Evaluation of hypercoagulable state in patients with malignancies by using prothrombin fragment F1 + 2]

In order to elucidate the activation of the coagulation cascade in patients with malignant neoplasms, we measured the levels of plasma prothrombin fragment F1 + 2, which is liberated in the process of thrombin generation. Twenty healthy adults (Group A), 29 patients with malignancies not complicated with DIC (Group B) and 4 patients with DIC (Group C) were evaluated. The values of F1 + 2 in Group C (2.38 +/- 0.55 nmol/l) were significantly higher (p < 0.01) than those in Group A (0.52 +/- 0.19 nmol/l) and B (0.86 +/- 0.68 nmol/l). Many patients in Group B showed higher levels of F1 + 2 compared to normal subjects, however, no significant differences were found between Group A and B. With respect to other coagulation molecular markers such as TAT, D-Dimer and PIC, F1 + 2 levels revealed positive correlation to those levels. Concerning the clinical course of DIC, elevated levels of F1 + 2 normalized much rapidly than those of TAT and D-Dimer by continuous administration of heparin. In conclusion, the measurement of plasma F1 + 2 is important in monitoring the activation of coagulation system in patients with malignancies, especially with respect to early detection and treatment of DIC.     

Comparison of prothrombin fragment 1 + 2 with thrombin-antithrombin III complex in plasma of patients with disseminated intravascular coagulation.

Plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT) are thought to be specific indicators of thrombin generation. To assess whether these two parameters behave similarly in vivo, we compared the plasma levels of F1 + 2 with TAT in 41 patients with disseminated intravascular coagulation (DIC). Both F1 + 2 and TAT were markedly elevated in patients with DIC compared to healthy subjects. Although a positive correlation was found between F1 + 2 and TAT (r = 0.585, P < 0.001) there was a large scatter among individuals. In addition, plasma concentrations of TAT were much lower than F1 + 2. The correlation between the TAT/F1 + 2 ratio and antithrombin III was weak (r = -0.268, P = 0.09). The TAT/F1 + 2 ratio was positively correlated with TAT (r = 0.481, P = 0.002), indicating that the difference in molar concentrations between F1 + 2 and TAT decreased as the TAT value increased. Serial determinations of these parameters showed that plasma TAT values changed roughly in parallel with F1 + 2 in the majority of patients. Although further studies are required to further clarify the observed differences between F1 + 2 and TAT, both parameters would be equally useful for the precise detection of haemostatic activation in patients with DIC.     

Disseminated intravascular coagulation in liver cirrhosis

We measured thrombin-antithrombin III complex (TAT), soluble fibrin (SF) and D-dimer levels in 51 patients with liver cirrhosis to determine whether these tests provide new evidence for the presence of disseminated intravascular coagulation (DIC) in liver cirrhosis. TAT levels (median, range) were increased in the patient group (4.2 micrograms/l, 1.8-60.0) compared to the reference group (2.0 micrograms/l, range 1.5-7.6 micrograms/l). SF levels (0 nmol/l, range 0-80 nmol/l) were also increased in the patients as compared to the controls (0 nmol/l, 0), but there was no correlation between TAT and SF levels (r = 0.23, p less than 0.98). TAT levels did not correlate with AT-III levels (r = -0.36, p less than 0.49), but there was an inverse correlation between SF and AT-III (r = 0.60, p less than 0.001). If AT-III levels were above 0.30 U/ml, SF levels remained low, whereas SF levels were increased in patients with AT-III levels below 0.30 U/ml. These findings suggest that if sufficient AT-III is present, thrombin formation is adequately controlled, whereas at low levels of AT-III, thrombin escapes inactivation by AT-III and may act upon fibrinogen, leading to the formation of SF and a low-grade DIC. SF levels correlated well with D-dimer levels (r = 0.55, p less than 0.001), which is consistent with DIC and secondary fibrinolysis. In conclusion: (1) thrombin formation is increased in liver cirrhosis, as indicated by increased TAT levels in 21 of 51 patients; (2) the plasma concentration of AT-III appears to be of major importance for the development of DIC. The present study provides evidence for DIC in severe liver cirrhosis when AT-III levels are less than 0.30 U/ml.     

