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Natural and synthetic antifibrinolytics in cardiac surgery.

In an effort to reduce morbidity associated with transfusion of blood products, the use of antifibrinolytics to decrease bleeding and transfusions after cardiopulmonary bypass (CPB) is receiving widespread attention. The predominant haemostatic defect induced by CPB and, therefore, the mechanisms by which natural (aprotinin) or synthetic antifibrinolytics (sigma-amino-caproic acid, tranexamic acid) exert their effects have been difficult to define. Nonetheless, all three substances appear to be effective in the treatment or in the prevention of excessive bleeding associated with cardiac surgery. However, the administration of these drugs should not attempt to replace meticulous surgical and anaesthetic care. In particular, the importance of an appropriate transfusion practice cannot be overemphasized. The efficient use of these, sometimes expensive, drugs must take into account not only the initial cost, but also the short- and long-term economic consequences for the health care provider of using, or not using, a given medication. Unfortunately, the comprehensive data on which authoritative conclusions may be reached are not yet available. Pending availability of these data, the present use of antifibrinolytics at the Montreal Heart Institute is the following: (1) patients undergoing elective primary myocardial revascularization or valve surgery do not receive prophylactic antifibrinolytics; (2) patients undergoing repeat myocardial revascularization, repeat valve surgery, or primary or repeat combined procedures, receive prophylactic sigma-aminocaproic acid; (3) sigma-aminocaproic acid may be used to treat excessive chest drainage in the postoperative period; (4) the prophylactic and the therapeutic uses of low doses of aprotinin are currently under investigation.

Aminocaproic Acid↗

Antifibrinolytics in orthotopic liver transplantation: current status and controversies.

This article reviews the current status and controversies of the 3 commonly used antifibrinolytics-epsilon-aminocaproic acid, tranexamic acid and aprotinin-during liver transplantation. There is no general consensus on how, when or which antifibrinolytics should be used in liver transplantation. Although these drugs appear to reduce blood loss and decrease transfusion requirements during liver transplantation, their use is not supported uniformly in clinical trials. Aprotinin has been studied more extensively in clinical trials and appear to offer more advantages compared to two other antifibrinolytics. Because of the diverse population of liver transplant recipients and the potential adverse effects of antifibrinolytics, especially life-threatening thromboembolism, careful patient selection and close monitoring is prudent. Further studies addressing the risks and benefits of antifibrinolytics in the setting of liver transplantation are warranted.

Aminocaproic Acid↗

Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis.

Although several randomized controlled trials (RCTs) have shown the efficacy of antifibrinolytic drugs in liver transplantation, their use remains debated due to concern for thromboembolic complications. None of the reported RCTs has shown a higher incidence of these complications in treated patients; however, none of the individual studies has been large enough to elucidate this issue completely. We therefore performed a systematic review and meta-analysis of efficacy and safety endpoints in all published controlled clinical trials on the use of antifibrinolytic drugs in liver transplantation. Studies were included if antifibrinolytic drugs (epsilon-aminocaproic acid, tranexamic acid (TA) or aprotinin) were compared with each other or with controls/placebo. Intraoperative red blood cell and fresh frozen plasma requirements, the perioperative incidence of hepatic artery thrombosis, venous thromboembolic events and mortality were analyzed. We identified 23 studies with a total of 1407 patients which met the inclusion criteria. Aprotinin and TA both reduced transfusion requirements compared with controls. No increased risk for hepatic artery thrombosis, venous thromboembolic events or perioperative mortality was observed for any of the investigated drugs. This systematic review and meta-analysis does not provide evidence for an increased risk of thromboembolic events associated with antifibrinolytic drugs in liver transplantation.

Adult↗

Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy.

