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PubMed1989

Current status of antifibrinolytic drugs.

Antifibrinolytic drugs, in particular, epsilon-aminocaproic acid and tranexamic acid, have been used in the management of a wide range of both bleeding and non-haemorrhagic disorders. Recognition of their side-effects and complications, comparison of their efficacy with other forms of therapy and more critical evaluation of their value has reduced the range of their definitive indications to a limited number of relatively uncommon situations; these comprise primary hyperplasminaemia, menorrhagia in women in whom oestrogens are contraindicated or in those with von Willebrand's disease, severe traumatic hyphaema, dental extraction in haemophiliacs and hereditary angioedema in patients in whom treatment with anabolic steroids is contraindicated. In a few conditions the possible benefit of antifibrinolytic agents, alone or supplementary to other forms of therapy, is unresolved; these include upper gastrointestinal bleeding, recurrent epistaxis and abruptio placentae.

Antifibrinolytic Agents↗

PubMed1989

Hemostasis associated with abnormalities of fibrinolysis.

Hemostatic plugs consist of platelet aggregates and fibrin mesh containing blood cells and plasma components. Hemostatic efficiency depends on the rate of formation of hemostatic plugs as well as the structural integrity and stability of the formed hemostatic plugs. Fibrin elements are major constituents contributing to the structural integrity and stability, but they are subject to fibrinolytic activity occurring spontaneously after fibrin formation. Fibrinolysis is usually suppressed by endogenous inhibitors. Increase of a profibrinolytic component or deficiency of an inhibitor would result in an accelerated fibrinolysis, causing a premature lysis of hemostatic plugs before restoration of injured vessels, leading to a hemorrhagic tendency. Such a state can be seen typically in patients with congenital deficiency of alpha 2-plasmin inhibitor or a hereditary increase of plasminogen activator, and it is also seen in acquired situations such as amyloidosis, liver cirrhosis, disseminated intravascular coagulation (particularly in patients with acute promyelocytic leukemia) and thrombolytic therapy. The hemorrhagic tendency can be well controlled by an administration of an antifibrinolytic agent: epsilon-aminocaproic acid or tranexamic acid. In contrast to an accelerated fibrinolysis causing a hemorrhagic tendency, retarded fibrinolysis may predispose an individual to a thrombotic tendency. Retarded fibrinolysis may be due to either an increase in plasminogen activator inhibitors or decrease of plasminogen activators. Quantitative or qualitative deficiency of plasminogen may also lead to a thrombotic tendency.

Antifibrinolytic Agents↗

PubMed2001

Pharmacologic preservation of the hemostatic system during cardiac surgery.

Bleeding after cardiac surgery remains a major potential problem. Numerous pharmacologic approaches to attenuating hemostatic system activation in cardiac surgery patients have been studied to further improve patient management. Therapeutic approaches studied include inhibiting thrombin generation or activation, preserving platelet function, and decreasing the need for transfusion of allogeneic blood products. Pharmacologic approaches to reduce bleeding and transfusion requirements in cardiac surgery patients are based on either preventing or reversing the defects associated with the CPB-induced coagulopathy. The increasing use of platelet inhibitors (clopidogrel and IIb/IIIa receptor antagonists) and new anticoagulants (low-molecular weight heparins, pentasaccharide, recombinant hirudin, bivalirudin, and argatroban) also pose interesting problems in managing cardiac surgery patients. Aprotinin and lysine analogues (epsilon-aminocaproic acid and tranexamic acid) have become mainstay therapeutic agents to prevent bleeding and the potential need for allogeneic transfusion. Newer therapies that are important to consider include the potential of recombinant activated factor VIIa as a therapy for refractory bleeding after cardiac surgery.

Blood Loss, Surgical↗

PubMed1997

The human ENO1 gene product (recombinant human alpha-enolase) displays characteristics required for a plasminogen binding protein.

