Plasmin-alpha 2-plasmin Inhibitor Complex Research Articles

Antithrombin III activity and platelet count are more likely to decrease in twin pregnancies than in singleton pregnancies.

It is not known whether antithrombin III activity and platelet count are more likely to decrease in women with twin pregnancies than singleton pregnancies. We enrolled 56 consecutive women with twin pregnancies and 692 consecutive women with singleton pregnancies. Antithrombin III activity and platelet count were determined at 26-31 weeks and again at 32-40 weeks of gestation. Thrombin-antithrombin complex, and plasmin-alpha2 plasmin inhibitor complex were measured simultaneously in some women. In twin pregnancies, both antithrombin III activity (111 +/- 8.2%) and platelet count (244 +/- 60 x 109/l) at 28.6 +/- 1.0 weeks decreased over time to 91 +/- 12% and 205 +/- 59 x 109/l, respectively, at 35.2 +/- 1.2 weeks; these decreases were significantly greater than in singleton pregnancies. However, a small number of women with singleton pregnancies had a significant decrease in antithrombin III activity in the absence of preeclampsia. The serum thrombin-antithrombin complex was significantly higher in twin pregnancies than in singleton pregnancies (9.7 +/- 4.2 ng/ml vs. 6.7 +/- 4.4 ng/ml, respectively, p < 0.01), and this increase correlated significantly with the decrease in antithrombin III activity in twin pregnancies (r = -0.459, p < 0.001). Antithrombin III activity and platelet count show a greater decrease in twin than in singleton pregnancies, perhaps due to a greater increase in thrombin generation.

Depressed plasma activity of plasminogen or alpha2 plasmin inhibitor is not due to consumption coagulopathy in septic patients with disseminated intravascular coagulation.

We have attempted to determine whether depressed plasma plasminogen and alpha2 plasmin inhibitor (or alpha2 antiplasmin) activity is, as a result of consumption coagulopathy, a specific finding of disseminated intravascular coagulation (DIC) in septic patients. The hemostatic parameters of 139 septic patients (68 with DIC and 71 without DIC) were analyzed. Among the group as a whole, plasma activities of plasminogen and alpha2 plasmin inhibitor were significantly depressed in septic patients with DIC relative to those without DIC (P < 0.01 and P < 0.05, respectively). Notably, a significant correlation was observed between plasma levels of albumin and plasminogen activity, as well as between plasma levels of albumin and alpha2 plasmin inhibitor activity both in septic patients with DIC and those without DIC. However, no significant correlation was observed between plasma levels of plasmin-alpha2 plasmin inhibitor complex (PIC) and plasminogen activity, nor between PIC and alpha2 plasmin inhibitor activity either in septic patients with DIC or those without DIC. We concluded that depressed activity of plasminogen or alpha2 plasmin inhibitor is not as a result of consumption coagulopathy, but rather a result of low synthetic function of the liver in septic patients with DIC.

An enhanced fibrinolysis prevents the development of multiple organ failure in disseminated intravascular coagulation in spite of much activation of blood coagulation.

To investigate the relationship between fibrinolytic enhancement and the development of multiple organ failure (MOF) in disseminated intravascular coagulation (DIC). To detect the useful prognostic index for outcome in DIC. Case-control study. A department of internal medicine in a university hospital, a clinical division for diagnosis and treatment, mainly of respiratory diseases, hematologic diseases, DIC, and other diseases requiring critical care medicine. A total of 69 DIC patients, 31 with MOF. None. The DIC patients with MOF had more elevated levels of tissue plasminogen activator antigen (t-PA) and plasminogen activator inhibitor antigen (PAI), and more depressed levels of plasmin-alpha2 plasmin inhibitor complex (PIC) and fibrin/fibrinogen degradation products than those without MOF, although no significant difference in thrombin-antithrombin complex (TAT) levels was observed. A fibrinolytic enhancement (shown by PIC) was parallel to an activation of blood coagulation (shown by TAT) in DIC patients without MOF, although no such fibrinolytic enhancement was provoked even by much activation of blood coagulation in DIC patients with MOF. Whereas all the patients without MOF were restored from DIC, 14 of 31 patients with MOF were unable to be restored from DIC and died. A significant increase in plasma levels of t-PA and PAI under the condition of sustained hemostatic activation was observed in the patients who died. Enhanced fibrinolysis was considered to be the important defense mechanism in preventing the development of MOF in DIC. The increases in plasma levels of t-PA and PAI were poor prognostic markers in DIC. Further careful study may be useful to clarify whether the fibrinolytic therapy is beneficial in clinical DIC patients with MOF.