Hemostatic study before onset of disseminated intravascular coagulation

Early diagnosis is necessary for the treatment of disseminated intravascular coagulation (DIC), but criteria for the stage preceding the diagnosis of DIC (pre-DIC) have not yet been established. To clarify hemostatic abnormalities that occur before the onset of DIC, we performed hemostatic studies in 117 patients within at least a week before the onset of DIC (pre-DIC), in 237 patients with DIC, and in 50 patients without DIC or pre-DIC (non-DIC). Levels of FDP, PT, and fibrinogen, and platelet counts were significantly abnormal after the onset of DIC, but not before. Thrombin-antithrombin III complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), and FDP-D-dimer levels were significantly higher before the onset of DIC compared to the non-DIC patients. Hemostatic abnormalities were observed within a week before the onset of DIC. Monitoring the plasma levels of TAT, PIC, and FDP-D-dimer might be useful for the diagnosis of a pre-DIC condition.     

Clinical significance of thrombin-antithrombin III complex and plasmin-alpha 2 plasmin inhibitor complex in chronic liver diseases

Thrombin-antithrombin III complex (TAT) and Plasmin-alpha 2 plasmin inhibitor complex (PIC) were examined in fifty two cases of various chronic liver diseases. TAT was significantly elevated in cases of hepatocellular carcinoma (HCC), but PIC did not show significant changes in any chronic liver diseases. Elevations of TAT and PIC were seen in cases of HCC accompanied by tumor enlargement and extensive tumor thrombosis. In cases of HCC undergoing transcatheter arterial embolization (TAE), TAT and PIC increased on the next day after TAE, and tended to recover with time, returning to almost normal at fourth week. Prolongation of prothrombin time, elevation of FDP and positive FM test were noted more often in liver cirrhosis with disseminated intravascular coagulation (DIC) than in severe liver dysfunction without DIC. Of five cases confirmed as DIC, only three cases were diagnosed as DIC by DIC score. On the other hand, TAT and PIC were significantly elevated in DIC cases. Especially, TAT exceeded 30 ng/ml in all DIC cases. TAT was regarded to be useful for the diagnosis of DIC in severe liver dysfunction.     

Induction of Autoimmune Colitis by Yersinia enterocolitica 60-kilodalton Heat-Shock Protein

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-α₂ plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.     

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.     

Significance of hemostatic molecular markers during disseminated intravascular coagulation in patients with liver cirrhosis treated by endoscopic embolization for esophageal varices.

We studied the quantitative changes of hemostatic molecular markers with time during the course of disseminated intravascular coagulation (DIC) induced by endoscopic embolization using thrombin for esophageal varices in nine patients with liver cirrhosis. The plasma levels of D-dimer, a product of plasmin degradation of cross-linked fibrin, and thrombin-antithrombin-III complex (TAT) were significantly higher in patients before treatment when compared with 60 healthy individuals. The plasma levels of TAT, D-dimer, and plasmin alpha 2-plasmin inhibitor complex (PIC) increased significantly 5-15 min after thrombin injection into the varices, earlier than the changes of conventional coagulofibrinolytic factors, reached a maximum level after 180 min, and started to decline after 1 day. Although the plasma PIC level returned to normal after 7 days, both TAT and D-dimer were still above the pretreatment level. Although there was no change in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) increased significantly after 5 min. The plasma level of plasminogen activator inhibitor type 1 (PAI-1) showed only a slight elevation after treatment. We propose that the hemostatic molecular markers TAT, D-dimer, and PIC are suitable for the early diagnosis of DIC after endoscopic embolization using thrombin in patients with liver cirrhosis and that the increase of PAI-1 is too small for the regulation of fibrinolysis due to t-PA in DIC occurring in liver cirrhosis.     

