Tranexamic acid--an old drug still going strong and making a revival.

Experience with tranexamic acid, an indirect fibrinolytic inhibitor, started as soon as it was released from Shosuke Okamoto's lab in the early 1960s. It was first prescribed to females with heavy menstrual blood loss and to patients with hereditary bleeding disorders. Soon the indications were widened to elective surgery because of its blood saving effects. Contraindications are few, most important is ongoing venous or arterial thrombosis and allergy to tranexamic acid, and the doses has to be reduced in renal insufficiency. In randomized controlled trials, however, patients with other risk factors are excluded as well (patients with history of cardiovascular disease, thromboembolism, bleeding diathesis, renal failure with creatinine >250µmol/L, pregnancy, and patients on treatment with anticoagulants). Recent meta-analyses of several randomized controlled trials in orthopedic arthroplasty have shown that tranexamic acid reduces peri- and postoperative blood loss, blood transfusion requirements and reoperations caused by bleedings. In general, the preoperative dose was 10-15mg/kg i.v. (or 1g), followed or not, by one or two doses, some as continuous infusion i.v. To validate relationship between dose and effect more data are needed. No evidence was found of increased thromboembolic accidents or other adverse events in the patients on tranexamic acid compared to the control groups. In major cardiac surgery tranexamic acid has been used in a large number of controlled trials with various dosing schemes in which the highest dosages seem to be associated with neurotoxicity; therefore a maximum total dose of 100mg/kg especially in patients over 50years of age is recommended by ISMICS (International Society for Minimally Invasive Cardiothoracic Surgery). Other indications for tranexamic acid are reviewed here as well. In recent years the extensive trial in severe trauma with massive bleedings using tranexamic acid was presented, CRASH-2 (Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage) comprising more than 20,000 patients. It showed that the survival was increased when tranexamic acid was given early after the accident compared to placebo; further studies are taking place is this field to get more information. Of utmost importance is the ongoing WOMAN (World Maternal Antifibrinolytic) a randomized, double-blind, placebo controlled trial among 15,000 with clinical diagnosis of postpartum haemorrhage bearing in mind that each year a large number of women in low and middle income countries, die from causes related to childbirth. In summary, we consider tranexamic acid is a drug of great value to reduce almost any kind of bleeding, it is cheap and convenient to use and has principally few contraindications. It may be added, that tranexamic acid is included in the WHOs list of essential medicines.

Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry.

Acquired hemophilia A is a rare bleeding disorder caused by autoantibodies to coagulation FVIII. Bleeding episodes at presentation are spontaneous and severe in most cases. Optimal hemostatic therapy is controversial, and available data are from observational and retrospective studies only. The EACH2 registry, a multicenter, pan-European, Web-based database, reports current patient management. The aim was to assess the control of first bleeding episodes treated with a bypassing agent (rFVIIa or aPCC), FVIII, or DDAVP among 501 registered patients. Of 482 patients with one or more bleeding episodes, 144 (30%) received no treatment for bleeding; 31 were treated with symptomatic therapy only. Among 307 patients treated with a first-line hemostatic agent, 174 (56.7%) received rFVIIa, 63 (20.5%) aPCC, 56 (18.2%) FVIII, and 14 (4.6%) DDAVP. Bleeding was controlled in 269 of 338 (79.6%) patients treated with a first-line hemostatic agent or ancillary therapy alone. Propensity score matching was applied to allow unbiased comparison between treatment groups. Bleeding control was significantly higher in patients treated with bypassing agents versus FVIII/DDAVP (93.3% vs 68.3%; P = .003). Bleeding control was similar between rFVIIa and aPCC (93.0%; P = 1). Thrombotic events were reported in 3.6% of treated patients with a similar incidence between rFVIIa (2.9%) and aPCC (4.8%).

Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2).