Predictive values of coagulation/fibrinolysis parameters for the termination of pregnancy complicated by severe preeclampsia.

We investigated coagulation/fibrinolysis parameters for significant differences between patients with early-onset severe preeclampsia (< 32 weeks gestation, wG) and those with late-onset severe preeclampsia (> or = 32 wG). A decrease in antithrombin (AT), protein C (PC), and free protein S (PS) activities and an increase in plasmin-alpha2-plasmin inhibitor complex (PIC), thrombin-antithrombin complex (TAT), and FDP D-dimer (D-dimer) were observed. However, there were no statistical differences between the two groups. Once preeclampsia occurred and it developed severe, the changes in coagulation/fibrinolysis parameters became more severe in spite of early-onset preeclampsia or late-onset preeclampsia. We also investigated coagulation/fibrinolysis abnormalities in 101 patients with severe preeclampsia. A significant increase in WBC, RBC, Hb, Ht, TAT, PIC, and D-dimer and a significant decrease in platelet (Plt) counts and AT activity were observed. deltaPlt (the difference between platelet counts in early gestation and before delivery) was -5.0 x 10(4)/microL in cases with severe preeclampsia. Among patients with severe preeclampsia, coagulation/fibrinolysis changes before delivery were typical for patients with cesarean section compared with those with successful vaginal delivery. These facts suggest that an excessive hypercoagulable state is associated with the termination of pregnancy resulting from the aggravation of preeclampsia. From the viewpoint of coagulation/fibrinolysis changes, the termination of pregnancy could be recommended when the levels of parameters exceed the following values; deltaPlt > -6.0 x 10(4) microL, D-dimer > 4 microg/mL, AT activity < 79%, TAT > 26 ng/mL, and PIC > 1.2 microg/mL. Particularly, deltaPlt and D-dimer are useful bedside predictive markers in order to decide the optimal time for the termination of pregnancy in patients with severe preeclampsia.

Mental stress and physical exercise increase platelet-dependent thrombin generation.

Thrombin generation is an important factor in the pathogenesis of thrombogenic disorders and acute coronary syndromes. Increase in mental stress has been associated with the initiation of the acute coronary syndromes, but the exact mechanism is not known. The present study examined the effects of physical exercise and mental stress on platelet-dependent thrombin generation. Twelve healthy men (mean age 34.2 +/- 2.4 years) underwent a treadmill exercise test and a mental stress test by performing mental arithmetic. Platelet-dependent thrombin generation and plasma concentrations of catecholamines, thrombin-antithrombin III complex (TAT), plasmin-alpha2 plasmin inhibitor complex (PIC), and plasminogen activator inhibitor-1 (PAI-1) were measured before, immediately after, and at 10 and 30 min after stress. Thrombin generation increased significantly immediately after exercise, followed by rapid normalization. Mental stress caused a significant increase in thrombin generation 10 min after stress. While plasma concentrations of epinephrine, norepinephrine, and dopamine were elevated immediately after exercise, and rapidly returned to baseline, only plasma norepinephrine increased immediately after mental stress. TAT and PIC concentrations did increase immediately after exercise; however, PAI-1 remained unchanged. The increase in thrombin generation with exercise and mental stress was unaffected by treatment with 81 mg/day of aspirin of 7 days. However, it was inhibited by a single oral 40-mg dose of metoprolol. Both exercise and mental stress cause an increase in platelet-dependent thrombin generation, which was suppressed by beta-blocker therapy, but not by aspirin.

Plasma and platelet plasminogen activator inhibitor-1 in patients with acute myocardial infarction.

