[The other heparin cofactor].
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Antithrombins↗
Biomedical subjects
B Boneu
Publications and source records attributed to B Boneu.
The role of the hematocrit in bleeding.
Low hematocrit is an often neglected cause in the pathogenesis of a prolonged bleeding time in an anemic patient. There has been ample evidence in the literature, indicating a relationship between hematocrit and the bleeding time; and that the transfusion of RBCs may correct the prolonged bleeding time often observed in anemic patients. It is unclear how a low hematocrit causes a prolongation in the bleeding time; however, two hypotheses have been put forward. First, in small blood vessels, blood flow is such that the RBCs cause the physical dispersion of platelets towards the subendothelial surface, thus promoting interaction with the blood vessel wall. Secondly, following injury to a small blood vessel, RBCs activate platelets by releasing small amounts of adenosine diphosphate (ADP) into the microvasculature following the hemolysis that often occurs during hemostasis. The fact that the hematocrit influences the bleeding time may be of clinical importance in the treatment of anemic patients, particularly those presenting a bleeding tendency.
Adenosine Diphosphate↗
Plasma fibrinolytic activity in a group of hypogonadic men.
Fibrinolytic activity in response to venous occlusion (fibrin plate assay and tissue plasmogen activator antigen) was measured in 19 hypogonadic men (group 1), 23 non-hypogonadic men with deep venous thrombosis (DVT) antecedents and 20 healthy men (control group). Four hypogonadic men had DVT antecedents. Two of 20 controls were low responders against 6/19 and 6/23 in groups 1 and 2, respectively, (non-significant difference). The four hypogonadic men with DVT antecedent had abnormal response to venous occlusion. Whether defective fibrinolysis is causally related to hypogonadism cannot be established from these results but this study indicates that the combination of defective fibrinolysis, hypogonadism and DVT in man is relatively common.
Fibrin↗
Study of platelet alpha 2-adrenoceptors in Parkinson's disease.
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Aged↗
Effect of pentosan polysulphate administration in man on the formation of covalent complexes between heparin cofactor II and thrombin generated in plasma by contact activation.
An assay for the quantification of pentosan polysulphate (PPS) in plasma is described. As PPS has been shown to potentiate thrombin inhibition by the second heparin cofactor (HC II), the principle of this assay was to measure the formation of covalent complexes between HC II and the thrombin generated in plasma after contact activation and recalcification. The complexes were quantified by using purified 125I-HC II added to the plasma as a tracer and SDS-polyacrylamide gel electrophoresis (SDS-PAGE). The assay was sensitive to low PPS concentrations (limit of detection: 0.1 microgram/ml) and therefore suitable for the measurement of PPS in plasma after its administration to man. The clearance of PPS was studied in 3 subjects receiving respectively 10, 50 and 100 mg intravenously (IV) and in 3 subjects receiving 35 mg subcutaneously (SC). PPS was still detectable 8 h after 50 and 100 mg IV and 6 h after 35 mg SC. The activated partial thromboplastin time (APTT) was, in comparison, relatively insensitive but for concentrations above 1 microgram/ml the values derived from the APTT and from the SDS-PAGE method fitted. The results were also in general agreement with those reported by McGregor et al. (5) who used a sensitive competitive binding assay. This indicates that low concentrations of PPS previously measured chemically are also pharmacologically active in plasma.
Adult↗
Comparative turn-over of heparin cofactor II and antithrombin III in baboons. Influence of heparin and pentosan polysulfate administration.
