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Surgical repair of congenital diaphragmatic hernia during extracorporeal membrane oxygenation: hemorrhagic complications and the effect of tranexamic acid.

Extracorporeal membrane oxygenation (ECMO) was incorporated in a strategy of delayed repair of congenital diaphragmatic hernia (CDH) and was used for preoperative stabilization in patients who were unresponsive to maximal conventional treatment. If ECMO was required for preoperative stabilization the diaphragmatic defect was repaired while the patient was on ECMO. In the early experience with this approach all patients suffered from bleeding complications. Therefore, we adopted the use of antifibrinolytic therapy with tranexamic acid (TEA) during and immediately after CDH repair on ECMO. The efficacy of TEA was studied in an unblinded study using historical controls by comparing the postoperative blood loss and the transfusion requirements of red blood cells (RBC) in patient groups treated without (n = 9) and with TEA (n = 10). Patients who received TEA had significantly less bleeding at the surgical site than patients not receiving TEA (57 v 390 mL, P = .005) and had significantly lower RBC transfusion requirements than patients not receiving TEA (1.13 v 2.95 mL/kg/h, P = .03). In the very first two patients of the TEA group we encountered fairly severe thrombotic complications. TEA may have contributed to those complications. Based on the authors' experience they conclude: (1) TEA is effective in reducing postoperative blood loss, hemorrhagic complications, and RBC transfusion requirements associated with CDH repair on ECMO. (2) TEA may be responsible for thrombotic complications. (3) The appropriate, empirically established, dosage and administration patterns of TEA for CDH repair during ECMO seem to be one bolus of 4 mg/kg TEA intravenously 30 minutes before the anticipated CDH repair and a continuous infusion of 1 mg/kg/h TEA during the 24 hours after CDH repair.

Antifibrinolytic Agents↗

Oral nimodipine reduces prostaglandin and thromboxane production by arteries chronically exposed to a periarterial haematoma and the antifibrinolytic agent tranexamic acid.

The calcium antagonist nimodipine blocks the effects of many vasoconstrictors of cerebrovascular smooth muscle and may reduce the incidence of delayed cerebral ischaemia following subarachnoid haemorrhage though not necessarily by inhibiting the development of angiographic cerebral vasospasm. Post-haemorrhagic CSF contains abnormally large quantities of various eicosanoids that partly reflect enhanced production by cerebral arteries. Does nimodipine affect this process? The extra-arterial and intra-arterial production of PG6 keto-F1 alpha, PGE2, PGF2 alpha and TXB2 were measured in perfused common carotid arteries taken from rabbits in which the arteries had been ensheathed by blood clot in vivo for 7 days. All rabbits were given the antifibrinolytic agent tranexamic acid to retard resolution of the clot, and half were given oral nimodipine (2 mg/kg/day) for 10 days. Nimodipine significantly reduced the extra-arterial production of TXB2 during the third and fourth hours of perfusion and, less consistently, the production of PGF2 alpha, PGE2 and PG6 keto-F1 alpha. Lutrol, the solvent for nimodipine, had no such effect.

6-Ketoprostaglandin F1 alpha↗

Influence of combined neural blockade, H1- and H2-receptor and serotonin2-receptor blockade, indomethacin and tranexamic acid on leucocyte, temperature and acute-phase protein response to surgery.

Body temperature, P-cortisol, P-glucose, P-transferrin, P-orosomucoid, P-IgM, hematocrit and total and differential leucocyte counts were investigated in 16 men undergoing inguinal herniotomy. The patients were randomized to epidural analgesia (n = 8) or epidural analgesia + assumed blockade of prostaglandin synthesis, blockade of receptors for histamine1, histamine2 and serotonin2, and inhibition of fibrinolysis with indomethacin, astemizole, ranitidine, ketanserin and tranexamic acid, respectively (n = 8). The rectal temperature and blood granulocyte counts rose significantly and similarly after surgery in both groups. Acute-phase protein (transferrin and orosomucoid) changes were also similar in both groups, as were P-cortisol and P-glucose, which did not increase in response to the neural blockade. Other factors than neural stimuli, prostaglandins, histamine, serotonin and activation of fibrinolysis are concluded to be effective in releasing postoperative leucocytosis, rise in body temperature and changes in acute-phase proteins.

Acute-Phase Proteins↗

A comparative study of the postoperative allogeneic blood-sparing effects of tranexamic acid and of desmopressin after total knee replacement.

