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PubMedDate not supplied

[Effect of vascular surgery on values of thrombin-antithrombin III complexes in patients with atherosclerosis of lower limb arteries].

In 25 patients with atherosclerosis of lower limb arteries (ALLA) in whom vascular operation was performed, the level of thrombin-antithrombin III (TAT) complexes and antithrombin III (AT III) activity were determined in comprehensive studies of the blood clotting system. The comparative group for the assessment of operation effect on primarily not disturbed haemostasis in humans included 10 men operated on for inguinal hernia, while the control group consisted of 54 healthy people. Blood for the determinations was taken before the operation, on the day of the operation (0-30 minutes after the operation), on the first day after it, and also on the third day in patients with hernia, and on the 7th day in patients with ALLA. In the patients with ALLA, blood hypercoagulation features were found, expressed as increased level of TAT complexes in spite of lack of abnormalities in comprehensive coagulation studies, while in the patients with hernia only increased AT III activity was found. The surgical operation caused in the patients with ALLA enhancing of hypercoagulation which was evidenced by over threefold increase of TAT complexes on the day of the operation.

Adult↗
PubMed1994

Homozygous antithrombin deficiency: report of two new cases (99 Leu to Phe) associated with arterial and venous thrombosis.

Inherited antithrombin deficiency is associated with an increased risk of thrombosis, primarily venous rather than arterial. Most affected individuals have inherited only a single copy of an abnormal antithrombin (AT) gene. Homozygously affected individuals, although rare, have a severe thrombotic history of early onset and often affecting the arteries. We report two new cases of type II HBS (heparin binding site) deficiency in which the propositi are homozygous for the previously reported mutation 99 Leu to Phe, and who have a severe thrombotic history. These cases are considered alongside existing homozygote and compound heterozygote cases.

Antithrombins↗
PubMedDate not supplied

Plasma protein C and antithrombin III in patients with acute leukemia.

When compared to values recorded in the 32 healthy control subjects, plasma protein C activity was found to be significantly decreased in the 29 patients with acute leukemia and especially in those considered to be in a critical condition. On the other hand, plasma antithrombin III activity did not significantly differ from the values noted in control subjects. The concomitantly occurring high plasma fibrinogen levels and low serum cholinesterase activity were highly suggestive for a switch of hepatic protein synthesis towards the production of acute phase proteins. It is therefore considered that in the absence of a consumption coagulopathy, changes affecting plasma protein C and antithrombin III should be related to a modified pattern of hepatic protein synthesis.

Acute Disease↗
PubMed1978

[Progressive antithrombin activity in rabbit plasma. Role of alpha macroglobulins].

Immunological methods associated with a kinetic study of blood coagulation allowed us to show the influence of the 2 rabbit alpha macroglobulins on the plasma progressive antithrombin activity. This study allowed the authors to discuss the participation of the alpha macroglobulins during the fibrinoformation and to think that these proteins have an immediate antithrombin activity.

Animals↗
PubMed1994

Pharmacokinetic and antithrombotic properties of two pentasaccharides with high affinity to antithrombin III in the rabbit: comparison with CY216.