Heparin and pentosan polysulfate (PPS) interact in plasma with antithrombin III (AT III) and Heparin cofactor II (HC II) respectively. To assess the influence of heparin or PPS treatment on the metabolism of their respective cofactors, we performed a double tracer study in baboons receiving heparin or PPS. Purified AT III and HC II from human plasma were labelled with 131I and 125I respectively by the lactoperoxidase-glucose oxidase technique. The tracers had unchanged biological activities, were homogeneous in SDS-PAGE, migrated as native proteins by crossed immunoelectrophoresis in the presence of heparin or PPS and virtually coeluted with endogenous baboon proteins from heparin-agarose. Nine animals were randomly allocated to receive, during the metabolic study, heparin (500 IU/kg/d, n = 3), PPS (5 mg/kg,d, n = 3) or a placebo (n = 3) given in 2 daily subcutaneous injections. Heparin levels and anticoagulant effects were similar in extent and duration to those usually achieved in man. The plasma concentrations of AT III and HC II did not vary under treatment. The half-life of the elimination phase in the placebo group ranged from 1.95 to 2.33 d for AT III and from 1.96 to 2.21 d for HC II. There was no significant difference in the half-lives of the 2 inhibitors between the placebo group and the animals receiving heparin or PPS. This suggest that clinical conditions associated with heparin treatment may be important for the effect of heparin on AT III metabolism previously reported in patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Heparin fractions with high and low affinities to antithrombin III are cleared at different rates.
The clearance characteristics of standard heparin (SH) and its fractions with high and low affinity to antithrombin III (HAH and LAH respectively) were studied by injecting 125I-labelled SH, HAH and LAH intravenously into the rabbits in increasing doses. Serial blood samples were then collected from an indwelling cannula for measurement of clearance, based both on radioactivity and anticoagulant activity. For equivalent weights injected, the radioactivity of HAH was cleared more slowly from the circulation than that of either SH or LAH. The radioactivity of SH, in turn, was cleared more slowly than that of LAH. The clearance of HAH, measured both by radioactivity and by anticoagulant activity were similar, whereas the clearance of the radioactivity of SH was more rapid than its anticoagulant activity (i.e. anti-factor Xa activity). These observations suggest that the radioactivity clearance curves of SH reflect a "net" estimation of the more complex clearance curves of the different heparin moieties whereas the anticoagulant clearance curves of SH reflects the clearance of the anticoagulant activity of a specific heparin fraction, in this case, the clearance of the anti-factor Xa activity of HAH. These differences suggest that the HAH:LAH ratio is, at any given time, greater in vivo than the same ratio measured in vitro.
Animals↗
Low molecular weight heparin half life is prolonged in haemodialysed patients.
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Adult↗
An IgM lupus anticoagulant that neutralizes the enhancing effect of phospholipid on purified endothelial thrombomodulin activity--a mechanism for thrombosis.
An anticoagulant activity was isolated from the plasma of a patient with a strong lupus-like anticoagulant using gel filtration by high performance liquid chromatography. IgM were detected in this anticoagulant fraction which exhibited specificity towards 50% phosphatidylcholine - 50% phosphatidylserine vesicles and cardiolipin. These phospholipids were able to produce an apparent 3-fold enhancement of purified human protein C activation by human alpha-thrombin in the presence of purified human placenta thrombomodulin. In the absence of phospholipid, the anticoagulant fraction had no effect on thrombomodulin activity. The anticoagulant fraction could neutralize the enhancement of thrombomodulin activity by phospholipid in a dose-dependent manner. This study suggests that the neutralization of phospholipid might result in a reduced activation of protein C which could be responsible for the occurrence of thrombotic complications in a proportion of patients with lupus anticoagulants.
Aged↗
[Prolonged bleeding time in severe anemia].
The frequency and importance of prolonged bleeding time were studied in patients affected by a severe anemia (haemoglobin less than 8 g/dl). A Simplate bleeding time test was performed in 25 patients suffering from various haematological disorders, with a platelet count greater than 100,000/cu mm and a normal or increased factor VIII complex. Patients with acute leukaemia, myeloproliferative disorders or chronic renal impairment were excluded from the study. Bleeding time was prolonged in 12 patients; their mean haematocrit was not different from that of the 13 other patients whose bleeding time was in the normal range. Bleeding time was less prolonged than in patients with chronic renal insufficiency in spite of a lower mean haematocrit (previous study). Fifteen patients were investigated a second time after partial or full correction of the haematocrit; in all but one, the bleeding time was reduced and/or normalized. This study suggests that severe anaemia may be an additional hemorrhagic risk factor in patients with another cause of bleeding.
Anemia↗
Tolerance and biological activity of pentosan polysulfate after intramuscular or subcutaneous administration for ten days in human volunteers.
