Soluble plasma thrombomodulin levels in patients with chronic myeloproliferative disorder.

The plasma levels of soluble thrombomodulin (TM) were measured in 44 patients with chronic myeloproliferative disorder, 15 with polycythemia vera (PV), 29 with essential thrombocythemia (ET), and a group of 62 matched healthy controls. The younger patients had significantly lower TM levels (mean: 15.6 +/- 4.8 ng/mL) than the older patients (mean: 28.6 +/- 8.2 ng/mL, p < .001). Moreover, a significant negative correlation between platelet counts and plasma TM levels in healthy persons was noted (r = 0.317, p < .05). The only significant difference we found in plasma TM levels between patients and controls or among patients was between the young patients with ET (mean: 29.0 +/- 19.2 ng/mL) and young healthy controls (mean: 15.6 +/- 4.8 ng/mL). It is possible that younger ET patients with more active platelets are more susceptible to earlier vascular damage. The lack of any significant difference compared with the older patient population supports this hypothesis.

Value of thrombin-antithrombin III complexes in major orthopedic surgery: relation to the onset of venous thromboembolism.

This study evaluated (a) the possible changes of plasma levels of thrombin-antithrombin III complexes during hospitalization to predict venous thromboembolism in patients undergoing elective total hip replacement and (b) the sensitivity and specificity of thrombin-antithrombin III complexes in the late incidence of deep vein thrombosis when these patients are discharged from the hospital. In 50 consecutive patients (18 men, mean age = 63 +/- 8 years) a venous blood sample was obtained from each patient before surgery and postsurgery on days 5 +/- 2, 9 +/- 2, and 45 to evaluate the thrombin-antithrombin III complexes by the enzyme-linked immunosorbent assay as a part of a larger surveillance program. Six of 50 patients developed deep vein thrombosis, diagnosed by phlebography on the 45th day postsurgery. From the day before until the ninth day after surgery, mean values of the thrombin-antithrombin III complexes increased to a greater extent in patients with deep vein thrombosis than in those without, although the differences were not significant (from 14.8 +/- 11.2 ng/mL to 36.2 +/- 19.1 ng/mL in the former group and from 13.6 +/- 3.3 ng/mL to 22.4 +/- 5.1 ng/mL in the latter, p = NS). On the 45th day after surgery the mean value of the thrombin-antithrombin III complexes reduced less in patients with deep vein thrombosis (up to 9.9 +/- 1.9 ng/mL and to 25.2 +/- 17.2 ng/mL, respectively, p = NS). In addition, thrombin-antithrombin III complexes remained over the level reached on the fifth day only in the patients who developed deep vein thrombosis. On the 45th day after surgery, thrombin-antithrombin III complexes exhibited a sensitivity of 17%, a specificity of 86%, and an accuracy of 78% in differentiating the presence and absence of deep vein thrombosis as compared with phlebography. We conclude that after total hip replacement (a) serial measurement of the thrombin-antithrombin III complexes does not appear helpful in predicting venous thromboembolism during hospitalization, and (b) measurement of thrombin-antithrombin III complexes has a low diagnostic accuracy in diagnosing delayed deep vein thrombosis. However, the greater and persistent increase of thrombin-antithrombin III complexes level in patients who developed deep vein thrombosis may deserve further investigations.

Endothelial cell-associated tissue factor pathway inhibitor (TFPI) antigen in severe nondiabetic obese patients: effect of hyperinsulinemia.