This study compares the pharmacokinetic and the antithrombotic properties of two pentasaccharides with high affinity to antithrombin III with those of a conventional low molecular weight heparin, CY216, in the rabbit. On a weight basis, SR 90107A/ORG 31540 (natural pentasaccharide [NPS]) and SR 80027A/ORG 31550 (sulfated pentasaccharide [SPS]) were, respectively, 4.7 and 26 times more potent antifactor Xa inhibitory agents than CY216. They were devoid of antithrombin activity, whereas the antifactor Xa/antithrombin ratio of CY216 was 3.8. After bolus intravenous administration, the clearance (mL/kg/h) of CY216 decreased from 91 +/- 27 for the dose of 12.5 U/kg to 49 +/- 14 for the dose of 50 U/kg and then remained constant up to the highest dose tested (500 U/kg). The clearance of NPS was unrelated to the dose and comparable to that of CY216 over 50 U/kg, whereas that of SPS was 10 times lower. Consistent results were observed after continuous intravenous infusions for 9 hours and subcutaneous administration. The duration of the antithrombotic effect was compared after a single subcutaneous injection of 250 U/kg of either compound in the stasis-Wessler model using human serum as thrombogenic stimulus. Two hours after the injection, the three compounds provided a thrombus prevention of greater than 95% and mean plasma activities of 0.8, 0.9, and 1.9 U/mL for CY216, NPS, and SPS, respectively. Twelve hours after injection, the antithrombotic effects of CY216 and NPS had totally vanished, whereas that of SPS was 68%. At that time, the plasma anti-Xa activities were less than 0.06 U/mL for CY216 and NPS, but 1.1 U/mL for SPS. For the latter compound, significant antithrombotic effects and detectable anti-Xa activities were still recorded 48 hours after the injection. The antithrombotic potency of the three compounds was also compared as their ability to inhibit the growth of a standardized venous thrombosis during 4 hours. The lowest total doses providing the maximum inhibitory effect were 3,125, 1,428, and 62 micrograms/kg for CY216, NPS, and SPS, respectively. These doses generated mean steady state antifactor Xa activities of 1.06, 1.5, and 1.2 anti-Xa U/mL, respectively. These observations indicate that the amplification mechanisms triggered by thrombin bound to fibrin and leading to the generation of new thrombin are essential to ensure venous thrombosis growth and that these mechanisms may be efficiently inhibited by pure antifactor Xa targeting agents.

Animals↗
PubMed1994

Platelet function and antithrombin, plasminogen, and fibrinolytic activities in cats with heart disease.

Platelet function, antithrombin and plasminogen activities, and fibrinolytic capabilities in 11 cats with acquired heart disease were compared with results in 4 healthy cats. Of 11 cats with heart disease, 9 had hyperthyroidism with secondary cardiac dysfunction. One cat with hyperthyroidism had renal disease and heart failure, and of 2 cats with idiopathic hypertrophic cardiomyopathy, 1 also had renal disease. At the time of testing, 3 cats had thromboembolic events associated with the disease. Compared with healthy cats, cats with acquired heart disease had increased activity of antithrombin III, a protein that behaves as an acute-phase reactant. Plasminogen activity was decreased, although not significantly, in cats with acquired heart disease, compared with results in healthy cats. In cats with left ventricular dysfunction, clot retraction was decreased (marginal significance, P = 0.058) and might be attributed, in some cases, to the medications received by the cats. Dilute whole blood clots from all cats failed to lyse in vitro. This observation, at present, lacks adequate explanation. Platelets from cats with acquired heart disease, compared with platelets from healthy cats, had decreased responsiveness (aggregation and [14C]serotonin release) to adenosine diphosphate and increased responsiveness to collagen. Hyperthyroid cats were receiving various drugs (propranolol, atenolol, or diltiazem) to empirically treat clinical signs of disease attributable to cardiac dysfunction. Although numbers of cats in each group were small, definite trends were observed in the results of tests. Platelets from cats receiving atenolol had decreased responsiveness to adenosine diphosphate and unaltered responsiveness to collagen, compared with platelets from healthy cats, and may have decreased risk of thrombus formation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1994

Antithrombin III and trauma patients: factors that determine low levels.

A prospective (cohort) study was conducted to determine the incidence of low antithrombin III (AT III) levels and the association with selected clinical variables in adult trauma patients. One hundred sixty AT III levels were obtained on 50 consecutive trauma admissions to a community-based level I trauma center. Antithrombin III levels were drawn as soon after admission as possible and every other day thereafter. Thirty-one patients (62%) had at least one low AT III level (< 80%), whereas 15 concurrently drawn control levels were all > or = 90%. Low AT III levels were more common in patients with one or more of the following: base deficit less than -4 (39% vs. 0, p = 0.002); Injury Severity Score > 15 (48% vs. 16%, p = 0.04); and blood transfusion (32% vs. 5%, p = 0.04). All other variables (shock, surgical intervention, subcutaneous heparin, and sequential compression devices) were not statistically significant, although all six patients with shock had low levels. In conclusion, over 60% of adult trauma patients had low AT III levels at some time during hospitalization and these patients were clearly more severely injured. Further studies are required to determine if these patients are more susceptible to thromboembolic phenomena.

