RESUMO
Haemophilia patients with inhibitors require bypassing agents (BPA) like activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rFVIIa) to control bleeds. Adjunct tranexamic acid (TXA) may improve haemostasis. The objective of this study was to investigate safety and haemostatic effect of TXA given in combination with BPA. Healthy volunteers (N = 5) and haemophilia inhibitor patients (N = 6) were enrolled in a prospective case crossover design. Controls were treated with TXA 20 mg kg(-1) orally (O.R.) Patients were treated with aPCC 75 IU kg(-1) intravenous (I.V.) on day 1 followed by TXA 20 mg kg(-1) O.R. combined with aPCC 75 IU kg(-1) I.V. on day 2. A 14-day washout occurred before crossover to rFVIIa 90 µg kg(-1) I.V. ±TXA. Safety evaluation and blood sampling processes were performed at baseline, 15, 30, 60, 120, 180 and 240 min post treatment. Primary outcome was maximum clot firmness (MCF) evaluated by whole blood thromboelastometry using a TF + tissue plasminogen activator-based assay. Healthy controls showed a 20-fold increase in MCF following TXA. Adjunct TXA to aPCC or rFVIIa induced a significant increase in MCF (P < 0.0001) reaching levels indistinguishable from healthy controls treated with TXA (P > 0.05). Infusion of aPCC or rFVIIa alone induced only 3-10 fold increase in MCF from baseline, with a decline in MCF starting after 60-120 min. TXA did not increase the endogenous thrombin potential. No clinical or laboratory signs of thromboembolic events, disseminated intravascular coagulation, or hypercoagulability were observed. Combination of aPCC or rFVIIa with TXA normalizes clot stability in haemophilia patients with inhibitor as compared to healthy controls. No clinical or laboratory adverse events were observed.
Assuntos
Antifibrinolíticos/uso terapêutico , Fatores de Coagulação Sanguínea/uso terapêutico , Hemofilia A/tratamento farmacológico , Ácido Tranexâmico/uso terapêutico , Adulto , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Estudos Cross-Over , Hemofilia A/sangue , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tromboelastografia , Adulto JovemRESUMO
BACKGROUND: Hemophilia is characterized by abnormal thrombin generation and impaired clot stability. FXIII promotes clot stability and may be a useful adjunct treatment for hemophilia. OBJECTIVES: This study examined the clot stabilizing effects and safety of supra-physiological FXIII and explored the mechanisms via which FXIII exerts its effects in hemophilia A. METHODS: The effects of FXIII on clot formation and stability were examined using a thromboelastometry assay and blood samples collected from six patients with severe hemophilia A. The effect of FXIII on clot formation was also assessed using a murine model. The mechanisms of FXIII action in hemophilia A were explored by measuring thrombin generation, rates of FXIII activation and effects on clot permeability, pore size and fibrin fiber diameter. RESULTS: This study demonstrates that supra-physiological concentrations of FXIII stabilize clots in blood from patients with hemophilia by improving resistance to t-Pa-induced fibrinolysis even at low concentrations of FVIII (FVIII< 0.1 IU mL⻹, P < 0.05, anova). Addition of FXIII stoichiometrically up-regulates its activation, correcting the fibrin clot structure, reducing clot permeability and facilitating thrombin generation; FXIII significantly shortens ttPeak and lagtime (P < 0.05) in FVIII-deficient plasma, providing a novel explanation for its positive effects on clot stability and structure. The murine model indicates that supra-physiological FXIII is tolerated and does not significantly alter time to clot formation. CONCLUSION: The effects of FXIII on clot stability and physical clot structure are seen at low concentrations of FVIII, indicating that FXIII could be a useful treatment in a variety of clinical scenarios.
Assuntos
Fator XIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Animais , Coagulação Sanguínea , Humanos , Masculino , Camundongos , Microscopia EletrônicaRESUMO
BACKGROUND: Abnormal thrombin generation is considered the key defect in hemophilia. Conventional treatment seeks to correct this using coagulation factor replacement or bypassing agents, for example recombinant factor VIIa (rFVIIa). Previous studies demonstrate abnormal FXIII activation in patients with hemophilia. FXIII activation is essential for formation of structurally normal, stable clots. OBJECTIVES: The present study challenges the hypothesis that in hemophilia the use of plasma-derived FXIII (pdFXIII) in combination with rFVIIa will produce a greater improvement in clot stability than promotion of thrombin generation alone. METHODS: Fourteen individuals with severe hemophila A were enrolled. Whole blood was spiked ex vivo with buffer, rFVIIa (2 µg mL(-1)) or rFVIIa (2 µg mL(-1)) plus pdFXIII (10 µg mL(-1)). Whole blood thromboelastometry assessed clot stability, after activation with tissue factor (TF) (0.15 pm) plus tissue-type plasminogen activator (tPa) (2 nm). The primary outcome measure of clot stability was area under the elasticity curve (AUEC). RESULTS: The combination of pdFXIII and rFVIIa significantly improved clot stability as measured by AUEC (P < 0.05) compared with rFVIIa alone. CONCLUSION: The use of pdFXIII resulted in superior clot stability compared with solely enhancing thrombin generation and we suggest that increasing thrombin generation alone fails to fully correct dysregulation of clot-stabilizing mechanisms associated with bleeding disorders. Hemorrhage control in hemophilia may be improved using clot stabilizing drugs. FXIII shows potential as a novel agent.