Lymphangiectasia is a congenital or acquired disorder characterized by abnormal, dilated lymphatics with a variable age of presentation. We describe a case of lymphangiectasia with intestinal and pulmonary involvement in an adolescent female, who presented with many of the classic features including chylous pleural effusions, lymphopenia, hypogammaglobinemia, and a protein-losing enteropathy. She also presented with recurrent lower gastrointestinal bleeding, which is infrequently described. The patient did not improve with bowel rest and a low-fat medium-chain triglyceride diet and had little improvement with octreotide acetate therapy. However, she had a clinical response to antiplasmin therapy, trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid) in terms of serum albumin and gastrointestinal bleeding. She continues to have exacerbations of her condition, as well as persistent lymphopenia and chronic pleural effusions.

Adolescent↗

[Aprotinin in cardiac surgery: more risks than usefulness?].

Antifibrinolytic therapy with the serine protease inhibitor Aprotinin or the lysine analogues epsilon-aminocapronic acid or tranexamic acid is a therapeutic measure to reduce perioperative blood loss during cardiac surgery. In an international, prospective, non-randomised phase 4 observation study, Mangano et al. investigated the effectiveness and side-effects of Aprotinin, epsilon-aminocapronic acid and tranexamic acid in comparison to no antifibrinolytic therapy in a total of 4,374 patients who underwent cardiac surgery with extracorporeal circulation. In the opinion of Mangano et al. the results of this study question the safety and effectiveness of Aprotinin for reduction of perioperative blood loss by cardiac surgery patients. Despite a critical review of the study and results reported by Mangano et al., the authors of the present paper come to the conclusion that, in view of the availability of more reasonably priced alternatives in Germany, it appears to be sensible to give preference to tranexamic acid instead of aprotinin.

Aminocaproates↗

Characterization of gelatin-degrading metalloproteinase activities of the Dunning rat prostate tumor grown in nude mice.

Proteinase activities in the Dunning R-3327 prostatic tumor grown in nude mice and the dorsal lobe of the normal Copenhagen rat prostate were characterized using gelatin-containing SDS-polyacrylamide gel electrophoresis. Calcium-stimulated activities of approximately 33, 42, 64, 71, 76, 85, 98, 115, and 120 Kd as well as a 91 Kd calcium-independent proteinase were detected in the tumor, whereas the dorsal prostate showed calcium-dependent activities of approximately 62 and 80 Kd and a calcium-independent activity much greater than 120 Kd. The zymographic calcium-dependent proteinase patterns in the other rat prostatic lobes (a 62 Kd proteinase in the anterior lobe; 59, 62, and 67 Kd forms in the ventral lobe; and 52, 62, and 72 Kd activities in the lateral lobe) were distinctive from that of the tumor and of the dorsal lobe. The calcium-dependent and -independent proteinases of the tumor were active over a broad range of pH values with optimal activity near pH 8.0-8.4. The calcium-dependent activities were inhibited by EDTA and EGTA. Barium and strontium could partially substitute for calcium. The calcium-independent activities were not affected by these chelators nor by the proteinase inhibitors benzamidine, epsilon-aminocaproic acid, tranexamic acid, hydrocinnamic acid, or iodoacetate. Similarly, the metalloproteinase activities were not affected by the latter inhibitors. There was little change in the predominant molecular forms (64, 71, and 76 Kd) of proteinase following castration of tumor-bearing nude mice; however, the 98 Kd calcium-dependent activity decreased and the 91 Kd calcium-independent activity increased as a result of this treatment.

Adenocarcinoma↗

Perioperative approaches to coagulation defects.

Cardiac surgical procedures are known to be associated with coagulation defects and disordered hemostasis. Excessive perioperative and postoperative bleeding and the need for considerable volumes of blood and blood product transfusions are well recognized. The risks of blood transfusion with high donor-exposure levels have focused attention on blood conservation as a priority in reducing the complications of cardiac operations. Hemostatic defects may be related to patient-inherent coagulopathies, preexisting associated pathology, and preoperative drug therapy. In addition, hemostatic defects are induced during the operation itself. Two principal therapeutic approaches to this complex problem have evolved. Although different, these approaches are not mutually exclusive and may be used complementarily. The first is autotransfusion and the second is hemostatic drug therapy. Although many drugs have been tried, including antifibrinolytic agents (epsilon-aminocaproic acid, tranexamic acid), platelet-preserving agents (prostacyclin, dipyridamole), and desmopressin, the only drug that has shown significant and consistent efficacy in reducing bleeding in cardiac surgery patients is the serine protease inhibitor aprotinin. Aprotinin has been shown to be highly effective in reducing blood loss and blood and blood product transfusion requirements in high-risk patients. Clinical experience with aprotinin therapy in cardiac patients and specific issues such as dosage regimens and the target automated clotting time levels in patients on high-dose aprotinin therapy are outlined. Indications for the use of aprotinin and the balance between risk and benefit are discussed.

