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PubMed1998

Effect of a novel covalent antithrombin-heparin complex on thrombin generation on fetal distal lung epithelium.

Respiratory distress syndrome is characterized by fibrin deposition in the lung. Fibrin adversely affects surfactant function and stimulates proliferation of fibroblasts. There is evidence that these properties may be important to the development of bronchopulmonary dysplasia. Despite successful initial treatment of neonatal respiratory distress syndrome with surfactant, the incidence of bronchopulmonary dysplasia has not decreased. In previous studies, it has been demonstrated that rat fetal distal lung epithelium (FDLE) possesses both procoagulant and anticoagulant properties. In this report, we have demonstrated (using factor VII-deficient plasma) that tissue factor is expressed on the FDLE surface and promotes thrombin generation. To regulate thrombin within this procoagulant environment, we have developed a novel anticoagulant, antithrombin-heparin covalent complex (ATH) that can be retained within the lung after intrapulmonary instillation. We have demonstrated that ATH was superior to antithrombin plus standard heparin in suppressing thrombin generation (P < 0.001) and prothrombin consumption (P < 0.01) in recalcified defibrinated plasma on the surface of FDLE. Further studies with ATH in vivo need to be performed.

Adult↗

PubMed1992

Increased thrombin-antithrombin III complexes after 1 h of physical exercise.

Concentrations of thrombin-antithrombin III (TAT) complexes in plasma were previously reported to be increased after a 100-km run, while fibrinopeptide A (FPA) concentration remained unchanged. Thus, antithrombin III appears to neutralize thrombin generated during running and prevents fibrin formation. To determine the clinical relevance of these findings, we compared the effects of exhaustive running (1 h, n = 10) on the plasma concentrations of prothrombin fragments F1 and F2, TAT, FPA, and beta-thromboglobulin with the effects of recreational jogging (1 h, n = 10) and exhaustive bicycling on an ergometer (1 h, n = 8). Prothrombin fragments F1 and F2 and TAT concentrations increased significantly in each group. The most significant increase in TAT concentration was measured in the running group (from 1.72 +/- 0.49 to 3.61 +/- 1.03 ng/ml, P < 0.001). The best correlation was found between the postexercise TAT and lactate concentrations (r = 0.62, n = 28, P < 0.001). Mean FPA concentrations after exercise did not exceed normal values in any of the three groups analyzed. An increase in beta-thromboglobulin concentration was measured in the running and in the cycling group. Thus, thrombin is formed, in particular, when associated with anaerobic metabolism, and platelets are activated during high-intensity exercise.

Adult↗

PubMed2001

Correlation between grade III placenta and plasma antithrombin III activity in full term pregnancy.

We evaluated whether the presence of a grade III placenta correlates with blood hypercoagulability in pregnancy between 37 and 39 weeks of gestation. The placenta was graded by ultrasound in 155 healthy full-term women and the plasma levels of antithrombin III (AT III) activity, thrombin-antithrombin complex (TAT) and D-dimer were correlated with each placental grade. AT III activity levels tended to decrease with advancing placental grade from I to III (p < 0.05). D-dimer showed the same tendency while TAT did not. The incidence of reduced AT III activity levels (<70%) in women with a grade III placenta was about twice those in women with a grade II or I placenta, and that of AT III <80% was 3-fold greater. We concluded that the presence of a grade III placenta in full-term pregnancies correlates with blood hypercoagulability.

Adult↗

PubMed1995

L-asparaginase in acute lymphoblastic leukemia treatment: the role of human antithrombin III concentrates in regulating the prothrombotic state induced by therapy.

It is well known that L-asparaginase (L-Ase) treatment may cause thrombotic events in patients with acute lymphoblastic leukemia (ALL). The mechanism of this effect is not well understood although a reduction in plasma antithrombin III (AT III) levels is observed. In our study, a group of patients treated with L-Ase received AT III concentrates as adjuvant treatment. This adjuvant treatment reduced the levels of plasma D-dimer and thrombin-antithrombin complex, which are considered as early markers of a hypercoagulability state. These preliminary data suggest that large randomized trials will have to be conducted to improve our understanding of the role of AT III concentrates in ALL therapy.

Adolescent↗

PubMed1983

Chronic inflammatory bowel disease, deep-venous thrombosis and antithrombin activity.