This study reports on the tolerance and the pharmacological activity of pentosan polysulfate (PPS) administered to healthy volunteers for 10 days. Three groups of 10 subjects received either one daily injections of 100 mg of PPS by I. M. route (group I), or two daily injection of 50 mg of PPS by I. M. or S. C. route (groups II and III, respectively). In each group two random subjects received a placebo for the 10 days; on day 0, each subject was injected by a placebo. Clinical tolerance was checked by a daily physical examination; biological tolerance was assessed comparing the results of the main biochemical and haematological constants measured before starting the treatment (day 0) and 12 or 24 h after the end of the treatment (day 11). The pharmacological activity was measured on serial samples taken before treatment and between 1 and 6 h after the drug injection on days 1, 3 and 10; the results were compared to those obtained on day 0. Clinical tolerance was good. The biological side effects concern the transaminase levels and the platelet counts. An increase above the upper normal limit was observed in 18/24 and 3/24 for alanine and aspartic transaminase respectively. The mean platelet reduction ranged between 24 and 34% according to the groups. The drug injection induced a slight Quick time (PT) prolongation, no significant alteration of factors II, VII-X, V levels and of thrombin clotting time. The activated partial thromboplastin time (APTT) was significantly prolonged and there was a weak but significant circulating anti-Xa activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Dose-Response Relationship, Drug↗
Respective role of antithrombin III and heparin cofactor II in the in vitro anticoagulant effect of heparin and of various sulphated polysaccharides.
The in vitro anticoagulant effects of standard heparin (SH) and of seven other sulphated polysaccharides (SPS) were investigated by measuring activated partial thromboplastin time (APTT) prolongation of normal plasma and of plasmas selectively depleted of antithrombin III (AT III), of heparin cofactor II (HC II) and of both heparin cofactors. This allowed the determination of the relative contribution of each of the two heparin cofactors to the SPS anticoagulant effect. The SPS varied in their relative activities as catalysts of thrombin inhibition by purified AT III or HC II. The anticoagulant activities of heparin and dermatan sulphate were primarily attributable to their ability to enhance thrombin inhibition by AT III and HC II respectively. Heparin had an additional minor anticoagulant activity which was independent of both AT III and HC II. Pentosan polysulphate, high molecular weight dextran sulphate, heparin with low affinity for AT III and a sulphated heparin derivative had weaker anticoagulant activities in normal plasma than standard heparin. The anticoagulant activities of these last four SPS in plasma depleted of both AT III and HC II were similar to their respective activities in normal plasma. This suggests that these SPS act by directly preventing thrombin generation rather than by enhancing thrombin inhibition.
Antithrombin III↗
Heparin half-life and sensitivity in normal subjects and in patients affected by deep vein thrombosis.
In some patients affected with deep vein thrombosis (DVT) it is necessary to administer large doses of heparin to achieve proper anticoagulation. To investigate the clinical relevance of this phenomenon, we studied the heparin half-life and the heparin sensitivity after a bolus IV injection of 60 i.u. kg-1 in seven healthy volunteers and eight DVT patients investigated on day 1 or 2 and again between day 10 and 20 of the heparin therapy. The heparin half-life, the in vitro and ex vivo heparin sensitivity, were comparable in the healthy volunteers and in the patients at both times of investigation. However, there were large interindividual variations in the controls and in the patients, not correlated to the levels of any coagulation factors. Thus, the heparin hyperconsumption phenomenon occasionally observed in a given patient reflected individual characteristics and was no value in the diagnosis of DVT.
Adult↗
[Macrothrombocytosis and idiopathic thrombocytopenic purpura: effect of anticoagulant and prior fixation on the determination of platelet volume using the Coulter system].
This study was designed to evaluate the importance of anticoagulants and of prior fixation on the Coulter Counter platelet size determination in macrothrombocytosis occurring in patients affected with an idiopathic thrombocytopenic purpura (ITP). Native blood was sampled either in an iso-osmotic glutaraldehyde fixative solution at 37 degrees C or in standard citrated or EDTA vacutainers. Platelet size increased from the fixed whole blood sample to the unfixed standard citrate and EDTA samples. There was a good correlation between the three determinations. Of the 23 ITP cases 10 presented large sized platelets both in citrated and in fixed whole blood samples; however 4 of these patients presented a platelet size in the normal range in the EDTA samples. These results show that citrated blood samples are preferable to EDTA samples for detecting an increased platelet size in ITP and that ITP macrothrombocytosis does not result from an abnormal hypervolumetric shape change occurring in vitro after sampling.
