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)

Thrombus weight was used as a measure of the thrombus enhancing effect of drugs in 135 rats. The weight of thrombus formed in one hour, on a 20 x 0.5 mm platinum wire, inserted in the vena cava was taken as a measure of thrombosis. The change in thrombus weight which followed the injection of ellagic acid to activate the coagulation system, adenosine diphosphate to activate the platelets, and epsilon-aminocaproic acid to inhibit the fibrinolytic system, was measured. Pilot studies showed that the drug doses used brought about the appropriate changes in the factors named. The mean thrombus weight in 45 control animals was 1.93 mg. Ellagic acid increased it about five-fold, and epsilon-aminocaproic acid almost two-fold, while adenosine diphosphate reduced it by almost a half. Concurrent controls were used in each case. Clotting tests (whole blood clotting time, kaolin-activated whole blood clotting time, thrombin time, and partial thromboplastin time), performed at the end of the hour, showed no significant correlation with thrombus weight.
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PMID:Thrombus weight as a measure of hypercoagulability induced by drugs. 50 92

Thrombi were produced in 62 female white rats (Sprague-Dawley) by injection of thrombin in the right common carotid artery and in the left vena iugularis as well. Partly the vessels were ligatured proximal and distal of the thrombus, partly they were closed with one ligature. In this latter group (one ligature) the thrombus was exposed to the blood-pressure, while in the first group the thrombus was protected against the blood-waves. After 2, 4, 6, 8, 10 and 14 days as after 4 and 6 weeks the rats were sacrificed and the thrombosed vessel-segments were studied by light-microscope. In the arterie we found occlusive thrombi. In the veins the thrombi were higher in fibrin content than in the arteries. Between the thrombus and the endothelium of the vein-wall there was a sinus which became wider with aging of the thrombus. In the first days the progression of thrombus-organization was more rapid in veins than in arteries; endothelial cells, fibroblasts and capillary buds invaded the thrombus more extensive. In veins there was no difference in composition and organization of the thrombi of the two groups. In the thrombosed veins often small capillaries could be seen running through the vessel wall into the tissue of the organized thrombus but not in arteries. 6 weeks after thrombus-formation wide capillaries recanalized the veins, but the arteries were obturated by fibrous tissue with only a few small capillaries. Elastic fibres could be seen in the organized arterial thrombi earlier and more extensive than in the venous. In double ligatured arteries the organization of thrombi was more rapid than in arteries, in which the thrombus was influenced by the pulsating blood-pressure. In this latter group with only one ligature the organization-process was pronounced in the proximal part of the thrombus, which was higher in fibrin content. Next the ligature the thrombus was composed mainly of erythrocytes and hematoidin-needles. In this part of the thrombus the organization-process started with delay. From our findings we may conclude that the composition of a thrombus, the influence of the blood-pressure and the structure of the vessel-wall are important factors to explain the different temporal course and morphological pattern of thrombus-organization.
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PMID:[Organization of experimental thrombi in arteries and veins. A comparative study (author's transl)]. 120 44

Alteplase and saruplase are more fibrin-specific thrombolytic drugs than anistreplase. These and the thrombolytic drugs of the first generation (streptokinase and urokinase) have shortcomings and limitations. The prolonged intravenous maintenance infusions have been replaced by a bolus injection, accelerated infusions, or the combined intravenous administration of thrombolytic agents. Numerous truncated alteplase or saruplase molecules have been constructed by deletion and domain substitution or hybrids made of the two molecules without gaining in thrombolytic potency. Recombinant staphylokinase and plasminogen activator from bat saliva have some interesting properties and are being investigated. Thrombus-targeted thrombolytic drugs were constructed using monoclonal antibodies against fibrin fragments or against epitopes of activated platelets. Fibrin-specific thrombolytic drugs require the concomitant use of a potent antithrombotic drug to prevent reocclusion. Whether hirudin or synthetic thrombin inhibitors are superior to heparin and whether novel antiplatelet agents, including monoclonal antibodies to platelet receptors and disintegrins, are more effective than aspirin is under clinical investigation. The place of stable analogues of prostacyclin during thrombolytic treatment is still unsettled.
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PMID:Advances in thrombolytic therapy. 139 Mar 21