Of 34 patients with chronic inflammatory bowel disease (CIBD), 4 developed well-documented episodes of deep-venous thrombosis. All 4 patients had active disease at the time of thrombosis. This group was studied to determine if the tendency to deep-venous thrombosis in patients with CIBD was associated with reduced antithrombin activity by measuring the concentration of three thrombin inhibitors, antithrombin III (AT III), alpha 2-macroglobulin (alpha 2 M) and alpha 1-antitrypsin. 2 patients had low AT III levels and 10 had low alpha 2 M levels. 2 patients who developed deep-venous thrombosis had significantly low levels of both AT III and alpha 2 M. It is suggested that in patients with diseases predisposing to thrombosis and associated with low AT III levels, the measurement of alpha 2 M in addition to AT III may predict those particularly at risk.

Antithrombin III↗

PubMed1979

Platelet aggregation and antithrombin III levels in diabetic children.

We studied platelet function and antithrombrin III levels in 30 insulin-dependent diabetic children with no clinically evident vascular complications. 9 were in-patients and 21 were out-patients. The disease had been discovered within the previous 10 years. 25 control subjects of comparable age and body weight were studied simultaneously. Template bleeding time, threshold concentrations of ADP or adrenaline required to induce irreversible platelet aggregation and plasma antiherparin activity (platelet factor 4) did not differ significantly in control and patient groups. In contrast, the immunological levels of plasma antithrombine III were significantly higher in the diabetic group. These results suggest that diabetic children, with no clinical signs of microanigopathy, show no laboratory changes suggesting increased platelet function. The unxpected increase in the antithrombin III level could reflect a very early defense mechanism against activation of the blood clotting system.

Adenosine Diphosphate↗

PubMed1980

Determination of antithrombin III activities by different methods in diabetic patients.

Antithrombin III activity was determined by three techniques in 58 patients with maturity onset diabetes mellitus: a spectrophotometric assay, using the chromogenic substrate Chromozym TH; evaluation of antifactor Xa activity and an immunochemical technique. Although the biological antithrombin III activity was clearly reduced in individual subjects, there was only a slight nonsignificant reduction in the mean anti-thrombin III activity values as compared to normal subjects. No difference was observed between diabetics receiving insulin and subjects taking oral hypoglycemic agents or between diabetics without vascular complications and diabetics with vascular lesions.

Administration, Oral↗

PubMed1981

Antithrombin III versus prothrombin in liver cirrhosis.

In patients with liver cirrhosis, a close relationship was observed between the respective levels of antithrombin III and prothrombin, both below 50% in 20 our 27 patients. The absence of any thrombotic complication, despite low plasma antithrombin III, suggests that the preserved balance between the inhibitor and the zymogens of the inhibited enzymes could have a protective effect against thrombotic tendency.

Adult↗

PubMed1983

Molar antithrombin concentration in normal human plasma.

Crude, commercial thrombin preparations and purified bovine thrombin were incubated with normal human reference plasma and the amount of thrombin inactivated was calculated. 1 ml of human plasma inactivated 140-193 NIH U of the various crude thrombin preparations. In the presence of heparin, a lower thrombin-inactivating capacity of plasma was confirmed using crude thrombin, but this phenomenon was less pronounced with the purified thrombin preparation. The molar concentration of the purified bovine thrombin was determined by active site titration. Comparing with protein concentration (A280), this preparation was 92% pure. 1 ml of human plasma inactivated 2.57 mumol of thrombin in the absence of heparin, and 2.50 mumol with heparin. Assuming 1:1 stoichiometry in the thrombin-antithrombin reaction, these results suggest that the concentration of antithrombin in the pooled reference plasma is approximately 2.57 mumol/l or 0.15 g/l.

Animals↗

PubMed1989

Lowered antithrombin III activity and other clotting changes in homocystinuria: effects of a pyridoxine-folate regimen.

Few studies have dealt with blood-clotting changes in patients affected by homocystinuria. The aim of this contribution is to briefly review studies published so far on the topic and report the results of our investigation performed in 3 patients. At baseline we found reduced antithrombin III and factor VII levels in all the patients, in line with the results of other authors, and other slight and less constant changes such as lowered factor X activity and protein C antigen, and increased beta-thromboglobulin levels. During pyridoxine and folate treatment, antithrombin III activity rapidly returned to normal; factor VII increased and beta-thromboglobulin decreased. These blood-clotting abnormalities may play a role in the thrombotic tendency associated with homocystinuria. Their nature is still uncertain, but the improvement observed during active metabolic treatment suggests that the defect in amino acid transsulfuration of homocystinuria may directly affect synthesis or activity of some clotting factors.

