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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Intravascular fibrin deposition was induced in rabbits by endotoxin, the infusion of fibrin monomer (FM), and by the infusion of thrombin and EACA. A previously developed radioisotope technique was used to measure the fibrin deposits in various organs. Dipyridamole treatment of rabbits caused significant inhibition of fibrin deposition in all three experimental models. The drug also inhibited platelet consumption and, in the thrombin- and EACA-infused animals, fibrinogen consumption as well. The results obtained with dipyridamole were compared with the effect of thorotrast. It was concluded from this comparison that the effect of dipyridamole could not be attributed to inhibition of the reticuloendothelial system. It is postulated that dipyridamole inhibits the final step at which soluble FM is precipitated as fibrin in vivo.
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PMID:Inhibition of intravascular fibrin deposition by dipyridamole in experimental animals. 109 Mar 12

The inhibitory effect of dipyridamole (RA 8) and its two derivatives (RA 233 andSH 869) on platelet aggregation in platelet-rich plasma (PRP) AND IN SUSPENSIONSOF WASHED PLATELETS WAS EVALUATED USING 3 AGGRESSING STIMULI: ADP, thrombin, and collagen. Mean effective dose (ED'30) of RA 8 causing 50 percent inhibition of plateletaggregation of washed human platelets by ADP, collagen, or thrombin varied from 1.2 x 10'-7 to 1.8 x 10'-7M. On the other hand, RA 8 caused little inhibition aggregation in human PRP. RA 233 and SH 869 produced similiar degrees of inhibition ofplatelet aggregation in human PRP and in suspensions of washed human platelets.Platelet-poor plasma, fraction VI-acid glycoproteins, or purified alpha'1-acid glycoprotein complex was isolated by means of Sephadex G-25 gel filtration. It is postulated that the formation of this complex leads to the blocking of the capacity of RA 8to inhibit platelet aggragation. RA 233 and SH 869 had little capacity to form complexes with acid glycoproteins of human plasma. This may explain the effectiveness of these compounds in inhibiting platelet aggregation in PRP.
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PMID:Inihibition of human platelet aggregation by dipyridamole and two related compounds and its modification by acid glycoproteins of human plasma. 115 Nov 44

Platelets are central to the pathophysiology of an array of vascular disorders. Current platelet-inhibitor drugs reduce platelet aggregation through one of three pathways but do not prevent initial platelet adhesion. The most extensive clinical experience is with aspirin, an irreversible inhibitor of cyclooxygenase. Aspirin is clinically effective and has few gastrointestinal side effects if used at a dosage of 150 to 300 mg per day. Large clinical trials have documented the benefits of aspirin in arterial thromboembolic disease. It is effective in the primary and secondary prevention of myocardial infarction, including patients with unstable angina; reduces the acute thrombotic complications of coronary angioplasty and revascularization surgery; and also reduces cerebral ischemic events in patients with cerebrovascular disease. Aspirin is less effective for thrombi arising from the venous system or intracardiac chambers, which respond well to anticoagulants. Dipyridamole and sulfinpyrazone are most effective at preventing thrombosis on prosthetic surfaces. Dipyridamole reduces emboli from mechanical prosthetic valves when combined with warfarin and, unlike aspirin plus warfarin, does not increase bleeding complications. Newer agents such as ticlopidine and the thrombin inhibitor, hirudin, appear promising but require further evaluation. Because thrombin plays a critical role in mechanisms of arterial thrombosis, its inhibition appears promising for future therapy.
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PMID:Platelet inhibitor therapy. Agents and clinical implications. 217 12

