Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation.

We measured the plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI) activity and antigen in patients with disseminated intravascular coagulation (DIC) to examine the relationship between hypofibrinolysis and the pathogenesis of DIC. TAFI activity and antigen levels in the plasma were both significantly low in patients with DIC. TAFI activity in plasma was correlated with TAFI antigen, indicating that activity and antigen correspond well. The decrease of TAFI activity in DIC may be due to enhanced consumption. Since the plasma thrombin-antithrombin III complex (TAT) level was found to be elevated in DIC, increase of thrombomodulin-thrombin complex generation is suggested in this state. TAFI activity and antigen levels were negatively correlated with TAT and D-dimer, suggesting that the plasma levels of TAFI are reduced by thrombin generation. Since TAFI was not correlated with fibrinogen, plasma-alpha(2)plasmin inhibitor complex (PPIC) and tissue type plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complex, TAFI might be a secondary modulator of fibrinolysis. The TAFI activity in plasma was significantly low in patients with infection and in those with organ failure, suggesting that TAFI may play an important role in the mechanism of organ failure in DIC-associated sepsis. In brief, TAFI may play an important role in the pathogenesis of DIC and organ failure.

Plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tPA/PAI-1 complex in patients with disseminated intravascular coagulation and thrombotic thrombocytopenic purpura.

In this study, we examined changes in the plasma levels of total plasminogen activator inhibitor-I (PAI-I) and tissue-type plasminogen activator (tPA)/PAI-I complex in patients with disseminated intravascular coagulation (DIC) and in those with thrombotic thrombocytopenic purpura (TTP) to investigate the fibrinolytic function and its relation to organ failure. The plasma levels of total PAI-1 and tPA/PAI-I complex were significantly higher in patients with DIC, pre-DIC, and TTP than in those with non-DIC. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, thrombomodulin (TM), total PAI-I, and tPA/PAI-I complex were significantly higher in patients with organ failure than in those without organ failure. The plasma levels of total PAI-I and tPA/PAI-I complex were markedly increased in patients with acute leukemia. The plasma levels of total PAI-I, but not those of tPA/PAI-I complex, were significantly increased in patients with sepsis or with solid cancer. In all cases, total PAI-I or tPA/PAI-I complex was not significantly correlated with any hemostatic marker. Measurement of total PAI-I and tPA/PAI-I complex may be useful in the diagnosis of DIC.

Increased plasma thrombomodulin as a vascular endothelial cell marker in patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.

Several hemostatic and vascular endothelial cell markers were measured in 39 patients with thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) and in 20 healthy volunteers to examine the relationship between the occurrence of hemostatic abnormality or vascular endothelial cell injury and patient outcome. The plasma levels of von Willebrand factor, tissue plasminogen activator (TPA), plasminogen activator inhibitor (PAI-1), and the TPA-PAI-1 complex were significantly increased in TTP/HUS patients; however, the levels of these markers were not significantly different between TTP/HUS patients who survived and those who died, suggesting that these markers might not be directly related to outcome. The plasma levels of soluble granule membrane protein (GMP)-140 were significantly higher in TTP/HUS patients than in healthy volunteers, suggesting that platelets and vascular endothelial cells are activated or injured in TTP/HUS. There was no significant difference in GMP-140 levels between TTP/HUS patients with good and poor prognoses; this may be owing to the release of GMP-140 from platelets. The plasma thrombomodulin (TM) levels in TTP/HUS patients were significantly higher than in healthy volunteers; the plasma TM levels were significantly higher in patients who died than in patients who survived. These findings showed that TM levels reflect the outcome and that the outcome of TTP/HUS depends on the presence vascular endothelial cell injury. The plasma protein C and antithrombin levels were markedly reduced in TTP/HUS patients who died compared with those who survived. These findings suggest that reduced plasma antithrombin and protein C may be useful markers of systemic vascular endothelial injury. In conclusion, the results of this study showed that the outcome of TTP/HUS is related to vascular endothelial cell injury and that plasma TM, antithrombin, and protein C levels may be useful markers of systemic vascular endothelial cell injury.

Increased plasma levels of tissue factor pathway inhibitor-activated factor X complex in patients with disseminated intravascular coagulation.

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.

Plasma levels of activated protein C-protein C inhibitor complex in patients with hypercoagulable states.

