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PubMed1983

Serial pulmonary angiography in rats with pulmonary damage due to intravascular coagulation.

Serial pulmonary angiography was performed in 30 rats with pulmonary damage caused by injection of a fibrinolysis inhibitor, tranexamic acid (200 mg/kg body weight injected intraperitoneally) and bovine thrombin (500 NIH/kg body weight injected into the right atrium or ventricle). The degree of inhomogeneity of the capillary phase was graded and compared with that in a group of normal rats. Changes in the capillary phase were well correlated to other signs of lung trauma, namely increase in lung weight and microscopic occurrence of interstitial and alveolar oedema and of intravascular fibrin deposits. Increased lung weight similarly was found to be well correlated to increased interstitial oedema. It had also a distinct relationship to increased inhomogeneity of the capillary phase. The disturbance of the capillary phase may have been caused by mechanical blockage due to intravascular coagulation with microembolism, and interstitial oedema, vasospasm of precapillary arteries, or by arteriovenous shunting. Inhomogeneity of the capillary phase is consistent with a gross change in the ventilation/perfusion ratio, which could explain arterial hypoxaemia observed in other investigations.

Angiography↗
PubMed1995

Aprotinin in patients having coronary artery bypass graft surgery.

Any therapy must have a benefit and a risk. The benefit of aprotinin therapy in reducing bleeding is well known. Data presented over the past 12 months have confirmed this efficacy and the superiority and consistency of aprotinin therapy in direct comparison with other pharmacologic (desmopressin, tranexamic acid) and physical (administration of fresh platelet concentrate) interventions. The debate has now changed to focus on issues of the safety of this agent. In particular, concerns have been expressed as to the effect of this agent on renal function, thrombotic potential (and thus graft patency), and adverse reactions on a second exposure. Most recent reports show plasma creatinine concentrations are higher in treated than in nontreated patients on the 3rd or 4th postoperative day. The concentrations reached were not outside the clinical range, and there were no clinical sequelae of this biochemical abnormality. Focused studies have shown no effect of the use of aprotinin therapy on early graft patency or the incidence of thromboembolic complications. The reporting of hypersensitivity reactions following aprotinin administration suggests that the incidence is not different to other agents used in open heart surgery. Three reports of fatal or near-fatal cardiovascular collapse associated with the use of aprotinin followed the apparently inappropriate administration of the agent.

Aprotinin↗
PubMed2006

Noninhibitory PAI-1 enhances plasmin-mediated matrix degradation both in vitro and in experimental nephritis.

Plasminogen activator inhibitor-type 1 (PAI-1) is thought to be profibrotic by inhibiting plasmin generation, thereby decreasing turnover of pathological extracellular matrix (ECM). A mutant, noninhibitory PAI-1 (PAI-1R) was recently shown by us to increase glomerular plasmin generation and reduce disease in anti-thy-1 nephritis. Here, in vitro and in vivo studies were performed to determine whether enhanced plasmin-dependent ECM degradation underlies the therapeutic effect of PAI-1R. 3H-labeled ECM was produced by rat mesangial cells (MCs). The effect of wild-type PAI-1 (wt-PAI-1) and PAI-1R on ECM degradation by newly plated MCs was measured by the release of 3H into medium. In vivo, anti-thy-1 nephritis was assessed in normal, untreated diseased and PAI-1R treated rats with or without the plasmin/plasminogen inhibitor, tranexamic acid (TA). wt-PAI-1 totally inhibited plasmin generation and reduced ECM degradation by 76% when exogenous plasminogen was added. Although PAI-1R alone had no effect, PAI-1R in the presence of wt-PAI-1 reversed the wt-PAI-1 inhibition of ECM degradation in a time- and dose-dependent manner (P<0.001). Plasmin activity and zymography were consistent with ECM degradation. Plasmin inhibitors: alpha2-antiplasmin, aprotinin, and TA completely blocked PAI-1R's ability to normalize ECM degradation (P<0.001). Consistent with the in vitro results, TA reversed PAI-1R-induced reductions in glomerular fibrin and ECM accumulation. Other measures of disease severity were either unaltered or partially reversed. PAI-1R reduces pathological ECM accumulation, in large part through effectively competing with native PAI-1 thereby restoring plasmin generation and increasing plasmin-dependent degradation of matrix components.