BACKGROUND: Tissue hypoxia and reperfusion induce abnormal hemostatic function. Therefore, bleeding after total knee replacement (TKR) may be a result of a tourniquet-induced imbalance of the procoagulant and fibrinolytic systems. Because laboratory confirmation of tourniquet-induced abnormal hemostasis is difficult to obtain, indirect evidence must be sought. STUDY DESIGN AND METHODS: A prospective, single-blind study of 40 patients undergoing TKR was performed. In the tranexamic acid (TA) group, in the 30 minutes before the limb tourniquet was deflated, an IV bolus dose of TA (15 mg/kg) was administered. Thereafter, a constant IV infusion of 10 mg per kg per hour was administered until 12 hours after tourniquet deflation. In the desmopressin group, desmopressin (0.3 mg/kg) and saline were administered by a similar protocol. No blood was administered intraoperatively. A postoperative Hct <27 percent constituted the postoperative transfusion trigger. Patients were examined daily for signs of lower-limb deep vein thrombosis, and they underwent lower-limb Doppler ultrasound on postoperative Day 5. Three months after surgery, the incidence of delayed thromboembolic events was assessed. RESULTS: During the first 12 postoperative hours, blood accumulation in the surgical drain was significantly (p<0.05) lower in the TA group (162 mL +/- 129) than in the desmopressin group (342 mL +/- 169). From the sixth postoperative hour until 3 days postoperatively, Hct levels were significantly lower in the desmopressin group than in the TA group. Significantly more allogeneic blood was transfused in the desmopressin group (11 patients received 16 units) than in the TA group (3 patients each received 1 unit) (p<0.02). There were no clinical signs of deep vein thrombosis or abnormal Doppler ultrasound studies. Three months postoperatively, there were no thromboembolic events among the 37 patients interviewed. CONCLUSION: TA induces better blood sparing than desmopressin. Therefore, a tourniquet-induced increase in fibrinolysis is the likely cause of delayed bleeding after TKR surgery. However, before routine administration, the effect of TA on the incidence of thromboembolic events requires further investigation.

Aged↗

The effect of long-term, low-dose tranexamic acid treatment on platelet dysfunction and haemoglobin levels in haemodialysis patients.

Some previous studies suggest that activation of the fibrinolytic system may induce platelet dysfunction in haemodialysis patients. Accordingly, inhibition of fibrinolysis may improve platelet dysfunction, and speculatively increase haemoglobin levels. We tested this hypothesis. The study group comprised 22 patients (14 male, 8 female, median age 62), who had been on maintenance haemodialysis for more than one year. Patients were treated for three months with low-dose tranexamic acid (TXA), a potent anti-fibrinolytic agent. The dosages of erythropoietin and the haemodialysis procedure were not changed significantly during the study. We primarily followed platelet function (by in vitro closure time test) and haemoglobin values. Patients were divided into those with substantially prolonged (N = 9) and those with slightly delayed or normal (N = 13) in vitro closure time. Treatment with TXA resulted in a significant improvement of platelet function and increased levels of haemoglobin in the first group, and no changes in either platelet function or haemoglobin values in the second group. TXA in the dosage used was biologically active, since a significant decrease in plasminogen and D-dimer were found in both groups. No significant changes in other fibrinolytic parameters or von Willebrand factor were found. No complications in terms of arterial or venous thrombosis were observed. Our pilot study suggests that long-term, low-dose TXA treatment of haemodialysis patients with substantially prolonged in vitro closure time results in a significant improvement of platelet dysfunction and a significant increase in haemoglobin values. These new, promising results merit further investigation in larger studies.

Aged↗

Effect of combined therapy of danaparoid sodium and tranexamic acid on chronic disseminated intravascular coagulation associated with abdominal aortic aneurysm.

Chronic disseminated intravascular coagulation (DIC) is a well-known complication of aortic aneurysm. A 63-year-old man with bleeding tendency and a large palpable abdominal aortic aneurysm (AAA) was diagnosed as having fibrinolysis dominant DIC by the excessive activation of both coagulation and fibrinolysis (plasmin -alpha2 plasmin inhibitor complex concentration is usually >4 microg/ml). Although several treatments were tried, DIC could not be controlled until the patient was given combined therapy of danaparoid (1,250 U/12 h, bolus IV) and tranexamic acid (0.5 g x 3/day, oral administration). This therapy may be beneficial when control for bleeding is required without restricting the ambulatory movement of patients by continuous drip.

Anticoagulants↗

Comparison of the effects of aprotinin and tranexamic acid on blood loss and red blood cell transfusion requirements during the late stages of liver transplantation.