Plasma levels of activated protein C (APC)-protein C inhibitor (PCI) were significantly increased in patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), acute myocardial infarction (AMI), pulmonary embolism (PE), or deep vein thrombosis (DVT) and in patients undergoing hemodialysis (HD). Plasma levels of APC-alpha(1)-antitrypsin (AT) complex were significantly increased in patients with DIC and in those with TTP. Plasma levels of PCI were significantly decreased in patients with DIC, non-DIC, or TTP and in those undergoing HD. In the pre-DIC stage, the plasma levels of APC-PCI complex were significantly increased but not those of APC-alpha(1)-AT complex. These data suggest that measurements of APC-PCI complex and APC-alpha(1)-AT complex may be useful for the diagnosis of DIC. After treatment of DIC, the plasma levels of APC-PCI complex and APC-alpha(1)-AT complex were significantly decreased, but not those of PCI. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-alpha(2)-plasmin complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were markedly increased in patients with DIC or pre-DIC and were moderately increased in patients with non-DIC, TTP, AMI, PE, or DVT and in those undergoing HD. The receiving operating characteristic (ROC) analysis showed that SFM and the APC-PCT complex are useful markers for diagnosis of DIC. The specificity of plasma TAT and PPIC levels was low. The positive rate of APC-PCI complex was higher than 90% with DIC, TTP, AMI, PE, and it was higher than 60% with DVT and HD. Since the APC-PCI complex was elevated not only in patients with venous thrombosis but also in those with arterial thrombosis, components of the protein C pathway might be useful markers for the diagnosis of arterial thrombosis.

Coagulation tests and anti-phospholipid antibodies in patients positive for lupus anticoagulant.

We examined activated partial thromboplastin time, kaolin clotting time, mixing with normal plasma in kaolin clotting time, dilute Russell's viper venom time, dilute Russell's viper venom time at high lipid concentrations, anti-phospholipid antibodies, and anti-cardiolipin-beta2-glycoprotein I complex antibody in 135 patients with prolongation of activated partial thromboplastin time and diagnosed 86 patients positive for lupus anticoagulant. The sensitivity of activated partial thromboplastin time and dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio for lupus anticoagulant were markedly high, but the specificity of activated partial thromboplastin time for lupus anticoagulant was not markedly high. The specificity, but not the sensitivity, of kaolin clotting time-mixing with normal plasma in kaolin clotting time was markedly high. In summary, dilute Russell's viper venom time to dilute Russell's viper venom time-high lipid concentrations ratio gave high sensitivity as well as specificity, being the only assay to confirm this. Of the patients positive for lupus anticoagulant, 25% were positive for anti-phospholipid antibodies and 17% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody. Of the lupus anticoagulant-positive patients with thrombosis, 45% were positive for anti-phospholipid antibodies, 35% were positive for anti-cardiolipin-beta2-glycoprotein I complex antibody, 60% were positive for both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody, and only 17% were negative for anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. These findings suggest that lupus anticoagulant can be diagnosed by dilute Russell's viper venom time/dilute Russell's viper venom time-high lipid concentrations ratio, and that thrombosis in lupus anticoagulant-positive may be predictable from both anti-phospholipid antibodies and anti-cardiolipin-beta2-glycoprotein I complex antibody. Plasma tissue type plasminogen activator level in lupus anticoagulant patients was significantly increased, and plasma tissue type plasminogen activator and fibrin-D-dimer levels in lupus anticoagulant-positive patients with thrombosis were significantly higher than in those without thrombosis, suggesting that the diagnosis of thrombosis by hemostatic markers might be important in lupus anticoagulant.

Decreased tissue factor and tissue-plasminogen activator antigen in relapsed acute promyelocytic leukemia.

This study evaluated hemostatic data in 28 patients with newly diagnosed acute promyelocytic leukemia (APL) and 15 patients with relapsed APL. Activated partial thromboplastin time and prothrombin time were prolonged at initial onset of APL. Plasma level of fibrinogen was significantly decreased in patients with initial disease of APL, but it was not decreased significantly during the relapse of APL. Plasma fibrin and fibrinogen degradation products levels were significantly increased and platelet counts significantly decreased in both groups. Plasma levels of antiplasmin significantly decreased at initial onset but not during relapse. Plasma levels of antithrombin were within normal range in patients with initial disease but significantly decreased in those with relapse. Plasma levels of D-dimer, soluble fibrin monomer (sFM), plasmin-plasmin inhibitor complex (PPIC), and thrombin antithrombin complex (TAT) levels were significantly high in both groups. Plasma levels of PPIC, sFM, and D-dimer were significantly higher at initial onset of APL than during relapse. However, there was no significant difference in DIC score between patients with initial onset and those with relapse; plasma levels of tissue factor (TF) significantly increased in both groups, but they were significantly higher at initial onset of APL than during relapse. TF and tissue type plasminogen activator (t-PA) antigen levels in leukemic cell lysate were significantly increased in both groups, and they were significantly lower during relapse than at initial onset. Hemostatic abnormalities occurring in patients with relapsed APL might be the result of the decrease of TF and t-PA in leukemic cells. These findings suggest that DIC in APL patients with relapse might not be caused only by TF and t-PA and thus should be treated with different therapy from patients with initial onset of APL.