Thrombus extension in patients with venous thromboembolism is due to the accretion of fibrin onto existing thrombi. Extension is promoted by both circulating and thrombus-bound thrombin, which convert fibrinogen to fibrin. Heparin is an effective antithrombotic agent, but it requires continuous administration to achieve persistent inhibition of thrombus extension. Heparin is highly effective in inhibiting fluid phase thrombin, but is a relatively ineffective inhibitor of thrombus-bound thrombin. Hirudin, unlike heparin, inactivates both circulating and fibrin-bound thrombin and, therefore, has the potential to prevent thrombus extension even after a short course of treatment. The aim of this study was to evaluate the time course of the accretion of new fibrin onto preexisting rabbit jugular vein thrombi after a 3-hour infusion of saline, heparin, and hirudin. Heparin and recombinant (r)-hirudin (CGP 39399) were infused at doses that doubled the activated partial thromboplastin time (aPTT). At the end of the 3-hour infusions in rabbits treated with saline, heparin (0.75 mg/kg), or r-hirudin (1.25 mg/kg), accretion of 125I-fibrinogen was 59 +/- 5 micrograms, 34 +/- 4 micrograms, and 21 +/- 2 micrograms, respectively (heparin and r-hirudin v saline, P less than .01; r-hirudin v heparin, P less than .01). Three hours after the end of the infusions, the accreted 125I-fibrinogen in the saline-, heparin-, and hirudin-treated animals was 89 +/- 6 micrograms, 51 +/- 7 micrograms, and 23 +/- 3 micrograms, respectively; 9 hours after the end of the infusions, the accreted 125I-fibrinogen was 112 +/- 9 micrograms, 82 +/- 7 micrograms, and 25 +/- 3 micrograms, respectively. aPTT and thrombin clotting time (TCT) returned to the baseline value 90 minutes after the end of heparin or r-hirudin infusion. During in vitro experiments, human fibrin clots previously incubated in human plasma containing r-hirudin did not promote fibrinopeptide A (FPA) generation when washed and then incubated in human plasma in the absence of thrombin inhibitors. This persistent inhibition of FPA production was not observed after incubation in human plasma of human plasma clots preincubated with heparin. We conclude that heparin is effective in inhibiting thrombus extension while it is present in the circulation, but that this effect is rapidly lost after its plasma clearance. In contrast, the antithrombotic activity of r-hirudin is sustained beyond its plasma clearance, presumably because of its ability to inactivate thrombus-bound thrombin. Our findings indicate that r-hirudin might be an effective antithrombotic agent even when used for short periods.
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PMID:Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin. 149 36

