[Substantiation of choice of surgical treatment in patients with post-thrombotic disease].

The results of restoration treatment of 52 patients, suffering the lower extremities postthrombotic disease (LEPD). In all the patients there were conducted clinical examination, the venous system ultrasound duplex scanning, determination of D-dimer content and antithrombin-III activity in general and regional blood flow. In 80.8% patients the indications for performance of interventions, correcting venous hemodynamics disorders, were established. Determination of D-dimer and antithrombin-III levels in systemic and regional blood flow in conjunction with data of the venous system duplex scanning, have permitted to perform operative interventions differentially. This have had promoted to reduce the restoration stationary treatment duration by 25%, as well as the LEPD recurrences and trophic complications rate.

Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris.

OBJECTIVES: In a Phase I clinical trial, we studied the antithrombotic and clinical effects of the synthetic competitive thrombin inhibitor, argatroban, in 43 patients with unstable angina pectoris. BACKGROUND: Thrombin has a pivotal role in platelet-mediated thrombosis associated with atheromatous plaque rupture in patients with an acute ischemic coronary syndrome. However, the efficacy of conventional heparin therapy to prevent ischemic events is limited and has been surpassed by that of specific thrombin inhibitors in experimental models of arterial thrombosis. METHODS: Intravenous infusion of the drug (0.5 to 5.0 micrograms/kg per min) for 4 h was monitored by sequential measurements of coagulation times and of indexes of thrombin activity in vivo followed by a 24-h clinical observation period. RESULTS: Significant dose-related increases in plasma drug concentrations and activated partial thromboplastin times (aPTT), but no bleeding time prolongation or spontaneous bleeding, was observed. Myocardial ischemia did not occur during therapy but, surprisingly, 9 of the 43 patients experienced an episode of unstable angina 5.8 +/- 2.6 h (mean +/- SD) after infusion. This early recurrent angina was correlated significantly with a higher argatroban dose and with greater prolongation of aPTT but not with other demographic, clinical, laboratory and angiographic characteristics. Pretreatment plasma concentrations of thrombin-antithrombin III complex and fibrinopeptide A were elevated two to three times above normal values. During infusion, thrombin-antithrombin III complex levels remained unchanged, whereas a significant 2.3-fold decrease in fibrinopeptide A concentrations was observed. By contrast, 2 h after infusion, thrombin-antithrombin III complex concentrations increased 3.9-fold over baseline measurements together with return of fibrinopeptide A levels to values before treatment with argatroban. CONCLUSIONS: In patients with unstable angina, argatroban inhibits clotting (aPTT prolongation) and thrombin activity toward fibrinogen (fibrinopeptide A decrease), but in vivo thrombin (thrombin-antithrombin III complex) formation is not suppressed. However, cessation of infusion is associated with rebound thrombin (thrombin-antithrombin III complex) generation and with an early dose-related recurrence of unstable angina. Although the mechanism of this clinical and biochemical rebound phenomenon remains to be determined, its implication for the clinical use of specific thrombin inhibitors in the management of ischemic coronary syndromes may be significant.

Prevention of hepatic artery thrombosis in pediatric liver transplantation.

Hepatic artery thrombosis after orthotopic liver transplantation is a serious complication, especially in children. We report our experience with intensive anticoagulant therapy during and after living-related liver transplantation in pediatric recipients. Twenty-four patients between 5 months and 15 years of age were studied. The mean diameter of the anastomosed hepatic arteries was 2.7 mm. The anticoagulant therapy consisted of low-molecular-weight heparin, antithrombin III concentrates, prostaglandin E1, fresh frozen plasma, and a protease inhibitor. The profiles of the coagulation and fibrinolytic systems were monitored by measuring several parameters, including plasma levels of thrombin-antithrombin III complex, antithrombin III, plasmin-alpha 2 plasmin inhibitor complex, fibrin degradation product D-dimer, tissue type-plasminogen activator, and plasminogen activator inhibitor-1. Acceleration of the coagulation system and delayed recovery of the fibrinolytic system were observed during the early postoperative days. The plasma level of antithrombin III activity was maintained within the normal range by the administration of antithrombin III concentrates. None of the recipients developed hepatic artery thrombosis. Children have been reported to be at a greater risk of developing hepatic artery thrombosis than adults due to the small diameters of their hepatic arteries and the postoperative hypercoagulable state. We believe that the intensive anticoagulation therapy described in this study, the main concept of which is the early correction of imbalance between the coagulant and anticoagulant systems, could become a model for the prevention of hepatic artery thrombosis in pediatric liver transplantation patients.