Animals↗
PubMed1983

Effect of unilateral ureteral occlusion on fibrin deposition in the kidney and renal blood flow during intravascular coagulation in rat.

The effect of unilateral ureteral occlusion on fibrin deposition in the kidney and the interrelation of the fibrin deposition and the renal blood flow was studied in rat. Intravascular coagulation in the kidney was induced by infusion of thrombin and inhibition of fibrinolysis with tranexamic acid. The effects unilateral occlusion of the ureter for 1 and 24 h on fibrin deposition and renal blood flow were studied. Fibrin in the kidneys was quantitated by intravenous injection of 125I-labelled fibrinogen 24 h before the experiment. The renal blood flow was measured before and after infusion of thrombin by injection of 85Sr- and 141Ce-labelled microspheres into the left ventricle. After ureteral occlusion for 1 h the deposition of fibrin in the kidneys was unaffected. After 24 h substantially less fibrin deposition was found in the occluded than in the unoccluded kidney (0.3 +/- 0.2 and 5.7 +/- 1.6 mg, respectively; p less than 0.05). Before thrombin infusion the blood flow to the occluded kidney was less than that in the unoccluded kidney (2.1 +/- 0.8 and 3.7 +/- 1.2 ml/min, 100 g body weight, respectively; p less than 0.05). The blood flow after infusion of thrombin was equally reduced in both kidneys. The results contradict the hypothesis that vasoconstriction increases the amount of fibrin in the kidneys in thrombin-induced intravascular coagulation.

Animals↗
PubMed1991

[Changes in plasma histamine and catecholamines levels after injection of chymopapain in chemonucleolysis].

Because pruritus, erythema and tachycardia are observed in some patients during chemonucleolysis, a prospective study was designed to investigate the plasma levels of histamine and catecholamines occurring after an injection of chymopapain. Thirteen patients (11 men and 2 women), mean age 38 +/- 11 years, were studied. They all had negative prick skin tests, human basophil degranulation tests (HBDT) and radio-absorbent tests (RAST) to chymopapain. The patients were premedicated with 100 mg hydroxyzine and 3 g tranexamic acid. Sedation was carried out using 0.1 mg.kg-1 droperidol and 0.02 mg.kg-1 phenoperidine. The nucleosus pulposus was visualized with 3 ml of contrast medium (lopamiron 300); 2 ml of chymopapain were then injected. Blood samples were obtained at T1 (after the contrast medium, but before the chymopapain), and then 5, 10, 15, 20 and 30 minutes after the chymopapain. The usual haemodynamic parameters were recorded at the same times. Four patients had clinical signs (group I), whereas the other nine (group II) did not. There was an increase in histamine levels in three patients from group 1, as well as in two in group II (up to 33 nmol.l-1). However, mean histamine and catecholamines levels were comparable in both groups at all times, and between times, of sampling. There therefore was no relationship between clinical signs and the release of histamine or catecholamines. The premedication with an antihistamine may have protected the patients, but the signs reported by four patients may also be due to the chymopapain itself.

Adult↗
PubMed2000

Optimising local therapy during oral surgery in patients with von Willebrand disease: effective results from a retrospective analysis of 63 cases.