Anticoagulants↗
[Importance of standardization in the biological monitoring of anti-vitamin K therapy].
The aim of this work was to study certain causes of variation in the results of laboratory monitoring of treatment with vitamin K antagonists. Four centers participated in the study. In the initial phase, each center performed fifteen measurements of prothrombin time (PT) and activated partial thromboplastin time (APTT) on the same standard lyophilized plasma using its own usual reagents and its own methodology (protocol I). In the second phase of this study, each laboratory performed PT and APTT measurements on 30 frozen plasma specimens from patients receiving long term treatment with vitamin K antagonists using protocol I and protocol II (common reagents but own methodology). In the third phase, plasma from 19 patients receiving long term therapy with vitamin K antagonists were tested with common reagents and a standardized methodology (protocol III). the intralaboratory reproductability was very good; however, the use of common reagents and the standardization of methods greatly improved the intercenter reproductability. The use of common reagents allowed a stricter and a less contradictory interpretation of the tests.
Anticoagulants↗
Turnover study of heparin cofactor II in healthy man.
Heparin cofactor II (HC II) is a heparin-dependent inhibitor of thrombin, distinct from antithrombin III (AT III). This study was designed to evaluate its metabolism in healthy subjects. Purified HC II was labelled with 125I by the lactoperoxidase-glucose oxidase technique. The biological activity of the HC II was unchanged after labelling as was its migratory pattern by crossed immunoelectrophoresis in the presence of heparin or dermatan sulfate. Three healthy volunteers were injected with 10 microCi and the plasma radioactivity was measured daily. The data were approximated by a sum of two exponential terms and the metabolism of HC II was described by a two compartment mamillary system. The mean values of fractional catabolic rate, intravascular fraction and half-life of the elimination phase were respectively: 0.44 d-1, 0.60 and 2.53 d. These parameters are of the same order of magnitude as those reported in the literature for AT III. The plasma HC II concentration in the 3 subjects ranged from 61 to 82 micrograms/ml as estimated using our purified preparation. Accordingly, the absolute catabolic rate ranged from 1.17 to 1.36 mg X kg-1 X d-1.
Adult↗
Homozygous hemophilia A in a female.
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Aged↗
Effects of heparin, its low molecular weight fractions and other glycosaminoglycans on thrombus growth in vivo.
Low molecular weight heparin fractions (LMWH) are less hemorrhagic but are as effective as standard heparin (SH) in preventing experimentally-induced venous thrombosis. The effect of LMWH in preventing extension of established thrombi is unknown. We have compared the effects of two LMWH's (CY, PK), and a low molecular weight heparinoid (a dermatan/heparan/chondroitin mixture, OH) with SH on the prevention of extension of established venous thrombi, by measuring their ability to inhibit the accretion of 125I-fibrin onto venous thrombi pre-formed in rabbit jugular veins. Anticoagulant activity was assayed ex vivo by the APTT and a chromogenic anti-Xa assay, and the antithrombotic effect of these glycosaminoglycans was related to their anticoagulant effects. Autologous thrombi were formed in both jugular veins of each rabbit. The rabbits were then injected with 125I-fibrinogen and treated with a bolus dose of glycosaminoglycan or saline, followed by a continuous infusion for 4 hours. All four glycosaminoglycans significantly inhibited 125I-fibrin accretion (p less than 0.001). SH, CY and PK were equipotent at doses of 42.5-62.5 anti-Xa U/kg/hr in preventing fibrin accretion by 50%. Higher doses had no further effect. OH was significantly more potent than the other three glycosaminoglycans at any given dose (p less than 0.005). There was no correlation between the antithrombotic effect and the anticoagulant effects. We conclude that these LMWH's are as effective as SH in preventing extension of established thrombosis.
Animals↗