Several studies have demonstrated an increased level of plasma plasminogen activator inhibitor-1 (PAI-1) in patients with coronary artery disease (CAD). However, the concentration of PAI-1 in platelets, which accounts for more than 90% of the blood PAI-1, is unknown in these patients. The present study evaluated the concentrations of PAI-1 and several fibrinolytic factors in the plasma and platelets of patients with CAD and the serial changes in patients with acute myocardial infarction (AMI). All 72 subjects had coronary angiography and were divided into 3 groups: CAD(-) group without coronary artery stenosis or myocardial ischemia (n=20), CAD(+) group with either stable angina pectoris (n=18) or old myocardial infarction (n=12) with coronary artery stenosis, and the AMI group admitted within 24h of symptom onset who underwent successful percutaneous transluminal coronary angioplasty (n=22). The concentrations of plasma PAI-1, tissue plasminogen activator (t-PA), and t-PA x PAI-1 complex were similar in the CAD(-) and CAD(+) groups, but were greater on day 1 in the AMI group compared with the 2 CAD groups. There were no significant differences between the 3 groups in the plasma concentrations of thrombin antithrombin III complex (TAT), alpha2-plasmin inhibitor-plasmin complex (PIC), beta-thromboglobulin (beta-TG), and platelet factor 4 (PF-4). The platelet PAI-1 concentrations did not differ between the CAD(-) and CAD(+) groups, but was greater on day 1 in the AMI group compared to the CAD groups. The platelet beta-TG and PF-4 were similar between the 3 groups. In the AMI group, both the plasma and platelet PAI-1 concentrations were greater on day 1, but the plasma PAI-1 rapidly decreased by day 5 and remained low on day 28 compared with day 1. The platelet PAI-1 concentration gradually decreased by day 5 and was further decreased by day 28. The serial changes of the plasma t-PA and t-PA PAI-1 complex during the course of AMI were similar to those of the plasma PAI-1. A positive correlation was found between the plasma and platelet PAI-1 in all 72 patients, but not in the AMI group alone. These results suggest that the PAI-1 that has accumulated in platelets at the onset of AMI might be released in large amounts into the plasma, resulting in an increase in thrombus formation.

Study of cardiovascular risk factors and hemostatic molecular markers in elderly persons.

In this study, plasma concentrations of hemostatic molecular markers were investigated in 118 elderly persons with normal renal function (aged 65 to 97 years) who could manage their activities of daily living (ADL) by themselves, to find a strategy for conservation or elevation of ADL and quality of life (QOL). In all subjects, the frequency by which hemostatic markers exceeded their upper limit of normal range was 35.9% for thrombin-antithrombin HI complex (> or = 3.7 ng/ml), 38.3% for soluble fibrin monomer (> or = 4.0 microg/ml), 41.8% for D-dimer (> or = 1.0 microg/ml), 49.0% for plasmin-alpha2 plasmin inhibitor complex (> or = 1.0 microg/ml), and 53.7% for thrombomodulin (> or = 20 ng/ml). The mean plasma levels of these markers were slightly higher than the upper limit of their normal range. These markers were also investigated in samples of patients with and without cardiovascular risk factors and with and without cardiovascular diseases (ischemic heart disease and/or cerebral infarction). Furthermore, the results were analyzed in relationships between cardiovascular disease and cardiovascular risk factor or aging. The findings suggest that aging exerts a stronger influence on plasma levels of these hemostatic molecular markers than the presence of cardiovascular risk factors and cardiovascular diseases. From the viewpoint for conservation or elevation of ADL and QOL in elderly persons, also other factor, such as drug intake, lifestyle, aging, and so on, must be considered to clarify the relationship between the plasma levels of the hemostatic molecular markers and cardiovascular risk factors or cardiovascular diseases.

Monoclonal antibody specific for tissue factor pathway inhibitor-factor Xa complex