Aprotinin↗

Decreased Fc and C3 receptor function in macrophage populations which are refractory to migration inhibitory factor, C3 activators, and immune complex.

Guinea pig macrophage populations previously established to be either responsive or refractory to activation by migration inhibitory factor (MIF) and Lotus fucolectin in the macrophage migration inhibition (MMI) assay were further characterized for their MMI response to diverse effectors as correlated with their Fc and C3b receptor function. MIF-refractory populations were found to be uniformly unresponsive to the complement activators: bacterial lipopolysaccharide, cobra venom factor, zymosan, and immune complex. MIF-responsive macrophages were responsive to the same activators. Fc-mediated binding and phagocytosis of IgG-coated sheep erythrocytes (EA) were markedly depressed in freshly harvested refractory macrophages as compared to responsive cells. Fc phagocytosis by refractory populations increased rapidly during 24-28 hr in vitro culture to levels equal to that of responsive cells which corresponded with an increase in their MMI response to MIF. Refractory macrophages also had decreased C3b receptor function as shown by reduced binding and phagocytosis of EAC or serum-coated zymosan and displayed a greater loss in C3b binding capacity than responsive cells during 48 hr in vitro culture. Trypsinization of responsive macrophages rendered them refractory in their MMI response to the various activators and selectively reversed C3b-dependent binding without effect on Fc binding. The plasmin esterase inhibitors, epsilon-amino-n-caproic acid, tranexamic acid, and L-lysine, previously established to reverse the MMI response to MIF, FBP, and C3 activators were found to inhibit both Fc- and C3-dependent phagocytosis. These results indicate that macrophage populations which are refractory to migration inhibition by MIF and C3 activators also have reduced Fc- and C3b-mediated phagocytic functions as compared to more mature responsive populations.

Animals↗

Characterization of a renal medium chain acyl-CoA synthetase responsible for glycine conjugation in mouse kidney mitochondria.

Glycine conjugation of a series of benzoic acid derivatives was investigated in mouse kidney mitochondria. The chlorine and methyl substitutions in the para- and meta-positions of the benzene ring yielded an increase in glycine conjugation. The acids with a methoxy group showed a low degree of glycine conjugation. In addition, the acids with nitro or amino groups were conjugated to a slight extent with glycine. The in vitro conjugation of salicylic acid with glycine occurred not in liver but in kidney. The specificity of the renal medium chain acyl-CoA synthetase catalyzing the first reaction of glycine conjugation was also examined. The enzyme accepted not only medium chain fatty acids but also aromatic and arylacetic acids. The highest activity was shown with hexanoic acid. High activities were observed for benzoic acid derivatives with alkyl and alkoxyl groups in the para- and meta-positions of the benzene ring. An ortho-substituted acid exhibited no activity. In addition, the enzyme was less active with valproic acid, tranexamic acid, indomethacin and ketoprofen. The enzyme was inhibited by diflunisal, 2-hydroxydodecanoic acid and salicylic acid, which did not act as substrates. There was a poor correlation between the activity of the medium chain acyl-CoA synthetase and glycine conjugation of eleven substituted benzoic acids. These findings suggest that the present medium chain acyl-CoA synthetase is involved in glycine conjugation of the substituted acids in mouse kidney mitochondria, but there may be a larger contribution of another isoenzyme.

Animals↗

[Chronic, hemorrhage-induced iron deficiency anemia in Osler disease].