Plasminogen binds with low affinity in a lysine-dependent manner to many cell types. Previously, a 54 kDa plasminogen receptor found on the surface of U-937 cells was identified as an alpha-enolase-like molecule. The aims of this study were to determine whether recombinant alpha-enolase (r-alpha-enolase), encoded by ENO1, was a plasminogen binding protein and to generate polyclonal antibodies against this antigen. Plasminogen specifically bound r-alpha-enolase with a Kd 1.9 microM and approached saturation at 10 microM. Lysine-dependent plasminogen binding to r-alpha-enolase was demonstrated by a greater than 80% inhibition of binding by the lysine analogues epsilon-amino caproic acid and tranexamic acid, whilst only 14% inhibition occurred with the arginine analogue benzamidine. Removal of the C-terminal lysine residue of r-alpha-enolase with carboxy-peptidase B significantly reduced its plasminogen binding capacity, suggesting that binding required C-terminal lysine residue of r-alpha-enolase. Binding to r-alpha-enolase enhanced the activation rate of plasminogen by urokinase but prevented alpha 2-antiplasmin from binding plasminogen. Taken together, these data suggest that the gene product of human ENO1 encodes an authentic plasminogen binding protein.

Binding, Competitive↗

PubMed2001

Utilization of technologies to reduce allogeneic blood transfusion in the United States.

Concern over safety of the blood supply has led to the use of technologies to reduce allogeneic blood transfusion. The objective of this research was to determine the utilization of these technologies in the United States. We evaluated the following techniques: preoperative autologous donation (PAD), cell salvage (CS) and acute normovolemic haemodilution (ANH); and the following pharmaceuticals: aprotinin (APR), epsilon-aminocaproic acid (EACA), tranexamic acid (TXA), desmopressin (DDAVP) and recombinant human erythropoietin (EPO). In 1997, we conducted a cross-sectional mail survey of service chiefs at 1000 US hospitals randomly selected and stratified by status as a provider of open-heart surgery, geographical location and hospital bed size. Sixty-nine per cent (690) of hospitals responded to at least one of the four surveys sent to each hospital. Hospitals reported use of techniques more than pharmaceuticals (P < 0.001); PAD (83%, n = 206) and CS (82% n = 420) were used most frequently. Lack of familiarity was the most common reason cited for infrequent use of pharmaceuticals. Organizational characteristics (e.g. provision of open-heart surgery, size, geographical location, teaching status and type of hospital) were differentially associated with technology use. There is greater use of techniques than pharmaceuticals in US hospitals to reduce the need for allogeneic blood in the peri-operative setting. Providing open-heart surgery is strongly associated with the utilization of these technologies.

Biomedical Technology↗

PubMed1998

A risk-benefit assessment of aprotinin in cardiac surgical procedures.

Aprotinin, a naturally occurring serine protease inhibitor, has found widespread application during cardiac surgical procedures as a consequence of its ability to decrease blood loss and transfusion requirements. While its efficacy in a variety of clinical situations associated with increased risk of blood loss has been well established, at the same time, various complications including anaphylaxis, renal insufficiency, graft closure and arterial thromboses have been reported in association with aprotinin administration. In order to more fully evaluate the risks and benefits associated with aprotinin usage, this review first of all examines the hazards associated with transfusion of blood and blood products. Consideration is then given to various alternatives to allogeneic transfusion, including autologous predonation, acute normovolemic hemodilution, perioperative cell salvage and intraoperative plasma sequestration. A critique of other available pharmacological therapies, specifically desmopressin, aminocaproic acid and tranexamic acid, reviewing their modes of action, efficacy and associated complications, is then made. The role of aprotinin in cardiac surgery is then discussed and its pharmacology, including consideration of its antifibrinolytic, platelet preserving and anti-inflammatory effects is reviewed. Finally, an analysis of potential complications associated with aprotinin administration is undertaken. Issues involving its influence on specific measures of anticoagulation, namely partial thromboplastin time and activated clotting time, and issues relating to graft patency, hypothermic circulatory arrest, renal function, and allergic reactions are analysed and interpreted. In summary, this review concludes that most of the risks associated with aprotinin administration primarily involve inadequate anticoagulation and those of developing an allergic reaction, particularly upon aproptinin re-exposure. The benefits of aproptinin to decrease blood loss and transfusion requirements are confirmed, and there is evidence pointing to the intriguing possibility of a potential salutary effect on perioperative central nervous system complications.