Trypsin-activated pig plasmin and human plasmin activated by streptokinase (SK) caused aggregation of a suspension of washed platelets from human, rabbit, or pig blood. The platelet aggregation was reversible, but it was accompanied by a significant release of adenine nucleotides, serotonin, and platelet fibrinogen. Platelet fibrinogen was eventually digested. The effect of plasmin on platelets was inhibited by soybean trypsin inhibitor, epsilon aminocaproic acid, Persantin, prostaglandin E(1), and phenylbutazone. Short treatment of platelets with plasmin enhanced their sensitivity to ADP; however, this sensitivity was lost during longer incubation with plasmin. This enzyme also made platelets less sensitive to collagen and thrombin. Injecting SK into rabbits (10,000 U/kg body weight) caused a transitory drop of platelet count. These platelets lost part of their serotonin and fibrinogen. The administration of Persantin or of epsilon aminocaproic acid to rabbits before the injection of SK protected platelets from the loss of serotonin. Pretreatment with Persantin also resulted in partial protection of platelet fibrinogen in rabbits injected with SK. Platelets obtained from rabbits that had received both Persantin and SK were much more reactive with collagen than platelets obtained from rabbits injected with SK alone. Rabbits pretreated with Persantin did not show prolongation of the primary bleeding time that occurred after SK injection to control rabbits. It is suggested that plasmin generated after SK injection causes platelet release reaction in vivo. This may contribute to the hemostatic defect occurring during thrombolytic therapy or during systemic activation of fibrinolysis due to the other factors.
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PMID:Plasmin-induced platelet aggregation and platelet release reaction. Effects on hemostasis. 426 96

After the intravenous injection of Walker 256 tumour cells into rats the platelet count decreased rapidly and remained low during the following period of observation. The platelet decrease was closely related to the number of cells injected. Intra-arterial tumour cell injections required a considerably higher tumour cell count to produce a comparable thrombocytopenia. Non-viable tumour cells and tumour cell fragments induced a similar decrease of circulating platelets. Neither viable tumour cells nor tumour cell fragments aggregated rat platelets in vitro. The presence of fibrin monomers in tumour cell injected animals suggested intravascular fibrin deposition; the plasma fibrinogen level, however, did not decrease significantly. Isotope studies using (51)Cr labelled platelets revealed a rapid disappearance of the platelets from the circulation and their trapping in the lung-the primary site of tumour cell lodgement. Dipyridamole and ancrod pretreatment did not influence the decrease of platelets and their accumulation in the lung after tumour cell injection. In contrast, heparin completely prevented the thrombocytopenia and the platelet trapping in the lung. From the present experiments it is concluded that embolic tumour cells lead to early endothelial damage, resulting in local thrombin formation with subsequent irreversible platelet aggregation.
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PMID:The role of blood platelets in experimental metastases. 475 69

Thrombin induced thromboxane A2 and prostaglandin E2 production were significantly increased in platelets of streptozotocin induced diabetic rats as compared to non-diabetic control rats, while collagen induced thromboxane A2 production was decreased. Using exogenous arachidonic acid, prostaglandin E2 production, but not thromboxane A2 production, was increased in platelets from streptozotocin treated animals. Prostacyclin production in the diabetic aorta was significantly lowered; however, control levels of prostacyclin production resulted after incubation of the tissue with dipyridamole. Diabetic animals demonstrated a fivefold decrease in the endogenous arterial prostacyclin/platelet thromboxane A2 ration when thrombin or ADP was used to induce thromboxane A2 production. This elevated ratio could be a contributing factor to the vascular complications of diabetes. Dipyridamole, due to its ability to partially normalize this ratio, may be useful as a therapeutic agent in this and related vascular diseases.
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PMID:Alterations of the prostacyclin-thromboxane ratio in streptozotocin induced diabetic rats. 680 92