Acquired hemophilia A (AHA) is an autoimmune disease caused by an autoantibody to factor VIII. Patients are at risk of severe and fatal hemorrhage until the inhibitor is eradicated, and guidelines recommend immunosuppression as soon as the diagnosis has been made. The optimal immunosuppressive regimen is unclear; therefore, data from 331 patients entered into the prospective EACH2 registry were analyzed. Steroids combined with cyclophosphamide resulted in more stable complete remission (70%), defined as inhibitor undetectable, factor VIII more than 70 IU/dL and immunosuppression stopped, than steroids alone (48%) or rituximab-based regimens (59%). Propensity score-matched analysis controlling for age, sex, factor VIII level, inhibitor titer, and underlying etiology confirmed that stable remission was more likely with steroids and cyclophosphamide than steroids alone (odds ratio = 3.25; 95% CI, 1.51-6.96; P < .003). The median time to complete remission was approximately 5 weeks for steroids with or without cyclophosphamide; rituximab-based regimens required approximately twice as long. Immunoglobulin administration did not improve outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy. Outcome was not affected by the choice of first-line therapy. The likelihood of achieving stable remission was not affected by underlying etiology but was influenced by the presenting inhibitor titer and FVIII level.

Lack of very strong association between pre-treatment fibrinogen and PAI-1 with long-term mortality after coronary bypass surgery.

AIM: To explore the association between the coagulation protein fibrinogen and the fibrinolytic biomarker plasminogen activator inhibitor-1 (PAI-1) and the long-term mortality after coronary artery bypass grafting (CABG). PATIENTS AND METHODS: In 729 patients undergoing CABG at Sahlgrenska University Hospital, a blood sample for fibrinogen and PAI-1 was collected prior to the procedure. Patients were followed for 10 years. RESULTS: Among patients with high levels of fibrinogen (>3.6 g/l; median), the 10-year mortality was 32.3 vs. 20.7% among patients with fibrinogen levels below the median (p = 0.0005). However, patients with higher levels of fibrinogen were older and had an adverse risk factor pattern. When adjusting for these differences, pre-operative fibrinogen levels did not clearly appear as an independent predictor of long-term mortality. The 10-year mortality was similar in patients with high (25.3%) and low (26.5%) levels of PAI-1. CONCLUSION: Our results do not suggest that fibrinogen and PAI-1, when evaluated prior to the operative procedure, are strongly associated with increased mortality in the long-term after CABG, when other co-morbidity factors are simultaneously considered.

Serum from patients with chronic idiopathic thrombocytopenic purpura frequently affect the platelet function.

In most, but not all, cases of chronic idiopathic thrombocytopenic purpura (ITP), bleeding complications are known to occur when the platelet count is low. The present study investigates the effect of ITP sera on the in vitro platelet function of donor platelets. Sera from 58 ITP patients were investigated. Using an indirect monoclonal antibody specific immobilisation of platelet antigen (MAIPA) technique, GPIIb/IIIa and GPIb/IX specific antibodies were found in 23 and 20 patients, respectively. Twelve of them had antibodies against both glycoprotein (GP) complexes. The ITP sera's effect on donor platelets was investigated by aggregometry and the results were compared with the ones of 26 healthy donor sera. Grouped together, the ITP sera significantly impaired the ADP-induced platelet aggregation of donor platelets compared to the control sera; the mean relative aggregation response (T(max)) seen for the ITP and control sera were 82 +/- 21% and 92 +/- 7%, respectively (p = 0.0157). However, 6 ITP sera gave an enhanced aggregation response, whereas 17 ITP sera resulted in an impaired platelet aggregation, when using the mean +/- 2 S.D. recorded for the controls as the normal range. There was not any correlation between aggregation response, platelet number or the presence of GPIb/IX or GPIIb/IIIa specific antibodies, other than the fact that all ITP sera causing an enhanced aggregation were from patients with a platelet number less then 100 x 10(9)/l at the time of blood sampling. It is concluded that some ITP sera can either enhance or impair the platelet aggregation response, but in most cases, a normal response is obtained.