Tissue factor pathway inhibitor (TFPI), a Kunitz-type protease inhibitor with three tandem inhibitory domains (K1, K2 and K3), inhibits the initial reactions of the extrinsic blood coagulation pathway through its K1 and K2 domains. We prepared and characterized a monoclonal antibody (Mab8-1) against TFPI-factor Xa (TFPI-Xa) complex. The reactivities of Mab8-1 toward TFPI-Xa complex, TFPI without C-terminal (TFPI-C)-Xa complex, K1K2-Xa complex and K2K3-Xa complex were examined using a surface plasmon resonance analysis (Biacore). The Biacore system allowed a quantitative analysis of antibody-antigen interaction, in real time, from which the association and dissociation rate constants could readily be obtained. The bindings of Mab8-1 to TFPI-Xa complex, TFPI-C-Xa complex and K2K3-Xa complex were each concentration-dependent. However, no binding of Mab8-1 to the K1K2-Xa complex was observed. The binding of Mab8-1 to TFPI or Xa was also not observed. These results suggested that the epitope for Mab8-1 was exposed in the K3 domain of TFPI, which was generated by the conformational change after the formation of TFPI-Xa complex. We then developed an enzyme-linked immunosorbent assay method specific for TFPI-Xa complex using Mab8-1, and we used this assay to measure plasma levels of TFPI-Xa. The normal range assessed from analyses of plasma from 30 normal healthy volunteers was 17.7-66.7 with a mean of 35.5 +/- 11.7 pmol/l. In order to asses the clinical implication of TFPI-Xa complex in the plasma of patients with thrombotic disorders, plasma concentrations were measured in 37 patients with disseminated intravascular coagulation (DIC) caused by a variety of underlying diseases. The TFPI-Xa antigen levels were significantly higher in the patients with DIC (51.9 +/- 21.6 pmol/l) and the 36 patients with pre-DIC (55.1 +/- 20.2 pmol/l) than in the 137 non-DIC patients (37.9 +/- 13.1 pmol/l). In the patients with DIC or pre-DIC, there was no significant correlation between TFPI-Xa complex and the elevated levels of thrombin-antithrombin complex, plasmin-alpha2 plasmin inhibitor complex, D-dimer, soluble fibrin monomer, soluble thrombomodulin or tissue factor. These data indicate that the plasma level of TFPI-Xa seems to be a novel independent molecular marker of DIC and pre-DIC.

An Activated State of Blood Coagulation and Fibrinolysis in Patients with Abdominal Aortic Aneurysm

Background: Relationships between blood coagulation and the fibrinolysis system and morphology of aneurysms in patients with abdominal aortic aneurysm (AAA) are unknown. Methods: Preoperative and postoperative evaluations of hemostatic factors such as thrombin-antithrombin III complex (TAT), D-dimer, fibrinogen/fibrin degradation products (FDP), and platelet count were performed in 36 patients with atherosclerotic AAA. As control subjects, 25 age- and sex-matched healthy volunteers were analyzed for these hemostatic factors. In all patients, morphological evaluation of AAA included the largest diameter, tortuosity, and the thickness of intraluminal thrombus to be compared with preoperative levels of hemostatic factors such as alpha-2 plasmin inhibitor-plasmin complex (PIC), thrombomodulin (TM), von Willebrand factor (vWF), tissue factor (TF), and free form of tissue factor pathway inhibitor (F-TFPI). Results: The preoperative values of TAT, D-dimer, and FDP were significantly higher in AAA patients than in controls. Of all patients, 23 (64%) or 22 (58%) had TAT or D-dimer values greater than 8.2 ng/mL or 3.4 μg/mL (mean + 2SD of controls), respectively. The postoperative values of these hemostatic factors significantly improved, but were not normalized. The largest diameter of AAA correlated with the preoperative levels of TAT ( r = 0.566, P = 0.001), D-dimer ( r = 0.644, P = 0.0001), FDP ( r = 0.561, P = 0.0009), PIC ( r = 0.413, P = 0.0146), and F-TFPI ( r = 0.408, P = 0.0158). We have also found that tortuosity of AAA has relation not only to the preoperative levels of fibrinolytic factors but also to the plasma F-TFPI antigen levels. On the other hand, the preoperative levels of a marker of endothelial damage, such as TM or vWF, and TF did not correlate with those of F-TFPI in all patients. The maximum thickness of thrombus in AAA significantly correlated not only with the preoperative levels of TAT, D-dimer, FDP, and PIC, but also with AAA size. Conclusions: We have found evidence that an activated state of both blood coagulation and fibrinolysis in AAA patients is associated with the morphological characteristics of aneurysms.