Comparison of progressive antithrombin activity and the concentration of three thrombin inhibitors in nephrotic syndrome.

In order to compare the plasmatic progressive antithrombin activity to the concentration of three thrombin inhibitors, antithrombin III (AT III), alpha 2 macroglobulin (alpha 2 M), alpha 1 anti-trypsin (alpha 1, AT) in nephrotic syndrome, a prospective study was carried out on a group of 28 children affected with the disease. A dramatic reduction of the level of AT III and of alpha 1 AT, two inhibitors of molecular weight close to that of albumin, was observed. The decreased level of AT III was counterbalanced by an increase in alpha 2 M. This phenomenon accounts for the increased progressive antithrombin activity observed in all the affected children. It is suggested that the above compensatory mechanism explains the absence of thrombotic accidents in this series and that the benefit of heparin therapy is doubtful in these conditions.

Clinical utility of prothrombin fragment 1+2, thrombin antithrombin III complexes and D-dimer measurements in the diagnosis of deep vein thrombosis following total hip replacement.

BACKGROUND: Measurements of prothrombin fragment 1+2 (F1+2), thrombin antithrombin III complexes (TAT) and D-dimer plasma levels have been proposed as non-invasive screening tests to exclude postoperative deep venous thrombosis (DVT). We investigated the diagnostic efficacy of these coagulation activation markers to rule out postoperative DVT in patients undergoing hip surgery under antithrombotic prophylaxis. METHODS: In this substudy of a randomized double-blind thrombosis prophylaxis trial comparing three doses of desirudin (10, 15 or 20 mg b.i.d.) with unfractionated heparin (5000 IU t.i.d.) we used ELISA procedures to measure F1+2, TAT and D-dimer in 159 patients undergoing total hip replacement at baseline (day 0) and on postoperative days 1, 3 and 6. Bilateral venography was performed in all cases 8-11 days after surgery. RESULTS: For the F1+2 assay sensitivity ranged from 73 to 83% in the three postoperative days investigated, and negative predictive value (NPV) from 68 to 74%. For TAT and D-dimer sensitivity ranged from 71 to 73% and from 71 to 83% and NPV from 61 to 65% and from 61 to 74% respectively. INTERPRETATION: In terms of sensitivity and NPV F1+2 and D-dimer are equivalent and are superior to TAT. However, their accuracy is too low to rule out the presence of DVT after hip surgery under antithrombotic prophylaxis.

On the mechanism of coagulation inhibition on surfaces with end point immobilized heparin.

A well established technique to improve blood compatibility of artificial materials for use in the circulation is to coat the surface with heparin. The present report describes the antithrombin mediated inhibition of thrombin and factor Xa by surfaces modified with end point immobilized heparin. The reaction was followed by conventional chromogenic substrate based enzyme assays as well as by immunological measurement of the enzyme inhibitor (thrombin-antithrombin) complex formation. Both enzymes were rapidly inactivated by heparin surfaces after selective presaturation with antithrombin on the immobilized high affinity heparin molecules. The thrombin inhibitory capacity was enhanced when both high and low affinity heparin were preadsorbed with inhibitor. The main part of the thrombin-antithrombin complex formed remained bound to the surface, however, without functionally blocking the activity of the high affinity sequence of the immobilized heparin. Aliquots of recalcified plasma were slowly rotated in loops of heparinized tubing to investigate whether the main thromboresistant function of the surface was exerted at the level of thrombin or by inactivation of preceding enzymes. After 1 h no visible clotting occurred and only trace amounts of thrombin (0.07 IU/ml), measured as thrombin-antithrombin complexes, had been formed. In non-heparinized loops and in the test tube plasma clotted after 20 min. The thrombin generation when clotting occurred was in the order of 10 IU/ml. It is concluded that the immobilized heparin mediates inhibition of the coagulation cascade prior to prothrombin activation.

Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations.