Diagnosis of disseminated intravascular coagulation by hemostatic molecular markers.

In the present study, the positive rate of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), soluble fibrin monomer (sFM), and D-dimer for the diagnosis of disseminated intravascular coagulation (DIC) was evaluated. The study comprised 307 patients with DIC, 123 with pre-DIC, and 121 with non-DIC. Plasma levels of TAT, PPIC, sFM, and D-dimer were significantly higher in DIC and pre-DIC patients than in non-DIC patients. In DIC patients, the positive rate of sFM was high and that of D-dimer was low; the positive rate of PPIC was higher in patients with hematopoietic malignancy than in those without this disease. In pre-DIC patients, the positive rate of all markers was low (<0.16), and the positive rate of PPIC was relatively high. In non-DIC patients, the positive rate of all hemostatic markers was low (<0.16), that of sFM being the lowest. Scoring the positive rate of TAT, PPIC, and sFM disclosed the following results: 72% of DIC patients had three or more points, 17.6% of pre-DIC patients had three or more points, and almost all (96.6%) non-DIC patients had two or less points. Scoring the positive rate of TAT, PPIC, and D-dimer disclosed the following results: 52.9% of DIC patients and 27.4% of pre-DIC patients had three or more points and almost all (96.7%) non-DIC patients had 2 or less points. These data suggest that the combination of TAT, PPIC, and sFM is useful for making the diagnosis of DIC.

Increased hemostatic molecular markers in patients undergoing anticoagulant therapy.

We evaluated several molecular markers of hemostasis in 92 patients with hypercoagulable states treated with anticoagulant therapy. In all patients, the average values of the international normalized ratio (INR) were 1.70 +/- 0.50; this increase in INR was not, however, significant in patients under thrombotest (TT) monitoring. There were no thrombotic or severe bleeding complications in these patients during a period of 27 months. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were slightly increased, suggesting that anticoagulant therapy was not completely effective in our Japanese patients based on the values of the TT. The INR was negatively correlated with TT, protein C, and protein S and particularly with TT between 10 and 80%. The range of TT was not correlated with the plasma level of TAT, PPIC, D-dimer, or sFM, but the range of INR was correlated with the plasma level of TAT, D-dimer, and sFM. The percentage of TAT, D-dimer, and sFM within normal range was significantly lower in patients with high INR. These findings show that INR is better than TT for the monitoring of warfarin therapy and that the therapeutic values of INR during the anticoagulant therapy should be > 1.7 in Japanese patients.

Hemostatic abnormalities in patients with thrombotic complications on maintenance hemodialysis.

Before hemodialysis (HD), plasma levels of tissue factor (TF), free-TF pathway inhibitor (TFPI) and thrombomodulin (TM) were significantly higher in patients with HD than in healthy volunteers. Plasma levels of (T-F) TFPI and plasmin plasmin inhibitor complex (PPIC) were significantly higher in patients with HD than in healthy volunteers. During HD, plasma levels of TF and (T-F) TFPI were not significantly increased, but plasma levels of total TFPI and free TFPI at 1 hour after and at the end of HD were significantly increased, compared with levels before start of HD. Plasma level of PPIC 1 hour after start of HD was significantly higher than before start of HD, and plasma levels of thrombin antithrombin complex (TAT), PPIC, D-dimer, TM, and protein C (PC) at the end of HD were significantly higher than before start of HD. In patients with thrombosis complications, plasma TF levels were significantly higher than in patients without thrombotic complications during HD. Plasma levels of PC were significantly lower in patients with thrombotic complications than in patients without thrombotic complications. There was no significant difference between both groups during HD in hemostatic parameters, with the exception of TF and PC. Hemostatic abnormalities existed in patients with HD; especially, increased TF and decreased PC might cause thrombotic complications.