Comparison of extradural and general anaesthesia on the fibrinolytic response to total knee arthroplasty

Extradural anaesthesia is associated with lower incidences of deep vein thrombosis after total knee arthroplasty. It is not known if the type of anaesthesia influences thrombogenesis or fibrinolysis during knee surgery performed under tourniquet. We studied 31 patients allocated randomly to receive either extradural or general anaesthesia for primary unilateral total knee arthroplasty performed under tourniquet. Radial artery blood samples were obtained before surgery, during surgery with the tourniquet inflated and on deflation of the tourniquet. Plasma samples were assayed for markers of thrombin generation and fibrinolysis. Two of the circulating indices of thrombin generation, fibrinopeptide A and thrombin-antithrombin complexes, increased to a similar degree in the perioperative period in both groups. Fibrinolytic activity was similar in both groups, as measured by tissue plasminogen activator (t-PA) antigen, t-PA activity, t-PA-plasminogen activator inhibitor complexes, alpha 2-plasmin inhibitor-plasmin complexes and D-dimer. Extradural and general anaesthesia did not result in significant differences in either thrombin generation or fibrinolytic activity during total knee arthroplasty performed under tourniquet.

25. Coagulation factor XI: rather a fibrinolytic inhibitor than a coagulation factor

Post-cardiac arrest syndrome (PCAS) is often associated with disseminated intravascular coagulation (DIC), thus leading to the development of multiple organ dysfunction syndrome (MODS). The aim of this study was to examine the pathophysiological relationships between coagulation, fibrinolysis and fibrinolytic shutdown by evaluating the levels of coagulofibrinolytic markers, including soluble fibrin, thrombin-activatable fibrinolysis inhibitor (TAFI), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPAIC), plasmin-alpha2 plasmin inhibitor complex (PPIC), neutrophil elastase and fibrin degradation product by neutrophil elastase (EXDP).Fifty-two resuscitated patients were divided into two groups: 22 DIC and 30 non-DIC patients.The levels of soluble fibrin, PPIC, tPAIC, EXDP and neutrophil elastase in the DIC patients with PCAS were significantly higher than those observed in the non-DIC patients. The values of the tPAIC and JAAM DIC scores were found to be independent predictors of increased SOFA scores in the DIC patients. The MODS patients demonstrated significantly higher levels of soluble fibrin and tPAIC; however, the levels of TAFI and EXDP were identical between the patients with and without MODS. In addition, positive correlations were observed between the levels of tPAIC and EXDP in the patients with non-MODS; however, no correlations were observed between these markers in the MODS patients.Thrombin activation and fibrinolytic shutdown play important roles in the development of organ dysfunction in PCAS patients. Neutrophil elastase-mediated fibrinolysis cannot overcome the fibrinolytic shutdown that occurs in DIC patients with PCAS, thus resulting in the development of MODS.

Earthquake-Induced Potentiation of Acute Risk Factors in Hypertensive Elderly Patients: Possible Triggering of Cardiovascular Events After a Major Earthquake

Objectives. We sought to investigate the potentiation of acute risk factors after the Hanshin-Awaji earthquake (7.2 on the Richter scale).Background. The frequency of cardiovascular events increases just after a major earthquake, but the causative factors have not been fully investigated.Methods. We studied the changes in cardiovascular risk factors in 42 elderly outpatients with well-controlled hypertension living near the epicenter (Awaji-Hokudan districts) 7 to 14 days after the earthquake when the major felt-aftershocks persisted. They all experienced the highest stress grading of 6 (catastrophic stress) according to the DSM-III-R. To study the hemostatic profile and endothelial cell state, we measured the blood pressure (BP), hematocrit and lipid profiles as well as fibrinogen, a marker of fibrin turnover (d-dimer), fibrinolytic factors (plasmin-alpha2–plasmin inhibitor complex [PIC], tissue-type plasminogen activator [t-PA] antigen and t-PA inhibitor [PAI] activity) and an endothelial cell-derived marker (von Willebrand factor [vWF]).Results. Systolic and diastolic blood pressures and other variables increased after the earthquake. Before and after the earthquake, the median (25th to 75th percentiles) systolic BP was 152 (range 142 to 164) and 170 mm Hg (range 161 to 178), respectively (p < 0.0001), and the diastolic BP was 83 (range 79 to 88) and 91 mm Hg (range 84 to 96), respectively (p < 0.0001). Of blood viscosity determinants, hematocrit was 38.1% (range 40.7% to 35.9%) and 39.7% (range 42.9% to 38.3%), respectively (p < 0.001), and fibrinogen 316 (range 272 to 360) and 335 mg/dl (range 307 to 391), respectively (p < 0.05). Von Willebrand factor was 128% (range 74% to 148%) and 148% (range 100% to 178%), respectively (p < 0.01); d-dimer was 410 (range 285 to 633) and 560 ng/ml (range 391 to 888), respectively (p < 0.0001); and PIC was 0.74 (range 0.58 to 0.91) and 0.75 μg/ml (range 0.58 to 1.1), respectively (p < 0.05). In contrast, lipid profiles did not change after the quake. When the patients were classified into the high stress and moderate stress groups according to the degrees of damage to their house and injury to family members, the levels of fibrinogen, vWF, PIC and t-PA antigen were increased only in the former group, whereas BP, hematocrit and d-dimer levels were increased in both groups. These abnormalities of acute risk factors, except for vWF, were transient and decreased to prequake levels by 4 to 6 months after the quake.Conclusions. Earthquake-induced stress seems to induce transient increases in BP, blood viscosity determinants and fibrin turnover and to prolong endothelial cell stimulation. The potentiation of these acute risk factors might contribute to the occurrence of cardiovascular events just after a major earthquake in elderly subjects with hypertension.(J Am Coll Cardiol 1997;29:926–33)© 1997 by the American College of Cardiology