We report the history of a 77-year-old man with Osler-Weber-Rendu disease (hereditary hemorrhagic telangiectasia) who suffered from recurrent epistaxis and chronic bleeding anemia for many years. Hereditary hemorrhagic telangiectasia is a rare congenital disease, that is characterized by telangiectases of the nasal and oral mucosa, the gastrointestinal tract and the skin. Arteriovenous malformations of the lung and the brain may be present. The genetic and pathologic features, the clinical manifestations and the differential diagnosis are shortly presented. The management is not validated by controlled studies and is mainly based on clinical experience. It involves supportive therapy with iron supplementation and erythrocyte transfusions, if needed, for chronic bleeding anemia, aminocaproic acid, tranexamic acid or oestrogen-progesterone therapy to prevent mucosal bleeding, cauterisation, photocoagulation, transcatheter embolotherapy or surgery to treat the vascular abnormalities.

Aged↗

Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity.

Lp(a) is a major inherited risk factor for premature atherosclerosis. The mechanism of Lp(a) atherogenicity has not been elucidated, but likely involves both its ability to interfere with plasminogen activation and its atherogenic potential as a lipoprotein particle after receptor-mediated uptake. We demonstrate that Lp(a) stimulates production of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin in cultured human coronary artery endothelial cells (HCAEC). This effect resulted from a rise in intracellular free calcium induced by Lp(a) and could be inhibited by the intracellular calcium chelator, BAPTA/AM. The involvement of the LDL and VLDL receptors in Lp(a) activation of HCAEC were ruled out since Lp(a) induction of adhesion molecules was not prevented by an antibody (IgGC7) to the LDL receptor or by receptor-activating protein, an antagonist of ligand binding to the VLDL receptor. Addition of alpha2-macroglobulin as well as treatment with heparinase, chondroitinase ABC, and sodium chlorate did not decrease levels of VCAM-1 and E-selectin stimulated by Lp(a), suggesting that neither the low density lipoprotein receptor-related protein nor cell-surface proteoglycans are involved in Lp(a)-induced adhesion molecule production. Neither does the binding site on HCAEC responsible for adhesion molecule production by Lp(a) appear to involve plasminogen receptors, as levels of VCAM-1 and E-selectin were not significantly decreased by the addition of glu-plasminogen, the lysine analog epsilon-aminocaproic acid, or by trans-4-(aminomethyl)-cyclohexanecarboxymethylic acid (tranexamic acid), which acts by binding to the lysine binding sites carried on the kringle structures in plasminogen. In contrast, recombinant apolipoprotein (a) [r-apo(a)] competed with Lp(a) and attenuated the expression of VCAM-1 and E-selectin. In summary, we have identified a calcium-dependent interaction of Lp(a) with HCAEC capable of inducing potent surface expression of VCAM-1 and E-selectin that does not appear to involve any of the known potential Lp(a) binding sites. Because leukocyte recruitment to the vessel wall appears to represent one of the important early events in atherogenesis, this newly described endothelial cell-activating effect of Lp(a) places it at a crucial juncture in the initiation of atherogenic disease and may lead to a better understanding of the role of Lp(a) in the vascular biology of atherosclerosis.

Arteriosclerosis↗

Laryngeal oedema due to hereditary angioedema.

A case is reported in which a young man suffering from hereditary angioedema was admitted with severe airway obstruction due to groww pharyngeal and laryngeal oedema. Tracheostomy was necessary. The rationale of treatment with epsilon aminocaproic acid, tranexamic acid and fresh frozen plasma is discussed. The patient subsequently underwent dental extractions under general anaesthesia with tracheal intubation without complications.

Adult↗

[Angioedema is caused by a defect in C1-inhibitor synthesis].