Thrombus formation on collagen fibrils was quantified at venous (100/s) and arterial (650/s and 2,600/s) wall shear rates in blood from patients with various subtypes of von Willebrand disease (vWD) and with hemophilia A (HA). Nonanticoagulated blood was drawn directly from an antecubital vein over purified type III collagen fibrils exposed in parallel-plate perfusion chambers. Blood-collagen interactions were differentiated and quantified by morphometry as platelet adhesion, thrombus height, thrombus volume, and deposition of fibrin strands. Sixteen patients with vWD, including four type III, six type I, four type IIA, and two type IIB, were compared with 26 normal subjects and nine patients with HA, including six severe HA and three mild HA. Platelet adhesion and thrombus formation at 2,600/s were significantly decreased in blood from patients with vWD type III, IIA, and IIB, but not in blood from patients with type I and in HA. The abnormal thrombus formation was apparently not related to the decreased levels of factor VIII (F.VIII), because thrombus height and volume were normal in severe and mild HA. Thrombus formation at 650/s was also significantly decreased in patients with vWD type III, IIA, and IIB and slightly reduced in type I. Significant reduction in thrombus volume and height was also observed in blood from patients with severe HA, but not in mild HA. Thrombus dimensions were not affected at 100/s in the vWD subtypes. However, significantly decreased thrombus height and virtually absent fibrin deposition were observed in blood from patients with severe HA. Apparently, F.VIII supports thrombus formation at low and intermediate shear conditions, presumably through the generation of thrombin. In contrast, von Willebrand factor (vWF) mediates not only platelet adhesion, but also thrombus formation at intermediate and high shear rates. Thus, the relative contribution of coagulation (F.VIII) and platelet function (vWF) in thrombus formation appears to be shear rate dependent, but having optimal effects at different shear conditions.
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PMID:Shear rate-dependent impairment of thrombus growth on collagen in nonanticoagulated blood from patients with von Willebrand disease and hemophilia A. 149 39

Thrombotic diseases increase in incidence with advancing years and this might be partly due to an increased propensity for fibrin formation in older individuals. Accordingly we decided to investigate whether the time taken to generate 50% thrombin activity in vitro varied with the age of the plasma donor. Coagulation was initiated in defibrinated, diluted plasma by contact activation and thrombin activity measured using the chromogenic substrate, S2238. The rate of thrombin generation was assessed by measuring the time taken to reach 50% maximal activity (T50/s). There was a highly significant negative correlation between T50 and age, T50 declining from 93 s at 19 years to 71 s at 65 years (r = -0.637, p less than 0.0001). A strong negative correlation was demonstrated between T50 and FVII level (r = -0.415, p = 0.0007) and FVIII:C level (r = -0.465, p = 0.0001). Although FVII concentration correlated with age (r = 0.307, p = 0.014) no relationship was seen between age and FVIII:C. These data suggest that coagulation rates in plasma accelerate with age.
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PMID:Thrombin activity by intrinsic activation of plasma in-vitro accelerates with increasing age of the donor. 164 29

Thrombotic or thromboembolic occlusion of a cerebral artery is the most common pathophysiologic mechanism of acute ischemic stroke. An antithrombotic agent would therefore appear to be an ideal medication for treatment of this condition. Heparin is an effective anticoagulant, but it has poor bioavailability and effects on thrombin and platelets that predispose it to life-threatening complications such as hemorrhage and thrombocytopenia. Low-molecular-weight (LMW) heparins have better bioavailability, a higher anti-Xa:anti-IIa ratio, and less effect on platelets than heparin; yet their heterogeneity has hampered their proper investigation in clinical trials and it has not yet been proven that they exhibit less tendency toward hemorrhage and thrombocytopenia than conventional heparin. The LMW heparinoid, Org 10172, is superior to standard heparin in terms of its bioavailability, anti-Xa:anti-IIa ratio, and lack of effect on platelets. It is less likely than heparin and many LMW heparins to induce thrombocytopenia. Like the various heparins, Org 10172 exhibits dose-dependent hemorrhagic tendencies, yet preliminary studies have found doses that are safe for use in patients with acute ischemic stroke. These studies also suggest that Org 10172 may improve outcome and lessen mortality in this population. A prospective, randomized, double-blind, controlled trial is needed to establish the potential efficacy of Org 10172 in patients who suffer acute or progressing ischemic stroke.
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PMID:Low-molecular-weight heparins and heparinoids and their use in acute or progressing ischemic stroke. 170 55