Adult↗
PubMed1993

Antithrombotic effects of synthetic pentasaccharide with high affinity for plasma antithrombin III in non-human primates.

The pentasaccharide (PS) comprising the minimal heparin structure capable of binding with antithrombin III (ATIII) and exhibiting anti-factor Xa (anti-fXa) activity in plasma without producing detectable antithrombin activity, has been evaluated for its relative antithrombotic and antihemostatic effects in a baboon model combining both platelet-rich and fibrin-rich thrombosis. Thrombosis was produced in a two-component thrombogenic device incorporated into an exteriorized femoral arteriovenous (AV) shunt in baboons; the proximal component constituted a segment of collagen-coated tubing and induced platelet-rich arterial-type thrombus, while the distal component consisted of an expanded chamber producing static and disturbed flow and initiated fibrin-rich venous-type thrombosis. Thrombus formation was measured as the deposition of 111In-platelets and the accumulation of 125I-fibrin. PS was administered intravenously to maintain plasma anti-fXa activity at three different levels: a) low dose (LD) 0.3 +/- 0.1 U/ml; b) intermediate dose (ID) 0.6 +/- 0.1 U/ml; and c) high dose (HD) 5.6 +/- 0.4 U/ml. In untreated controls, thrombus formed rapidly, reaching a plateau by 40 min of 2.3 +/- 0.2 x 10(9) platelets and 0.62 +/- 0.04 mg fibrin deposited on the collagen segments, and 1.9 +/- 0.4 x 10(9) platelets and 3.3 +/- 0.4 mg fibrin accumulated in the chambers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Platelet, antithrombin, and fibrinolytic activities in taurine-deficient and taurine-replete cats.

Cats with cardiomyopathy, especially dilated cardiomyopathy associated with taurine deficiency, often develop systemic thrombi. To investigate the relation of taurine deficiency to formation and persistence of thrombi, cats were made taurine-deficient by consumption of a casein-based taurine-deficient diet, then were evaluated for anticoagulant and profibrinolytic activities and platelet function. The cats served as their own controls in the taurine-replete state; then, values were compared for the taurine-deficient state. Plasma (P < 0.01), blood (P < 0.05), and platelet (P < 0.05) taurine concentrations were decreased markedly after cats consumed the taurine-deficient diet for 6 weeks, compared with baseline concentrations before diet. Compared with the taurine-replete state, taurine deficiency induced significantly (P < 0.05) increased mean antithrombin III activity, no significant change in plasminogen and fibrinolytic activities, and similar clot retraction/lysis test results. Decreased (P < 0.01) adenosine diphosphate (ADP)-induced platelet aggregation and [14C]serotonin release, and slightly increased (P < 0.05) collagen-induced platelet [14C]serotonin release, but unchanged collagen-induced platelet aggregation were observed in taurine-deficient cats, compared with taurine-replete cats. Changes in antithrombin III activity most likely reflected hepatocellular acute-phase reaction, which indicates that taurine deficiency may induce a stress-responsive state. Results of platelet function testing indicate that taurine may modulate platelet responsiveness to physiologic agonists, but not in consistent manner. That platelets from the taurine-deficient cats had decreased responsiveness to ADP, but increased responsiveness to collagen is surprising, because irreversible aggregation is mediated by release of granule-associated ADP after sufficient initial stimulus.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Diphosphate↗
PubMed1993

[Pregnancy and thrombophilia in women with congenital deficit of antithrombin III, protein C, protein S or plasminogen: analysis of 39 cases].