Adolescent↗

PubMed1991

Antithrombin III activity is not related to plasma homocysteine concentrations.

Arterial and venous thromboembolic events represent frequent and life-threatening complications in homocystinuric patients and are responsible for their early deaths. Reduced levels of antithrombin III activity in homocystinuric patients have recently been reported. So, high plasma L-homocysteine concentration could play a role in the low antithrombin III activity level. In the present study, we have studied the relationship between total plasma homocysteine and inhibitors of blood coagulation levels in 16 patients with malignancies who received bone marrow grafts. There were no correlations between homocysteine values and inhibitors of blood coagulation levels. So, while the defect in amino acid transsulfuration that is responsible for homocystinuria can directly affect the synthesis or activity of some clotting factors, homocysteine concentration is not responsible for this effect.

Adult↗

PubMed1991

Coagulation and fibrinolysis in orthotopic liver transplantation: role of the recipient's disease and use of antithrombin III concentrates. S. Orsola Working Group on Liver Transplantation.

In this study we report the data obtained from extensive haemostatic testing of 25 patients undergoing orthotopic liver transplantation and the results of an open randomized pilot trial of antithrombin III concentrate administration during surgery. Marked differences in transfusional needs and in pre- and intraoperative blood coagulation and fibrinolytic changes were observed between recipients with liver cirrhosis and those with primary biliary cirrhosis. In the former, the increases in tissue-type plasminogen activator activity, total euglobulin fibrinolytic activity, and fibrin-derived degradation products occurred earlier and were more marked, as were the signs of increased thrombin formation. Supplementation of antithrombin III concentrate during surgery failed to induce significant changes in the main parameters studied and in the transfusional needs.

Adult↗

PubMed1993

Prothrombin fragment 1 + 2 and thrombin-antithrombin complex measurements indicate continuous and progressive intraoperative thrombin generation in liver transplantation.

Prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin complex (TAT) have been measured in the different surgical phases in 40 patients undergoing 43 orthotopic liver transplantations (OLT), in order to study thrombin generation throughout the surgical procedure. F1 + 2 and TAT progressively rose from preoperative values (1.47 +/- 0.92 nmol/l and 22.41 +/- 19.15 ng/ml, respectively) to the end of anhepatic phase (5.97 +/- 2.20 nmol/l, 64.24 +/- 11.30 ng/ml), whereas changes in circulating antithrombin III (ATIII) were negligible in this period. Thrombin generation continued to slightly but significantly increase immediately after liver graft reperfusion (F1 + 2 6.87 +/- 1.65 nmol/l, TAT 89.32 +/- 7.54 ng/ml), and ATIII levels decreased from 70.61 +/- 12.28 to 57.16 +/- 9.57%. Higher preoperative values of F1 + 2 were associated with larger requirements of both packed red blood cells and fresh frozen plasma (FFP) in the host liver explantation phase, whereas the lowest basal levels of ATIII were related to a higher plasma expense in the whole OLT procedure. The activation of circulating prothrombin begins early in OLT, and adequate FFP infusion is capable of maintaining appropriate circulating thrombin-inhibitory activity.

Adolescent↗

PubMed1987

Preeclampsia as chronic disseminated intravascular coagulation. Study of two parameters: thrombin-antithrombin III complex and D-dimers.

Determinations of coagulation/fibrinolysis parameters thrombin-antithrombin III complex (TAT) and D-dimers (cross-linked fibrin degradation product) were carried out in order to prove that preeclampsia is a chronic disseminated intravascular coagulation (DIC) state. Besides the parameters TAT and D-dimers, antithrombin III (ATIII), fibrin degradation products and platelets were measured as well. Even in normal pregnancy there is an activation of coagulation, reflected in a hypercoagulative state that is proceeding down to the formation of thrombin. This thrombin is, however, nearly completely inactivated by ATIII, so that no fibrin is formed. This inactivation is solely reflected by the increase of TAT in the blood. In preeclampsia, however, where no such rapid changes as in acute DIC occur, the increase of TAT is accompanied by a decrease of ATIII and platelet counts and an increase of D-dimers; this demonstrates much more clearly the chronic DIC nature of preeclampsia than the results from studies carried out so far.

Antithrombin III↗

PubMed2004

Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin.

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH's better bioavailability and more predictable dose response.