Thrombus removal using percutaneous rotational thrombectomy (PRT), followed by tissue plasminogen activator (t-PA), was studied by contrast angiography and fiberoptic angioscopy in a canine femoral artery model of thrombosis. After thrombus induction and following each treatment, comparisons were made between angioscopy and angiography for the detection of thrombus and subintimal dissection. Angioscopic images were scored in a blinded fashion for lining, protruding, or occlusive thrombus (class 1,2, or 3) as well as estimated wall coverage by thrombus. Angiograms were studied for percent diameter stenosis and the presence of flaps. Following external forceps crush injury of 18 arteries, two hour occlusion, and injection of thrombin, mean angiographic stenosis was 66%, thrombus coverage by angioscopy was 81%, and mean angioscopy class was 2.5. Following PRT, stenosis decreased to 27% (p less than 0.008), thrombus coverage was reduced to 49% (p less than 0.02), and angioscopy class dropped to 2.0 (p less than 0.07). After t-PA treatment, these values were further reduced to 25% (p = NS), 26% (p less than 0.02), and 1.3 (p less than 0.008), respectively. In comparison to angiography, subintimal dissection (seen as flaps) and thrombus (lining, protruding, or occlusive) were present significantly more often by angioscopy (p less than 0.001). It is concluded that PRT results in significant thrombolysis, apparent by angiography and angioscopy. Follow-up t-PA can produce additional, incremental thrombolysis, apparent only by angioscopy. A beneficial role for t-PA following mechanical thrombolysis is suggested by this model. The superior sensitivity of angioscopy for detection of flaps and thrombus is underscored by this study.
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PMID:Thrombolysis by rotational thrombectomy followed by tissue plasminogen activator: evaluation by angioscopy. 176 46

Angioplasty procedures with balloons, cutters or lasers all may greatly enlarge the arterial lumen, but luminal diameter may decrease because of mural thrombus in 70% to 80%, smooth muscle proliferation, vasoconstriction or recoil. Thrombin binds to arterial wall matrix and fibrin within a thrombus. Heparin dose-dependently decreases platelet and thrombus deposition but does not eliminate these even at high doses. Specific thrombin inhibition started before angioplasty experimentally prevents mural thrombus and limits platelet deposition to a single layer or less. Experimentally, anticoagulant and antifibrin effects occur at lower antithrombin blood levels and lower activated partial thromboplastin times (1.7 times control). Because platelets are so sensitive to thrombin, the higher level of thrombin inhibition required may occur at a specific level (activated partial thromboplastin time greater than or equal to 2 times control); this is not defined in humans. The duration of therapy is not defined in animals or humans. Thrombus and thrombin may be related to cellular proliferation.
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PMID:Importance of antithrombin therapy during coronary angioplasty. 184 31

Plaque rupture of the thinned, weak fibrous cap infiltrated by macrophages and overlying a pool of lipid in the arterial wall initiates the acute thrombotic event of unstable angina. Thrombosis may be advanced within minutes. Most lesions that precede plaque rupture are minor (less than 50% stenosis); thus, thrombus greatly contributes to sudden flow limitation and onset of symptoms. If thrombosis can be totally blocked (not possible with current antithrombotic agents), clinical events should be preventable, and endogenous thrombolysis may be possible within days. Local and systemic factors contribute to arterial thrombosis. With type III injury (fissure into plaque or media) platelet-rich thrombus anchors in the fissure, tracks along the site of deep injury, extends into the lumen, and requires the highest blood level of specific thrombin inhibition (a molar concentration that inhibits the total concentration of prothrombin in circulating blood). Thus, the thrombin content requiring inhibition in type III injury is highest. Local factors for thrombosis associated with type III injury include the rheology of blood flow (increased shear rate forces platelets to the periphery) and substrates in the arterial wall. Plaque substrates include the more thrombogenic collagens (types I and III and diabetic or glycosylated collagen), tissue thromboplastin, lipid gruel, thrombin bound to arterial wall matrix, and decreased prostacyclin. There is a direct relation between platelet deposition (thrombus) and local vasoconstriction, which may perpetuate each other. Thrombus as a substrate is more thrombogenic than type III arterial injury.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathogenesis of thrombosis in unstable angina. 189 63


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