BACKGROUND: Pregnancy, delivery and puerperium are situations which increment the risk of thromboembolic complications in women who are carriers of congenital heterozygotic deficits of type I antithrombin III (ATIII), protein C (PC) or protein S (PS). The aim of this study was to analyze the experience of the authors and propose therapeutic conduct in each case. Furthermore, the spontaneous losses of pregnancy related with these deficits were studied. METHODS: Thirty-nine women, seventeen with ATIII deficit, fifteen with PC deficit and four with a deficit of PS and three with a plasminogen (Pg) deficit totalling 79 pregnancies and 51 thrombotic episodes sixteen of which were related with the pregnancy, delivery or puerperium were studied. The antigenic and functional activity of ATIII, PC, PS and Pg were determined. RESULTS: The incidence of thrombosis for the ATIII deficit during pregnancy was 39%, which was greater, of statistical significance (p = 0.046), than the 15% observed during puerperium. In women with a deficit of PC, the incidence of thrombosis was 4.5% during pregnancy and 14% during puerperium with no significant difference between the two situations. The incidence of thrombosis during pregnancy and postpartum in the deficit of ATIII was significantly higher (p < 0.025) than that observed for the deficit of PC. For women with a deficit of PS and Pg the incidence of thrombosis was nul in pregnancy and puerperium. CONCLUSIONS: Pregnancy and puerperium are situations which trigger thrombotic phenomena and increase the risk of the same in women with a deficit of antithrombin III and protein C and, to a lesser degree, the deficit of protein S or plasminogen. A strict control of these situations and individualized treatment is required according to the type of deficit, presence of previous thromboembolic history and anticoagulant history at the time of pregnancy. No increase in the risk of loss of pregnancy in any of the deficits studied was observed.

Adult↗
PubMed1993

Structural studies on the bacterial lyase-resistant tetrasaccharides derived from the antithrombin III-binding site of porcine intestinal heparin.

Three discrete tetrasaccharide structures which are resistant to Flavobacterium heparinase and heparitinases I and II were isolated from porcine intestinal heparin after exhaustive digestion with a mixture of all the above enzymes, and the tri-, tetra-, and penta-sulfated structures were determined by negative ion mode fast atom bombardment mass spectrometry and 500-MHz 1H NMR analysis as delta 4,5GlcA beta 1-4GlcNAc (6-sulfate)alpha 1-4GlcA beta 1-4GlcN(N,3-disulfate), delta 4,5 GlcA beta 1-4GlcNAc(6-sulfate)alpha 1-4GlcA beta 1-4GlcN (N,3,6-trisulfate), and delta 4,5GlcA beta 1-4GlcN (N,6-disulfate)alpha 1-4GlcA beta 1-4GlcN(N,3,6-trisulfate). The three components share the 3-O-sulfated reducing GlcN and the 6-O-sulfated internal GlcN, indicating that they are structural variants derived from the nonreducing portion of the minimal pentasaccharide sequence required for binding to antithrombin III. Isolation of the pentasulfated component has never been reported. Their unexpected resistance to heparitinases I and II indicates that 3-O-sulfation of the reducing GlcN contributes to the resistant nature of these tetrasaccharides to the enzymes. The present study demonstrates that the nonreducing trisaccharide portion of the structural variants of the antithrombin III-binding pentasaccharide sequence can be isolated in tetrasaccharides resistant to heparinase/heparitinases I and II, while the rest of the repeating region is degraded into disaccharide units. The lyase treatment is applicable to evaluation of heparin/heparan sulfate preparations in terms of the presence or absence of the specific structure containing the 3-O-sulfated GlcN representing biosynthetic precursors, intermediates or final products of the binding site.

Animals↗
PubMed1993

Lasting safe interruption of endarterectomy thrombosis by transiently infused antithrombin peptide D-Phe-Pro-ArgCH2Cl in baboons.

