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A case is reported in which protracted and massive bleeding from polycystic kidneys was treated successfully with epsilon aminocaproic acid with no adverse effects. Our experience with this case suggests that a short trial with epsilon aminocaproic acid is a reasonable choice before surgical intervention in patients bleeding from polycystic kidneys.
Simultaneous intravenous administration to rats of epsilon-aminocaproic acid and high doses of plasminogen tissue activator from the pig heart was shown to prevent fibrinolysis changes induced by the tissue activator. Amben completely suppressed the action of the tissue activator at the blood concentration 15 times less than that of epsilon-aminocaproic acid. A greater effect of amben on the blood activator level was noted. Contrykal exerted only slight effect on fibrinolysis stimulated by the tissue activator.
Three new dipeptides of E-aminocaproic acid were synthesized and their antifibrinolytic activity was examined. H-EACA-L-Trp-OH possess stronger antifibrinolytic activity than H-EACA-L-Tyr-OH and H-EACA-L-Leu-OH. Antifibrinolytic activity of H-EACA-L-Gly-OH was smallest.
Administration of epsilon-aminocaproic acid, a fibrinolytic inhibitor, either orally or from an impregnated IUD, had no effect on numbers of implanted embryos, their viability, or their diameters at Day 10 of pregnancy.
The crystallographic structure of the plasminogen kringle 4-epsilon-aminocaproic acid (ACA) complex (K4-ACA) has been solved by molecular replacement rotation-translation methods utilizing the refined apo-K4 structure as a search model (Mulichak et al., 1991), and it has been refined to an R value of 0.148 at 2.25-A resolution. The K4-ACA structure consists of two interkringle residues, the kringle along with the ACA ligand, and 106 water molecules. The lysine-binding site has been confirmed to be a relatively open and shallow depression, lined by aromatic rings of Trp62, Phe64, and Trp72, which provide a highly nonpolar environment between doubly charged anionic and cationic centers formed by Asp55/Asp57 and Lys35/Arg71. A zwitterionic ACA ligand molecule is held by hydrogen-bonded ion pair interactions and van der Waals contacts between the charged centers. The lysine-binding site of apo-K4 and K4-ACA have been compared: the rms differences in main-chain and side-chain positions are 0.25 and 0.69 A, respectively, both practically within error of the determinations. The largest deviations in the binding site are due to different crystal packing interactions. Thus, the lysine-binding site appears to be preformed, and lysine binding does not require conformational changes of the host. The results of NMR studies of lysine binding with K4 are correlated with the structure of K4-ACA and agree well.
Sixty patients scheduled for elective coronary artery bypass graft operations were randomly assigned to receive epsilon-aminocaproic acid or placebo to test whether antifibrinolytic therapy would decrease postoperative bleeding. A small but significant decrease in bleeding was observed in the treated group without complications resulting from treatment with epsilon-aminocaproic acid.
Epsilon aminocaproic acid (EACA) has been used to prevent rebleeding in patients with subarachnoid hemorrhage (SAH). Although this agent does decrease the frequency of rebleeding, several reports have described thrombotic complications of EACA therapy. These complications have included clinical deterioration and intracranial vascular thrombosis in patients with SAH, arteriolar and capillary fibrin thrombi in patients with fibrinolytic syndromes treated with EACA, or other thromboembolic phenomena. Since intravascular fibrin thrombi are often observed in patients with fibrinolytic disorders, EACA should not be implicated in the pathogenesis of fibrin thrombi in patients with disseminated intravascular coagulation or other "consumption coagulopathies." This report describes subtotal infarction of the kidney due to thrombosis of a normal renal artery. This occlusion occurred after EACA therapy in a patient with SAH and histopathological documentation of recurrent SAH. The corresponding clinical event was characterized by marked hypertension and abrupt neurological deterioration.
The occurrence during phlebography of massive intravascular coagulation involving the inferior vena cava, the right cardiac cavities and the entire pulmonary arterial network suggested that epsilon-aminocaproic acid administered before phlebography was responsible for this complication. The mechanisms of reactions to contrast media are still poorly understood, but these reactions are known to include, in some cases, disseminated intravascular coagulation. This phenomenon was histologically demonstrated in our patient, and it may be suggested that its strong enhancement by the antifibrinolytic agent had resulted in the fatal accident. In view of the possibility of such lethal reactions, the advisability of administering epsilon-aminocaproic acid--a drug widely used in France for the prevention and treatment of contrast media reactions--should be reconsidered.