The effect of high-dose aprotinin treatment on hemostatic activation during cardiopulmonary bypass in pediatric patients having cardiac operations was investigated. Sixty patients weighing less than 10 kg undergoing cardiac operations for different types of congenital heart diseases were studied: 20 patients were treated with aprotinin 2 x 15,000 KIU/kg, 20 patients with 2 x 30,000 KIU/kg, and 20 patients without aprotinin treatment served as the control group. Different split products of fibrinogen and/or fibrin and the fibrinolytic activity on fibrin plates were measured to assess fibrinolytic activation. F1/F2 prothrombin fragments, thrombin-antithrombin III-complex, and fibrin monomers were measured to estimate thrombin activation. There was a significant dose-dependent reduction in fibrin-fibrinogen split product formation during cardiopulmonary bypass: In the high-dose aprotinin group the concentration of the split products at the end of bypass was 1.5 +/- 0.6 micrograms/ml, compared with 3.4 +/- 3.0 micrograms/ml in the low-dose aprotinin group and 6.7 +/- 3.5 micrograms/ml in the control group (p < 00.5). Fibrinolytic activation on fibrin plates was also significantly reduced by aprotinin. Fibrin monomer formation was significantly diminished at the end of cardiopulmonary bypass in the high-dose group: 9.2 +/- 5.2 micrograms/ml compared with 21.6 +/- 14 micrograms/ml in the control group (p < 00.5). Elastase in complex with alpha 1-protease inhibitor at the end of bypass was increased to the same amount in the three groups: 784 +/- 278 ng/mL (control group), 693 +/- 189 ng/ml (low-dose aprotinin), and 719 +/- 270 ng/mL (high dose aprotinin) (no significant difference). Blood loss 6 hours postoperatively was significantly (p < 00.5) less in the high-dose group (99 +/- 32 ml/m2) than in the control group (164 +/- 87 ml/m2; low-dose group: 160 +/- 106 ml/m2). These observations suggest an attenuation of hemostatic activation during cardiopulmonary bypass with less plasmin formation and, because of inhibition of contact activation, less thrombin generation with aprotinin treatment. Thus the thrombotic-thrombolytic equilibrium is kept more balanced after cardiopulmonary bypass. High-dose aprotinin treatment is recommended for pediatric patients undergoing cardiac operations.

Effects of low-dose warfarin on antithrombin III levels in morbidly obese patients.

Morbid obesity has been associated with increased risks for thrombotic diseases. Patients with morbid obesity are shown to have decreased activity and decreased concentration of antithrombin (AT) III. This deficit can be corrected by giving the patients low doses of the oral anticoagulant warfarin. The same beneficial effect was not observed in normal lean control volunteers in whom the levels of AT III were normal at all times. Thus, it may be possible to offer prophylactic protection against the effects of having depressed levels of AT III in patients at increased risk for thrombotic diseases without using full anticoagulant doses of warfarin, including morbidly obese patients.

No benefit of reduced heparinization in thoracic aortic operation with heparin-coated bypass circuits.

BACKGROUND: Heparin coating of the cardiopulmonary bypass circuit attenuates inflammatory response and confer clinical benefits in cardiac operations. The positive effects may be amplified with reduced systemic heparin dosage. We studied markers of inflammation and coagulation in thoracic aortic operations with heparin-coated circuits and standard vs reduced systemic heparinization. METHODS: Thirty patients were randomized to standard (group S; 300 IU/kg initially; activated clotting times [ACT] > 480 seconds; 5,000 IU in prime; n = 16) or reduced (group R; 100 IU/kg initially; ACT > 250 seconds; 2,500 IU in prime; n = 14) dose systemic heparin. The following markers were analyzed perioperatively: (a) inflammatory response; acute phase cytokine interleukin-6, and granulocytic proteins myeloperoxidase and lactoferrin; (b) complement activation; factor C3a and the C5a-9 terminal complement complex [TCC]; and (c) coagulation; thrombin-antithrombin III complex. RESULTS: The clinical outcome did not differ between groups. Four (29%) patients in group R had a perioperative thromboembolic event. All studied markers were significantly elevated during and throughout cardiopulmonary bypass in both groups. Maximal values were higher in group R for all variables except for TCC. There were no statistically significant intergroup differences regarding markers of inflammation, complement activation, or coagulation activation. CONCLUSIONS: The blood trauma in thoracic aortic operation is extensive, as reflected by the elevation of the studied biochemical markers, even when heparin-coated cardiopulmonary bypass circuits are used. In this study, we did not detect any benefits, either biochemical or clinical, of reducing the dose of systemic heparin.

Changes of the levels of antithrombin III in patients with cerebrovascular diseases.