Elevated tissue factor levels in leukemic cell homogenate.

Tissue factor (TF) antigen and activity were measured in leukemic cell homogenates. In leukemic cell homogenate, especially that of acute promyelocytic leukemia (APL), both TF antigen and activity were significantly higher than these levels in the mononuclear cells obtained from healthy volunteers. Both TF antigen and activity were significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. In leukemic cell homogenates, there was a close correlation between TF antigen and TF activity. The TF activity/TF antigen ratio was significantly higher in myelocytic leukemia than in lymphocytic leukemia cells. As the TF activity was not increased in lymphocytic leukemia cell homogenates to which were added phospholipids, the decrease in TF activity in lymphocytic leukemia might not be due to phospholipid in the leukemic cell membrane. Values for TF activity, TF antigen, and the TF activity/TF antigen ratio in leukemic cell homogenate from patients with disseminated intravascular coagulation (DIC) were significantly higher than those in patients without DIC. Therefore, the measurement of TF antigen and activity in leukemic cells could be useful for the prediction of DIC.

[Plasma D-dimer levels in patients with deep vein thrombosis].

Hemostatic abnormalities were examined in 40 patients with deep vein thrombosis (DVT), 40 patients treated with warfarin, and 30 healthy volunteers. Plasma D-dimer levels were measured by an enzyme linked fluorescent assay (ELFA; Vidas-D-dimer) and an enzyme immunosorbent assay (ELISA; D-dimer-ELISA). Plasma levels of D-dimer, thrombin-antithrombin complex (TAT), soluble fibrin monomer (SFM) were significantly higher in patients with DVT than in the other groups. Both the sensitivity and specificity of D-dimer for diagnosis of DVT were the highest among hemostatic molecular markers examined. The most adequate cut off value of Vidas-D-dimer was 0.6 microgram/ml. Plasma levels of Vidas-D-dimer were well correlated with D-dimer ELISA, SFM and TAT. As the time of measurement for Vidas-D-dimer is less than one hour, the measurement of D-dimer using a EFLA might be useful for the diagnosis of DVT in bed side.

Effects of PAF on histamine H1 receptor mRNA expression in rat trigeminal ganglia.

The application of platelet-activating factor (PAF) to the nasal mucosa of humans has been shown to increase histamine-induced hyper-reactivity. To test the hypothesis that PAF acts by increasing the reactivity of sensory nerve endings in the nasal mucosa to histamine, we examined PAF-stimulated rat trigeminal nerve ganglion cells. We found that relatively low concentrations of PAF (10(-12)-10(-9) M) induced increased histamine H1 receptor mRNA expression. This increase appeared as early as 1 h after PAF stimulation, peaked at 4 h, and disappeared after 24 h. The PAF receptor antagonist WEB2086 inhibited the increased expression of histamine H1 receptor mRNA induced by PAF, suggesting that the effects of PAF are mediated by specific receptors. This PAF effect was abolished by actinomycin D, suggesting that PAF induces de novo transcription of histamine H1 and/or PAF receptor mRNA. PAF may be important in the hyper-responsiveness of nasal mucosa exposed to histamine.

Plasma sFas and sFas ligand levels in patients with thrombotic thrombocytopenic purpura and in those with disseminated intravascular coagulation.

Fas, a member of the tumor necrosis receptor superfamily, is 36 kD surface protein containing a single transmembrane region and induces apoptosis by Fas-Fas ligand binding. Soluble Fas (sFas) is produced as the form lacking 21 amino acid residues containing the transmembrane domain by alternative splicing. We found that the plasma sFas levels of 33 patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), 19 patients with disseminated intravascular coagulation (DIC), and 10 non-DIC patients with multiple organ failure (MOF) were significantly higher than those of 21 non-DIC patients without organ failure and those of 25 healthy volunteers. The plasma sFas ligand levels of the TTP/HUS patients, the DIC patients, and the non-DIC patients with MOF were significantly higher than those of the non-DIC patients without organ failure and those of the healthy volunteers. The plasma sFas levels were significantly correlated with the plasma sFas ligand levels in all subjects. The plasma thrombomodulin (TM) levels were increased significantly in the TTP/HUS patients, the DIC patients, and the non-DIC patients with MOF compared with the levels of the non-DIC patients without organ failure and the healthy volunteers. The plasma sFas antigen levels were correlated significantly with the plasma TM levels in all subjects. These findings suggest that the increases of sFas and sFas ligand that cause apoptosis might be related to the vascular endothelial cell injuries in TTP and DIC with organ failure.