Thrombin generation in acute promyelocytic leukemia

Six patients with disseminated intravascular coagulation (DIC) in association with acute promyelocytic leukemia (APL) were studied with sensitive radioimmunoassays that are able to quantitate the extent of thrombin generation within the human circulation. The levels of prothrombin activation fragment, F1 + 2, and thrombin-antithrombin complex (TAT) were obtained at clinical presentation and were then followed serially in several patients during induction chemotherapy. The antileukemic therapy often resulted in a rise in the plasma levels of these molecular species. Simultaneous measurements of fibrinopeptide A (FPA) were also obtained, and the concentrations of this polypeptide were correlated with the levels of F1 + 2 and TAT in patients who were not receiving heparin. Nine individuals with other morphological subtypes of acute nonlymphocytic leukemia (ANLL) were investigated and were usually found to have increased levels of F1 + 2, TAT, and FPA at clinical presentation. However, the magnitude of the elevations was considerably greater and the correlation between TAT and FPA levels was stronger in APL than in ANLL. These studies provide direct evidence that patients with APL, as well as ANLL, generate excessive amounts of thrombin within their vascular system. Furthermore, the data suggest that the concentrations of F1 + 2, compared with the levels of FPA, may be a more sensitive indicator of hemostatic system hyperactivity in individuals with DIC.     

Hemoperfusion With a Polymyxin B Fiber Column Decreases Clotting Activity

We investigated whether hemoperfusion with a polymyxin B column (DHP‐PMX) was able to improve coagulation abnormalities in patients with sepsis. Sixteen patients with sepsis were enrolled in the study. They all had signs of systemic inflammatory response syndrome due to infection and a mean arterial blood pressure ≥65mm Hg (irrespective of the use of catecholamines). A thermodilution catheter was inserted prior to DHP‐PMX for intravenous infusion, and DHP‐PMX was performed twice within 24 h for 3 h each time. Circulating levels of thrombin–antithrombin complex (TAT), plasmin‐α2 plasmin inhibitor complex (PIC), the TAT/PIC ratio, and plasminogen activator inhibitor‐1 (PAI‐1) were measured six times. Before DHP‐PMX, the TAT level was 24.5 ± 8.3 ng/mL, the PIC level was 2.5 ± 1.1 µg/mL, the TAT/PIC ratio was 13.9 ± 3.5, and the PAI‐1 level was 143.0 ± 24.4 ng/L. The TAT level, TAT/PIC ratio, and PAI‐1 were all significantly lower (P < 0.05) after 48 hr compared with before DHP‐PMX, but no significant change of PIC was observed. In these patients with sepsis, fibrinolysis was inhibited by PAI‐1, whereas clotting activity was significantly increased. This coagulation/fibrinolysis imbalance was improved by DHP‐PMX. The present results suggest that indirect inhibition of clotting activity can be achieved in patients with sepsis through adsorption of lipopolysaccharide by DHP‐PMX.     

Anticoagulant factor concentrates in disseminated intravascular coagulation: rationale for use and clinical experience.

Natural inhibitors of coagulation, in other words, antithrombin (AT), the protein C system, and tissue factor pathway inhibitor (TFPI), play an important role in controlling the activation of coagulation during disseminated intravascular coagulation (DIC). Furthermore, they may not only influence coagulation but also attenuate inflammatory responses during sepsis. Low circulating levels of AT and protein C have been associated with poor outcome. Replacement therapy with AT, activated protein C (APC), and TFPI has been shown to attenuate thrombin generation and to reduce mortality in experimental sepsis models. Experience with AT and APC in patients is promising. Data from large phase III trials of AT and APC as treatment of patients with severe sepsis will soon be available. Recombinant TFPI is currently in phase II clinical trials for severe sepsis.     

Importance of measuring plasma thrombin-antithrombin III complex levels when using antithrombin III concentrate therapy in fulminant hepatic failure.

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6 h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.     

