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Early decrease in suture line breaking strength. The effect of proposed collagenase inhibition.

Rats were subjected to end-to-end intestinal anastomosis. Breaking strength with the sutures in place, i.e., suture-holding capacity, was measured in different groups immediately after suture and after 24 h. The synthetic kallikrein-plasmin inhibitor S-2441, the inhibitor of plasminogen activation tranexamic acid (Cyklokapron), and the metalloprotease inhibitor tiopronin (Thiola), were studied regarding their effect on breaking strength of the intestinal anastomoses. There was a marked decrease in breaking strength at 24 h in the controls. This decrease was diminished by all of the substances tested. Their effect was probably due to an inhibition of collagenase.

Animals↗

Hyperfibrinogenolysis in disseminated adenocarcinoma.

We present the case of a 42-year-old woman with a recently acquired bleeding tendency. Coagulation studies and response to antifibrinolytic therapy suggested primary hyperfibrinogenolysis: markedly low levels of fibrinogen and alpha2-antiplasmin, normal levels of antithrombin III, protein C and protein S combined with an only borderline low number of platelets without evidence of microangiopathic haemolytic anaemia. A suspected causative adenocarcinoma of the lung was demonstrated. She was treated successfully with tranexamic acid and cryoprecipitate, until the tumor progressed and hyperfibrinogenolysis progressed to diffuse intravascular coagulation. Differential diagnosis of these coagulation disorders, with similar etiology, clinical and laboratory findings is reviewed. Therapeutic implications are discussed.

Adenocarcinoma↗

Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study.

OBJECTIVES: We undertook an international, multicenter study to describe the clinical picture and to estimate the bleeding risk in a group of obligatory carriers of type 3 von Willebrand disease (VWD). PATIENTS AND METHODS: Obligatory carriers (OC) of type 3 VWD were identified by the presence of offspring with type 3 VWD or by being an offspring of a type 3 patient. Normal controls were age- and sex-matched with the obligatory carriers. A physician-administered standardized questionnaire was used to evaluate hemorrhagic symptoms at presentation. A score system ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion) was used to quantitate bleeding manifestations. Odds ratios were computed for each symptom. RESULTS: Ten centers participated to the study, enrolling a total of 35 type 3 VWD families, with 70 OC. A total of 215 normal controls and 42 OC for type 1 VWD were also included. About 40% of type 3 OC had at least one bleeding symptom compared to 23% of normal controls and 81.8% of type 1 OC (P < 0.0001 by chi-squared test), showing that type 3 OC clearly represent a distinct population from type 1 OC. The clinical situations associated with an increase of bleeding risk in type 3 OC were epistaxis [odds ratio 3.6; 90% confidence intervals (CI) 1.84-21.5], cutaneous bleeding (odds ratio 5.5; 90% CI 2.5-14.1) and postsurgical bleeding (odds ratio 16.3; 90% CI 4.5-59). The severity of bleeding score correlated with the degree of factor (F) VIII reduction in plasma. CONCLUSIONS: OC for type 3 VWD represent a distinctive population from type 1 OC. These patients, however, present with more frequent bleeding symptoms in comparison to normal controls, especially in case of significantly low FVIII. Desmopressin and/or tranexamic acid might be useful to prevent or treat bleeding in these cases.

Adolescent↗

Overall survival results of non-small cell lung cancer patients: chemotherapy alone versus chemotherapy with combined immunomodulation.

The effect on long-term survival of immunomodulation adjuvant to various cytotoxic chemotherapy regimens in non-small cell lung cancer (NSCLC) was evaluated in 669 patients followed up between 1974 and 1987. Four hundred seventeen patients were treated only by cytotoxic chemotherapy and served as controls. Two hundred fifty-two patients received warfarin (W), levamisole (L) and tranexamic acid (T) for adjuvant immunomodulation. These drugs, especially when given in combination (W + L + T), led to a significant (p less than 0.05) enhancement of survival in patients with advanced NSCLC, independent of the cytotoxic regimen used.

Adjuvants, Immunologic↗

The regulation of liver regeneration by the plasmin/alpha 2-antiplasmin system.