Animals↗

PubMed2004

Avoidance of bleeding during surgery in patients receiving anticoagulant and/or antiplatelet therapy: pharmacokinetic and pharmacodynamic considerations.

Perioperative management of chronically anticoagulated patients and/or patients treated with antiplatelet therapy is a complex medical problem. This review considers the pharmacokinetic and pharmacodynamic properties of commonly used antiplatelet and anticoagulant drugs with special emphasis on loss of effects after discontinuation and possible counteracting (or antidote) strategies. These drugs are aspirin (acetylsalicylic acid), ticlopidine/clopidogrel, abciximab, tirofiban and eptifibatide, heparin (unfractionated and low-molecular-weight), warfarin and direct thrombin inhibitors. Since the pharmacological mechanisms of some of these drugs are based on irreversible or slowly reversible effects, their pharmacokinetic profiles are not necessarily predictive for their pharmacodynamic profiles. A close and direct relationship between plasma concentrations and effects is seen only for the glycoprotein (GP) IIb/IIIa inhibitors tirofiban and eptifibatide with a fast off-rate for dissociation from the GPIIb/IIIa receptor, and for direct thrombin inhibitors (hirudin and argatroban). For other compounds, drug concentrations in plasma and pharmacodynamic effects are not closely correlated because of, for example, irreversible binding to their target (aspirin, clopidogrel and abciximab), inhibition of the generation of a subset of clotting factors with differing regeneration and degradation rates (coumarins) or sustained binding to the vascular wall (heparins). Surgery in patients on anticoagulant and/or antiplatelet therapy may be categorised as: (i) elective versus urgent; and (ii) cardiopulmonary bypass (CPB) versus non-CPB. Monotherapy with clopidogrel or aspirin need not be discontinued in elective non-CPB surgery, and temporary discontinuation of warfarin should be accompanied by preoperative intravenous heparin only in selected high-risk patients. Vitamin K as an antidote for warfarin should only be used subcutaneously and solely in urgent/emergency surgery. In elective surgery requiring CPB (coronary artery bypass grafting), it is recommended to discontinue aspirin 7 days preoperatively in patients with a low risk profile. Patients requiring urgent CPB surgery (e.g. after failure of a percutaneous coronary angioplasty with or without coronary stent deployment) are usually pretreated with several antiplatelet agents (e.g. aspirin and clopidogrel, together with a GPIIb/IIIa inhibitor) together with unfractionated or low-molecular-weight heparin. With judicious planning, urgent/emergency cardiac surgery can be safely performed on these patients. Delaying surgery (e.g. for 12 hours in patients treated with abciximab) should be considered if possible. Standard heparin doses should be given to achieve optimal anticoagulation for CPB. Prophylactic use of aprotinin (intra- and/or postoperatively), aminocaproic acid or tranexamic acid should be considered. Early (in the operating theatre prior to chest closure) and judicious use of replacement blood products (platelets) should be commenced when clinically indicated.

Anticoagulants↗

PubMed1991

Haemostasis in oral surgery--the possible pathogenetic implications of oral fibrinolysis on bleeding. Experimental and clinical studies of the haemostatic balance in the oral cavity, with particular reference to patients with acquired and congenital defects of the coagulation system.

Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after oral surgery. Further investigations are necessary in order to clarify these aspects, and should include extensive laboratory analyses to reveal rare congenital defects such as factor XIII- and alpha 2-antiplasmin deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticoagulants↗

PubMed1991

Actin is a noncompetitive plasmin inhibitor.