Response of Fibrinolytic Proteins and Endothelin 1 to Venous Occlusion in Patients on Chronic Hemodialysis

The main purpose of the present study was to determine whether any abnormalities in the response of fibrinolytic activity to venous occlusion could be observed in patients undergoing chronic hemodialysis (HD patients). A 10-min venous occlusion test was performed in 13 HD patients and in 9 healthy subjects. The arm opposite to the arteriovenous fistula was occluded in HD patients. The following factors were measured: tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), plasmin-alpha2-plasmin inhibitor complex (PIC), stabilized fibrin degradation product (D-dimer), and von Willebrand factor antigen determined by enzyme immunoassay, and endothelin 1 by radioimmunoassay with two antibodies. Preocclusion levels of PIC, D-dimer, von Willebrand factor, and endothelin 1 were significantly higher and those of t-PA significantly lower in HD patients than in controls. During the occlusion, there was a positive correlation between the percent changes in t-PA and von Willebrand factor and between those in von Willebrand factor and PIC. There was no correlation between percent and absolute changes during the occlusion in endothelin 1 and those in t-PA, PAI-1, PIC, D-dimer, or von Willebrand factor. There was no significant difference between HD patients and controls as to the percent changes in hematocrit, t-PA, PIC, D-dimer and von Willebrand factor. HD patients demonstrated a significantly greater percent change in PAI-1 than controls. The mechanism by which endothelin 1 is released in response to the occlusion appears to differ from that for t-PA, PAI-1, and von Willebrand factor. PAI-1 may be readily released in response to stimuli to blood vessels in HD patients.

Interleukin-6 is a useful marker for early prediction of the severity of acute pancreatitis.

Twelve patients with acute pancreatitis admitted to our department between January 1993 and December 1994 were studied prospectively and classified into two groups (severe group, five patients; mild group, seven patients), according to the criteria for grading severity of acute pancreatitis proposed by the Research Committee for Intractable Diseases of the Pancreas, Japanese Ministry of Health and Welfare (1990). To evaluate markers for early estimation of the severity of acute pancreatitis, we measured serum changes in various parameters. In the severe group interleukin-6 (IL-6) levels were increased significantly 5, 24, 72, and 120 h after the onset (p < 0.01), compared with the mild group. C-reactive protein (CRP), thrombin antithrombin III, and alpha 2-plasmin inhibitor plasmin complex levels were significantly increased only at the 72-h time point. Peak values of interleukin-8 (IL-8) and soluble human E selectin were observed at 5 and 72 h, respectively, after the onset. There was a significant correlation between IL-6 at 5 h and both pancreatic secretory trypsin inhibitor (r = 0.85) and CRP (r = 0.94) at 72 h. We therefore conclude that IL-6 is a useful marker for assessment of the severity of acute pancreatitis in its early stages.