Bleeding after dental extractions is very frequent in patients with von Willebrand disease (vWD) and in the past often necessitated transfusions with factor VIII/von Willebrand factor concentrates (vWFc). To evaluate the benefits of a standard local therapy on bleeding complications during oral surgery, 63 consecutive patients with vWD were analysed retrospectively. All types of vWD were included: type 1 (n=31), type 2 (n=22) and type 3 (n=10). All the patients had dental extractions or periodontal surgery at the same hospital by the same oral surgeons. All cases had been given tranexamic acid (TA) before and for 7 days after surgery. As additional local therapy fibrin glue (FG) was used during surgery in several patients. Additional systemic therapies were: desmopressin (DDAVP, 0.3 microg kg-1) and fVIII/vWF concentrates (vWFc, 40 U kg-1) given as a single dose before surgery. The 29 subjects (46%) treated locally did not bleed. Among the remaining cases, 24 (38%) were given DDAVP as additional systemic therapy and 6 (9.5%) received vWFc. There was bleeding after surgery in only two cases who had been given local FG (type 2 B) or systemic vWFc (type 3), but bleeding was stopped with an additional local application of FG. Our data suggest that a standard local therapy with TA and FG with DDAVP can prevent bleeding complications during oral surgery in the majority of patients (84%) with vWD and reduce the need for concentrates, with all their possible complications and high costs.

Adolescent↗
PubMed1990

[Evaluation of the treatment of aneurysmal meningeal hemorrhage with antifibrinolytic agents, calcium inhibitors and maintenance of effective blood volume].

To prevent and treat the ischemic complications due to the vasospasm, this report suggest the management of aneurysmal subarachnoid haemorrhage by the association of antifibrinolytics (tranexamic acid) to lower the risk of rebleeding, calcium channel blockers (nimodipine), and the keeping of an effective total blood volume (thanks to volume expansion and dopamine). From 88 patients aged from 4 to 73, two thirds were admitted at latest 48 h after the aneurysmal rupture Emergency surgery was carried out in the case of a compressive hematoma, early surgery (between the first and the third day) on the grades I, II and III of Hunt and Hess without any signs of angiographic vasospasms (40% of this series), delayed surgery for the others (27.5%), 10% didn't undergo any surgery. Only three patients (3.4%) presented rebleeding leading to death. The features of the whole series are: 51% recovered without any after effects, 22% had mild neurological deficiency, 10% had severe neurological deficiency and 17% died after their release from hospital. This protocol allowed a decrease in the ischemic complications due to the vasospasm and in the rate of rebleeding during the waiting interval when an angiographic or a clinical vasospasm allowed no surgery.

Adolescent↗
PubMed1989

Effects of an inhibitor of angiotensin converting enzyme (Captopril) on pulmonary and renal insufficiency due to intravascular coagulation in the rat.

Induction of intravascular coagulation and inhibition of fibrinolysis by injection of thrombin and tranexamic acid (AMCA) in the rat gives rise to pulmonary and renal insufficiency resembling that occurring after trauma or sepsis in man. Injection of Captopril (1 mg/kg), an inhibitor of angiotensin converting enzyme (ACE), reduced both pulmonary and renal insufficiency in this rat model. The lung weights were lower and PaO2 was improved in rats given this enzyme-blocking agent. The contents of albumin in the lungs were not changed, indicating that Captopril did not influence the extravasation of protein. Renal damage as reflected by an increase in serum urea and in kidney weight was prevented by Captopril. The amount of fibrin in the kidneys was also considerably lower than in animals which received thrombin and AMCA alone. It is suggested that the effects of Captopril on the lungs may be attributable to a vasodilatory effect due to a reduction in the circulating level of Angiotension II and an increase in prostacyclin (secondary to an increase in bradykinin). Captopril may, by the same mechanism, reduce the increase in glomerular filtration that is known to occur after an injection of thrombin, thereby diminishing the aggregation of fibrin monomers in the glomeruli, with the result that less fibrin will be deposited and thus less kidney damage will be produced.

Acute Kidney Injury↗
PubMed2005

Collagen deposition in myocardium after inhibition of fibrinolytic activity.