Dynamic fluctuations of biological activities and antigen amounts of antithrombin III (AT-III) in acute cerebrovascular diseases were analyzed and evaluated. (1) AT-III levels assayed by both biological and immunological methods showed a gradual decrease with increasing age, and levels in patients with cerebral thrombosis were lower than those in patients with cerebral hemorrhage. (2) AT-III in cerebral thrombosis decreased slowly after administration of urokinase. After administration of aspirin (acetylsalicylic acid), however, AT-III levels increased presumably due to inhibition of coagulation activities. (3) Both biological activities and antigen amounts of AT-III increased after administration of an AT-III preparation, but the measured value, especially that of biological activity, was dissociated from the expected one, due to changes of the coagulation system after an operation.

Activated protein C: alpha 1-antitrypsin (APC: alpha 1 AT) complex as a marker for in vitro diagnosis of prethrombotic states.

The purpose of the study was to test whether APC: alpha 1AT complex is a useful clinical marker of the activation of coagulation. The rationale for this is that activated protein C may appear in circulation at an early stage of blood coagulation, when subcoagulant amounts of thrombin are formed. Given the relatively higher half-life of APC: alpha 1AT as compared to that of thrombin:AT-III (TAT) complexes, we hypothesized that APC:alpha 1AT could represent an amplification of the thrombin generated in the first events of coagulation. Using sandwich ELISA's we measured APC: alpha 1AT and TAT complexes as well as complexes of AT-III with its target proteases in normal subjects and in several clinical groups of patients prone to thrombotic episodes, including pregnancy, preeclampsia, hemodialysis, gynecological tumors, diabetes and oral contraceptives. APC: alpha 1AT complex was significantly increased in all clinical groups as compared to normal subjects and showed relatively higher increases than did TAT and ATM complexes in the majority of the groups studied. There was a significant and positive correlation between APC: alpha 1AT and TAT complex levels in the majority of the groups, as well as between TAT and ATM and between APC: alpha 1AT and ATM complex levels. We conclude that APC: alpha 1AT complex can be used as a sensitive marker of prethrombotic states.

Antifactor Xa levels in four patients with burn injuries who received enoxaparin to prevent venous thromboembolism.

Four patients with severe burn injuries received enoxaparin 40 mg twice/day subcutaneously for the prophylaxis of venous thromboembolism (VTE). Peak antifactor Xa levels were measured 4 hours after administration of a dose, and trough antifactor Xa levels were measured 30 minutes before the next scheduled dose. Ultrasonography was performed once/week to assess the presence of VTE. Any occurrence of major bleeding was documented in the patients' charts. All patients had trough antifactor Xa levels below 0.1 U/ml. Enoxaparin dosages were subsequently adjusted to achieve trough antifactor Xa levels of 0.1-0.2 U/ml. This required dosages higher than those typically recommended for VTE prophylaxis (40 mg every 24 hrs or 30 mg every 12 hrs). One patient needed more than 60 mg every 12 hours. No patient had a venous thromboembolic event or major bleeding. The low antifactor Xa levels that were observed suggest that a reduced dose-response relationship may exist between subcutaneously administered enoxaparin and antifactor Xa activity in patients with severe burn injuries. Prospective studies should be performed to further investigate this relationship.

Is heparin therapy necessary in CAPD peritonitis?

OBJECTIVE: Heparin therapy in continuous ambulatory peritoneal dialysis (CAPD) peritonitis seems well established; it is costly due to the necessity of hospitalization. There are no clinical studies that show a benefit of such a treatment. The aim of this study was to investigate whether heparin therapy in CAPD peritonitis is necessary. DESIGN AND PATIENTS: 194 samples of peritoneal dialysates were collected from 17 patients over a period of 24 months. Samples were subdivided into three groups: those without peritonitis (< 100 leukocytes/microL), those with mild peritonitis (100-499 leukocytes/microL), and those with severe peritonitis (> or = 500 leukocytes/microL). MEASUREMENTS: The number of leukocytes per microL dialysate and total protein concentrations were determined. Furthermore, dialysate concentrations of thrombin-antithrombin III- (TAT-) complexes (indicator of thrombin formation), D-dimers (indicator of fibrinolysis), and plasminogen activator inhibitor 1 (PAI-1) were measured. RESULTS: The dialysate protein concentration progressively increased from no peritonitis to mild and severe inflammation. In parallel, dialysate TAT-complex and D-dimer concentrations increased. Thrombin-antithrombin III-complex and D-dimer concentrations correlated strongly in 179 cases (r = 0.76; 62 samples showing peritonitis, 117 samples with no evidence of peritonitis). In the remaining 15 samples of 3 patients, high PAI-1 levels (> 40 ng/mL) and low D-dimer concentrations were found. Eleven of the 15 samples showed evidence of peritonitis. In these 11 samples with evidence of peritonitis, high levels of TAT-complexes were detected, while D-dimer concentrations were found to be very low, pointing to a blocked fibrinolysis. The PAI-1 levels were not related to leukocyte counts or protein concentrations in the dialysates. CONCLUSIONS: Based on our findings, the routine intraperitoneal administration of heparin in CAPD peritonitis is not necessary. In rare cases an imbalance between coagulation and fibrinolysis due to high PAI-1 levels exists (15 of 194 dialysate samples, 11 of the 15 samples showing peritonitis). These cases--which do require heparinization--can be identified by demonstrating low D-dimer levels in CAPD dialysate at times of peritonitis.