Hemostatic molecular markers before the onset of disseminated intravascular coagulation.

We retrospectively measured various hemostatic markers in 240 patients with disseminated intravascular coagulation (DIC) before the onset of DIC and in 110 non-DIC patients, and examined their usefulness for the diagnosis of pre-DIC. Changes in prothrombin time ratio and fibrinogen levels were not significant before the onset of DIC. The plasma levels of fibrinogen and fibrin degradation products before the onset of DIC were increased and the platelet count was gradually reduced in nonleukemic patients; these changes were already significant in the non-DIC state. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were increased before the onset of DIC. In leukemic patients, the plasma levels of sFM on day 5, those of TAT on day 3, and D-dimer on day 1, were significantly increased before the onset of DIC. The levels of most hemostatic markers 7 days before the onset of DIC were not different from those observed in the non-DIC state. In nonleukemic patients, only D-dimer, sFM, and TAT levels were significantly increased 7 days before the onset of DIC compared with values in the non-DIC state. The positive rate of hemostatic markers for the diagnosis of DIC, TAT, and PPIC were high during the pre-DIC and non-DIC groups. The plasma levels of sFM and D-dimer were low in non-DIC and increased gradually during the pre-DIC state. These findings suggest that hemostatic molecular markers such as sFM, D-dimer, and TAT are useful for the diagnosis of pre-DIC, although their cutoff values were different among various diseases.

Increased truncated form of plasma tissue factor pathway inhibitor levels in patients with disseminated intravascular coagulation.

To evaluate that the relationship between the truncated form of tissue factor pathway inhibitor (TFPI) and the stage of disseminated intravascular coagulation (DIC), we measured the plasma levels of tissue factor (TF) antigen and the intact and truncated forms of TFPI antigens in 41 patients with DIC, 12 with pre-DIC, and 20 with non-DIC. The plasma TF and total TFPI antigen levels were significantly higher in patients with DIC than in non-DIC patients. Plasma levels of intact TFPI antigen in the pre-DIC groups were significantly lower than in the non-DIC and DIC groups. The truncated form of TFPI antigen levels in DIC patients were significantly increased compared with those in non-DIC and pre-DIC patients. The fact that the intact form of TFPI was decreased in pre-DIC patients compared with that in non-DIC patients, suggests that it is consumed in the pre-DIC state and that hypercoagulability occurs in pre-DIC patients. The increased level of the truncated form of TFPI in DIC patients may be attributed to proteolysis of the intact form of TFPI in these patients. The increased level of the truncated form of TFPI may be a useful index for the diagnosis of DIC.

Hemostatic markers in Japanese patients undergoing anticoagulant therapy under thrombo-test monitoring.

The objective of this study was to evaluate several molecular markers of hemostasis in 84 patients with hypercoagulable state, treated with warfarin under thrombo-test (TT) monitoring; TT was expressed as percent of control (TT%). In all patients, the average values of international normalized ratio (INR) of prothrombin time (PT;PT-INR) was 1.68+/-0.49; this increase in PT-INR was not, however, significant in patients under TT% monitoring. There were no thrombotic or severe bleeding complications in these patients during a period of 2 years. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were slightly increased, suggesting that anticoagulant therapy was not completely effective in our Japanese patients based on the values of TT%. Activated partial thromboplastin time, PT-INR, TT% and protein C activity were significantly correlated with the dose of warfarin; fibrinogen, activated thromboplastin, TAT, PPIC, D-dimer, sFM, protein S and thrombomodulin were not significantly correlated with the dose of warfarin. The PT-INR was negatively correlated with TT%, protein C and protein S, and the correlation between PT-INR and TT-INR was better than that between PT-INR and TT%. The range of TT% was not correlated with the plasma levels of TAT, PPIC, D-dimer or sFM, but the range of PT-INR was correlated with the plasma level of TAT, D-dimer and sFM. The percentage of TAT, D-dimer and sFM within normal range was significantly low in patients with high PT-INR. These finding showed that PT-INR is better than TT% for monitoring the anticoagulant therapy with warfarin, and that TT should be expressed as INR. The values of PT-INR should be more than 1.7 during the anticoagulant therapy with warfarin in Japanese patients with high risk of thrombosis.