Proper function of the heart directly depends on the protection of the myocardial architecture. The fibrinolytic system plays an important role(s) in the protection of myocardial architecture and aiding the pumping function of the heart. We investigated the effect of fibrinolytic system inhibition by tranexamic acid (TXA) on cat myocardium and collagen, which are important constituents of the extracellular matrix. Twenty-eight cats (seven per group) were used. Isotonic saline was administered to the control group (C) and TXA (200 mg/kg) diluted isotonic saline given to experimental groups 1 and 2 (E1 and E2). Experimental group 3 (E3) animals received 100 mg/kg TXA intravenously daily for 7 days. Bloods were drawn from groups C, E1, and E2, and fibrinolytic activity was determined by the euglobulin lysis time, fibrinogen degradation products and fibrin plate lytic area diameters. The group C and group E1 cats were sacrificed following the infusion. The group E2 and group E3 animals were sacrificed at 24 h and day 7, respectively. Light and electron microscopy, along with the collagen contents of the myocardium, were used to examine the myocardial tissues. Electron microscopic examination in groups E1 and E2 showed inter-myofibrillar edema, glycogen loss, mitochondrial swelling and disorganization of Z-bands, and a decrease of pinocytotic vesicles in capillary endothelial cells. In group E3, increases of collagen fibrils in intercellular areas and perivascular areas were noted. Biochemical analyses revealed a highly significant collagen accumulation in the myocardium in group E3 (P < 0.01) as compared with group C. These findings suggest that accumulation of the extracellular matrix containing collagen in the myocardium by fibrinolytic system inhibition may be responsible for the abnormal myocardial architecture, leading to cardiomyopathy and altered cardiac function .

Animals↗
PubMed2001

The use of technologies to decrease peri-operative allogenic blood transfusion: results of practice variation in Israel.

BACKGROUND: Concern about the side effects of allogeneic blood transfusion has led to increased interest in methods of minimizing peri-operative transfusion. Technologies to minimize allogeneic transfusion include drugs such as aprotinin, desmopressin, tranexamic acid and erythropoietin, and techniques such as acute normovolemic hemodilution, cell salvage and autologous pre-donation. OBJECTIVE: To survey the current use in Israel of these seven technologies to minimize allogeneic blood transfusion. METHODS: Our survey was conducted in 1996-97 in all hospitals in Israel with more than 50 beds and at least one of the following departments: cardiac or vascular surgery, orthopedics, or urology. All departments surveyed were asked: a) whether the technologies were currently being used or not, b) the degree of use, and c) the factors influencing their use and non-use. The survey was targeted at the heads of these departments. RESULTS: Pharmaceuticals to reduce allogeneic blood transfusion were used in a much higher proportion in cardiac surgery departments than in the other three departments. Pre-operative blood donation was used in few of the cardiac, urologic and vascular surgery departments compared to its moderate use in orthopedic departments. The use of acute normovolemic hemodilution was reported in a majority of the cardiac departments only. Moderate use of cell salvage was reported in all departments except urology where it was not used at all. CONCLUSION: There is considerable practice variation in the use of technologies to minimize exposure to peri-operative allogeneic blood transfusion in Israel.

Aprotinin↗
PubMed1998

Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations.

BACKGROUND: Postoperative bleeding still remains a serious problem in bypass surgery. This study evaluated fibrinolysis and perioperative low-dose antifibrinolytic regimens adjusted to the time course of fibrinolysis. METHODS: In a prospective, randomized study of 42 patients undergoing bypass grafting, patients received low-dose aprotinin (group A; n = 14) or low-dose tranexamic acid (group TA; n = 14) intraoperatively and postoperatively, respectively, with no antifibrinolytics for comparison (group C; n = 14). Parameters of procoagulation, fibrinolysis, and activated factor VII were measured preoperatively, intraoperatively, and postoperatively. Blood loss was determined up to 24 hours. RESULTS: The level of thrombin-antithrombin III complex was significantly decreased postoperatively in the treatment groups (group A and TA versus C: 25 +/- 14 and 19 +/- 10 microg/L, respectively, versus 40 +/- 21 microg/L; p < 0.05). Levels of plasmin-antiplasmin complexes were significantly decreased postoperatively in group A (607 +/- 231 microg/L) versus group C (825 +/- 225 microg/L) (p < 0.05) but were increased in group TA (1,145 +/- 394 microg/L) versus group C (p < 0.05). At all times intraoperatively and postoperatively, levels of D-dimers were significantly decreased in group A and group TA versus control (p < 0.001), indicating that fibrinolysis persists after the operation. Intraoperatively, the factor VIIa level decreased significantly in group A (20 +/- 8 mU/mL) versus group C (31 +/- 15 mU/mL) (p < 0.05), but not in group TA (32 +/- 15 mU/mL). Blood loss was significantly lower in group A (135 +/- 37 mL) and group TA (155 +/- 71 mL) versus group C (354 +/- 170 mL) (p < 0.001). CONCLUSIONS: This low-dose aprotinin regimen adjusted to perioperative fibrinolysis reduces blood loss significantly in coronary bypass grafting. For further progress in this subject, clinical investigations of individual fibrinolysis-adjusted antifibrinolytic treatment seems warranted.