Imbalance between thrombin and plasmin activity in disseminated intravascular coagulation. Assessment by the thrombin-antithrombin-III complex/plasmin-alpha-2-antiplasmin complex ratio.

We investigated the imbalance between thrombin and plasmin activity in vivo with various grades of severity of disseminated intravascular coagulation (DIC) in relation to the underlying diseases. Plasma thrombin-antithrombin-III complex (TAT) and plasmin-alpha 2-antiplasmin complex (PAP) levels were measured in 133 blood samples obtained from patients with DIC. The TAT/PAP ratio was higher in patients with sepsis or solid cancer than in those with hematologic malignancies. In acute promyelocytic leukemia (APL), the TAT levels were the highest, but the PAP levels were even higher and the TAT/PAP ratio was the lowest. As for the severity of DIC, in mild DIC, both thrombin and plasmin activities were increased. In moderate DIC, the TAT/PAP ratio increased, and thrombin activity was much more predominant. However, in severe DIC, the ratio decreased, and plasmin activity became excessive. In 3 patients with acute myeloblastic leukemia, APL and pancreatic cancer, respectively, the PAP level remained high during heparin therapy although the TAT level was decreased. When tranexamic acid was given, the PAP level was selectively reduced, and the TAT/PAP ratio was markedly decreased along with clinical improvement. These results indicate that monitoring of the TAT/PAP ratio may contribute to decisions regarding the institution and performance of combination therapy for DIC using anticoagulants and antifibrinolytic agents.     

Hemostatic molecular markers in nephrotic syndrome

Quantitative changes of hemostatic molecular markers were studied in patients with nephrotic syndrome. The plasma levels of fibrinopeptide A (FPA), thrombin-antithrombin III complex (TAT), products of thrombin activation, and fragment F1 + 2 (F1 + 2), a product of prothrombin activation, were measured by enzyme immunoassay in 21 patients with nephrotic syndrome and in 16 normal controls. The mean value of FPA was 17.5 ± 7.5 ng/ml (mean ± SD) in nephrotic patients and 4.5 ± 0.3 ng/ml in normal controls (P < 0.02); F1 + 2 concentration was 1.4 ± 0.3 ng/ml in nephrotic patients and 0.5 ± 0.1 ng/ml in normal controls (P < 0.001); TAT level was 1.0 ± 0.3 μg/l in nephrotic patients and 0.2 ± 0.1 μg/l in normal controls (P < 0.05). These data indicated intravascular hemostasis activation. Based on these results, we propose that low antithrombin III level in nephrotic patients may be due to both urinary loss and intravascular consumption. © 1993 Wiley-Liss, Inc.     

Dynamic fluctuations in blood of thrombin/antithrombin III complex (TAT)

The dynamic fluctuation of thrombin-antithrombin III complex (TAT) was studied in blood obtained during the daytime (at 9 AM, noon, 3 PM), during extracorporeal circulation and during the course of disseminated intravascular coagulation (DIC), to certify whether the level of TAT in blood can reflect the generation of thrombin. In 10 healthy male volunteers, the mean values of TAT (micrograms/liter) were 1.74 (+/- 1.36) at 9 AM, 1.22 (+/- 0.47) at noon, and 1.25 (+/- 0.68) at 3 PM. TAT did not show a daytime fluctuation, unlike fibrinolytic factors. The mean values of TAT in 38 hemodialyzed patients were 4.83 (+/- 2.8) before the initiation, 6.59 (+/- 4.39) in the first hour, and 13.42 (+/- 10.96) at the end of a dialysis session. In 20 patients undergoing open heart surgery, the mean value of TAT was increased during cardiopulmonary bypass (CPB) and decreased with time after the end of surgery. The fibrinopeptide A (FPA) value was increased with TAT during CPB but achieved a maximum level immediately after heparin neutralization by protamine. In 20 patients with DIC, the values of TAT varied from 5.8 to 297 micrograms/liter in the blood at the onset of DIC. In seven of eight patients treated with low-molecular-weight heparin (LMW-H), the values of TAT and FPA were lower 24 hr after LMW-H than before the treatment. These results suggest that the level of TAT in blood reflected the formation of thrombin and could serve as a sensitive parameter of activated coagulation in circulating blood.     