Aberrations of the tissue factor pathway in patients positive for lupus anticoagulant.

To evaluate the relationship between the tissue factor (TF) pathway and lupus anticoagulant (LA), in the present study, we measured the plasma levels of TF antigen and TF pathway inhibitor (TFPI) antigen in patients positive for LA. Plasma TF and TFPI levels in LA-positive patients were significantly higher than levels in healthy volunteers (p < 0.01). In LA-positive patients, there were no significant differences in plasma TF and TFPI levels between patients with and without thrombosis. In patients with thrombosis, there was no significant difference in the plasma TF level between LA-positive and LA-negative patients; however, the plasma TFPI level in LA-positive patients was significantly lower than that in LA-negative patients (p < 0.01). We also examined the TF pathway in human umbilical venous endothelial cells (HUVEC) incubated with plasma of LA-positive patients, LA-negative patients, and healthy volunteers. TF activity was significantly higher (p < .05) in HUVECs incubated with the plasma of LA-positive patients than in cells incubated with the plasma of the other two groups (p < .01). However, there was no significant difference in TFPI antigen levels among the media of HUVECs incubated with the plasma of all groups. The viability of HUVEC incubated with the plasma of LA-positive patients with thromboses, LA-positive patients without thromboses, and LA-negative patients with thromboses were significantly lower than that of HUVECs incubated with the plasma of healthy volunteers (p < .01). These findings suggest that abnormalities of the TF pathway plays an important role in the mechanism of hypercoagulability in LA-positive patients. LA may affect vascular endothelial cells causing thrombogenesis.

Changes in plasma tissue factor pathway inhibitor levels during the clinical course of disseminated intravascular coagulation.

In healthy volunteers, the plasma total tissue factor pathway inhibitor (TFPI) level was 68.7+/-14.1 ng/ml; the plasma free TFPI level, 17.7+/-5.4 ng/ml; the lipoprotein-associated TFPI (LP-TFPI), 51.1+/-12.0 ng/ml; the free TFPI/total TFPI ratio 0.26+/-0.07; and the plasma tissue factor levels were 149+/-46 pg/ml. Plasma tissue factor levels in patients with disseminated intravascular coagulation (DIC) were significantly higher than those in pre-DIC patients or in non-DIC patients. Plasma total-TFPI, free-TFPI and LP-TFPI levels were significantly higher in DIC patients than those in pre-DIC patients or in non-DIC patients. Before the onset of DIC, the plasma levels of tissue factor gradually increased, and 3 days before the onset of DIC they were significantly higher than those in non-DIC patients. The plasma levels of tissue factor reached their highest level 1 day before the onset of DIC and gradually decreased after the onset of DIC. Plasma levels of total-TFPI, free-TFPI, and LP-TFPI gradually increased before the onset of DIC, and the total-TFPI and LP-TFPI reached their highest levels at the onset of DIC. Plasma free-TFPI reached highest level one day after the onset of DIC. During the clinical course of DIC, the plasma level of tissue factor was the first to increase, then that of LP-TFPI and finally the free-TFPI plasma levels. These differences in the peak plasma levels of tissue factor, free-TFPI, and LP-TFPI might be related to the clinical course of DIC.

Increased thrombopoietin levels in idiopathic thrombocytopenic purpura patients with a poor response to steroid therapy.

The serum thrombopoietin (TPO) levels in 61 idiopathic thrombocytopenic purpura (ITP) patients were found to be slightly increased compared with those of 29 normal subjects. The TPO levels of the 15 ITP patients who had a poor response to steroid therapy (i.e. an unchanged platelet count) were higher than those of the 22 ITP patients who had a good response to steroid therapy (i.e. an increased platelet count) and the normal subjects. The TPO levels in the 15 ITP patients whose platelet count was higher than 10 x 10(4)/microl after the discontinuation of steroid therapy significantly higher than those of the normal subjects. The platelet-associated immunoglobulin G (PAIgG) levels in the ITP patients who had a poor response to steroid therapy were slightly increased compared with the normal subjects and the ITP patients who had a good response to the steroid therapy and the nine ITP patients who did not undergo the steroid therapy. The serum TPO level was negatively correlated only with the megakaryocyte count in the ITP patients, and the megakaryocyte count in the ITP patients who had good responses to the steroid therapy was higher than that in those who had poor responses. These data suggest that serum TPO levels might be important for the prediction of the outcome of ITP patients who receive steroid therapy.