Photoimmobilization of dipyridamole (Persantin) was accomplished through the use of a new synthetic conjugate molecule, 1. Persantin is a powerful inhibitor of platelet activation and aggregation and is widely used as a vasodilator. Conjugate 1 consists of triply protected dipyridamole [three of the four hydroxyl groups carry a tert-butyldimethylsilyl (TBDMS) protective group) and the photoreactive 4-azidobenzoyl group. A short hydrophilic spacer chain, derived from triethylene glycol, separates the protected dipyridamole system and the photoreactive group. Compound 1 was immobilized on polyurethane sheets (Pellethane D-55) through irradiation with ultraviolet (UV) light, and the protective groups were removed afterward. The resulting modified polyurethane surfaces were characterized by different physicochemical techniques: UV extinction, contact angle measurements (captive bubble technique), and X-ray photoelectron spectroscopy (XPS). The UV extinction measurements showed the presence of 13 +/- 1 nmol of immobilized dipyridamole/cm2. The contact angle measurements revealed that the modified surface was markedly more hydrophilic than the control (i.e. unmodified polyurethane). XPS measurements clearly established the presence of immobilized dipyridamole in the outermost layers of the modified surface. This was especially clear from the XPS spectra recorded at a low take-off angle (approximately 6 degrees). Furthermore, the XPS spectra showed that the TBDMS protective groups had been quantitatively removed during the deprotection/washing treatment. The in vitro blood compatibility of the modified surface was studied with the thrombin generation assay as developed in our group, as well as with scanning electron microscopy. The thrombin generation test produced a lag time of 1275 s for the modified surface, as opposed to 569 s for the control. Scanning electron microscopy showed that far fewer platelets adhere to the modified surface (approximately 7 x 10(3)/mm2) as compared to the control (approximately 6 x 10(2)/mm2). Taken together, the experimental data reveal that the modified surface has excellent blood compatibility in vitro. It is discussed that the use of conjugate 1 leads to simultaneous exposure of dipyridamole at the modified surface and to a marked increase of the surface hydrophilicity, which is likely to hamper adsorption of plasma proteins. The combination of these effects is uniquely related to the molecular buildup of 1. Conjugate 1 will be used in future work that is aimed at preparing small-caliber polyurethane vascular grafts with a blood compatible lumenal surface.
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PMID:Synthesis of a new photoreactive derivative of dipyridamole and its use in the manufacture of artificial surfaces with low thrombogenicity. 917 34

The purpose of this study was to investigate platelet effects on postischemic heart function in conjunction with adenosine effects on intracoronary platelet adhesion. Homologous platelets were infused into the coronaries of isolated guinea pig hearts, either during low-flow ischemia or during reperfusion, and external heart work (EHW) and intracoronary platelet adhesion were determined. In most experiments, thrombin was added to the perfusate. The influence of endogenous adenosine was studied by use of the uptake blocker dipyridamole and the unspecific adenosine-receptor blocker theophylline, the A1-receptor blocker 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), and the A2-receptor blocker 3,7-dimethyl-1-propargylxanthine (DMPX). The importance of nitric oxide and prostaglandin I2 (PGI2) was tested by using nitro-L-arginine (NOLAG) and indomethacin, respectively. When platelets were applied with thrombin during low-flow ischemia, EHW recovered to only 63 +/- 4% of the preischemic value, as compared with 89 +/- 3% without platelets (p < 0.05). Despite thrombin, platelets incurred no significant functional loss when applied in the first minute of reperfusion (but again in the fifth minute); however, when theophylline was also present, recovery of EHW amounted to only 42 +/- 12%. Intracoronary adhesion of platelets was negligible without thrombin, and highest during low-flow ischemia with thrombin (35 +/- 3% of the applied number). No adhesion occurred during the first minute of reperfusion, whereas in the fifth minute, adhesion was again 20.8 +/- 4%. Dipyridamole increased adenosine release and attenuated adhesion at this time. Theophylline increased adhesion in the first minute of reperfusion (33 +/- 6.4%), whereas NOLAG and indomethacin proved to be ineffective. DPCPX and DMPX each increased platelet retention during the first minute of reperfusion, their effects being additive. Intracoronary adhesion of platelets induced by thrombin in isolated hearts can reduce postischemic recovery of heart function. During reperfusion, but not during low-flow, endogenous adenosine can prevent platelet adhesion and loss of myocardial function, an action mediated both by A1- and A2-receptor-dependent mechanisms.
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PMID:Adenosine endogenously released during early reperfusion mitigates postischemic myocardial dysfunction by inhibiting platelet adhesion. 967 36