Effects of recombinant human erythropoietin on physiological inhibitors of coagulation in children on continuous ambulatory peritoneal dialysis.

The effects of recombinant human erythropoietin (rHuEPO) on plasma and peritoneal effluent levels of antithrombin III (AT-III), protein C (PC) activity, and protein S (PS) activity were evaluated in 10 uremic children on continuous ambulatory peritoneal dialysis (CAPD). The findings were compared with values obtained from ten healthy children. Levels of AT-III and of PC and PS activity in plasma and peritoneal effluent were measured before, and at 8 and 12 weeks after, rHuEPO treatment. Baseline levels of AT-III and PC activity in plasma were lower than the control values. Levels of PC activity increased during the trial, while levels of AT-III remained unchanged, and levels of PS activity decreased. Baseline levels of PC activity in peritoneal effluent were lower than those obtained during rHuEPO treatment, while no change in peritoneal levels of PS activity and AT-III was observed after rHuEPO treatment. A significant positive correlation was seen between plasma and peritoneal levels of PC activity at baseline. A significant positive correlation was also seen between plasma levels of PS activity and hemoglobin at week 12, and a significant negative correlation between plasma levels of AT-III and albumin at week 8. No correlation was found between the plasma natural coagulation inhibitors and CAPD duration. These results suggest that plasma PS activity can be decreased, and plasma PC activity increased, by rHuEPO treatment in children.

D-dimer and thrombin-antithrombin III complex levels uncorrelated with phlebographic findings in 11 total knee replacement patients.

D-dimer and thrombin-antithrombin III complex (TAT) were assayed in 11 patients at various times pre- and post-operatively in order to determine the possible value of these parameters in screening for thromboembolic complications. Phlebography revealed distal thrombosis in 6 of the 11 patients. The D-dimer level, already elevated before surgery, increased at day 1 and remained high at days 5 and 10. Two methods were used for the assays and showed strongly correlated results. The TAT level increased at day 1 and then progressively returned toward basal values. No difference was observed at any time between patients with or without thrombosis. The results in surgical patients undergoing knee replacement suggest that neither D-dimer nor TAT assays are valid screening procedures for post-operative DVT. Nevertheless, in view of the small number of patient studied, further work is required to confirm these results.

[Alteration of serum levels of endotoxin, polymorphonuclear leukocyte elastase, and the molecular markers of the coagulation and fibrinolytic system in the patients with esophageal cancer and lung cancer before and following operation].

The serum levels of endotoxin, polymorphonuclear leukocyte elastase (PMN-E), and the coagulation and fibrinolytic markers (D-dimer, TAT) were measured in the patients with esophageal cancer, lung cancer, and benign pulmonary tumors before and after the operation; on the day of operation, and the 1st, 3rd, and 7th postoperative day. The biological responses of the patients under surgical stress were evaluated. In the patients without complications, the endotoxin levels measured by the Toxicolor method and the PMN-E levels did show any significant increase in the early postoperative period, and they returned to the normal levels by the 7th postoperative day. On the contrary, in the patients with postoperative complications, they continued to increase throughout the study period. The endotoxin levels measured by the Endospacy test did not show any significant changes postoperatively. The D-dimer and TAT levels showed their highest values on the first postoperative day. The serum levels of endotoxin, PMN-E, and molecular markers of the coagulation and fibrinolytic system in the patients under surgical stress may be useful factors in predicting the postoperative outcome.