Deficit of the first component of complement inhibitor (C1-inhibitor, C1-inh) may clinically be manifested as angioedema. The disease is characterized by episodic swellings of mucosa and subcutaneous tissue at different locations of the body. Laryngeal swelling can be life-threatening. The major mediators of edema are discussed to be bradykinin and C2b derived peptides. These mediators increase capillary permeability. Antifibrinolytic agents (aminocaproic acid, tranexamic acid) and attenuated androgens (danazol or stanazolol) are used for prophylaxis. Prolonged use both of them might result in more or less severe side effects. In experiments in vitro it has been shown that IFN-gamma, IL-1, IL-6 have a stimulatory effect on C1-inh synthesis. We want to verify the practical use of probiotics as natural inductors of IFN-gamma synthesis for elevating C1-inh level.

Adolescent↗

Synthetic antifibrinolytics are not associated with an increased incidence of baffle fenestration closure after the modified Fontan procedure.

OBJECTIVE: To determine if the lysine analog antifibrinolytic agents, epsilon-aminocaproic acid and tranexamic acid, are associated with early closure of the baffle fenestration after the modified Fontan procedure. DESIGN: Retrospective chart review. SETTING: University hospital. PARTICIPANTS: Seventy-four successive patients underwent the modified Fontan procedure. Three patients received aprotinin and were excluded. A total of 71 patients were analyzed. INTERVENTIONS: Charts were examined for variables known to be associated with baffle fenestration closure in the modified Fontan procedure. MEASUREMENTS AND MAIN RESULTS: Occurrence of baffle fenestration closure, oxygen saturation, central venous pressure, left atrial pressure, transpulmonary gradient, chest tube drainage volume, chest tube drainage duration, intensive care unit (ICU) duration, and total inpatient duration were compared between the 33 patients who received antifibrinolytics and the 38 patients who did not. One patient of 71 had baffle fenestration closure in the first 48 hours after surgery. Oxygen saturation, central venous pressure, left atrial pressure, transpulmonary gradient, chest tube drainage volume, chest tube drainage duration, days in ICU, and total inpatient duration were not significantly different between the two groups. CONCLUSIONS: Use of epsilon-aminocaproic acid and tranexamic acid is not associated with early baffle fenestration closure after the modified Fontan procedure. It is concluded that these agents can be used without increasing the risk of spontaneous baffle fenestration closure.

Aminocaproic Acid↗

The risk associated with aprotinin in cardiac surgery.

BACKGROUND: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition--namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken. METHODS: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.) RESULTS: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss. CONCLUSIONS: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

Adult↗

Review and application of serine protease inhibition in coronary artery bypass graft surgery.

PURPOSE: Current pharmacologic agents, aprotinin, epsilon aminocaproic acid, and tranexamic acid, used to decrease blood loss and transfusion requirements during coronary artery bypass graft (CABG) surgery are discussed. Aprotinin is the only agent that also modulates the systemic inflammatory responses that are generated by contact activation during CABG surgery. These responses are largely mediated by serine proteases such as kallikrein, thrombin, and plasmin. SUMMARY: Aprotinin is a naturally occurring polypeptide that has a concentration-dependent effect to inhibit serine proteases. Two aprotinin dosing regimens are indicated in the United States (U.S.) for prophylactic use to reduce perioperative blood loss and the need for blood transfusion in patients undergoing cardiopulmonary bypass (CPB) during the course of CABG surgery. Serum concentrations achieved with the full-dose regimen inhibit both kallikrein and plasmin activity resulting in attenuation of the systemic inflammatory response to bypass, whereas serum concentrations achieved with the half-dose regimen only inhibit plasmin activity. The efficacy and safety of aprotinin have been studied in randomized controlled trials in over 5,000 patients. Aprotinin is well tolerated compared to placebo. Treatment-emergent adverse events are similar to those associated with CPB surgery. However, because aprotinin is a bovine protein, there is a small, but manageable risk of hypersensitivity reactions. Epsilon aminocaproic acid and tranexamic acid are lysine analogs that reduce bleeding by inhibiting the conversion of plasminogen to plasmin, a serine protease responsible for breaking down fibrinogen to fibrin. Although they are commonly used to decrease bleeding associated with CABG surgery with CPB, they are not currently approved by the U.S. Food and Drug Administration (FDA) for CABG surgery. CONCLUSION: Aprotinin is the only agent that has an FDA indication to prevent blood loss and transfusion during CABG surgery, and the additional benefit of attenuating the systemic inflammatory response associated with CABG with CPB.

