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Antithrombin III was evaluated in 21 patients admitted with Echis carinatus envenomation. Although there was evidence of incoagulability in all patients and elevated fibrin degradation products, mean antithrombin III levels were found to be significantly greater than in controls. This result suggests that Echis carinatus venom (echarin) may bypass the consumption of antithrombin III molecules.
A simple assay procedure for antithrombin III is described. The synthetic product benzoyl-Phe-Val-Arg-p-nitroanilide (S-2160) is used as substrate. By thrombin p-nitroaniline is split from the tripeptide molecule. The yellowish color of this split product can be measured in a photometer. Inactivation of thrombin by antithrombin III results in inhibition of this reaction. The percentage of thrombin inhibited is in direct relation to the activity of antithrombin III. Various modifications were tested to optimate the method. Comparable results were obtained between the coagulation method of HENSEN and LOELIGER and the photometric method.
The factor Xa inactivating function of antithrombin III is measured automatically by an amidolytic method, adapted to a centrifugal analyser. Plasma is diluted in buffer with heparin. In stage I, diluted plasma is incubated with excess factor Xa. Heparin accelerates the saturation of antithrombin with factor Xa. In stage II, remaining factor Xa is determined with the chromogenic substrate Bz-Ile-Glu-Gly-Arg-pNA. The precision of the present assay compares favourably with that of the clotting assays and immunoassay. There is a close correlation (r = 0.82) between the results obtained with this assay and the immunoassay of antithrombin III.
Antithrombin III, factor VIII, fibrinogen and fibrinolytic activity were measured in two groups of long-standing insulin-dependent diabetic subjects (24 with proliferative retinopathy, 24 without detectable retinopathy) and 24 non-diabetic controls. Mean antithrombin III (+/- 1 SD) was 115.9 (+/- 15.1), 109.8 (+/- 18.1) and 101.4% (+/- 12.5), respectively, in the retinopathy, non-retinopathy and control groups. Statistical significance was obtained when comparing the retinopathy and control groups (p < 0.001) and when comparing all 48 diabetics collectively with controls (p < 0.01). Mean factor VIII coagulant activity was 137.5 (+/- 37.0), 126.2 (+/- 58.2) and 97.0% (+/- 38.7), respectively, in the three groups. Again the differences between all diabetics and controls (p < 0.01) were statistically significant. Similar increases were observed for other modalities of factor VIII activity. Fibrinolytic activity was significantly increased in both diabetic groups but fibrinogen levels, although increased, were not statistically different from levels in controls. It is suggested that the observed changes are more likely to be secondary to the development of retinopathy and that the increase in antithrombin III activity is due to an increase in alpha 2-macroglobulin.
The effect of heparin, hirudin, and a synthetic thrombin inhibitor on antithrombin III, fibrinogen and platelets was studied in a rat model of disseminated intravascular coagulation (DIC) induced by thrombin infusion. Antithrombin III is consumed during thrombin infusion to a limited degree. Simultaneous administration of exogenous thrombin inhibitors ameliorates the consumption of fibrinogen and platelets. At high thrombin doses, tolerated only during additional administration of thrombin inhibitors, heparin leads to increased consumption of antithrombin III, whereas hirudin and the synthetic inhibitor do not. In every case, the thrombin effect on fibrinogen and platelets is inhibited.
Immunoglobulin G (IgG) isolated from the blood plasma of a patient with secondary antiphospholipid syndrome (APS) expresses fibrinogen-clotting and amidolytic activity (the thrombin activity in 20 micromole IgG is equivalent to approximately 5 nmole pure thrombin), and activates factor XIII. Hirudin (1 microM) decreases the intrinsic thrombin activity of the APS IgG by only 25%, whereas it inhibits completely pure thrombin with equivalent activity. Under conditions, when antithrombin inactivates 60% of the thrombin activity in the presence of normal IgG, the APS IgG protects almost completely the added thrombin against inactivation by antithrombin. Heparin, however, partially relieves this protective effect and at the same time it facilitates the inhibition of the intrinsic thrombin activity by antithrombin. The APS IgG reduces the thrombin activity in protein C activation assay by 50% compared to the activity in the presence of normal IgG. All described properties are related to the Fab fragment of the antibody. The IgG preserving the fibrin-generating activity of thrombin with concomitant protection against inhibitors unravels a new aspect of the thrombotic mechanism in APS. This condition is probably rare: only one out of 23 examined patients with primary or secondary APS expresses IgG with the described properties.