Aged↗
PubMed1985

Effect of various agents on ovarian plasminogen activator activity during ovulation in pregnant mare's serum gonadotropin-primed immature rats.

The plasminogen activator/plasmin synthetic substrate S-2251 was used to measure the effect of indomethacin, cycloheximide, colchicine, dexamethasone, tranexamic acid, and aprotinin on the elevation of ovarian plasminogen activator (PA) that normally occurs during ovulation in the rat. Young Wistar rats were weaned on the morning of Day 21, given 4.0 IU of pregnant mare's serum gonadotropin (PMSG) s.c. at 0800 h on Day 22, and given 10.0 IU of human chorionic gonadotropin (hCG) on Day 24. These animals normally began ovulating between 0000 and 0200 h on Day 25. The induced ovulation rate was 11.5 +/- 2.2 ova/rat, based on the number of ova in the oviducts of control animals at 0900 h on Day 25. In the controls, PA activity in extracts of homogenized ovaries increased 3-fold from 0.125 +/- 0.010 OD units just before the administration of hCG to 0.371 +/- 0.021 at 12 h after hCG, i.e., near the time of ovulation. Indomethacin, in doses of 0.1-1.0 mg/rat, inhibited ovulation but did not inhibit the normal increase in PA activity, whereas indomethacin at the high dose of 10.0 mg/rat inhibited both ovulation and PA activity. Cycloheximide, at a dose of 0.1 mg/rat, was given at 12 h before hCG, immediately after hCG, and at 9 h after hCG. This agent inhibited ovulation most effectively when given at 12 h before hCG, yet it inhibited PA activity most effectively when given immediately after or at 9 h after hCG. Colchicine, at a dose of 0.1 mg/rat, inhibited ovulation, but not PA activity, when it was given 1 h before hCG.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

No interplay between the pathways mediating coagulation and inflammation in tissue factor-induced disseminated intravascular coagulation in rats.

OBJECTIVE: Previous reports have suggested an interplay between the pathways mediating coagulation and inflammation in endotoxemia and sepsis. The present study was designed to examine whether cross-signaling between the pathways mediating coagulation and inflammation occurs, as suggested by the pattern of cytokine production observed following tissue-factor (TF)-induced disseminated intravascular coagulation (DIC). DESIGN: Prospective, comparative, experimental study. SETTING: Laboratory at a university hospital. SUBJECTS: Male Wistar rats, aged 6-7 wks, and weighing 160-170 g. INTERVENTIONS: Male Wistar rats were administered TF (3.75 units/kg every 4 hrs), TF, and tranexamic acid (TA; 50 mg/kg every 4.5 hrs) or lipopolysaccharide (30 mg/kg every 4 hrs) via the tail vein, and blood was sampled at 0, 4, 8 and 12 hrs. MEASUREMENTS AND MAIN RESULTS: Subsequent alterations in thrombin-antithrombin complex and fibrinogen levels, as well as platelet counts, indicated that the severity of both types of experimental DIC (TF-induced and lipopolysaccharide-induced) was similar with respect to hemostatic activation and development of consumption coagulopathy. In lipopolysaccharide-induced DIC, a sharp increase in plasma tumor necrosis factor levels was observed at 4 hrs, after which a sharp decline was noted. Plasma levels of interleukin-6 were markedly increased at 4 hrs, after which a sustained elevation was observed for the duration of the experimental period (tumor necrosis factor, 1270 +/- 280, 180 +/- 40, and 120 +/- 30 pg/mL at 4, 8 and 12 hrs, respectively; interleukin-6, 5810 +/- 1320, 4850 +/- 730, and 5230 +/- 1280 pg/mL at 4, 8 and 12 hrs, respectively). On the other hand, tumor necrosis factor and interleukin-6 were not detected following TF-induced DIC (0 +/- 0 at 4, 8, and 12 hrs for both tumor necrosis factor and interleukin-6). In the TF+TA group, significant increases in tumor necrosis factor and interleukin-6 were observed, compared with the TF group. CONCLUSIONS: There is no overt interplay between the pathways mediating coagulation and inflammation in TF-induced DIC, as observed in lipopolysaccharide-induced DIC.