Aprotinin↗

Inhibition of the activation of the first component of complement, C1, by various amino acids or peptides.

The effects of various amino acids (or their analogues) and peptides on the activation or consumption of human complement by erythrocytes bound with hemolysin or heat-aggregated immunoglobulin G (aggIgG) were studied by using the hemolysis of hemolysin-bound erythrocytes, the consumption of complement by aggIgG in the serum, the hydrolysis of acetyl tyrosine ethyl ester by activated Cl (Cls), Cl hemolysis and a newly developed enzyme immunoassay, which directly measures interaction between Clq and aggIgG. Amino acids or peptides which were proposed to comprise Clq binding sites of the C2 region of IgG or their analogues were used. CH50 was inhibited by lysine or arginine to the largest extent, but other amino acids, including tranexamic acid and epsilon-amino caproic acid were not inhibitory up to 60 mM. The consumption of serum complement by aggIgG was prevented by arginine or lysine (about 60% inhibition at 60 mM) and by histidine to a lesser extent. The activation of Cls in the Cl complex by aggIgG precipitated at pH 5.5 was most inhibited by lysine, and to a lesser extent by tranexamic acid, arginine and epsilon-aminocaproic acid, but not glutamic acid or glycine. The results of Cl hemolysis indicated that, of all amino acids soluble at neutral pH, lysine and arginine were most effective in the inhibition of Cl hemolysis. Tranexamic acid and epsilon-aminocaproic acid were less effective, and glycine and norleucine were hardly effective. Among the dipeptides used, those that are composed of aromatic amino acids were very effective in the inhibition of Cl hemolysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

Stabilization of plasmin by lysine derivatives.

Plasmin is a serine protease with trypsin-like specificity and is activated from plasminogen by several plasminogen activators. Since plasmin has lysine binding site in its heavy chain, lysine derivatives react with plasmin and then modify its activity. The effects of lysine derivatives such as epsilon-aminocaproic acid (EACA) and tranexamic acid on bovine plasmin activity were investigated. In the absence of lysine derivatives, the bovine plasmin activity which was evaluated as the amidolytic activity was reduced in a time- or temperature-dependent manner. However, the bovine plasmin activity became stable upon adding EACA or tranexamic acid. When plasmin was incubated at 4 degrees C for 1, 3 or 5 days without lysine derivatives, the plasmin activity decreased to 43.9%, 19.9% and 11.9% of the initial activity, respectively. On the other hand, when plasmin was incubated at 37 degrees C for 1, 3 or 5 days with tranexamic acid, its activity remained at 110%, 95.6% and 85.9%, respectively. After bovine plasmin had been incubated for 5 days at 4 degrees C in the absence of tranexamic acid, the plasmin activity declined to less than 20%. However, when bovine plasmin had been incubated for 5 days at 37 degrees C in the presence of tranexamic acid, the residual plasmin activity was more than 80%. A similar effect of EACA on bovine plasmin was observed, but it was weaker than that of tranexamic acid. Reversed-phase HPLC followed by SDS-PAGE demonstrated that bovine plasmin was degraded into several fragments. Amino acid sequencing of these fragments revealed that the Lys77-Arg78 or Arg78-Ile79, Arg342-Met343 and Arg557-Ile558 peptide bonds in the bovine plasmin molecule were cleft, respectively. Only the fragment consisting of the amino acid region from Met343 to the C-terminal amino acid, Asn786, exhibited amidolytic activity. In proportion to inactivation of the bovine plasmin, this fragment disappeared. The above findings suggest that lysine derivatives react with bovine plasmin and then stabilize the activity of plasmin by preventing the degradation of active fragment (Met343-Asn786).

Amino Acid Sequence↗