Actin, one of the most abundant cellular proteins, circulates at micromolar concentrations in peripheral blood. Because actin released from dying cells may be trapped in fibrin clots that form at sites of tissue injury, we examined the effects of actin upon lysis of fibrin clots in vitro. Incorporation of native rabbit skeletal muscle actin into fibrin clots slowed their rates of lysis for periods of up to 24 h, an effect not seen when comparable concentrations of human IgG or bovine serum albumin were added instead. Actins isolated from a variety of sources inhibited plasmin's hydrolysis of the synthetic substrate S-2251 in a noncompetitive manner, with a Ki of a 0.6-3.1 microM. Inhibition was rapid, but covalent actin-plasmin complexes were not formed. Both epsilon-aminocaproic acid and tranexamic acid prevented actin's inhibition of plasmin, suggesting that accessible lysine residues of actin interact with the kringle (lysine-binding) regions of plasmin. Neither of the high-affinity actin-binding proteins of plasma (plasma gelsolin and vitamin D-binding protein) prevented actin from inhibiting plasmin. These findings suggest that actin released into the extracellular space following cell death may modulate plasmin action, and hence a number of plasmin-dependent biological responses, at sites of inflammation and tissue injury.

Actins↗

PubMed1984

The pathology of dysfunctional uterine bleeding.

The mechanism of dysfunctional uterine bleeding remains unknown. Recent studies suggest that the majority of cases of dysfunctional uterine bleeding are due to local endometrial, or myometrial, dysfunction. Changes in the pattern of production of prostaglandins PGE2, PGF2 alpha, prostacyclin and thromboxane and increased fibrinolytic activity in the endometrium have been implicated in this disorder. Successful treatment of excessive menstrual bleeding with the prostaglandin synthetase inhibitor mefenamic acid and the fibrinolytic inhibitors epsilon amino caproic acid and tranexamic acid further substantiates the role of prostaglandins and fibrinolysis in pathological menstruation. The relationship between uterine mast cells, heparin-like activity and menstrual bleeding still needs to be elucidated. Further studies are required to improve our understanding of the pathogenesis of dysfunctional uterine bleeding, so that advances can be made in a specific treatment to restore normal menstrual function.

Blood Platelets↗

PubMed1995

Complement component C7 is a plasminogen-binding protein.

Ab deposition, whether by reaction with the specific Ag or by preformed immune complexes, is followed by activation and deposition of complement components. Tissue destruction is observed in the Ab- and complement-induced lesions. The proteolytic enzyme plasmin is thought to participate in the Ab- and complement-mediated organ pathology. Plasmin is generated from plasma-derived plasminogen by cell-derived plasminogen activators (PAs). Two types of PAs are known, urokinase-type PA (uPA) and tissue-type PA (tPA). We investigated whether the PA system and the complement system can interact to promote local plasmin generation. Among the terminal complement components C5b6, C7, C8, and C9, the nonenzymatic component C7 is a plasminogen-binding protein. Radioligand binding studies revealed that the isolated component, as well as C7 after its incorporation into the terminal complement complex C5b-9, can bind plasminogen. Binding was inhibited by the lysine analogues 6-aminohexanoic acid and tranexamic acid, implicating the lysine binding sites of plasminogen into the binding interaction. tPA-mediated plasminogen activation was enhanced in the presence of C7. Based on these findings, an interaction is proposed between the complement system and the plasminogen activator system; a mechanism that may focus plasmin activity to structures that have been tagged by Ab and complement deposition.

Autoradiography↗

PubMed1997

Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene.