Because measurements of hemostatic factors might aid the prediction of cardiovascular clinical events, we investigated the long-term prognostic importance of selected hemostatic factors in patients with angina pectoris. At recruitment, 209 patients underwent clinical assessment and coronary angiography, and a range of hemostatic factors were measured. During the follow-up period of 9 years, 58 patients (28%) suffered a cardiac event (acute myocardial infarction or death from cardiac causes). The risk of cardiac events was positively related to baseline measurements of fibrinogen (risk ratio per SD [RR] increase 1.29, 95% confidence interval [CI] 0.99 to 1.68, P=.06) and negatively related to antithrombin III activity measurements (RR 0.75, 95% CI 0.59 to 0.95, P=.02). No other hemostatic factor measured was significantly related to the risk of having a cardiac event. Worsening of angina in the few weeks before and ejection fraction evaluation at the initial angiography were both strongly related to the risk of cardiac events. However, the relationships of fibrinogen and antithrombin III measurements to risk remained almost unchanged after adjusting for worsening of angina and ejection fraction. Fibrinogen and antithrombin III may have an important etiologic role in the prognosis of patients with angina pectoris.
A prospective study was undertaken to elucidate the effect, if any, of total parenteral nutrition on plasma Antithrombin III levels. A total of 309 patients were included in the study. The patients suffered from cancer, or chronic illness, or major trauma which necessitated total parenteral nutrition. Each patient acted as his own control. Pre and postinfusion Antithrombin III levels were measured at regular intervals. Statistically, the results of the study have shown that total parenteral nutrition does not significantly alter Antithrombin III levels.
Thirty patients scheduled for elective myocardial revascularization and having undergone preoperative heparin treatment have been admitted to this prospective, randomized study. The aim of the study was to test two different strategies for preserving circulating antithrombin III (AT-III) during cardiopulmonary bypass. Patients in the control group (group C, n = 10) were treated with a standard heparinization (300 IU/kg). Patients in group A (n = 10) received the same management plus two doses of purified antithrombin III (1000 IU each). Patients in group GA received 200 IU/kg heparin and a continuous infusion of heparin (100 IU/kg/h) and gabexate mesilate (2 mg/kg/h) plus the same dose of antithrombin III as group A. Both group A and group GA demonstrated a preservation of circulating AT-III when compared to group C; this effect was more pronounced in group GA. The total heparin dosage was less in group GA than in groups A and C. Purified AT-III administration is recommended in heparin pretreated patients; the addition of gabexate mesilate to this protocol decreases the heparin requirement and increases the AT-III preservation.
Moderate haemodilution enhances coagulability in vitro and in vivo as measured by thrombelastography (TEG). The mechanism has never been established. We have conducted an in vitro study to determine whether the effect can be moderated or prevented when the reduction in antithrombin III caused by dilution is prevented by supplementation. Blood from 20 volunteers was divided into four samples. One sample was not diluted and served as control (C). Another was diluted (by 20%) with saline (S). The third was diluted by 20% with saline plus two units of antithrombin (AT III) (SA). The fourth remained undiluted, with two units of added AT III (CA). Coagulation was measured in all four samples using the TEG. In a separate laboratory study, the levels of AT III were measured in control samples and compared with levels after 20% dilution, and 20% dilution with two units of AT III added to the diluent. Enhanced coagulation was demonstrated in saline-diluted samples (S) by shortening of r- and k-times, and increased alpha angle. In the SA samples, r-time shortening was prevented; k-time shortening and alpha-angle increase persisted, but to a reduced degree (difference from saline-only dilution P<0.051). There were no differences between samples C and CA. A predictable drop of AT III (24.2%) occurred with saline dilution, while AT III levels in the AT III/Saline group were similar to the undiluted control. Haemodilution-induced coagulation enhancement is attenuated, but not prevented, if AT III levels are maintained in the normal range. This is in keeping with the established concept of an antithrombin threshold preventing positive coagulation feedback into the intrinsic pathway.