Nafamostat mesilate reduces blood-foreign surface reactions similar to biocompatible materials

Nafamostat mesilate (FUT-175) is a synthetic serine protease inhibitor that inactivates coagulation, fibrinolysis, and platelet aggregation. Nafamostat mesilate may suppress the blood-foreign surface reaction similar to biocompatible materials by blocking factor XIIa. We performed an in vitro study of cardiopulmonary bypass (CPB) with fresh human blood among the following three groups: standard CPB sets (C), biocompatible CPB sets (B), and standard CPB sets with FUT-175 (10 mg/L) (F). A clinical study using these same CPB groups also was performed in 45 patients undergoing aortocoronary bypass operations (15 patients each). We injected FUT-175 at 40 mg/h during CPB. In the in vitro study, both groups B and F showed significantly lower levels of coagulation factors, thrombin-antithrombin III complex, fibrinopeptide A, beta-thromboglobulin, complement C3a, granulocyte elastase, and free hemoglobin than group C at the conclusion of the study. Thrombin-antithrombin III complex and free hemoglobin in group F also were lower than in group B. The platelet count remained at a higher level in group F than in the other groups. Separation of bradykinin was suppressed most significantly in group F. In the clinical study, group F also showed significantly lower levels of alpha 2-plasmin inhibitor plasmin complex and C3a than both groups C and B. There were minimal levels of free hemoglobin in group F. Nafamostat mesilate may contribute major beneficial effects toward conservation of blood during CPB and prevention of coagulopathy after CPB.

Sustained activation of blood coagulation in patients with cerebral thrombosis.

Recent progress in the measurements of the hemostatic markers enables us to assess the detailed profiles of hemostatic activation in various diseases. To evaluate the degree of hemostatic system activation in patients with cerebral thrombosis, detailed coagulation studies were performed in 28 patients with acute-phase cerebral thrombosis and in 36 with chronic-phase cerebral thrombosis, together with 6 with chronic-phase cerebral hemorrhage and 37 age-matched healthy volunteers. In both acute-phase and chronic-phase cerebral thrombosis, plasma levels of thrombin-antithrombin III complex, plasmin-alpha 2-plasmin inhibitor complex and D-dimer were significantly higher, and antithrombin III and protein C were significantly lower than those in the normal group. Plasma fibrinogen concentration was significantly higher in chronic-phase cerebral thrombosis than that in chronic-phase cerebral hemorrhage. No significant difference was found in these variables between acute-phase and chronic-phase cerebral thrombosis. In addition, there was no difference in these parameters between chronic phase cerebral hemorrhage and normal subjects. These findings indicate that a sustained activation of coagulation and fibrinolysis is present in cerebral thrombosis, and it might contribute to the pathogenesis of cerebral thrombosis.

Alterations in coagulation and fibrinolysis after surgery for aortic aneurysm.

We investigated the alterations in the coagulation and fibrinolysis systems after aortic aneurysm surgery under cardiopulmonary bypass (CPB) while using newly developed "molecular markers". Fibrinogen and antithrombin III (AT-III) decreased after surgery but returned to normal values within three days. The thrombin-antithrombin III complex (TAT) and plasmin-alpha-2-plasmin inhibitor complex (PIC) both showed increased values even preoperatively, which indicated that coagulation and fibrinolysis were activated in some patients with an aortic aneurysm. Both markers maintained a high level for at least 14 days after surgery. The fibrin degradation product (FDP) also showed an increased value before and after surgery. These results apparently showed that coagulation/fibrinolysis had already been activated in some patients and maintained such a state for at least 14 days after surgery. The relation of activated system and postoperative organ dysfunction as well as the means to suppress such activation are also discussed.

Coagulation activity is increased in the left atrium of patients with mitral stenosis