Animals↗
PubMed2002

Biochemical and morphological alterations in lungs induced by experimental inhibition of fibrinolytic activity.

The fibrinolytic system is known to play an important role in the protection of lung architecture and function. This study investigated the effects on lungs of inhibiting the fibrinolytic system using tranexamic acid (TXA). Thirty cats were used, 15 experimental and 15 control. TXA was administered intravenously to the experimental animals for 3 h at 200 mg/kg (acute) and 7 days at 100 mg/kg (chronic). Blood samples were obtained from the carotid artery. The acute dose cats were sacrificed at 3 h and 24 h and the chronic dose cats at 8 days. Samples of inflated and fixed lung were examined morphologically and their collagen contents were determined. Fibrinolytic activity in blood samples was determined by fibrinogen degradation products levels, fibrin plate lytic area diameter, and the euglobulin lysis time. Hyperemia, lung interstitial oedema, haemorrhaging, inflammatory cell infiltration, pneumocyte type II cell proliferation, thrombosis and emphysema-related changes, characterized by enlargement of air spaces accompanied by destruction of alveolar walls, were observed in experimental cats group. None of these alterations except hyperemia and lung interstitial oedema were observed in two control animals. Electron microscopy results revealed oedema fluid in the interstitium, proliferation of pneumocyte type II cells, thickening of the alveolar septa and presence of marked amounts of collagen. Vacuoles were seen in the capillary endothelial cells. Elastic tissue was observed as elastic masses and partly disrupted, although elastic fibers were not prominent in all parts of the interstitium. Collagen content in the chronic dose experimental group was significantly higher than in all control and acute dose experimental groups. The inhibition of fibrinolytic system appears to have caused the emphysematous alterations, alveolar wall destruction and collagen accumulation possibly by causing microthromboses leading to mechanical blockage-ischemic changes, or by causing secondary fibrinolysis as a result of fibrin degradation products affecting local plasminogen activators and proteases. An injury-repair process also appears to have occurred.

Animals↗
PubMed1997

The Fab-fragment of a PAI-1 inhibiting antibody reduces thrombus size and restores blood flow in a rat model of arterial thrombosis.

The effect of PRAP-1, a Fab-fragment of a PAI-1-inhibiting polyclonal antibody, on thrombus size and arterial blood flow was studied in a rat model of arterial thrombosis. It was shown that exposure of the carotid artery to FeCl3 led to the rapid formation of an occlusive thrombus with a morphology similar to that of arterial thrombi found in humans. Tranexamic acid (50 mg/kg), an inhibitor of fibrinolysis, increased thrombus size (p = 0.014) when given intravenously (i.v.) prior to the FeCl3-exposure. Heparin (1000 U), when given i.v. after FeCl3, did not affect the thrombus size per se, but caused a reduction in the interindividual variation of the size of the thrombus (p < 0.05). Thus, heparin was included in all the subsequent experiments. An i.v. infusion of t-PA (1 mg/kg/h), starting before thrombus formation, induced a 3.3 fold increase in the perfusion rate (p = 0.006) and a 67% reduction in the thrombus size (P < 0.001). PRAP-1, an inhibitor of rat PAI-1 activity, was given i.v. as a bolus followed by an infusion. Two doses of PRAP-1 were studied (7.5 and 15 mg/kg/h), and the administration of the PAI-1 inhibitor was started 10 min before FeCl3. The lower PRAP-1 dose caused a 3.8 fold increase in perfusion rate (p = 0.036), a 1.44 fold increase in the time to occlusion (p = 0.034), and the thrombus size was decreased by 18% (p = 0.104). The corresponding effects of the high PRAP-1 dose were a 6.5 fold increase in perfusion rate (p < 0.001), a 1.6 fold increase in time to occlusion (p = 0.038) and a 32% reduction in thrombus size (p = 0.016). It is concluded that an inhibitor of PAI-1 activity, PRAP-1, caused a moderate decrease in thrombus size and partly restores blood flow in a rat model of arterial thrombus. This finding suggests a potential role for an inhibitor of PAI-1 in the treatment of arterial thrombosis.