To evaluate the relative antithrombotic efficacy and hemostatic safety of antithrombin therapy for vascular thrombus formation at sites of mechanical vascular injury, we administered the potent and specific irreversible synthetic antithrombin D-PHE-PRO-ARG chloromethyl ketone (D-FPRCH2Cl) after performing carotid endarterectomies in baboons. The continuous intravenous infusion of D-FPRCH2Cl, 100 nmol/kg per minute for 1 hour, abolished acute carotid endarterectomy thrombosis for at least 48 hours. The plasma level of D-FPRCH2Cl during the infusion was maintained steady at 7.2 +/- 0.9 mumol/L, but decreased rapidly after discontinuing its infusion (T50 17 minutes). Platelet deposition, measured in real time using autologous 111In-platelet scintillation camera imaging, was 1.51 +/- 0.40 x 10(8) platelet/cm in the 14 treated animals 90 minutes postoperatively, compared with 11.7 +/- 1.16 x 10(8) platelet/cm in 14 heparin-treated controls (P < .002). The antithrombotic benefit was equivalent for treatment begun either 5 minutes before (nine animals) or 15 minutes after (five animals) reestablishing flow in the operated vessel, ie, 1.59 +/- 0.36 x 10(8) platelet/cm versus 1.35 +/- 0.51 x 10(8) platelet/min, respectively; P > .5. Endarterectomy thrombosis remained decreased for at least 48 hours postoperatively, as determined by the ratio between net 111In-platelet radioactivity at the endarterectomized site versus whole blood (ratio 0.82 +/- 0.25 in the treatment group v 3.03 +/- 0.51 in heparin controls at 90 minutes, P < .005; and 0.85 +/- 0.23 v 3.25 +/- 0.48 at 48 hours, P < .002). The marked reduction in endarterectomy thrombosis in treated animals at 48 hours was confirmed by scanning electron microscopy. Thrombin activity formed rapidly and became immediately bound to thrombus on thrombogenic segments in untreated control studies; treatment with D-FPRCH2Cl irreversibly inactivated the thrombus-bound thrombin. Hemostatic function, as measured by bleeding time (BT), activated partial thromboplastin time (APTT), and prothrombin time (PT) was impaired throughout the intravenous administration of D-FPRCH2Cl (BT > 30 minutes, APTT > 150 seconds, PT > 50 seconds); BT, APTT, and PT values were normal 30 minutes after discontinuing the infusions. As expected, blood loss into the surgical wound was substantial in nine animals receiving therapy initiated before restoring flow in the operated vessel (mean 95 mL, range 45 to 130 mL). By contrast, beginning D-FPRCH2Cl therapy in five animals 15 minutes after restoring arterial flow, a time when surgical hemostasis had been achieved, prevented excessive blood loss (mean 15 mL, range 10 to 35 mL; P < .01 compared with earlier treatment) without compromising the antithrombotic effects.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Chloromethyl Ketones↗
PubMed1996

Factor VIIa and antithrombin III activity during severe sepsis and septic shock in neutropenic patients.

Septic shock and multiple organ failure may be associated with coagulation activation, disseminated fibrin formation, and consumption of coagulation inhibitors such as antithrombin III. We have evaluated prospectively coagulation measurements in patients with severe chemotherapy-induced neutropenia. This group of patients was chosen because of their high risk of developing severe septic complications, thus allowing serial prospective coagulation testing before and during evolving sepsis or septic shock. Sixty-two patients with febrile infectious events were accrued to the study. Of these, 13 patients progressed to severe sepsis and 13 additional patients to septic shock as defined according to standard diagnostic criteria. At the onset of fever, factor (F) VIIa activity, FVII antigen and antithrombin III (AT III) activity decreased from normal baseline levels and were significantly lower in the group of patients who progressed to septic shock compared with those that developed severe sepsis (medians: 0.3 v 1.4 ng/mL, 21 v 86 U/dL and 45% v 95%; P < .001). The decrease of these measurements in septic shock was accompanied by an increase in prothrombin fragment 1+2 (median: 3.6 v 1.4 nmol/L; P = .05), a marker of thrombin generation. These differences were sustained throughout the septic episode (P < .0001). FVIIa and AT III levels of < 0.8 ng/mL and < 70%, respectively, at onset of fever predicted a lethal outcome with a sensitivity of 100% and 85%, and a specificity of 75% and 85%, respectively. In contrast, FXIIa-alpha antigen levels were not different between groups at onset of fever but increased modestly during the course of septic shock (P = .001). Thus, septic shock in neutropenic patients is associated with increased thrombin generation. Furthermore, both FVIIa and AT III measurements are sensitive markers of an unfavorable prognosis.