BACKGROUND/AIMS: The regeneration after liver injury is regulated by the release and activation of several growth factors. The role of the plasmin/alpha(2)-antiplasmin (alpha(2)-AP) system in liver regeneration was investigated. METHODS: CCl(4) was injected intraperitoneally into the mice deficient (-/-) in fibrinolytic factors: alpha(2)-AP-/-, plasminogen (Plg) -/-, and Plg-/-.alpha(2)-AP-/-, and wild-type (WT) mice. The liver tissue was examined for its microscopic appearance, fibrinolytic activity, and fibronectin levels. RESULTS: In the gene deficient and WT mice, the livers exhibited the same extent of necrosis 2 days after the CCl(4) injection. The livers of the WT mice normalized after 7 days, and the alpha(2)-AP-/- mice normalized after 5 days. In contrast, the livers of the Plg-/- and Plg-/-.alpha(2)-AP-/- mice remained in the damaged state until 14 days after the liver injury. The injection of anti-alpha(2)-AP antibody in the WT mice improved the regeneration after the liver injury, and the injection of tranexamic acid in the alpha(2)-AP-/- mice reduced. CONCLUSIONS: These results suggest that the plasmin/alpha(2)-AP system played an important role in hepatic repair via clearance from the injury area.

Animals↗

Lymphocytic lymphoma and acquired C1 esterase inhibitor deficiency.

We report a 59-year-old woman who had progressive symptoms of angioedema for 3 years, culminating in an attack of laryngeal stridor. C1 esterase inhibitor deficiency was confirmed and treatment with tranexamic acid produced considerable clinical benefit and improvement in complement levels. Two years later she developed clinical evidence of lymphocytic lymphoma. Splenectomy resulted in rapid correction of complement abnormalities. The patient received 6 months of chemotherapy after surgery and remained asymptomatic with normal complement levels 4 years later.

Angioedema↗

Dental surgery in patients with severe factor XI deficiency without plasma replacement.

Bleeding following dental extraction is frequently the first manifestation of severe factor XI deficiency. Safe oral surgery has previously been performed in such patients by using plasma replacement therapy with or without concomitant administration of antifibrinolytic agents. The aim of this study was to determine whether such patients can undergo safe dental extractions using only an antifibrinolytic agent. The study group consisted of 19 patients with severe factor XI deficiency (factor XI:C level less than 14 U/dl) who had previously bled following dental extractions (14 patients) or other trauma (five patients). Tranexamic acid, 1 g q.i.d., was given from 12 h before surgery, until 7 days afterwards. No excessive bleeding was observed following dental extractions. One patient had slight oozing after 3 days which ceased spontaneously. Thus, plasma replacement no longer appears necessary for patients with severe factor XI deficiency requiring dental extractions.

Adult↗

The management of perioperative bleeding.

Excess perioperative bleeding remains a major complication following surgery, resulting in increased morbidity and mortality. The principal causes of non-surgical haemostatic perioperative bleeding are a pre-existing undetected bleeding disorder, related to the nature of the operation itself or from coagulation abnormalities arising from massive blood loss. Very often, it is a combination and coexistence of various pathologies. Identifying patients at risk remains a major component of preventing excessive blood loss. Understanding the haemostatic changes occurring in the perioperative period, especially in complex procedures like cardiopulmonary bypass and orthotopic liver transplantation is crucial in developing new strategies for the management of perioperative bleeding. Pharmacological interventions, especially aprotinin, tranexamic acid, desmopressin and increasingly, recombinant VIIa are being used both in prophylaxis and therapeutically to stop bleeding. The use of near patient testing like thromboelastography and platelet function analyser has allowed for more detailed assessment of the various steps of haemostasis. One of the main goals is to reduce the usage of allogeneic blood transfusion and its attendant risks.

Aprotinin↗

A study of complement functions in a family with hereditary angioneurotic edema.

A study of some complement functions was performed in two patients affected with hereditary angioneurotic edema (HAE) - mother and daughter - from a Southern Italy family (Apulia) and in three of their relatives. A decreased level of the C1 esterase plasma inhibitor was found in both the patients, who were treated with tranexamic acid with a slight, but definite improvement. However, the disease could not be traced beyond two generations in the pedigree and a couple of ascendants was found who were free from HAE both from the clinical standpoint and from that of the laboratory evaluation of complement functions. The possibility that HAE arose in the family through a mutational event is discussed.