BACKGROUND: Epsilon-aminocaproic acid (EACA) is commonly infused during cardiac surgery using empiric dosing schemes. The authors developed a pharmacokinetic model for EACA elimination in surgical patients, tested whether adjustments for cardiopulmonary bypass (CPB) would improve the model, and then used the model to develop an EACA dosing schedule that would yield nearly constant EACA blood concentrations. METHODS: Consenting patients undergoing elective coronary artery surgery received one of two loading doses of EACA, 30 mg/kg (group I, n = 7) or 100 mg/kg (group II, n = 6) after CPB, or (group III) a 100 mg/kg loading dose before CPB and a 10 mg x kg(-1) x h(-1) maintenance infusion continued for 4 h during and after CPB (n = 7). Two patients with renal failure received EACA in the manner of group III. Blood concentrations of EACA, measured by high-performance liquid chromatography, were subjected to mixed-effects pharmacokinetic modeling. RESULTS: The EACA concentration data were best fit by a model with two compartments and corrections for CPB. The elimination rate constant k10 fell from 0.011 before CPB to 0.0006 during CPB, returning to 0.011 after CPB. V1 increased 3.8 l with CPB and remained at that value thereafter. Cl1 varied from 0.08 l/min before CPB to 0.007 l/min during CPB and 0.13 l/min after CPB. Cl2 increased from 0.09 l/min before CPB to 0.14 l/min during and after CPB. Two patients with renal failure demonstrated markedly reduced clearance. Using their model, the authors predict that an EACA loading infusion of 50 mg/kg given over 20 min and a maintenance infusion of 25 mg x kg(-1) x h(-1) would maintain a nearly constant target concentration of 260 microg/ml. CONCLUSIONS: EACA clearance declines and volume of distribution increases during CPB. The authors' model predicts that more stable perioperative EACA concentrations would be obtained with a smaller loading dose (50 mg/kg given over 20 min) and a more rapid maintenance infusion (25 mg x kg(-1) x h(-1)) than are typically employed.
Patients suffering from a subarachnoid hemorrhage who were admitted to the Neurosurgical Unit of the Royal Perth Hospital during the period 1971 to 1979 were assessed with regard to the effectiveness of preoperative treatment with epsilon-aminocaproic acid, kanamycin, and reserpine. Forty-two patients who were treated with epsilon-aminocaproic acid had a rebleed rate of 2.3% compared to 1 9.7% rebleed rate in appropriately selected controls. Patients treated with kanamycin and reserpine had a preoperative cerebral vasospasm rate of 32% compared to a 26% rate in controls; however, kanamycin and reserpine were found useful for decreasing the postoperative complications of cerebral vasospasm.
The isotopic method described previously for quantification of plasmin- (125)I by disc gel electrophoresis was modified by inclusion of euglobulin precipitation to expand its applicability to plasmas containing low radioactivity of plasmin- (125)I and plasminogen- (125)I. It was found that the euglobulin precipitation method precipitates 72.4+/-2.1 (sd)% of both plasmin- (125)I and plasminogen- (125)I. Using this method and plasminogen- (125)I as a tracer, studies were first made of the effects of heparin and epsilon-aminocaproic acid in dogs on plasmin- (125)I generation in responese to a single injection of urokinase and to venous injury; second, of the effects of venous occlusion and thrombosis on plasmin- (125)I generation; and third, in vitro studies of plasminogen- (125)I affinity to fibrin and its activation in blood clots. The venous injury was produced by the damage of venous endothelium by an injection of 90% phenol and the thrombosis by a thrombin injection into an occluded vein. Heparin and epsilon-aminocaproic acid under the present experimental conditions inhibited about 78 and 100%, respectively of plasmin- (125)I generation by the urokinase injection. Similar inhibitory effects of heparin and epsilon-aminocaproic acid were observed on plasmin- (125)I generation in response to venous injury. The venous occlusion caused a small degree of plasmin- (125)I generation, but thrombin thrombosis did not seem to stimulate the generation of plasmin- (125)I. The in vitro studies showed that plasminogen- (125)I does not have a specific affinity to fibrin and is incorporated into blood clots in approximately equal concentrations as those in serum during clotting processes, and that blood clots per se do not stimulate plasmin- (125)I generation. These results suggest that injured veins release considerable amounts of vascular plasminogen activators into circulation and that these play an important role in thrombus dissolution in vivo.
A method for the analysis of epsilon aminocaproic acid in plasma or serum has been developed. This report describes a simple and rapid assay with a small sample (20 microliter) by reverse phase high performance liquid chromatography. The supernatant is derivatized with fluorescamine after acetonitrile deproteinisation. Linearity, sensibility and accuracy are good. Save time extraction allows quick determination of many samples.
