Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ability of recombinant platelet factor 4 and protamine to neutralize heparin after cardiopulmonary bypass was compared in anesthestized baboons. Clotting titration curves of heparinized baboon blood demonstrate an anticoagulant effect of protamine that is not seen with recombinant platelet factor 4. Neither drug caused meaningful changes in central pressures or cardiac output within 30 minutes after injection. After 30 minutes of cardiopulmonary bypass, recombinant platelet factor 4 normalized thrombin times and activated partial thromboplastin times within minutes of injection, but protamine did not. Neither drug altered bleeding times. Recombinant platelet factor 4 caused a species-specific leukopenia in baboons and significantly increased activated complement protein 3 (C3a) more than protamine. However, the increase in plasma C3a was small and neither drug caused a significant increase in plasma neutrophil elastase-alpha 1 proteinase inhibitor complex. We conclude that recombinant platelet factor 4 is effective and safe in baboons, does not have an anticoagulant effect with excess concentration, and reverses in vivo heparin more rapidly than protamine. The data support progression to a clinical trial.
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PMID:Reversal of heparin anticoagulation by recombinant platelet factor 4 and protamine sulfate in baboons during cardiopulmonary bypass. 771 25

To clarify the effect of atrial fibrillation (AF) on the fibrino-coagulation system, fibrino-coagulation parameters in the paroxysmal period of AF were determined in 13 patients with paroxysmal atrial fibrillation (PAF) and compared with those in the non-paroxysmal period of AF, and with those in normal subjects. Estimated titers of hemoglobin and hematocrit in the paroxysmal period of AF were significantly higher than those in the non-paroxysmal period and also higher than those in normal subjects. The activated partial thromboplastin time in the paroxysmal period was also longer than that in the non-paroxysmal period of AF or in normal subjects. However, other estimated parameters, such as prothrombin time, fibrinogen, thrombin-antithrombin III, beta-thromboglobulin, platelet factor 4, D-dimer and plasmin inhibitor complex, did not show any significant deviation. These results conflict with those of previous reports which indicated that the fibrino-coagulation system was enhanced in cases of chronic AF. Our results suggest that there is no significant activation of the fibrino-coagulation system, except for obvious hemoconcentration, within the first few hours after the onset of PAF. Thus, in terms of the properties of blood coagulation, thromboembolism is preventable if antiarrhythmic therapy is administered within several hours after the onset of PAF.
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PMID:Effect of atrial fibrillation on the fibrino-coagulation system--study in patients with paroxysmal atrial fibrillation. 780 80

Lactoferrin is a prominent component of neutrophil secondary granules, and its blood concentration is increased in certain inflammatory diseases. In contrast to the well-described biochemical characterization of lactoferrin as an iron-binding protein, its physiologic role in the regulation of inflammation and other host defense mechanisms is unclear. In this report, we provide evidence that lactoferrin has a potent heparin-neutralizing activity during thrombin inhibition by the serine proteinase inhibitors (serpins) antithrombin and heparin co-factor II. Activated neutrophil supernatant, which contains lactoferrin and other heparin-binding proteins, could neutralize the heparin-dependent antithrombin-thrombin inhibition reaction. The addition of lactoferrin to plasma corrected the heparin-induced prolongation of blood plasma coagulation as measured by the activated partial thromboplastin time (aPTT). Treatment of whole blood with specific inflammatory mediators, fMLP, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) increased the concentration of both plasma lactoferrin and platelet factor 4 while inhibiting the blood anticoagulant activity of heparin as measured by the aPTT. These results suggest that the prothrombotic sequelae of some inflammatory processes may be partly due to various agonists that release neutrophil lactoferrin, which can then neutralize glycosaminoglycan-dependent serpin-thrombin inhibition reactions.
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PMID:Neutralization of heparin activity by neutrophil lactoferrin. 781 95

We administered a dose of unfractionated heparin (UFH) and two doses of a low molecular weight heparin (LMWH) to healthy volunteers by SC injection. The doses given were: a) UFH, 5000 IU, which represents 8.7 mg of > 5,400 MW active heparin (ACLM) and no < 5,400 active heparin (BCLM), b) enoxaparin 40 mg (3.4 mg ACLM, 2.2 mg BCLM) and c) enoxaparin 1 mg/kg body weight (on the mean 75 mg, containing 6.4 mg ACLM and 4.1 mg BCLM). We determined the effect on thrombin generation in platelet rich plasma (PRP) between 1 and 8 h after injection. UFH administration caused only a 5-8% inhibition of the thrombin potential (i.e. the area under the thrombin generation curve). Significantly higher inhibition of the thrombin potential was seen after administration of both doses of enoxaparin. To wit 9-26% at the low dose and 29-46% at the high dose. UFH injection caused a prolongation of the lag-time before the thrombin burst. Only with the high dose of enoxaparin the lag-times were significantly more prolonged with enoxaparin than with UFH. Excess amounts of platelet factor 4 (PF4) were able to neutralize completely the anti-thrombin activity in normal plasma spiked with enoxaparin as well as in plasma samples obtained after SC enoxaparin injection. With a large excess of PF4 the anti-factor Xa activity could be inhibited to a maximum of 50%. This indicates that ACLM (above critical length material, MW > 5400) is neutralized completely by PF4 whereas BCLM (below critical length material, MW < 5400) is not.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The effect of subcutaneous injection of unfractionated and low molecular weight heparin on thrombin generation in platelet rich plasma--a study in human volunteers. 790 78