Adult↗
PubMed1996

Use of enzyme-linked immunosorbent assay to measure thrombin-antithrombin III complexes in horses with colic.

OBJECTIVES: To evaluate new ELISA for measurement of thrombin-antithrombin III (TAT) concentration, and to correlate the values to other tests of hemostasis in horses with colic. DESIGN: Plasma TAT concentration and 8 other hemostasis analytes were measured in horses with colic at hospital admission and during the next 4 days. Retrospectively, data were analyzed by outcome, broad-category diagnosis, and clinical management, and for correlation between TAT and other assays. ANIMALS: 100 horses with colic. PROCEDURE: Plasma samples were evaluated for TAT, fibrinogen, and fibrin degradation products concentrations; antithrombin III (ATIII), protein C, alpha 2-antiplasmin, and plasminogen activities; prothrombin time (PT); and activated partial thromboplastin time. RESULTS: Changes were indicative of a hypercoagulable state, most severe in nonsurviving horses, characterized by increased TAT concentration; decreased ATIII, protein C, and plasminogen activities; and increased PT. Nonsurvivors had significantly increased TAT concentration compared with that in survivors, without regard to sample collection time; however, compared over time, TAT was significantly increased only at admission. Highest TAT concentration was in nonsurvivors with inflammatory intestinal lesions. There was significant negative correlation between TAT and ATIII, protein C, alpha 2-antiplasmin, and plasminogen values, and significant positive correlation between TAT and PT, and fibrin degradation products values. CONCLUSIONS: Plasma TAT reflects the current state of coagulation system activation and is a good assay for early diagnosis of the hypercoagulable state in horses with the most severe forms of colic. CLINICAL RELEVANCE: Measurement of equine TAT provides further information to characterize the hypercoagulable state in horses to aid in case management.

Analysis of Variance↗
PubMed1996

Long-term persistence of biological activity following administration of Enoxaparin sodium (clexane) is due to sequestration of antithrombin-binding low molecular weight fragments--comparison with unfractionated heparin.

We have previously reported (Brieger D, Dawes J. Thromb Haemost 1994; 72: 275-80) that the prolonged anti-Xa amidolytic activity following intravenous administration of the low molecular weight heparin Enoxaparin sodium is mediated by small molecules derived from the injected drug, and an antithrombin binding penta/hexasaccharide can be detected in the circulation as late as 1 week after administration. To investigate the mechanism underlying this persistence we administered 125I-labelled fractions of Enoxaparin sodium and unfractionated 125I-heparin to rabbits. Both 125I-heparin and the radiolabeled high molecular weight (> 6000 Da) Enoxaparin sodium were more effectively cleared from the circulation than the smaller components of LMW heparin. However, our data suggest that the circulating biologically active penta/hexasaccharide was not an unmodified component of the injected drug but was derived from a subpopulation of molecules of intermediate molecular weight (1800-6000 Da) which was retained in the tissues. Significant quantities of both Enoxaparin sodium and unfractionated heparin were retained in the internal organs. We propose that the sequestered subpopulations of Enoxaparin sodium and unfractionated heparin follow different catabolic routes. After administration of both unfractionated and LMW heparin additional antithrombin binding material was released into the circulation by a bolus dose of heparin. This material was not contained on circulating blood cells and was probably sequestered on the endothelium.

Animals↗
PubMed1995

Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/Org31540) with high affinity to antithrombin III in man.