Adolescent↗

Initial plasmin-degradation of fibrin as the basis of a positive feed-back mechanism in fibrinolysis.

This study deals with the effect of fibrin on the transformation of Glu-plasminogen to Glu-plasmin during fibrinolysis. It focuses particularly on changes in fibrin effector function caused by plasmin-catalysed fibrin degradation. Conversion of 125I-labelled Glu-plasminogen to Glu-plasmin was catalysed by urokinase or tissue plasminogen activator, in the presence of different preparations of progressively degraded fibrin. Plasmin catalysis of Glu-plasminogen and the fibrin (derivative) effector was inhibited by aprotinin. The presence of intact fibrin enhanced the rate of Glu-plasmin formation catalysed by tissue plasminogen activator, but not by urokinase. The presence of initially plasmin-cleaved fibrin, however, increased the rates of Glu-plasmin formation with both activators, as compared to those found with intact fibrin. The rate enhancements induced by initial plasmin degradation of the fibrin effector were associated with an increase in its affinity to both Glu-plasminogen and tissue plasminogen activator, suggesting causal relationships. The weak binding of urokinase was unaffected by fibrin degradation, indicating that effector function was solely exerted on the Glu-plasminogen moiety of urokinase-activated systems. Further degradation of fibrin decreased the stimulating effect on Glu-plasmin formation. This decrease occurred at an earlier stage of degradation with tissue plasminogen activator than with urokinase, indicating that greater integrity of the fibrin effector is necessary for its optimal interaction with the tissue plasminogen activator than with Glu-plasminogen. Concentrations of tranexamic acid that saturate low-affinity lysine-binding sites nearly completely dissociated the binding of Glu-plasminogen to degraded fibrin, but not to intact fibrin. In analogy with the binding of lysine analogues to these sites, the conformation of Glu-plasminogen may be altered by binding to degraded fibrin, thus giving rise to the increased activation rate.

Catalysis↗

Recombinant plasminogen activator inhibitor-1 reverses the bleeding tendency associated with the combined administration of tissue-type plasminogen activator and aspirin in rabbits.

The major side effect of thrombolytic therapy is bleeding; however, the pathogenesis of this potential complication is not well understood. Accordingly, we examined the effects of aspirin and recombinant human tissue-type plasminogen activator (rt-PA) on serial template bleeding times and on hemostasis parameters in rabbits. The administration of intravenous aspirin (15 mg/kg) produced a slight prolongation in bleeding times, from 2.1 +/- 0.5 to 2.6 +/- 0.5 min (mean +/- SD, n = 26, P less than 0.01), whereas rt-PA (1 mg/kg per h for 2 h) lengthened the bleeding time from 2.4 +/- 0.3 to 3.2 +/- 0.6 min (n = 5, P = NS). Combination of aspirin with 0.5 mg/kg per h of rt-PA for 2 h prolonged the bleeding time from 2.5 +/- 0.4 to 6.2 +/- 0.9 min (n = 10, P less than 0.01), with an associated fibrinogen decrease of approximately 15%. The combination of aspirin with 1 mg/kg per h of rt-PA for 2 h prolonged the bleeding time from 3.0 +/- 0.3 to 8.3 +/- 1.4 min (n = 8, P less than 0.01) and simultaneously induced a decrease of plasma fibrinogen by approximately 40%. Virtually all animals treated with rt-PA and aspirin manifested a bleeding tendency, as evidenced by spontaneous rebleeding at sites of previously performed template bleeding times or oozing at the femoral venous catheterization site. Intravenous bolus injection of 1 mg/kg of guanidine hydrochloride-reactivated recombinant human plasminogen activator inhibitor-1 (rPAI-1) at the end of the rt-PA infusion resulted in complete reversal, within 5 min, of the prolongation of the bleeding time, and in a disappearance of the bleeding tendency. Nonreactivated rPAI-1 and tranexamic acid were significantly less potent in reversing the bleeding time prolongation. These findings indicate that aspirin and rt-PA given separately do not markedly affect the template bleeding time, but in combination induce a marked prolongation associated with a significant bleeding tendency. This bleeding time prolongation can be rapidly normalized by the administration of reactivated rPAI-1.