BACKGROUND: During liver transplantation (LT), profound activation of the fibrinolytic system can contribute significantly to perioperative bleeding. Prophylactic administration of antifibrinolytic agents has been shown to reduce blood loss and the need for allogeneic transfusion in these conditions. STUDY DESIGN AND METHODS: This prospective randomized trial included 51 cirrhotic patients undergoing LT. Patients were randomly assigned to receive either 280 mg of aprotinin (AP) followed by 70 mg per hour or 40 mg per kg tranexamic acid (TA) followed by 40 mg per kg per hour, administered from the end of the anhepatic phase until 2 hours after reperfusion of the graft, and the effects on blood loss and red blood cell (RBC) transfusion requirements were compared. Transfusion policy was standardized in all patients. In addition, the biological effects of the two drugs, as assessed by coagulation and fibrinolytic markers obtained during surgery, were evaluated in a subgroup of patients from each treatment group and compared with an historical control group that did not receive antifibrinolytic drugs. RESULTS: There was no significant difference between the two groups in perioperative blood losses (AP, 6200 [4620-8735] mL; TA, 5945 [4495-8527] mL; median [range]) or in RBC transfusions requirements (AP, 9 [6.75-15.25] units; TA, 10 [6.5-13.5] units). Inhibition of fibrinolysis was observed with both drugs compared with the control group. Coagulation appeared to be activated more with AP, however, whereas fibrinolysis was inhibited more by TA. CONCLUSION: Blood losses and RBC transfusion requirements were comparable regardless of the drug administered. TA may be as valuable as AP for controlling fibrinolysis in LT.

Adult↗

[Tranexamic acid reduces blood loss and the need of blood transfusion after knee arthroplasty].

Already, four relevant prospective, randomised studies have shown a reduction of about 50% in both the postoperative blood loss and the need for blood transfusion on the first postoperative day in patients who received prophylactic TXA when operated on for a total knee replacement. The initial dose should be given about 10-15 minutes before the tourniquet is released, the reason being that the incidence of DVT at this time has not been sufficiently documented when TXA is given before the tourniquet is applied. In these studies, increased incidence of DVT has not been found in the TXA group, although the patients were only examined clinically. The best effect is thought to be accomplished with a bolus of 10-15 mg/kg, eventually repeated every 6-8 hours during the first postoperative day. A repeat dose, however, seems to decrease the total postoperative blood loss only marginally. Tranexamic acid reduces postoperative bleeding and the need for transfusion during knee replacement.

Antifibrinolytic Agents↗

Comparison of tranexamic acid and prednisolone in the treatment of traumatic hyphema. A randomized clinical trial.

OBJECTIVE: Oral antifibrinolytics, oral steroids, and no oral treatment are the preferred medical treatments for traumatic hyphema. Antifibrinolytics and steroids have decreased the chance of rebleeding in some studies but failed to alter the clinical course in others. Rate of secondary hemorrhage seems variable among different geographic and ethnic groups of patients. Comparison of the treatments in each population is necessary to document the most effective method of preventing recurrent hemorrhage. DESIGN: Randomized, placebo-controlled, clinical trial. PARTICIPANTS: Two hundred thirty-eight patients in whom hyphema developed after a blunt trauma entered the study. INTERVENTION: Eighty patients received 75 mg/kg per day oral tranexamic acid (TA) divided into 3 doses, 80 patients received a placebo with the same number of tablets and frequency as those of the TA group, and 78 patients received 0.75 mg/kg per day oral prednisolone divided into 2 doses. MAIN OUTCOME MEASURE: Secondary hemorrhage during the hospital course was measured. RESULTS: Secondary hemorrhage occurred in 8 patients (10%) of the TA group, 14 patients (18%) of the prednisolone group, and 21 patients (26%) of the placebo group. The difference between the incidence of rebleeding between TA and placebo groups was statistically significant (P = 0.008). Patients receiving a placebo had a greater chance of secondary bleeding than did patients receiving TA (odds ratios = 3.2; 95% confidence interval = 1.3, 7.5). The incidences of rebleeding were not significantly different in placebo versus prednisolone groups (P = 0.21) and TA versus prednisolone groups (P = 0.15). CONCLUSION: In a population with a high rate of secondary bleeding, TA is more effective than oral prednisolone or no oral treatment in preventing rebleeding among patients with traumatic hyphema.

Administration, Oral↗

Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid.

C1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗

Determination of a prodrug of tranexamic acid in whole blood by reversed-phase liquid chromatography after pre-column derivatization with fluorescamine.

A sensitive high-performance liquid chromatographic (HPLC) method for a prodrug of tranexamic acid (KABI 2161) in whole blood is described. Since KABI 2161 is rapidly hydrolysed in whole blood the samples are collected directly into the extraction tubes and extracted immediately. After pre-column derivatization with fluorescamine the derivatives are analysed by reversed-phase liquid chromatography on a C(8)-Nucleosil column using an eluent mixture of phosphate buffer and acetonitrile (pH 3). The eluent is monitored by a fluorescence detector. Determinations as low as 10 ng ml(-1) of KABI 2161 in whole blood can be made when 0.5 ml blood is analysed. The precision of the method is 4.1% (RSD) at the 300 ng ml(-1) level and 6.9% (RSD) at the 50 ng ml(-1) level.

Journal Article↗