregation, malondialdehyde, thromboxane B2, 6-keto-prostaglandin F1 alpha, and microcirculation

Acute disseminated intravascular coagulation (DIC) is a life-threatening condition that may be encountered in many situations, especially in cases of shock with uncontrollable hemorrhage. Anisodamine, an alkaloid extracted from a Chinese herb, is well known for its dramatic therapeutic effect on DIC. Sixty male rabbits were used to establish an acute DIC model. A total of 240 blood samples were taken for laboratory assays of changes in blood coagulation factors, platelet count, platelet adhesion, platelet aggregation, malondialdehyde (MDA), thromboxane B2 (TXB2), and 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Changes of the microcirculatory status and the rate of the blood flow in the conjunctival capillaries of 60 rabbits were observed with WXS-II microcirculation microscope. Pathological sections of the lungs and kidneys were studied. Our investigation showed the presence of microthrombi in the microvasculature. After treatment with anisodamine, the prothrombin time stayed in the normal range, fibrinogen consumption was lessened, adenosine-diphosphate-induced platelet aggregation was inhibited, thromboxane B2 and malondialdehyde concentrations were significantly lower than in the control group, and the elevated quantity of 6-keto-PGF1 alpha was spared. We concluded that the anti-platelet-aggregating, microcirculation-facilitating, thromboxane-B2-inhibiting, malondialdehyde-inhibiting, and 6-keto-PGF1 alpha-sparing effects of anisodamine are the important mechanisms of its dramatic therapeutic effect on DIC.     

Antithrombin III, plasminogen and alpha 2 antiplasmin in jaundice. Clinical usefulness and prognostic significance.

In this prospective study, antithrombin III, plasminogen and alpha 2 antiplasmin which are synthetised by the liver were measured and compared with the Normotest, Thrombotest and fibrinogen concentrations in 92 consecutive jaundiced patients. Antithrombin III appeared to be the most discriminant coagulation test in differentiating hepatocellular from cholestatic jaundice. A high correlation was observed between antithrombin III, plasminogen and alpha 2 antiplasmin values suggesting that the liver synthesis of these parameters was closely linked. The prognostic significance of the blood coagulation tests in patients with jaundice has been studied. In parenchymatous liver disease, antithrombin III, plasminogen and alpha 2 antiplasmin were superior to the Normotest, Thrombotest and fibrinogen concentrations in predicting the prognosis of the patients at the time of admission. In cholestatic jaundice, however, none of the blood coagulation tests studied had a prognostic significance.     

Decreased plasma activity of antithrombin or protein C is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation

We investigated whether depressed plasma antithrombin and protein C activity, considered as a specific finding of disseminated intravascular coagulation (DIC), is due to consumption coagulopathy in septic patients with DIC. An analysis of hemostatic parameters was performed in 139 septic patients (68 with DIC and 71 without DIC). Plasma activity of antithrombin and protein C tended to be significantly decreased in septic patients with DIC but not in those without DIC (p < 0.001). However, when the septic patients were classified into three groups according to the albumin (or choline esterase) level, no significant differences in antithrombin activity or protein C activity were observed between the patients with and without DIC in any of the subgroups. Notably, neither the plasma activity of antithrombin nor protein C was decreased even in septic patients with DIC who had normal plasma levels of albumin (or choline esterase). No significant correlation was observed between plasma levels of thrombin-antithrombin complex (TAT) and antithrombin activity, or between plasma levels of TAT and protein C activity either in septic patients with DIC or without DIC. It is reasonable to conclude that the markedly reduced plasma activity of antithrombin and protein C is not due to consumption coagulopathy in septic patients with DIC.     

Systemic oxygen saturation and coagulation factor abnormalities before and after the fontan procedure

Coagulation factor abnormalities are believed to predispose to increased risk for thromboembolism after the Fontan procedure. Recent data, however, suggest that coagulation abnormalities may precede the operation. This study determined coagulation factor abnormalities in patients with single-ventricle congenital heart defects before the Fontan procedure and compared the findings with age-matched post-Fontan patients and control subjects. Liver function, coagulation factor levels, and pulse oximetry readings were determined in 11 pre-Fontan patients aged 9.3+/-5.6 years. The results were compared with those of 11 age-matched post-Fontan patients, at 9.1+/-2.4 years after the Fontan procedure, and 11 age-matched controls by simple analysis of variance and post hoc Tukey's test. Liver function was normal in patients before and after surgery apart from mildly elevated bilirubin levels in post-Fontan patients (p=0.027). When compared with controls, pre-Fontan patients had significantly lower levels of protein C; protein S; antithrombin III; and factors II, V, VII, and X and longer prothrombin times (all with p<0.05). When compared with post-Fontan patients, pre-Fontan patients had similarly lower levels of free protein S (p<0.001), protein C (p=0.06), and antithrombin III (p=0.001). Systemic oxygen saturation correlated positively with the levels of anticoagulants (protein C, protein S, antithrombin III) and procoagulants (factors II, V, VII, and X) (all with p<0.05, r=0.33 to 0.61). In conclusion, the findings suggest that coagulation factor abnormalities precede the Fontan procedure and tend to normalize after the operation, relating perhaps to improved systemic oxygenation.     

Global fibrinolytic capacity in pediatric patients with sepsis and disseminated intravascular coagulation.

There are many complex pathophysiologic changes of the coagulation system in sepsis. The fibrinolytic system was evaluated in septic children using the global fibrinolytic capacity (GFC), a new technique reflecting the overall fibrinolytic activity. The study consisted of 24 children with sepsis, 36 children with sepsis plus disseminated intravascular coagulation (DIC), and 20 healthy age-matched control individuals. Compared with controls, 86% of sepsis patients and 87% of sepsis plus DIC patients had decreased GFC levels. Between the sepsis plus DIC and sepsis groups there was no significant difference in terms of GFC levels. While 19 patients (52.7%) died in the sepsis plus DIC group, only three patients (12.5%) died in the sepsis group. When survivors and nonsurvivors were compared in terms of coagulation tests, there were significant differences for protein C, antithrombin, platelet, fibrinogen, aspartate aminotransferase, alanine aminotransferase, prothrombin time, and white blood cell values. In conclusion, the level of GFC reduced in most of the pediatric sepsis patients but no difference was observed between patients with sepsis and patients with sepsis plus DIC. While inhibition of fibrinolysis is an important finding in sepsis, the mortality is mainly associated with the presence of end-organ damage and the status of coagulation parameters.     

Disseminated intravascular coagulation in lupus erythematosus with acute liver damage.

A case of disseminated intravascular coagulation (DIC) in a patient with systemic lupus erythematosus (SLE) with acute liver dysfunction is described. A 37-year-old man with SLE developed acute DIC and marked liver damage after fracture of the right clavicle and pharyngitis. Treatment with high-dose steroids, heparin, antithrombin III, gabexate mesilate, and antibiotics resulted in prompt improvement. The recovery of an SLE patient after acute DIC and marked liver damage is considered very rare. We report here such a case and discuss the previous reports.     

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.