Plasminogen activator inhibitor-1 (PAI-1), the primary inhibitor of tissue- and urokinase-type plasminogen activators, is considered a critical regulator of the fibrinolytic system. We previously reported a child with abnormal bleeding and complete PAI-1 deficiency caused by a frame-shift mutation in exon 4 of the PAI-1 gene. The purpose of this study was to provide genetic and clinical data on the extended pedigree of the original proband to better define the phenotype associated with PAI-1 deficiency. Allele-specific oligonucleotide hybridization was used to genotype individuals, and serum PAI-1 antigen was measured by enzyme-linked immunosorbent assay. By this approach we have identified 19 individuals who are heterozygous for the PAI-1 null allele and 7 homozygous individuals with complete PAI-1 deficiency. Clinical manifestations of PAI-1 deficiency were restricted to abnormal bleeding, which was observed only after trauma or surgery in homozygous affected individuals. A spectrum of bleeding patterns was observed, including intracranial and joint bleeding after mild trauma, delayed surgical bleeding, severe menstrual bleeding, and frequent bruising. Fibrinolysis inhibitors, including epsilon-aminocaproic acid and tranexamic acid, were effective in treating and preventing bleeding episodes. Other than abnormal bleeding, no significant developmental or other abnormalities were observed in homozygous PAI-1-deficient individuals. Heterozygous PAI-1 deficiency was not associated with abnormal bleeding, even after trauma or surgery. These observations define the clinical spectrum of PAI-1 deficiency and provide additional evidence to support the hypothesis that the primary function of plasminogen activator inhibitor-1 in vivo is to regulate vascular fibrinolysis.

Adolescent↗

PubMed1997

Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. The International Study of Peri-operative Transfusion (ISPOT) Investigators.

UNLABELLED: Concern about the side effects of allogeneic red blood cell transfusion has increased interest in methods of minimizing perioperative transfusion. We performed meta-analyses of randomized trials evaluating the efficacy and safety of aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid in cardiac surgery. All identified randomized trials in cardiac surgery were included in the meta-analyses. The primary outcome was the proportion of patients who received at least one perioperative allogeneic red cell transfusion. Sixty studies were included in the meta-analyses. The largest number of patients (5808) was available for the meta-analysis of aprotinin, which significantly decreased exposure to allogeneic blood (odds ratio [OR] 0.31, 95% confidence interval [CI] 0.25-0.39; P < 0.0001). The efficacy of aprotinin was not significantly different regardless of the type of surgery (primary or reoperation), aspirin use, or reported transfusion threshold. The use of aprotinin was associated with a significant decrease in the need for reoperation because of bleeding (OR 0.44, 95% CI 0.27-0.73; P = 0.001). Desmopressin was not effective, with an OR of 0.98 (95% CI 0.64-1.50; P = 0.92). Tranexamic acid significantly decreased the proportion of patients transfused (OR 0.50, 95% CI 0.34-0.76; P = 0.0009). Epsilon-aminocaproic acid did not have a statistically significant effect on the proportion of patients transfused (OR 0.20, 95% CI 0.04-1.12; P = 0.07). There were not enough patients to exclude a small but clinically important increase in myocardial infarction or other side effects for any of the medications. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the number of patients exposed to perioperative allogeneic transfusions in association with cardiac surgery. IMPLICATIONS: Aprotinin, desmopressin, tranexamic acid, and epsilon-aminocaproic acid are used in cardiac surgery in an attempt to decrease the proportion of patients requiring blood transfusion. This meta-analysis of all published randomized trials provides a good estimate of the efficacy of these medications and is useful in guiding clinical practice. We conclude that aprotinin and tranexamic acid, but not desmopressin, decrease the exposure of patients to allogeneic blood transfusion perioperatively in relationship to cardiac surgery.

Aminocaproic Acid↗

PubMed1985

Source of fibrin/fibrinogen degradation products in the CSF after subarachnoid hemorrhage.

