Co-administration of low molecular weight heparin enhances the profibrinolytic effect of warfarin through different mechanisms.
OBJECTIVE
Treatment with vitamin K antagonists (VKA) reduces fibrinolytic resistance through the inhibition of thrombin-mediated activation of thrombin activatable fibrinolysis inhibitor (TAFI). Because low-molecular weight heparin (LMWH) is co-administered with VKA during initiation of anticoagulant treatment, we evaluated the effect of dual anticoagulation on fibrinolytic resistance.


METHODS
Two groups of patients were studied: 1) patients on stable warfarin; 2) patients starting oral anticoagulant therapy, who were evaluated during dual anticoagulation and after enoxaparin withdrawal. Only samples with an INR between 2 and 3 were compared. The resistance of clots to t-PA-induced fibrinolysis was evaluated in blood and plasma by thromboelastography (TEG) and turbidimetry, respectively.


RESULTS
In patients on dual anticoagulation, blood fibrinolysis time (TEG) was significantly shorter than in patients on warfarin alone and significantly correlated with LMWH level. The profibrinolytic effect was partly ascribable to a reduction of thrombin-dependent TAFI activation: 1) thrombin and TAFIa generation were significantly reduced by dual anticoagulation; 2) the addition of enoxaparin to warfarin-blood reduced TAFI-mediated fibrinolysis inhibition. Patients on dual anticoagulation also displayed a reduction in clot strength, a phenomenon known to reduce fibrinolytic resistance. The profibrinolytic effect of LMWH co-administration was not seen in plasma, likely because TAFIa generation was below the threshold required to inhibit fibrinolysis.


CONCLUSIONS
Co-administration of LMWH in patients under VKA reduces the fibrinolytic resistance of blood clots via TAFI-dependent and TAFI-independent mechanisms. Further studies are warranted to assess the clinical implications of these findings.
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Francesca
F
Incampo
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Cosimo
C
Carrieri
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Rita
R
Galasso
Thrombosis and Haemophilia Center, Policlinico, Bari, Italy.
Renato
R
Marino
Thrombosis and Haemophilia Center, Policlinico, Bari, Italy.
Cosimo P
CP
Ettorre
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Nicola
N
Semeraro
Department of Biomedical Sciences and Human Oncology, Aldo Moro University, Bari, Italy.
Mario
M
Colucci
D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D014859:Warfarin / Q000008:administration & dosage*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D014859:Warfarin
Clot resistance; Enoxaparin; TAFI; Thrombin; Thromboelastography