Acquired coagulation factor inhibitors include pathologic immunoglobulins that specifically bind to coagulation factors and either neutralize their procoagulant activity, accelerate their clearance from the circulation, or have proteolytic activity to degrade them into inactive polypeptides. Here, an autoantibody against prothrombin is described in a patient with serious hemorrhagic diatheses. The autoantibody exerts its influence by a previously unknown mechanism in which it inhibits coagulation through aberrant activation of the proenzyme in a catalytic manner. The antibody-bound prothrombin formed a stable stoichiometric complex with antithrombin III, consisting of intact prothrombin and an antithrombin III molecule cleaved at the (393)Arg-(394)Ser bond. The antibody dissociated from prothrombin after the complex formation with antithrombin III. Although the bound antibody elicited protease activity from prothrombin, the complex was not able to convert fibrinogen to fibrin or to activate protein C. Thus, this is the first description of an autoantibody that induces protease-like activity from a human proenzyme, permitting subsequent neutralization by its physiological inhibitor. (Blood. 2001;97:3783-3789)
We designed a unique anticoagulant decapeptide, which possesses two O-sulfated tyrosine residues, based on the structure of hirudin's C-terminal functional domain. We first prepared a series of octa-, nona- and decapeptides with no sulfation, Suc-Phe-Glu-Pro-Ile-Pro-Glu-Tyr-Tyr-X-OH [X = bond, Leu or Leu-Gln], by a solution phase method and measured their thrombin times (TT) using human thrombin and rabbit plasma. The shortest octapeptide (3a) showed full antithrombin activity comparable to that of the lead compound hirudin (54-65), and the longest decapeptide (3c) prolonged TT most potently with an IC50 value of 5.8 microM. We consequently converted 3c to a disulfated decapeptide (NF-22) with SO3.pyridine complex and compared its antithrombin activity with that of known hirudin-related peptides: hirugen, MDL28050 and hirulog-1. NF-22 showed potent antithrombin activity with an IC50 value of 0.3 microM, being more potent than hirugen and MDL28050 (IC50 values of 4.0 microM and 1.1 microM, respectively). NF-22 was as potent as hirulog-1. NF-22 showed no change in activity in aqueous solution for 10 d at 60 degrees C, and remained about 90% unchanged in rat plasma on incubation for 24h at 37 degrees C, whereas the corresponding unsulfated peptide (3c) was completely digested under the same condition. NF-22 appears to be one of the most potent and stable peptide anticoagulants among the hirudin analogs.
Incubation of antithrombin with a series of synthetic reactive loop peptides showed that 6-mer and 7-mer peptides, P14-P9 and P14-P8 of antithrombin respectively, induced loop-sheet polymerisation and binary complex formation. These peptides are likely to anneal to the upper part of the dominant A-sheet, favouring sheet opening and allowing insertion of a second reactive loop in the lower part of the A-sheet to form polymers. The insertion of longer peptides filled the A-sheet beyond the P7 position and prevented polymerisation. Heparinised antithrombin was more resistant to polymerisation and peptide insertion, indicating that heparin induces a conformational change that closes the A-sheet and expels the reactive loop.
The success of thrombolytic therapy for acute stroke has demonstrated that neurologic outcome can be improved with timely treatment. However, the severely restricted use of thrombolytics has reinforced the need to develop alternative and complementary therapies. Antithrombin and antiplatelet agents represent promising therapeutic approaches for stroke management. Antiplatelet therapy has modestly improved outcome in both acute stroke (aspirin) and in secondary stroke prevention (aspirin with or without dipyridamole; adenosine receptor antagonists), although bleeding and other adverse events associated with antithrombin therapy have largely negated their potential benefit. These findings have prompted innovative solutions to the pharmacokinetic and pharmacodynamic challenges that are crucial to advancing these strategies for acute, primary and secondary stroke therapy. Currently, inhibitors of the platelet surface glycoprotein IIb/IIIa (GP IIb/IIIa, fibrinogen) receptor are being examined in clinical trials while antithrombin therapies focus on thrombin antagonists and inhibitors as well as inhibitors of Factor Xa. Further advances in stroke treatment will include combination therapies. Additionally, the successful design of future drug therapies will result from a more complete understanding of the activity of these agents not only on platelet function and the coagulation cascade, but also for their effects on the endothelium and within the brain parenchyma. The sum of these activities will allow for the maintenance of cerebral blood flow, blood-brain barrier integrity and neuronal function.