In 48 patients with a subarachnoid hemorrhage, levels of fibrin/fibrinogen degradation products (FDP's), total protein, and plasminogen were measured in the cerebrospinal fluid (CSF) between Days 9 and 15 after the bleed. Of these 48 patients, 22 received tranexamic acid. Despite a significant reduction in the incidence of rebleeding in patients taking tranexamic acid, no difference in FDP levels was found between patients receiving tranexamic acid and a control group of patients who were not; nor was any relationship evident between FDP levels and rebleeding. In patients with detectable levels of FDP's, CSF protein and plasminogen values were also increased, and FDP's were found more frequently in the CSF of patients with an impaired level of consciousness or with a neurological deficit. These findings suggest that in the 2nd week after subarachnoid hemorrhage, the presence of FDP's in the CSF reflects a damaged blood-CSF barrier rather than ongoing local fibrinolysis in the subarachnoid space. A finding of FDP's in the CSF is, therefore, an unreliable monitor of antifibrinolytic treatment in subarachnoid hemorrhage and cannot be used for selecting patients at high risk of rebleeding.

Blood Physiological Phenomena↗

PubMed1995

Differential inhibition with antifibrinolytic agents of staphylokinase and streptokinase induced clot lysis.

The inhibitory effects of antifibrinolytic amino acids on clot lysis induced with recombinant staphylokinase (SakSTAR) or with streptokinase (SK) were evaluated in a human plasma milieu in vitro and in a hamster pulmonary embolism model in vivo. Addition of tranexamic acid to a system composed of 60 microliters 125I-fibrin-labeled plasma clots submerged in 0.5 ml human plasma, caused dose-dependent inhibition of lysis; complete lysis in 120 min required 30 nM SakSTAR or 100 nM SK and was reduced to 50% with 0.015 mM or with 0.07 mM tranexamic acid, respectively. Aprotinin also produced dose-dependent inhibition; lysis with SakSTAR or with SK was reduced to 50% of the control value with 8 KIU/ml or with 10 KIU/ml aprotinin, respectively. Thus, in human plasma in vitro the antifibrinolytic potency of tranexamic acid was 5-fold higher towards SakSTAR than towards SK, whereas that of aprotinin was comparable towards both agents. In hamsters with pulmonary embolism given 0.063 mg/kg SakSTAR or 0.20 mg/kg SK over 30 min, the antifibrinolytic potency of tranexamic acid, administered as a single bolus injection or as a bolus injection followed by continuous infusion, was 8- to 10-fold higher towards SakSTAR than toward SK (50% reduction of clot lysis with SakSTAR at 12.5 mg/kg, as compared to 100-150 mg/kg with SK). In contrast, aprotinin was equipotent towards SakSTAR and SK (50% reduction of clot lysis with 2,000 to 2,700 KIU/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1992

The effect of warm heart surgery on postoperative bleeding.

The effects of normothermic systemic perfusion (35 degrees to 37 degrees C; n = 73) were compared with those of moderately hypothermic systemic perfusion (25 degrees to 29 degrees C; n = 73) with respect to blood loss, transfusion requirements, and platelet levels in 146 patients undergoing isolated, primary coronary artery bypass grafting. In addition, most patients were given an antifibrinolytic medication during operation as follows: tranexamic acid (10 gm intravenously; n = 63), epsilon-aminocaproic acid (15 gm intravenously; n = 63), or no drug as a control. (n = 20). Normothermic patients tended to bleed less at 24 hours (warm, 864 +/- 42 ml and cold, 918 +/- 68 ml), but these differences were not statistically significant. Patients receiving either tranexamic acid or epsilon-aminocaproic acid, regardless of perfusion temperature, bled less after 6, 12, and 24 hours than did cold control patients (p less than 0.05). Warm control patients also bled less than did cold control patients after 6 or 12 hours (p less than 0.05), and neither drug further reduced blood loss in these patients. Circulating platelet levels were better preserved in patients receiving either tranexamic acid or epsilon-aminocaproic acid and in patients with warm perfusion and no drug than in cold control patients. Normothermic systemic perfusion, tranexamic acid, and epsilon-aminocaproic acid each reduced postoperative blood loss and preserved platelets.