Animals↗

T-cell lymphokines, interleukin-4 and gamma interferon, modulate the induction of vascular smooth muscle cell tissue plasminogen activator and migration by serum and platelet-derived growth factor.

Platelet-derived growth factor (PDGF)-induced smooth muscle cell (SMC) fibrinolysis is necessary for SMC migration. In order to determine whether the T-cell lymphokines interleukin-4 (IL-4) and gamma interferon (gamma-IFN) affect SMC fibrinolysis and migration, we examined the effects of human recombinant IL-4 and gamma-IFN on human aortic SMC tissue-type plasminogen activator (TPA), urokinase-type plasminogen activator (UPA), and plasminogen activator inhibitor type-1 (PAI-1) antigen production, as determined by enzyme-linked immunosorbent assays. Although IL-4 had no direct effect on SMC TPA antigen, IL-4 potentiated SMC TPA antigen levels and activity in conditioned media and cellular lysates in media containing 2% fetal bovine serum but did not change UPA or PAI-1 production. gamma-IFN attenuated IL-4 augmentation of SMC TPA antigen production in conditioned media, although gamma-IFN itself had no direct effects on SMC TPA and PAI-1 antigen production. IL-4 augmented PDGF induction of SMC TPA antigen. gamma-IFN inhibited PDGF induction of SMC TPA antigen and IL-4 potentiation of this process. gamma-IFN diminished the promigratory effects of both IL-4 and PDGF on in vitro SMC migration. Tranexamic acid, a plasmin inhibitor, abrogated the stimulation of SMC migration by IL-4. Therefore, IL-4 and gamma-IFN modulate the induction of SMC TPA and SMC migration by 2% fetal bovine serum and PDGF.

Analysis of Variance↗

[Acute normovolemic hemodilution combined with inhibition of fibrinolysis and use of cell saver in total hip arthroplasty].

INTRODUCTION: Transfusion with homologous blood is not without costs for the recipient: An increased risk of postoperative infections must be anticipated, and the risk of transfusion-transmitted viral infections is of growing concern. This has increased the interest for methods which can reduce the need for intraoperative blood transfusion. The goal of this study was to determine if acute normovolemic hemodilution combined with fibrinolytic inhibition and the use of cell saver can reduce the need for homologous blood transfusion in total hip arthroplasty compared to the cellsaver technique alone. MATERIAL AND METHODS: 145 patients undergoing total hip arthroplasty in spinal anesthesia were included in the study. They were all operated by the same surgeon. In group A (N = 64) only the cell saver was used, whereas in group B (N = 81) it was combined with acute normovolemic hemodilution and use of the fibrinolytic inhibitor tranexamic acid. RESULTS: The total blood loss and the need for homologous blood transfusion were significantly smaller in group B than in group A. DISCUSSION: Although the cell saving technique is effective in total hip arthroplasty, this study demonstrates that a further reduction of blood loss and homologous blood transfusion can be achieved by combining the method with acute normovolemic hemodilution and pharmacological inhibition of fibrinolysis.

Antifibrinolytic Agents↗

A retrospective survey of fibrinolysis as an indicator of poor outcome after cardiopulmonary bypass and a possible early sign of systemic inflammation syndrome.

A retrospective survey was undertaken of 142 adults who had undergone cardiac surgery with cardiopulmonary bypass. According to the manufacturer's instructions for thromboelastography, patients were identified as showing evidence of fibrinolysis if after coming off bypass the Ly30 index was > or =7.5%. In the 20 fibrinolytic patients, fibrinolysis was readily corrected by tranexamic acid but these patients needed more colloid and more vasopressor support than the non-fibrinolytic patients. There were three deaths, all in the fibrinolytic patients. It is possible that fibrinolysis is a marker for onset of systemic inflammation syndrome. It is recommended that, until the association between fibrinolysis and worse outcome is investigated further, patients showing fibrinolysis early after cardiopulmonary bypass should not be discharged too soon from intensive care.

Aged↗

Rendu-Osler-Weber disease: experience with 56 patients.