UNLABELLED: Renal dysfunction is a common serious complication after cardiac surgery. Reports of proteinuria and hyperkalemia after cardiac surgery with epsilon-aminocaproic acid (EACA) have therefore raised concerns for renal safety. Since EACA renders these markers unreliable, we used perioperative change in creatinine clearance (DCrCl) to test the hypothesis that EACA is associated with greater reductions in creatinine clearance after heart surgery, particularly for patients with renal disease. We evaluated data from all elective primary coronary bypass patients during EACA introduction at our institution (July 1, 1991-December 31, 1992; 10 g iv bolus pre-cardiopulmonary bypass, then 1 g/h for 5 h). DCrCl was calculated using preoperative (CrPre) and postoperative peak serum creatinine values, using the Cockroft-Gault equation. Patients with CrPre > or = 133 micromol/L were also separately analyzed. Evaluated patients (n = 1502, +/-EACA; 581/905, 16 exclusions) included 233 with CrPre > or = 133 micromol/L (+/-EACA; 98/135). Multivariate analyses confirmed several known risk factors, but no association between DCrCl and EACA in all patients (P: = 0.66), and the subgroup with CrPre > or = 133 micromol/L (P: = 0.42). IMPLICATIONS: In a large population of primary Coronary Artery Bypass Graft including a subset with preoperative renal dysfunction, there were no postoperative reductions in creatinine clearance attributable to epsilon-aminocaproic (EACA) administration. This retrospective study suggests that moderate epsilon-aminocaproic acid dosing during cardiac surgery is safe for the kidney; however, this inference is based on a single marker of renal dysfunction and requires prospective confirmation using a variety of tests of renal function.
The effect of epsilon-aminocaproic acid (EACA) on the degradation of aqueous pollen extracts was studied by isoelectric focusing, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and immunoblotting. The extracts were stored at 4 degrees C for 7 days and at 37 degrees C for 1, 4, and 7 days. Addition of 0.1 mol/L of EACA before storage partly protected the extract from degradation. The protective effect of EACA could be demonstrated most clearly by immunoblotting, suggesting that more epitopes were preserved in an antigenic configuration. The stabilizing effect increased with higher EACA concentrations.
BACKGROUND: Epsilon aminocaproic acid (EACA) is an antifibrinolytic drug that has been used to control hemorrhage by stabilizing the thrombus. It has been used in thrombocytopenic patients largely on an empiric basis. METHODS: Concerns regarding side effects have limited the use of this drug. The authors reviewed their experience with EACA at the Cleveland Clinic Foundation from 1997 to 2003. RESULTS: Of 77 patients with thrombocytopenic hemorrhage, 51 (66%) patients achieved a complete response and 13 (17%) patients achieved a partial response, resulting in a decrease in platelet and red blood cell transfusions. Adverse effects were manageable in this set of patients with severe underlying disease. CONCLUSIONS: Based on this experience, EACA may be a valuable adjunctive therapy in the treatment of patients with thrombocytopenic hemorrhage.
A total of 9 patients with macroscopic hematuria from various causes, none with evidence of disseminated intravascular coagulation, received low oral, divided doses (approximately 150 mg. per kg. per day) of epsilon aminocaproic acid for up to 21 consecutive days. The hematuria was controlled effectively without overt clinical reactions. Parameters of hepatic and renal function, indicators of muscular damage, were studied in detail in 3 patients. No significant abnormalities were found. The use of small doses of epsilon aminocaproic acid was not accompanied by significant complications and appeared to be effective in special situations for the control of urinary bleeding. This therapy may have indications in a number of urological states accompanied by excessive hematuria.
UNLABELLED: Despite the efficacy of antifibrinolytic drugs in reducing bleeding after cardiac surgery, concerns remain regarding their potential to promote thrombosis. We examined the effect of the antifibrinolytic drug, epsilon-aminocaproic acid (EACA) on fibrinolysis and thrombin generation during cardiac surgery. Forty-one adults undergoing primary coronary artery bypass graft surgery requiring cardiopulmonary bypass (CPB) were prospectively randomized in a double-blind trial to receive either saline or EACA. A loading dose of 150 mg/kg EACA was given before anesthetic induction, followed by a 15 mg x kg(-1) x h(-1) infusion, which continued until 3 h after CPB. Plasma samples for the measurement of D-dimer, thrombin-antithrombin III, and soluble fibrin were obtained before surgery, 1 h on CPB, and 3 and 20 h after CPB. In the EACA group, fibrinolytic activity, as measured by D-dimer, was significantly decreased 3 h after CPB, (0.51 +/- 0.15 mg/L vs 1.13 +/- 0.14 mg/L, P < 0.005). Decreased fibrinolytic activity was accompanied by decreased bleeding in the EACA group (660 +/- 127 mL vs 931 +/- 113 mL, P < 0.05). No differences in the generation of thrombin or soluble fibrin were apparent between the two groups. Suppression of fibrinolytic activity in the absence of concomitant reductions in thrombin generation suggests that EACA could potentiate a hypercoagulable prethrombotic state in the perioperative setting. IMPLICATIONS: In a randomized, prospective trial of primary cardiac surgery, we demonstrated that the synthetic antifibrinolytic drug epsilon-aminocaproic acid suppresses fibrinolysis with no effects on thrombin generation. These results suggest the potential for synthetic antifibrinolytic drugs to induce a hypercoagulable prethrombotic state in the perioperative setting.
A case of severe, unilateral essential hematuria was managed with epsilon aminocaproic acid. An extended remission of the hematuria was achieved with 24 Gm given orally in four divided doses daily, maintained for two weeks, then tapered by 2 Gm per day. The risks reported with this therapy are considered.