Temporal changes in clot lysis and clot stability following tranexamic acid in cardiac surgery.

: Cardiac surgery induces a multifactorial coagulopathy. Regular use of tranexamic acid (TXA) is becoming standard of care. Clinical challenges include selecting optimal dosing regimen and balancing the benefit versus risk of additional dosing with antifibrinolytics. The objective was to evaluate the effect of TXA by assessing kinetic properties of plasma clot formation, clot stability, and clot fibrinolysis. The study was a prospective case follow-up of 28 patients undergoing cardiac surgery (mean age 63.9 years, 29% women). Blood samples were analysed at seven time points during the first 48 h after surgery. All patients were treated with TXA, 2 g at start surgery, 1 g during extra corporeal circulation, and 1 g after reversal of heparin. An automated clot lysis assay using tissue factor and tissue plasminogen activator (tPA) was performed to evaluate clot formation, stability, and fibrinolysis. TXA protects against facilitated fibrinolysis and induces up to 13-fold increase in clot stability. All patients showed complete resistance to tPA-induced fibrinolysis during the first 6 h after cardiac surgery declining to 33% of patients at 48 h. Impaired renal function was associated with prolonged resistance to tPA-induced fibrinolysis. Despite inhibition of fibrinolysis with TXA, the overall clot stability declines and the kinetic properties of clot formation were impaired after cardiac surgery. TXA induces a multifold increase in clot resistance to fibrinolysis but does not affect clot formation or clot stability. Monitoring the level of resistance to fibrinolysis may prevent overdosing in particular in patients with impaired renal function.

An in-vitro assessment of tranexamic acid as an adjunct to rFVIII or rFVIIa treatment in haemophilia A.

Haemophilia is characterised by defective thrombin generation, reduced clot stability and spontaneous bleeding. Treatment with factor VIII (FVIII) concentrate or bypassing agents (e.g. recombinant factor VIIa (rFVIIa)) is generally effective. Occasionally, haemostasis is not achieved, which may reflect a failure of factor concentrate to normalise clot stability. Tranexamic acid (TXA) is often used to aid haemostasis in surgery (e.g. joint replacements and dental procedures). Used routinely as an adjunct, it may enhance clot stability and allow effective, reliable, and cost-effective treatment at lower doses of factor concentrate. This study hypothesised that clot stabilising adjunct TXA is required in addition to factor substitution to normalise clot stability in whole blood from patients with severe haemophilia A. The in vitro effect of varying concentrations of recombinant FVIII or recombinant FVIIa and adjunct TXA on whole blood clot stability was measured by thromboelastometry. Coagulation was triggered by tissue factor and clots were challenged with tissue plasminogen activator. The area under the elasticity curve was the primary endpoint. High concentrations of FVIII and rFVIIa increased clot stability to levels that were not significantly different from controls (Mean ± SD: control 112,694 ± 84,115; FVIII 78,662 ± 74,126; rFVIIa 95,918 ± 88,492). However, the response was highly variable between individuals and demonstrates why some patients show clinical resistance to treatment. Addition of TXA resulted in normalised clot stability in all individuals, even when combined with the lowest doses of factor concentrate. The results support the concept that a more efficient, reliable and cost effective treatment may be obtained if TXA is combined with factor concentrates to treat individuals with haemophilia.

Experience with pegylated interferon α-2a in advanced myeloproliferative neoplasms in an international cohort of 118 patients.

The Philadelphia negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are associated with substantial vascular and transformative complications. Standard therapy for high-risk disease, particularly in patients that have failed initial therapy, remains controversial. Non-pegylated interferon has previously been shown to be effective in controlling erythrocytosis, thrombocytosis and thrombotic complications, but was found to have poor tolerability and excessive adverse effects. Recently, pegylated interferon alpha-2a was introduced and found to be better tolerated and less toxic than standard interferon. In addition, in recent phase II trials, pegylated interferon alpha-2a therapy was found to induce both hematologic and molecular remissions. We retrospectively analyzed 118 myeloproliferative patients who underwent pegylated interferon alpha-2a treatment. Responses were evaluated by ELN, IWG-MET and EUMNET standardized criteria sets and adverse effects were analyzed.

Fibrinogen as a hemostatic agent.

Coagulation factor I (fibrinogen) plays an essential role in the hemostatic system by bridging activated platelets and being the key substrate for thrombin in establishing a consolidating fibrin network. Fibrinogen is synthesized in the liver and the plasma concentration is 1 to 5-4.0 g/L. During recent 10 years, fibrinogen has been recognized to play an important role in controlling hemorrhage. Dilutional coagulopathy induced by colloid plasma expanders is characterized by fibrinogen deficiency and dysfunctional fibrin polymerization. Trauma and use of extracorporeal circulation is also known to reduce levels of fibrinogen. A series of laboratory experiments and experimental animal studies have suggested fibrinogen as a potent hemostatic agent. These data are supported by retrospective surveys as well as a series of prospective proof of principal clinical trials. This article provides a description of the biochemistry and mechanisms of fibrinogen as well as the etiology for developing fibrinogen deficiency. Furthermore, it summarizes laboratory and experimental data on the role of fibrinogen in dilutional coagulopathy and addresses laboratory monitoring issues. Finally, it lists retrospective and prospective studies, which have been designed to assess the clinical efficacy and safety of hemostatic intervention with fibrinogen concentrate.

Solulin increases clot stability in whole blood from humans and dogs with hemophilia.

Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)-deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor-initiated fibrin formation and tissue-plasminogen activator-induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/µM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses.

The role of fibrinogen: a new paradigm in the treatment of coagulopathic bleeding.

Fibrinogen is involved in both primary and secondary hemostasis, playing an important role in platelet aggregation and the establishment of a fibrin network. Recent evidence suggests that very high levels of fibrinogen act as antithrombin and can reduce endogenous thrombin potential and compromise clot stability, particularly following a low tissue factor stimulus. Several laboratory methods for measuring plasma fibrinogen concentrations are available, but results vary depending on the type of method and the use of artificial colloid plasma expanders. Adopting only the Clauss method can provide erroneously high levels when used in patients who have received colloid plasma expanders. This may contribute to a hazardous delay or complete lack of treatment. Multiple in vitro experiments, animal studies, and proof-of-principle randomized, clinical studies have recently suggested that hemostatic intervention with a fibrinogen concentrate may be efficient and safe in controling perioperative bleeding. In particular, fibrinogen concentrate has a key role in improving clotting function and reducing blood loss in settings such as trauma and cardiothoracic surgery. However, prospective studies are needed to determine the clinical efficacy and safety of fibrinogen concentrate when used as a hemostatic intervention for patients with massive bleeding due to trauma or surgery.