Intimal hyperplasia after percutaneous transluminal coronary angioplasty (PTCA) or vascular surgical procedures remains a significant problem despite current antithrombotic therapy. The use of the current antithrombotic drugs, namely heparin + chronic aspirin (ASA) +/- oral anticoagulants, is based upon the assumptions that: i) heparin blocks thrombin generation and/or accelerates thrombin inhibition by antithrombin III (ATIII); ii) aspirin acetylates platelet cyclooxygenase, thereby preventing thromboxane A2 (TxA2) synthesis; and iii) oral anticoagulants reduce the availability of vitamin K-dependent procoagulants, thereby reducing the risk of thrombus formation. Albeit beneficial, this approach has a number of shortcomings and limitations: i) when thrombin binds to an injured vessel wall, it becomes resistant to inhibition by heparin/ATIII; thus, surface-bound thrombin remains active, stimulating further thrombus formation, smooth muscle cell proliferation and subsequent hyperplasia; ii) while TxA2 inhibition reduces platelet reactivity, platelets are able to respond to multiple stimuli generated at the time of, or after, vessel wall injury; and iii) heparin, aspirin and the oral anticoagulants all render the patient hemostatically defective and at risk of bleeding. Recent studies suggest that alternate therapeutic approaches can inhibit thrombogenesis more effectively at the time of injury, thereby not only inhibiting hyperplasia more effectively than the currently used drugs, but also reducing (or eliminating) the need for long-term therapy. For example, we suggest that the heparin cofactor II (HCII) catalysts, dermatan sulfate and Intimatan, inhibit surface-bound thrombin more effectively than heparin/ATIII, thereby inhibiting intimal hyperplasia effectively. Their effects are achieved when the drug is given only at the time of injury; i.e. with no further antithrombotic therapy. Other studies indicate that injured vessel wall thrombogenicity can be reduced by pretreatment with Persantine (dipyridamole) or with certain fatty acid supplements which either increase vessel wall cAMP and/or 13HODE synthesis. These increases are associated with decreased vessel wall thrombogenicity, which, in turn, is associated with decreased intimal hyperplasia. Such results suggest that vessel wall repair is achieved more effectively by targeting antithrombotic drugs directly at the vessel wall thrombogenicity per se rather than indirectly by altering the circulating blood cells and systemic coagulant system.
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PMID:A rationale for targeting antithrombotic therapy at the vessel wall: improved antithrombotic effect and decreased risk of bleeding. 1009 89

In vivo platelet activation results are often confounded by activation induced in vitro during the preparative procedures. We measured ex vivo (basal) and in vitro (thrombin-induced) platelet activation in sodium citrate, ethylenediaminetetraacetic acid (EDTA), and Citrate Theophylline Dipyridamole Adenosine (CTAD) whole blood specimens. Determinations were made by measurements of platelet density (mean platelet component: MPC concentration) on the Advia 120 Hematology System. The MPC has been previously shown to correlate with a fluorescence flow cytometric method, also determined in this study, using the surface expression of CD62P. Moreover, platelet shape and structure changes in EDTA and CTAD anticoagulated whole blood specimens were characterized by transmission electron microscopy (TEM). Observations made using the Advia 120 Hematology System platelet density parameter, MPC, in the absence of thrombin were 25.7 +/- 0.9 g/dl, 27.9 +/- 0.9 g/dl and 24.8 +/- 1.2 g/dl in sodium citrate, EDTA and CTAD whole blood specimens, respectively. Addition of thrombin induced a significant change in platelet MPC for sodium citrate (21.9 +/- 1.9 g/dl; p<0.0001) and EDTA (23.2 +/- 0.9 g/dl; p<0.0001) whole blood specimens. In contrast, thrombin had no effect on MPC measured in whole blood taken into CTAD tubes. In vitro fluorescence flow cytometric platelet activation experiments measuring the percentage of platelets expressing anti-CD62P showed increase in sodium citrate specimens from 9.2 +/- 7.0 to 55.5 +/- 23.1 % (p<0.0001) and in EDTA specimens from 1.9 +/- 1.7 to 64.6 +/- 12.4 % (p<0.0001) after addition of thrombin. However, in blood taken into CTAD tubes, there was no significant change. Studies on platelets isolated from whole blood in CTAD showed activation by thrombin indicating that platelets in CTAD, while protected in its presence remained functional upon its removal. When observed by TEM over time, platelets in EDTA appear more activated and contain fewer granules than platelets in CTAD. We conclude that CTAD demonstrates in vitro platelet activation inhibition and may be useful in stabilizing ex vivo platelet activation. The novel platelet activation parameter, MPC, measured by an automated routine hematology system, using customized proprietary software, may be used in conjunction with CTAD, a stabilizing anticoagulant, to measure the ex vivo platelet activation state in whole blood specimens. TEM studies verify shape modifications and simultaneous retention of intracellular granules at early post-venipuncture time periods in CTAD specimens.
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PMID:Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy. 1459 91


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