Recombinant platelet factor 4 (rPF4) efficiently neutralized heparin anticoagulant activity in rats without the adverse effect of protamine sulfate (PS) (Circulation 1992; 85: 1102). This study confirmed that rPF4 and PS neutralized heparin in rats. In vitro addition of excess PS but not rPF4 to plasma prolonged the activated partial thromboplastin time. Injection of rPF4 or PS 2 min following injection of 3H-heparin augmented loss of radioactivity from the circulation over the first 2 min but did not affect the half life of 3H-heparin for the next 58 min. PS was coupled to 4-(p-Azidosalicylamido)butylamine (ASBA), radioiodinated and purified by means of heparin-agarose chromatography. Heparin prevented the rapid loss of 125I-rPF4 from the circulation within the first 2 min but modestly increased loss of radioiodinated derivatized PS. Heparin extended the half-life of derivatized radioiodinated PS (measured between 2 and 60 min after injection) while modestly shortening that of 125I-rPF4. Both radioiodinated heparin binding proteins accumulated predominantly in liver and kidney. A greater percentage of radioactivity was found in these organs with rPF4 than with PS but more PS was found in urine. A larger percentage of radioiodinated derivatized PS than 125I-rPF4 was undetected. These results indicate that rPF4 and PS affect the kinetics of heparin clearance similarly but that organ deposition of the two agents may differ and offer an explanation of different physiological effects seen previously.
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PMID:Evaluation of recombinant platelet factor 4 and protamine sulfate for heparin neutralization: clotting and clearance studies in rat. 809 89

The pharmacologic characteristics of low-molecular-weight (LMW) heparins and unfractionated heparin are reviewed, and clinical trials comparing LMW heparins with unfractionated heparin for the initial treatment of deep-vein thrombosis (DVT) are described. LMW heparins are derived from native heparin and range in mass from 3000 to 8000 daltons. All LMW heparins contain the antithrombin III-specific pentasaccharide unit found on unfractionated heparin. LMW heparins are stronger inhibitors of factor Xa than unfractionated heparin, but their mechanisms of action, like that of unfractionated heparin, is predominantly the inhibition of thrombin. The efficacy of LMW heparins in the prophylaxis of DVT is not correlated with activated partial thromboplastin time (APTT); monitoring of APTT or anti-factor Xa may not be necessary. Compared with unfractionated heparin, LMW heparins have a lower affinity for heparin cofactor II, platelet factor 4, von Willebrand factor, and vascular epithelium. Subcutaneously administered LMW heparins are more bioavailable than s.c. unfractionated heparin. In clinical trials in patients with DVT, LMW heparins (dalteparin, enoxaparin, nadroparin, and tinzaparin) have resulted in venography scores similar to those obtained with unfractionated heparin. Frequencies of recurrent thromboembolism and bleeding complications were also similar. Dalteparin and logiparin were effective when administered in single daily subcutaneous doses; this could lead to lower treatment costs. Additional studies are needed to compare LMW heparins and unfractionated heparin with respect to efficacy, bleeding complications, mortality, and cost. LMW heparins may be valuable alternatives to unfractionated heparin for the treatment of DVT.
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PMID:Low-molecular-weight heparins for the treatment of deep-vein thrombosis. 813 6