Objectives. This study investigated the hemostatic status of the right and left atria in patients with mitral stenosis.Background. Systemic thromboembolism is a serious major complication in patients with mitral stenosis. However, the pathogenesis of thromboembolism in mitral stenosis is not fully understood.Methods. We determined the plasma levels of biochemical markers for platelet activity (platelet factor 4 and beta-thromboglobulin) and status of thrombin generation (fibrinopeptide A and thrombin—antithrombin III complex) and fibrinolysis (D-dimer and plasmin—alpha2-plasmin inhibitor complex) in specimens of blood obtained from the peripheral vein and right and left atria of 12 consecutive patients with mitral stenosis who were undergoing percutaneous mitral valvuloplasty.Results. Plasma levels of platelet factor 4, beta-thromboglobulin, D-dimer and plasmin—alpha2-plasmin inhibitor complex in the patients did not differ significantly between the right and left atria, whereas levels of fibrinopeptide A and thrombin-antithrombin III complex in the left atrium were significantly higher than those in the right atrium (fibrinopeptide A in the left and right atria 19.35 ± 4.64 and 6.31 ± 0.75 ng/ml [mean ± SE], respectively, p < 0.02; thrombin-antithrombin III complex in the left and right atria 11.45 ± 2.29 and 3.98 ± 0.60 ng/ml, respectively, p < 0.01). Levels of fibrinopeptide A and thrombin-antithrombin III complex in the left atrium did not correlate with mean transmitral gradient, dimension of the left atrium or reciprocal of the mitral valve area. Peripheral blood plasma levels of von Willebrand factor antigen were significantly higher in the patients than in an age-matched control group of normal subjects (168 ± 25% and 99 ± 7%, respectively, p < 0.05) but showed no difference in the peripheral blood and right and left atria of the patients.Conclusions. The coagulation system is activated in the left atrium of patients with mitral stenosis even during anticoagulation.

Blood coagulation and fibrinolysis in eclamptic patients and their correlation with the clinical signs.

We studied the impact of blood coagulation and fibrinolysis on the clinical features of eclamptic patients (n = 20) in Bangladesh. The variables used were edema, proteinuria, blood pressure, number of convulsions, level of consciousness at the time of admission, thrombin antithrombin complexes (TAT), antithrombin (AT) III (%) activity and antigen, D dimer fibrin degradation product and alpha 2-plasmin inhibitor-plasmin complex (PIC) in plasma. Canonical correlation analysis was made to obtain clinical index, eclampsia index and two coagulation indices. On admission, the mean values of coagulation parameters were AT III activity: 83.2% (range 57-108), TAT complex: 47.6 ng/ml (range 11.5-60), D dimer: 1,693 ng/ml (range 417-8,276) and PIC 1.4 mg/ml (range 0.4-3.3). We found a significant correlation between the eclampsia index and clinical index (r = 0.601; p = 0.01). Gestosis index, clinical index, and eclampsia index have also a strong correlation with the coagulation index (r = 0.695, p < 0.005; r = 0.871, p < 0.0001 and r = 0.805, p < 0.0001, respectively). Coagulation and fibrinolysis were markedly activated in eclampsia. The correlation between the clinical status and coagulation status in this study suggested a close relation between the coagulation and the development and progression of the disease.

Low Incidence of Hemorrhagic Infarction Following Coronary Reperfusion with Nasaruplase in a Canine Model of Acute Myocardial Infarction. Comparison with Recombinant t-PA.

An examination was made of the coronary thrombolytic effects of nasaruplase in a canine model of acute myocardial infarction. The model was produced by selective injection of an artificial thrombus into the coronary artery stenosed by laser ablation. Intravenous nasaruplase (8 U/kg/min) showed an equivalent thrombolytic effect to a recombinant tissue-type plasminogen activator (rt-PA, 10,000 IU/kg/min) as assessed by reperfusion rate (78.6 versus 79.2%) and reperfusion time (37.4 +/- 5.2 versus 37.0 +/- 2.5 min). Nasaruplase decreased the plasma alpha 2-plasmin inhibitor (alpha 2-PI) level by 28% immediately after reperfusion, but hardly altered fibrinogen or plasmin-alpha 2-plasmin inhibitor complex (PIC) levels. By contrast, rt-PA significantly decreased plasma alpha 2-PI and fibrinogen levels, by 84% and 92% respectively, and, increased PIC level more than 70-fold. Hemorrhagic infarction occurred in 2 of 14 animals in the nasaruplase group and in 9 of 19 animals in the rt-PA group. In these animals, significant correlations were found between the ratio of the hemorrhagic infarction area to total infarct area and the plasma alpha 2-PI (r = -0.740, p < 0.05) or fibrinogen (r = -0.798, p < 0.05) concentrations, as well as between the recovery rate of left ventricular regional wall motion and the plasma alpha 2-PI (r = 0.924, p < 0.01) or fibrinogen (r = 0.864, p < 0.01) concentrations. It is concluded that nasaruplase is a potent thrombolytic agent which preserves left ventricular function with a lesser rate of hemorrhagic infarction than rt-PA. Further, nasaruplase administration results in recovery of left ventricular regional wall motion and systolic function, such as Vmax.