Increase in the D-dimer levels during treatment in patients with acute myelogenous leukemia.

Plasma concentration of thrombin-antithrombin III complex (TAT), tissue-type plasminogen activator (t-PA), plasminogen activator inhibitor 1 (PAI-1), PAI-2, D-dimer complex and urokinase-plasminogen activator (u-PA) activity were studied in 30 patients with acute nonlymphoblastic leukemia (ANLL), before and during antileukemic therapy. Fifteen patients showed signs of disseminated intravascular coagulation (DIC), 10 of them classified as M3, 2 as M2 and 3 as M5 subtypes. The initial levels of TAT complex were elevated in all ANLL patients. This increase was more pronounced in patients with DIC (p less than 0.05). TAT increased significantly during the treatment period in all cases. u-PA and PAI-1 levels were elevated but there were no statistically significant differences between patients with and without DIC. PAI-2 levels were below the limit of detection in controls and in patients. However, the initially elevated D-dimer complex levels were significantly higher in DIC cases (p less than 0.01) and they increased during the treatment period. A significant and positive correlation between D-dimer and TAT complex values was found in DIC patients (r = 0.68, p less than 0.001). The high TAT complex and D-dimer levels further increased during chemotherapy treatment strongly suggest a hypercoagulable state with secondary activation of fibrinolysis not severe enough to manifest itself as clinically evident DIC in the majority of cases.     

Cellular origin and procoagulant properties of microparticles in meningococcal sepsis

Patients with meningococcal sepsis generally suffer from disseminated intravascular coagulation (DIC). The aim of this study was to address whether these patients have elevated numbers of circulating microparticles that contribute to the development of DIC. Plasma samples from 5 survivors, 2 nonsurvivors, and 5 healthy volunteers were analyzed for the presence of microparticles by flow cytometry. Ongoing coagulation activation in vivo was quantified by enzyme-linked immunosorbent assay of plasma prothrombin fragment F(1 + 2), and procoagulant properties of microparticles in vitro were estimated by thrombin-generation assay. On admission, all patients had increased numbers of microparticles originating from platelets or granulocytes when compared with controls (P =.004 and P =.008, respectively). Patients had elevated levels of F(1 + 2) (P =.004), and their microparticles supported thrombin generation more strongly in vitro (P =.003) than those of controls. Plasma from the patient with the most fulminant disease course and severe DIC contained microparticles that expressed both CD14 and tissue factor, and these microparticles demonstrated extreme thrombin generation in vitro. We conclude that patients with meningococcal sepsis have elevated numbers of circulating microparticles that are procoagulant. These findings may suggest a novel therapeutic approach to combat clinical conditions with excessive coagulation activation.     

Determination of plasma soluble fibrin using a new ELISA method in patients with disseminated intravascular coagulation

We measured plasma levels of soluble fibrin (SF) in 98 patients suspected of having disseminated intravascular coagulation (DIC) using a newly developed enzyme-linked immunosorbent assay (ELISA) and investigated the correlations between SF determinations and measurements of other hemostatic molecular markers to determine the diagnostic usefulness of determinations of SF. Patients were classified into four groups according to their clinical and laboratory findings: overt DIC (n = 33), subclinical DIC (n = 23), hypercoagulability (n = 22), and non-DIC (n = 20). SF levels were significantly higher in patients with overt DIC compared with the other three groups and were significantly higher in the subclinical DIC and hypercoagulability groups compared with the non-DIC patients. SF levels increased significantly with each increase in the clinical stage. Although levels of thrombin-antithrombin III complex (TAT), prothrombin fragment 1 + 2 (PF₁₊₂), cross-linked fibrin degradation products (XDP), and plasmin-antiplasmin complex (PAP) were significantly increased in patients with overt DIC compared with non-DIC patients, the values of these hemostatic molecular markers did not consistently show an increase in association with advances in the disease stage. Plasma levels of SF in patients with overt DIC showed a positive correlation with levels of TAT, XDP, and FDP(E), but not with PF₁₊₂ and PAP. Analysis of receiver-operating characteristic curves showed that the sensitivity and specificity of SF were similar to those of XDP for diagnosis of DIC. The sensitivity and specificity of SF for diagnosis of overt DIC were both above 90% when the cut-off value was set at 65 μg/ml. Plasma levels of SF were also increased in patients with extravascular fibrin formation without DIC. Our findings suggest that measurement of plasma levels of SF by this ELISA method is useful for the diagnosis of DIC and the evaluation of the patient's clinical status. © 1996 Wiley-Liss, Inc.     