Rendu-Osler-Weber disease, or hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disease characterized by systemic vascular dysplasia. The prevalence varies and ranges, according to region, from 1/3500 to 1/5000. Data concerning Italy are not available. The diagnosis is based on the following criteria: family history, epistaxis, telangiectases and visceral arteriovenous malformations. The diagnosis is to be considered definite if three criteria are present and suspected if two criteria are present. From September 2000 to March 2002, 100 patients (63 males, 37 females, mean age 45.5 +/- 17.3 years) potentially affected by HHT were evaluated in the HHT Center of the "Augusto Murri" Internal Medicine Section at the University of Bari (on a day-hospital or hospitalization basis). The diagnosis of HHT was confirmed in 56 patients and suspected in 10. Magnetic resonance imaging revealed cerebral arteriovenous malformations in 8.5% of patients. In 14.6% of patients contrast echocardiography revealed pulmonary arteriovenous malformations subsequently confirmed at multislice computed tomography in all cases but one. In 48.2% of subjects hepatic vascular malformations were revealed by echo color Doppler ultrasonography, whereas abdominal multislice computed tomography was positive in 63.8% of patients. In 64% of the 25 patients, who underwent endoscopy, gastric telangiectases were found. In 3 out of 6 patients presenting with pulmonary arteriovenous malformations, embolotherapy was performed with success. In our patients, the use of tranexamic acid caused a reduction in the frequency of epistaxis. The future objectives of the HHT Center of Bari are to increase knowledge of the disease, to cooperate with other centers with the aim of increasing the number of patients studied and to avoid the limits of therapeutic and diagnostic protocols of a rare disease such as HHT.

Adult↗

Severe hyponatraemia secondary to desmopressin therapy in von Willebrand's disease.

A 42-year-old female with von Willebrand's disease was managed with desmopressin and tranexamic acid to aid haemostasis following a vaginal hysterectomy. Severe acute hyponatraemia (134 to 108 mmol/l) developed over two days, culminating in a generalized tonic-clonic seizure and cerebral oedema. Fluid restriction, cessation of desmopressin and hypertonic saline administration led to a full recovery. Desmopressin is known to reduce free water elimination and produce hyponatraemia, but its extent and rate of development in this patient was surprising. Close monitoring of serum sodium and fluid balance is recommended in these patients.

Acute Disease↗

Dental extractions in patients maintained on continued oral anticoagulant: comparison of local hemostatic modalities.

OBJECTIVE: The purpose of this study was to evaluate postoperative bleeding in patients treated with oral anticoagulant drugs who underwent dental extractions without interruption of the treatment and to compare the effect of 3 different hemostatic modalities. STUDY DESIGN: A total of 150 patients who underwent dental extractions were divided into 3 groups. Local hemostasis was carried out as follows: group 1 (119 extractions), with gelatin sponge and sutures; group 2 (117 extractions), with gelatin sponge, sutures, and mouthwash with tranexamic acid; group 3 (123 extractions), with fibrin glue, gelatin sponge, and sutures. RESULTS: Of 150 patients, 13 (8.6%) presented with postoperative bleeding: 3 patients from group 1, 6 patients from group 2, and 4 patients from group 3. CONCLUSIONS: Dental extractions can be performed without interruption in patients treated with oral anticoagulant. Local hemostasis with gelatin sponge and sutures is sufficient.

Administration, Oral↗

Experimental studies on the effect of induced antifibrinolysis on per-operative tumour cell shedding.

Previous experimental data suggested a pronounced inhibition of the spontaneous intravascular tumor cell shedding by induced antifibrinolysis. Furthermore, the growth rate of primary tumours was reduced. This initiated the present investigation, in which the effect of antifibrinolysis, induced with tranexamic acid, on the per-operative intravascular release of cells from a 20-methylcholanthrene induced rat sarcoma was studied. Tumour cell shedding was estimated by registration of the outgrowth of secondary tumours in animals transplanted intrasmuscularly or intravenously with blood from the operatively treated tumour area. Induced antifibrinolysis was not found to influence the intravascular shedding of tumour cells. However, a significantly increase release of tumour cells was found during biopsies on large primary tumours compared to the same operative procedure on small tumours.

Animals↗