Minori Shimura

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

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

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. Am. J. Hematol. 60:273–278, 1999.

Increased tissue factor pathway inhibitor in patients with acute myocardial infarction.

We examined hemostatic abnormalities in 23 patients with acute myocardial infarction (AMI), 10 with pulmonary embolism (PE), and 10 with deep vein thrombosis (DVT). At the onset of AMI, plasma levels of tissue‐type plasminogen activator (t‐PA), PA inhibitor‐I (PAI‐I), fibrin‐D‐dimer, thrombin‐antithrombin complex (TAT), and plasmin‐plasmin inhibitor complex (PPIC) were significantly increased. Both the plasma total TFPI and free‐TFPI levels in the AMI patients were significantly higher than those in the healthy volunteers, PE patients, and DVT patients. There was no significant difference in total TFPI or free‐TFPI among patients with PE, those with DVT, and healthy volunteers. One hour after percutaneous transluminal coronary angioplasty (PTCA) in the AMI group, the total TFPI level was further increased, and it was significantly reduced 24 hr after PTCA, to a level similar to that in healthy volunteers. Free‐TFPI showed a pattern similar to that of total TFPI. The ratio of free‐TFPI/total TFPI was highest 1 hr after PTCA. Increased TFPI in AMI patients might be released from ischemic tissues. Am. J. Hematol. 55:183–187, 1997.

Increased serum levels of thrombopoietin in patients with thrombotic thrombocytopenic purpura, idiopathic thrombocytopenic purpura, or disseminated intravascular coagulation

The serum levels of thrombopoietin (TPO) were measured in 16 patients with thrombotic thrombocytopenic purpura (TTP), 12 with hemolytic uremic syndrome (HUS), 10 with aplastic anemia (AA), 10 with disseminated intravascular coagulation (DIC), and 71 with idiopathic thrombocytopenic purpura (ITP). The serum TPO levels were measured with a sensitive sandwich enzyme-linked immunosorbent assay. The serum TPO level in the ITP group (1.68 ± 0.85 fmol/ml) were not significantly increased compared with those of the normal subjects. The TPO levels in the TTP (2.77 ± 1.38 fmol/ml) and HUS groups (5.77 ± 4.41 fmol/ml) were higher than those of the normal subjects. The patients with AA (12.7 ± 8.0 fmol/ml) and those with DIC (13.3 ± 5.7 mol/ml) had significantly higher serum TPO levels than did the normal subjects and ITP patients. The TPO levels were well correlated with the platelet counts in the TTP patients, and were negatively correlated with the platelet counts in the ITP patients. These results suggest that the serum TPO levels in some thrombocytopenic diseases are regulated not only by the platelet count and the megakaryocyte mass, but also by other factors.

Changes of plasma hemostatic markers during percutaneous transluminal coronary angioplasty in patients with chronic coronary artery disease

Changes of hemostatic parameters during percutaneous transluminal coronary angioplasty (PTCA) in 75 patients with chronic coronary artery disease were evaluated. Plasma levels of D‐dimer, soluble fibrin monomer, plasmin‐α2 antiplasmin inhibitor complex, and tissue factor (TF) were significantly increased in all patients with chronic coronary artery disease. The activity of antithrombin and protein C and the levels of protein C antigen were significantly decreased 1 hr after PTCA, but they returned to normal range 1 day after PTCA. There was no significant difference in the level of plasma APC‐PCI complex before and 1 hr after PTCA. The plasma levels of D‐dimer, soluble fibrin monomer, thrombomodulin, TF and PPIC were significantly decreased 1 hr, and the plasma levels of plasmin‐α2 antiplasmin inhibitor complex 1 day after PTCA. These findings suggest that the decrease of protein C and antithrombin resulted in activation of the coagulation system. One hour after PTCA, the plasma levels of (total‐free) TF pathway inhibitor (TFPI) were significantly decreased, but the plasma levels of total and free‐TFPI were significantly increased, suggesting that comsumption of (total‐free) TFPI occurs during PTCA. Overall, these findings suggest that the hypercoagulable state improves during PTCA and that transient decrease of antithrombin, protein C, (total‐free) TFPI or plasmin‐α2 antiplasmin inhibitor complex may cause restenosis of coronary artery. Am. J. Hematol. 61:238–242, 1999.

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 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. Am. J. Hematol. 60:94–98, 1999.

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 thrombo modulin (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 com plex (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 com plications 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 pa rameters, with the exception of TF and PC. Hemostatic abnormalities existed in patients with HD; espe cially, increased TF and decreased PC might cause thrombotic complications.

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.

Increased soluble fibrin monomer and soluble thrombomodulin levels in non-insulin-dependent diabetes mellitus.

We measured the plasma levels of fibrinogen, D-dimer, thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), soluble fibrin monomer (SFM), tissue-type plasminogen activator (t-PA) and thrombomodulin (TM) in patients with non-insulin-dependent diabetes mellitus (NIDDM). There were no significant differences in the hemostatic parameters between the 77 patients with NIDDM and healthy control subjects, although the plasma levels of fibrinogen, D-dimer, TAT, and PPIC in the NIDDM patients were slightly higher than those in the healthy controls. Among the NIDDM patients divided into three groups by the urinary albumin excretion (UAE) level, there was no significant difference in age or sex among the normo-, micro-, and macroalbuminuria groups, and the HbA1C level in the micro- and macroalbuminuria groups were slightly higher than those in the normoalbuminuria group. There was no significant difference in activated partial thromboplastin time, prothrombin time, fibrinogen, TAT, PPIC, D-dimer, or t-PA among these three groups. The plasma SFM and TM levels in the macroalbuminuria group were significantly higher than those in the normo- and microalbuminuria groups. The relationships between HbA1C and the hemostatic parameters were poor, but the plasma TM and SFM levels were significantly correlated with the urine albumin index.