Adult↗

PubMed2005

In vivo rabbit acute model tests of polyurethane catheters coated with a novel antithrombin-heparin covalent complex.

Catheter use has been associated with an increased risk of thrombotic complications. The objective was to make catheters less thrombogenic with the use of antithrombin-heparin covalent complex (ATH). The antithrombotic activity of ATH-coated catheters was compared to uncoated (control) and heparincoated catheters in an acute rabbit model of accelerated occluding clot formation. Anaesthetized rabbits were pre-injected with rabbit (125)I-fibrinogen, followed by insertion of test catheters into the jugular vein. Blood was drawn and held in a syringe, reinjected, then flushed with saline. The experiment was terminated when blood could no longer be withdrawn (occluding clot). Efficacy was defined as the ability of catheters to remain unoccluded. Clot formation, determined by measuring deposition of radiolabeled fibrin, was a secondary endpoint. ATH-coated catheters were resistant to clotting for the full 240-minute duration, while uncoated and heparin-coated catheters had an average clotting time of 78 and 56 minutes, respectively. The patency of ATH coating was dependant on intact heparin pentasaccharide sequences, rather than the chemistries of the basecoat, the PEO spacer arm, or the antithrombin (AT) protein. The ATH coating was stable to ethylene oxide sterilization, modest abrasion, protease attack, and the coating did not appear to leach off the catheter. Surface tension measurements showed that the ATH modified surface was more hydrophilic than uncoated control catheters or heparin-coated catheters. Thus, ATH-coated catheters are better at preventing clots than uncoated or heparin-coated catheters and show promise as an alternative to the currently available catheters in reducing thrombotic complications associated with its use.

Animals↗

PubMed1996

An increased uptake of prothrombin, antithrombin, and fibrinogen by the rabbit balloon-deendothelialized aorta surface in vivo is maintained until reendothelialization is complete.

The ability of the rabbit aorta intima-media (IM) layer to adsorb certain plasma proteins was measured for up to 20 months after a deendothelializing injury in vivo. Purified radioiodinated rabbit fibrinogen, antithrombin, or prothrombin was injected intravenously into either uninjured or sham-injured rabbits (controls) or rabbits at various times (5 minutes to 20 months) after a balloon-catheter injury to the aorta. After a 10-minute circulation time, a blood sample was taken, and the rabbit was exsanguinated rapidly (via a carotid cannula) and the aorta excised. Uptake of each radiolabeled protein was measured as bound radioactivity per square centimeter of platelet- or endothelium-free aorta IM and was compared with the radioactivity (ergo concentration) in blood at exsanguination. Fibrinogen adsorption by the IM was maximal at 5 minutes after injury (10.9 +/- 2.3 pmol/cm2 IM) and declined slowly to 4 to 6 pmol/cm2 at 12 months (controls: 0.8 +/- 0.1 pmol/cm2). Uptake of prothrombin (3.7 +/- 0.5 pmol/cm2 at 5 minutes) decreased to approximately 2 pmol/cm2 at 12 months (controls: 0.3 pmol/cm2). Antithrombin adsorption by the IM (3.3 +/- 0.4 pmol/cm2 at 5 minutes) paralleled that of prothrombin over 12 months (controls: 0.3 to 0.4 pmol/cm2), the molar ratio ranging from 0.8 to 1.2. At 20 months, the ballooned aorta had a significantly thickened intima and was approximately 90% reendothelialized. Injection of horseradish peroxidase (HRP) into rabbits at 1 or 12 months after balloon injury showed clearly that HRP activity was present throughout the entire depth of the deendothelialized, but not the reendothelialized, thickened intima. These results may indicate that an elevated turnover of hemostatic proteins continues within the deendothelialized intima after injury, conceivably until reendothelialization is complete.

Animals↗

PubMedDate not supplied

Deficiency of plasma protein S, protein C, or antithrombin III and arterial thrombosis.

Protein C and protein S are vitamin K-dependent coagulation factors that together act as an anticoagulant, and antithrombin III is a plasma protein that inhibits several activated factors in the coagulation cascade. Although deficiencies of any of these three proteins have been associated with deficiencies of these factors. We report one patient with a protein S deficiency, another with a protein C deficiency, and a third with an antithrombin III deficiency, each of whom who had extensive arterial thrombosis. We suggest that deficiencies of these proteins may constitute risk factors for arterial thrombosis.

Adult↗