It has been suggested that the extrinsic coagulation system plays a crucial role in the initiation of blood coagulation in atherosclerotic disease and that TFPI, the inhibitor of the factor VIIa/tissue factor complex, bound to the endothelial cells, could prevent in vivo blood clotting. Because obesity has a role in the pathogenesis of atherosclerotic cardiovascular disease, we measured TFPI antigen plasma levels (ng/mL) by ELISA at baseline and 5 minutes after an IV bolus of 20 IU/kg body weight of unfractionated commercial mucous heparin in 12 obese patients with a mean body mass index (BMI) of 41.4 +/- 1.4 kg/m2 and 14 normal-weight control subjects (BMI 23.1 +/- 1.3 kg/m2). All subjects were submitted to an OGTT. The obese patients displayed a normal glucose tolerance. However, they had a different glucose-induced hyperinsulinemia (14.9 +/- 2.0 versus 7.8 +/- 0.8 mU/L, p < 0.01). Total serum cholesterol did not differ between controls and obese patients, whereas plasma triglycerides were higher in the latter group. Basal TFPI antigen plasma levels were similar in obese and controls (83.8 +/- 5.0 versus 77.7 +/- 3.5 ng/mL, p = N.S.). In contrast, after heparin a significantly lower rise in TFPI antigen plasma levels was observed in obese patients (511.2 +/- 43.4 ng/mL) (p < 0.003). Moreover, a significant inverse correlation was found between the heparin-stimulated TFPI antigen plasma levels and both BMI and basal plasma insulin concentrations. Thus, the link between insulin level and endothelial cell-associated TFPI could at least partially explain why obese patients are more prone to develop cardiovascular disorders.

Tissue factor pathway inhibitor (TFPI) antigen plasma level in patients with interstitial lung disease before and after heparin administration.

The extrinsic pathway is probably the predominant pathway in initiating blood coagulation in inflammatory lung diseases. Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor of factor VIIa/tissue factor in the presence of factor Xa. As it has been shown recently that TFPI plasma levels are increased under acute inflammatory conditions, we studied TFPI antigen plasma levels before and after injecting 20 IU/kg body weight of unfractionated heparin into 49 patients with different stages of sarcoidosis, into 9 with idiopathic pulmonary fibrosis, and into 15 normal controls. TFPI, before injecting heparin, was significantly increased in all sarcoidosis stages (stage I: 97.6 +/- 6.4 ng/mL; stage II: 116.2 +/- 11.9 ng/mL; stage III: 116.3 +/- 7.3 ng/mL) and in idiopathic pulmonary fibrosis (116.8 +/- 16.1 ng/mL), as compared to the control group (77.7 +/- 3.3 ng/mL). No correlation was found between the intensity of the activity of sarcoidosis, measured as BAL white cell count, and TFPI. Five minutes after heparin administration the rise in TFPI was lower, although not statistically significant, in all sarcoidosis stages than in controls. In contrast, idiopathic pulmonary fibrosis had a similar or even higher TFPI elevation than the control group. In sarcoidosis the elevated TFPI and the lower capacity by endothelial cells to release TFPI after heparin may represent a compensatory mechanism to prevent blood clotting and/or the endothelial cell dysfunction of the microvasculature in this condition. In contrast, the extensive mesenchymal cell proliferation present in idiopathic pulmonary fibrosis could explain our findings, as it has been shown that cultured human mesangial cells produce and release TFPI.

Tissue factor pathway inhibitor (TFPI) activity in uremic patients during hemodialysis.

We studied tissue factor pathway inhibitor (TFPI) activity during hemodialysis in 10 uremic patients who were not receiving anticoagulant for at least 120 minutes. TFPI activity before dialysis was normal (patients 107 +/- 5.8%, controls 104 +/- 4.5%). During extracorporeal circuit it rose progressively with a statistically significant difference, reaching a plateau between 60 and 120 minutes. Since thrombin induces a marked redistribution and release of TFPI from stimulated endothelial cells and platelets contain about 10% of TFPI activity that is secreted following activation it is possible that thrombin-induced release of TFPI by endothelium and platelets could account for the increased TFPI we found during hemodialysis. To investigate this possibility we measured during dialysis beta-thromboglobulin (beta-TG), thrombin-antithrombin complex (TAT) and prothrombin fragment 1.2 (F 1.2). The increased levels of beta-TG, TAT and F1.2 we noted during extracorporeal circuit are in keeping with this concept. One hundred eighty minutes after initiation of dialysis, by which time all patients were receiving heparin there was a further increase in TFPI (to more than 200% of baseline), due to the presence of the glycosaminoglycan. This was due the previously reported displacement by heparin of the major intravascular pool of TFPI, from endothelial cell surfaces.