Serial coagulation studies were done in four women with acute fatty liver of pregnancy. All had coagulopathy, laboratory evidence of diffuse intravascular coagulation, and marked depletion of plasma antithrombin III. Two of these women had persistent intravascular coagulation for 4 days after delivery. The others had prompt control of intravascular coagulation coincident with elevation of the antithrombin III concentration by plasma transfusion. Severe antithrombin III depression may be a major cause of the persistent intravascular clotting and can be corrected by plasma transfusion.
We described the perioperative management of a patient with congenital antithrombin III deficiency using temporal inferior vena cava filter. A 30-year-old man with congenital antithrombin III deficiency was scheduled for artificial head replacement of the hip joint under general anesthesia. He was diagnosed as having congenital antithrombin III deficiency when he had had an episode of venous thrombosis after artificial head replacement of the right hip joint. He had been taking warfarin as an anticoagulant, and it was discontinued three days before surgery. To prevent perioperative thrombus formation, the plasma AT III activity was maintained above 80% before, during and after surgery using AT III concentrates. We also placed the temporal inferior vena cava filter. There was no serious thrombosis or embolism perioperatively. The use of the filter during the perioperative period helped to avoid development of serious thrombosis and embolism.
A procedure is presented for the purification of Factor IX from human plasma. The final product is homogeneous as judged by disc gel electrophoresis and sodium dodecyl sulfate gel electrophoresis. Furthermore, it is completely free of other coagulation component activities. Factor IX is converted to its enzymatically active form by the addition of small quantities of Factor IXa in the presence of calcium ions. This activated species is added to purified antithrombin-heparin cofactor and the interaction is studied in the presence and absence of heparin. Antithrombin-heparin cofactor is found to be a progressive, time-dependent inhibitor of Factor IXa and neutralizes approximately 57% of this enzyme's proteolytic activity within 30 min. The addition of heparin dramatically accelerates the rate of this interaction with virtually complete inhibition of Factor IXa occurring within 15 s. Sodium dodecyl sulfate gel electrophoresis of reduced and nonreduced proteins indicates that antithrombin-heparin cofactor functions as a potent inhibitor of Factor IXa by forming an undissociable complex with the enzyme which is stable in the presence of denaturing or reducing agents (or both). This complex represents a 1:1 stoichiometric combination of enzyme and inhibitor. Heparin increases the rate of formation of this complex without affecting its dissociability or stoichiometry.
BACKGROUND: Thrombophilia is caused mainly by disturbances of hemostasis involving excessive coagulation system activation, reduction of anticoagulation system (antithrombin III, protein C, protein S, RAPC) or fibrinolytic activity. MATERIAL/METHODS: In 34 young patients (aged <40 years) with recurrent deep venous thrombosis (>2 incidents) the activity of antithrombin III, protein C, S, platelet count, adhesion and aggregation, APTT, stipven-kephalin, prothrombin time and INR were investigated. Fibrinogen, factor XIII, ELT, FDP, Ag t-PA levels, antigen concentration and PAI-1 activity were determined. Patients with idiopathic DVT, after elimination of most important thromboembolism risk factors, were qualified for the study. DVT was confirmed in all patients by phlebography, plethysmography and ultrasonography. Results were compared with a group of 54 healthy controls. RESULTS: In almost 50% of patients with recurrent DVT (15/34) decrease of at least one plasma coagulation inhibitor (AT III, PC, PS) level was observed. In the patient group (with AT III and/or PC and/or PS decrease) statistically significant reduction of kaolin-kephalin time in comparison with controls was observed (a<0. 01). Analysis of fibrinolysis system demonstrated significant factor XIII level decrease (to 58.3%), fibrinogen level increase, ELT prolongation, and fibrinogen and fibrin degradation product increase in comparison with controls. The patients demonstrated 3-fold higher t-PA antigen level (13.1 ng/ml, a<0. 0001) and over 3-fold higher PAI-1 activity (26.7 AU/ml, a<0. 001) than healthy controls. CONCLUSIONS: Reduced antithrombin III, protein C, protein S activity and excessive activation of the coagulation system with secondary fibrinolytic activity increase were found in patients with recurrent DVT.