Animals↗
PubMed2004

Significance of decreased plasma D-dimer levels following lipopolysaccharide-induced disseminated intravascular coagulation in rats.

Plasma D-dimer (DD) is considered to be one of the most useful markers in the diagnosis and assessment of disseminated intravascular coagulation (DIC). The present study was performed to clarify the role of DD in a rat model of lipopolysaccharide (LPS)-induced DIC in which low-molecular-weight heparin (LMWH) and tranexamic acid (TA) were used. We investigated whether a relationship exists between plasma DD levels and severity of DIC. Experimental DIC was induced in rats by a sustained 4-hour infusion of 30 mg/kg LPS administered via the tail vein (LPS group). Rats received either LPS alone (LPS group) or LPS combined with 200 U/kg LMWH (LPS+LMWH group) or 50 mg/kg TA (LPS+TA group) from -30 minutes to 4 hours. Blood was drawn from each rat at 4, 8, and 12 hours. Plasma levels of thrombin-antithrombin complex (TAT) and creatinine were suppressed in the LPS+LMWH group, and less glomerular fibrin deposition was observed compared with the LPS group. On the other hand, an increased level of creatinine and increased glomerular fibrin deposition were observed in the LPS+TA group compared with the LPS group. LMWH demonstrated a protective effect against LPS-induced DIC, resulting in increased survival at 12 hours, whereas TA had the opposite effect. From these results, it appears that LMWH protects against LPS-induced DIC, but TA exacerbates LPS-induced DIC. It was interesting that plasma levels of DD were almost completely suppressed by concurrent administration of either TA or LMWH in this LPS-induced DIC model. This finding suggested that plasma levels of DD were suppressed by inhibition of coagulation (reduced deposition of fibrin) in the LPS+LMWH group and that DD levels were also suppressed by inhibition of fibrinolysis (reduced degradation of fibrin by plasmin) in the LPS+TA group. Thus care should be taken when evaluating the significance of plasma DD levels, because suppressed levels can occur with progressive fibrin deposition and worsening organ dysfunction or improvement in the course of DIC.

Animals↗
PubMed1994

Suppression of thrombolysis in a canine model of pulmonary embolism.