The effect of blood access on platelets and clotting factors was investigated in 46 azotemic patients. Arteriovenous fistula was used in 10 patients (AVF group), and polyurethane double-lumen catheters were inserted through the subclavian vein in 6 patients (PUS group) or through the femoral vein in 15 patients (PUF group). Indwelling urokinase-immobilized single-lumen catheters and double-lumen catheters were placed in the femoral vein of 5 patients (UKS group) and 10 patients (UKD group), respectively. Blood cell counts, beta-thromboglobulin (beta-TG), platelet factor 4 (PF4), prothrombin time, and activated partial thromboplastin time were measured before insertion while catheters were indwelling and after catheters were pulled out. Although the platelet count decreased to 83% of the initial value during indwelling in the PUF group and 89% in the PUS group, it did not decrease in the AVF, UKS, and UKD groups. There were no differences between the PUF and PUS groups nor between the UKS and UKD groups. Plasma beta-TG increased in the PUF and UKD groups with indwelling catheters but did not change with the AVF. From these results, we conclude that the AVF did not activate platelets, the urokinase-immobilized catheter activated platelets, and the polyurethane catheter activated and decreased platelets. This might be due to the different surface properties of each blood access. Thus, the urokinase-immobilized catheter seems to be more favorable than the polyurethane catheter for emergency blood access.
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PMID:Effect of blood access on the platelets of azotemic patients initiating dialysis therapy. 821 44

Thirty healthy young women, non-smokers and of normal weight, used a combined oral contraceptive consisting of 20 micrograms ethinylestradiol and 150 micrograms desogestrel for 9 cycles. Before and during the 3rd, 6th and 9th cycles of contraceptive use, the following parameters were measured: triglycerides, total cholesterol, HDL-cholesterol, apolipoprotein A and B, prothrombin time, partial thromboplastin time, fibrinogen, antithrombin III, protein C, plasminogen, antiplasmin, tissue plasminogen activator, platelet count, platelet aggregation, beta-thromboglobulin and platelet factor 4. The ratios of total cholesterol/HDL-cholesterol and apolipoprotein A/B remained constant or showed only a slight increase. The clotting/fibrinolytic balance showed a similar trend. There was however, an inconstant but significant increase in antithrombin III and protein C. Platelet count and platelet function parameters were unmodified. Hence the contraceptive induced no substantial changes in lipid balance or blood clotting, at least during the study period.
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PMID:Evaluation of risk of thrombosis during use of low-dose ethinylestradiol-desogestrel oral contraceptive. 823 74

Differences in the activated partial thromboplastin time (aPTT) were shown when blood taken from patients receiving intravenous heparin therapy was collected into 5 ml and 1 ml citrate containers. Mean aPTTs were 27% shorter with the plasma from the 1 ml citrate containers (n = 23). These results were paralleled by a 37% reduction in the mean heparin concentration (n = 11) and a 77% increase in the mean platelet factor 4 (PF4) concentration (n = 7). This phenomenon is due to increased platelet activation and subsequent increased heparin neutralization in the 1 ml citrate container. In an attempt to overcome this, the citrate was removed from a 1 ml container and replaced with a buffered tri-sodium citrate solution containing theophylline, adenosine and dipyridamole anticoagulant (CTAD). Blood from heparinized patients taken into both 5 ml citrate and 1 ml CTAD showed a correction of the shortening artefact in the low volume container. The mean aPTT of plasmas from the 1 ml CTAD container showed an increase of 10% compared with the 5 ml citrate. There was no significant difference in the mean heparin or PF4 concentrations of blood taken into either container. The 1 ml CTAD tube described is a suitable collection container for monitoring heparin in neonates or patients who are difficult to venepuncture and overcomes the neutralization of heparin in part filled low volume containers.
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PMID:A low volume specimen container suitable for monitoring the aPTT of heparinized patients. 829 32

Anti-factor Xa methods have been generally accepted for the monitoring of heparin treatment mainly due to their sensitivity to LMWH and excellent performance on automated equipment. When such equipment is not available, as in small laboratories or on the night shift, there is a need for a simple manual method. In the present method, activated Factor X and a chromogenic peptide substrate are colyophilized in plastic cuvettes under conditions that avoid reaction between the two constituents. The assay is performed accordingly. Plasma (200 microliters) is diluted in 3.0 ml predispensed Tris buffer containing dextran sulfate 8000 to avoid losses of heparin due to platelet factor 4, for example. The diluted plasma (400 microliters) is added to a cuvette. The reagents are rapidly dissolved and the reactions start. The rate of Factor Xa inhibition is proportional to the heparin activity. During the incubation, the substrate is also hydrolyzed by the remaining enzyme. This combination of reactions is insensitive to changes in temperature making it possible to perform the assay at room temperature. After 10 minutes incubation, the reaction is stopped by adding 400 microliters of 5% acetic acid. The absorbance is read in a well-calibrated photometer and the results plotted on a graph available in the kit. Eleven commercially available heparins have been tested with the assay and they all fell within a narrow range, showing the relevance of using a standard plot for all heparins. The LMWH behaved differently and it may also be that they demand different therapeutic strategies.
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PMID:Coacute heparin: a new simple monotest for monitoring heparin treatment. 836 70


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