Clot Lifespan Model Analysis of the Effects of Warfarin on Thrombus Growth and Fibrinolysis: Role of Contact Protein and Tissue Factor Initiation

Abstract

Warfarin therapy has served as the backbone of chronic anticoagulation therapy for decades to prevent thrombotic morbidity secondary to blood-biomaterial interfaces. Unfortunately, thrombotic and bleeding complications are observed despite maintenance of therapeutic international normalized ratio (INR) values. We proposed to define the effects of warfarin therapy on thrombus growth and disintegration following contact pathway protein or tissue factor (TF) initiation. Normal subject or patient plasma with INR values between 1.8 and 9.6 were exposed to TF or celite and tissue-type plasminogen activator (tPA). Thrombus growth/disintegration kinetics were determined by changes in resistance over time with the clot lifespan model (CSLM), a thrombelastographic-based methodology. Data were collected until clot lysis time was observed. Linear relationships of the difference between the CLSM parameter values obtained from paired celite and TF-activated samples and corresponding INR value were determined and reported as r. The time to clot initiation was progressively prolonged with increasing INR values in all samples, and speed of clot formation, clot strength, and time to onset of fibrinolysis decreased as INR increased. Throughout the range of INR values tested, contact activation resulted in faster growing, stronger, and longer lived thrombi when compared with matched TF-activated plasma samples. Only the time to maximum rate of lysis was correlated with INR (r=0.36, p=0.005). INR values have little correlation with the difference between contact protein and TF-activated coagulation/fibrinolysis.