This paper reports the results of the first administration of the synthetic natural pentasaccharide with high affinity to antithrombin III (NP) in man. This study was mainly focused upon the pharmacokinetic properties and general tolerance of the compound. Subcutaneous injections of doses < 1.43 mg (1000 anti Xa IU) did not generate measurable anti-Xa activities. After subcutaneous injection of increasing doses from 1.43 to 22.9 mg (1000 to 16,000 anti-Xa IU) to young healthy volunteers, it was found that the maximal concentration (Cmax) and the area under curve (AUC) were linearly correlated to the dose, that the total plasma clearances (CI) were constant and almost 3 times lower than those of the current low molecular weight heparins. Cmax were reached between 1 h and 3 h after the injection and the half-lives (t 1/2) were remarkably constant (13.1 h to 13.9 h). During the first 24 h following the injection, around 50% of the total administered dose was recovered in the urine in an active form, indicating that kidney plays a major roles in the elimination of NP. Consistent with these results, when NP was administered to healthy elderly volunteers having a lower creatinine clearance, the half-life of the compound was longer and the clearance lower. At doses exceeding 22.9, Cmax, and AUC were slightly lower than expected, the percentage of the dose recovered in the urine and the total apparent plasma clearance increased, suggesting that the excess of NP unbound to antithrombin III was excreted faster. NP was also administered at various dosages once or twice a day for 7 days to 20 elderly volunteers. Due to the long half-life of the compound the "steady state" was obtained 2 to 3 days after the first injection at which the mean Cmax was increased 1.5 to 2 times. The general tolerance of the compound was excellent. No relevant prolongations of the prothrombin time, of the activated partial thromboplastin time or of the bleeding time were observed. A re-bleeding phenomenon of the bleeding time incision, probably related to friability of the haemostatic plug, occurred in 3 subjects treated with the highest dose regimens: single injection of 26.6 mg (20,000 anti-Xa IU) (young volunteers) and repeated injections of 11.4 mg (8,000 anti-Xa IU) once a day for 7 days (elderly volunteers). At these times, plasma NP concentrations were between 2.9 and 3.6 micrograms.ml-1 (2 and 2.5 anti-Xa IU.ml-1).

Adolescent↗
PubMedDate not supplied

Hemostatic balance during the acute inflammatory reaction; with special reference to antithrombin III.

Inflammatory reaction caused by intramuscular injections of turpentine in 5 rabbits led to an obvious increase of not only plasma fibrinogen and factor VIII: C levels, but also of plasma antithrombin III activity, measured by a chromogenic assay as heparin cofactor. This activity rose from 80% +/- 10,8 (mean +/- SEM) before the injection to 123% +/- 6,56 48 hours later. Changes affecting plasma fibrinogen level and antithrombin II activity were much lesser in a group of 5 rabbits given small doses of intravenous endotoxin. It is considered that acute inflammation is accompanied by the setting of the hemostatic balance at a higher level.

Acute-Phase Reaction↗
PubMed1997

Potent antithrombin activity and delayed clearance from the circulation characterize recombinant hirudin genetically fused to albumin.

In this study we sought to extend the plasma half-life while maintaining the potent antithrombin activity of hirudin. We hypothesized that gene fusion of hirudin to albumin would result in the expression of a slowly cleared hirudin molecule. A hirudin variant 3 (HV3) cDNA was obtained by gene synthesis, while a 1,996-bp full-length rabbit serum albumin (RSA) cDNA was selected from a rabbit liver cDNA library. Expression of the former in COS-1 cells conferred antithrombin activity on media conditioned by the cells, while expression of the latter resulted in the secretion of a 67-kD protein that reacted with mono-specific anti-RSA antibodies. Having shown independent expression of the two proteins, we next expressed two fusion proteins: HV3 linked via its C-terminus to albumin (HLA), and HV3 linked via its N-terminus to albumin (ALH). The former, but not the latter, inhibited both the amidolytic and fibrinogenolytic activities of thrombin. HLA also retained the dye-binding characteristics of RSA, as judged by Affi-Gel Blue chromatography. Highly similar concentrations of either commercial HV1 (40 nmol/L) or HLA (30 nmol/L) were required to halve the initial rate of thrombin reaction with chromogenic substrate S2238, suggesting the retention of high-affinity inhibition of thrombin by the fusion protein. An His-tagged form of HLA was purified by Ni2+-chelate affinity and heparin-Sepharose chromatography. The purified, radioiodinated protein was injected into rabbits, and demonstrated a catabolic half-life of 4.60 +/- 0.16 days. This represents an extension of hirudin half-life in vivo of greater than two orders of magnitude; gel analysis of HLA(H)6 recovered from rabbits showed that it circulated in intact form. Our results provide a rationale for future testing of the biological effects of HLA, and support our initial hypothesis.

Amino Acid Sequence↗