Aminocaproic Acid↗

PubMed1985

Monitoring of antifibrinolytic treatment in subarachnoid hemorrhage.

21 patients (aged 28-81 years) with recent subarachnoid hemorrhage (10 saccular aneurysms, 3 arteriovenous angiomas, 8 normal angiograms) were continuously infused with tranexamic acid at a dosage of 5 g daily for up to 14 days. Therapy was surveyed by daily measurement of the available plasminogen activity (aPl) with the chromogenic substrate S-2251 and by a modified bioassay, whereby the concentration of tranexamic acid was determined thrombelastographically and expressed as antifibrinolytic equivalent. In addition, a battery of blood coagulation tests was performed daily. 5 patients died, 1 after postoperative stroke, 3 as a result of general complications during intensive care treatment, but only 1 due to rebleeding. 4 patients were successfully operated during the first week, 1 patient after 2 weeks. aPl fell from 99.2% (SEM 3.0%, n = 21) before treatment to 72.9% (SEM 3.5%, n = 21) after 24 h and to the therapeutic level between 50 and 60% from day 2 on. The mean steady state of the antifibrinolytic equivalent corresponded to about 150 micrograms/ml of tranexamic acid during infusion. Intra- and interindividual changes were relatively small for aPl, when compared with the antifibrinolytic equivalent measured by the bioassay. In 2 elderly patients tranexamic acid infusion had to be terminated because of clinical and laboratory signs of disseminated intravascular coagulation, whereby aPl fell below the therapeutic range, elucidating that this method is a sensitive indicator for a hypercoagulable state and useful for the surveillance of therapy with antifibrinoltic agents.

Adult↗

PubMed2000

Nonsteroidal anti-inflammatory drugs for heavy menstrual bleeding.

BACKGROUND: Heavy menstrual bleeding is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Nonsteroidal anti-inflammatory drugs or prostaglandin synthetase inhibitors reduce prostaglandin levels which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. OBJECTIVES: The primary objective of this review was to investigate the effectiveness of non-steroidal anti-inflammatory drugs (NSAIDs) in achieving a reduction in menstrual blood loss in women of reproductive years with heavy menstrual bleeding (HMB). SEARCH STRATEGY: Electronic searches for relevant randomised controlled trials of the Cochrane Menstrual Disorders and Subfertility Group Register of Trials, MEDLINE, EMBASE, PsychLIT, Current Contents, Biological Abstracts, Social Sciences Index and CINAHL were performed. Attempts were also made to identify trials from citation lists of review articles and drug companies were approached for unpublished data. In most cases, the first author of each included trial was contacted for additional information. SELECTION CRITERIA: The inclusion criteria were randomised comparisons of individual NSAIDs with either each other, placebo or other medical treatments in women of reproductive years with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment induced) causes for their heavy menstrual blood loss. DATA COLLECTION AND ANALYSIS: Sixteen RCTs were identified that fulfilled the inclusion criteria for this review. The reviewers extracted the data independently and odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data of nine trials. The remaining seven trials were of crossover design with data unsuitable for pooling and their individual results were described in text form. MAIN RESULTS: As a group, NSAIDs were more effective than placebo at reducing heavy menstrual bleeding but less effective than either tranexamic acid or danazol. Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs but this did not appear to affect the acceptability of treatment. There was a non significant trend towards greater efficacy of NSAIDs compared to oral progestogen (luteal phase) and ethamsylate but no differences were demonstrated between NSAIDs and the progesterone releasing intra-uterine system (IUS) and the oral contraceptive pill, although these results were based on very small studies. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. REVIEWER'S CONCLUSIONS: NSAIDs reduce heavy menstrual bleeding when compared with placebo but are less effective than either tranexamic acid or danazol. However, adverse events are more severe with danazol therapy. In the limited number of small scale studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral progestogen given in the luteal phase, ethamsylate, oral contraceptive pill and the progesterone releasing IUS.

Anti-Inflammatory Agents, Non-Steroidal↗