BACKGROUND: The brisk fibrinolytic response of canines has impaired efforts to develop a canine model of chronic thromboembolic pulmonary hypertension. Difficulties in retaining chronic embolic residuals were partially overcome by administration of tranexamic acid (TXA) (Circulation. 1991;83:1272-1279.). In this study, we used type 1 plasminogen activator inhibitor (PAI-1), a major inhibitor of the endogenous fibrinolytic system, to determine its efficacy in the suppression of thrombolysis in canines. METHODS AND RESULTS: Thrombus was induced in the inferior vena cava of anesthetized mongrel dogs with thrombin and a special double-balloon catheter; 2 hours later, the thrombus was embolized. In one group of dogs, activated type 1 plasminogen activator inhibitor (PAI-1) (130 micrograms) was delivered directly into the forming thrombus; in another, TXA (110 mg/kg) was given intravenously before thrombus formation; in controls, thrombus was induced without inhibitors. Cross-linked fibrin degradation product (D-dimer) appeared in the blood of control animals within 1 hour of thrombus induction (176 +/- 62.5 versus 1.02 +/- 0.39 ng/mL baseline; mean +/- SEM), was maximal by 4 hours (413 +/- 110 ng/mL) and remained elevated at 24 hours (90.8 +/- 19.5 ng/mL). Compared with controls, PAI-1 and TXA suppressed D-dimer release by 80% and 85%, respectively, over the first 24 hours. One week later, animals were killed, and residual emboli were harvested. Perfusion scan defects persisted in all animals at this time, but there were no scan defect differences among groups. However, emboli recovered from animals receiving PAI-1 still harbored immunoreactive PAI-1 and were, on average, more than twofold greater in mass (393 +/- 56 mg) than emboli recovered from either controls (183 +/- 76 mg) or animals receiving TXA (180 +/- 80 mg). CONCLUSIONS: Intravenous TXA and intrathrombus PAI-1 effectively suppress thrombolysis for 24 hours in canines. Thromboemboli enriched with PAI-1 appear to resist lysis for longer periods of time (up to 1 week). These findings are consistent with the hypothesis that PAI-1 remains associated with the embolus, where it continues to inhibit lysis, whereas TXA eventually diffuses out of the embolus, allowing lysis to ensue.

Animals↗
PubMed1997

Aprotinin, an antifibrinolytic drug, attenuates bradykinin-induced permeability in conscious rats via platelets and neutrophils.

Two antifibrinolytic drugs, tranexamic acid (TXA) and aprotinin (APR), are used to improve the recovery of patients following cardiac surgery while reducing blood loss. Their mechanisms of action have yet to be fully understood. To investigate their possible mechanisms of action during cardiopulmonary bypass, we examined (i) the effects of TXA and APR on bradykinin (BK) induced vascular permeability (VP) in conscious rats, (ii) the roles of platelets and neutrophils in this reaction, and (iii) the effects of TXA or APR on BK responses in platelet- or neutrophil-depleted rats. Evans blue dye (EB) was used as the marker of extravasation. The animals were treated with antiplatelet serum for platelet depletion or with methotrexate for neutrophil depletion. In normal rats, BK increased VP in most tissues. Thrombocytopenia and neutropenia also increased basal VP. TXA had no significant effect whereas APR decreased basal VP. In the second series of experiments, APR significantly attenuated BK-induced increases in VP, whereas TXA was completely ineffective. Platelet depletion did not affect BK-induced increases of VP, except for a massive plasma exudation in the lung parenchyma. Neutrophil depletion also had no effect on BK-induced increases of VP, except for an attenuation in the duodenum. In the third and last series of experiments, TXA potentiated the effect of BK in the upper and lower bronchi of platelet-depleted rats, compared with the effects of TXA on BK in normal animals, except in the lung parenchyma, where TXA blocked the increase of VP induced by BK. APR also potentiated the effect of BK in the lower bronchi of platelet-depleted rats. Overall, the inhibitory effect of APR on the VP induced by BK in normal rats was attenuated in platelet-depleted rats. Like TXA, APR blocked the increase of VP induced by BK in the lung parenchyma of platelet-depleted rats. In neutrophil-depleted rats, TXA did not affect the permeabilizing response to BK. In those rats, the inhibitory effect of APR against BK increases of VP was attenuated. These results show that the beneficial effect of APR, but not TXA, following cardiac surgery may be attributed to the inhibition of plasma exudation mediated, in part, by BK. In addition, platelets and neutrophils do not appear to be involved in BK-mediated plasma exudation. However, both cell types are essential for the regulation of basal VP. Finally, the mechanism underlying the protective inhibitory effect of APR on BK-induced increases of VP involves, at least in part, platelets and neutrophils, since the inhibitory effect of APR is attenuated in thrombocytopenic and neutropenic rats. Both cell types are not involved in the action of TXA on VP. Therefore, maintaining platelet and neutrophil counts following cardiopulmonary bypass could enhance the protective effect of APR.

Animals↗