Prognostic significance of markers of thrombin generation in the acute and chronic phases of non cardioembolic ischemic stroke

BACKGROUND: Previous studies have shown there is activation of the hemostatic system, with thrombin generation, in the acute phase of stroke. Such an activation has unfavourable effects. It is still not known whether there is also a persistent hypercoagulability state in these patients as well as in subjects affected by acute coronary syndromes. METHODS: To know more about the issue, we measured plasma levels of the prothrombin fragment 1 + 2 (F1 + 2) and the thrombin-antithrombin III complex (TAT) in 40 consecutive patients with first ischemic non-cardioembolic stroke; 16 matched involutive cardiomyopathy patients served as the control group. TATs and F1 + 2 were also assessed six months after the onset of stroke symptoms. RESULTS: At baseline stroke patients had higher values than controls of both F1 + 2 and TAT (F1 + 2: 2.38 +/- 2.30 nmol/l vs 1.20 +/- 0.50; p < 0.03; TAT 16.11 +/- 19.60 ng/ml vs 5.51 +/- 4.29; p < 0.05) and these measurements were not related to the typical acute phase reactants. After 6 months F1 + 2 levels in stroke patients were still higher than controls (F1 + 2: 1.68 +/- 0.80 nmol/l vs 1.20 +/- 0.50; p < 0.05), but there were no differences from the baseline levels of F1 + 2 and TAT. According to survival curves mortality was significantly higher in patients with hypercoagulability (defined as F:1 + 2 and TAT levels more than two standard deviations above the mean). CONCLUSIONS: These data confirm that for stroke patients there is sustained activation of the blood coagulation system like in unstable angina and myocardial infarction these abnormalites may have unfavourable prognostic significance.     

Lepirudin blunts endotoxin-induced coagulation activation

During sepsis, lipopolysaccharide (LPS) triggers the development of disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney and decreased mortality in LPS-induced DIC. Accordingly, the effects of recombinant hirudin (lepirudin) was compared with those caused by placebo on LPS-induced coagulation in humans. Twenty-four healthy male subjects participated in this randomized, double-blind, placebo-controlled, parallel group study. Volunteers received 2 ng/kg LPS intravenously, followed by a bolus-primed continuous infusion of placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h for 5 hours) to achieve a 2-fold prolongation of the activated partial thromboplastin time (aPTT). LPS infusion enhanced thrombin activity as evidenced by a 20-fold increase of thrombin-antithrombin complexes (TAT), a 6-fold increase of polymerized soluble fibrin, termed thrombus precursor protein (TpP), and a 4-fold increase in D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP increased by only 50%, and D-dimer only slightly exceeded baseline values (P <.01 versus placebo). Concomitantly, lepirudin also blunted thrombin generation evidenced by an attenuated rise in prothrombin fragment levels (F(1 + 2), P <. 01 versus placebo) and blunted the expression of tissue factor on circulating monocytes. This experimental model proved the anticoagulatory potency of lepirudin in LPS-induced coagulation activation. Results from this trial provide a rationale for a randomized clinical trial on the efficacy of lepirudin in DIC. (Blood. 2000;95:1729-1734)