Bleeding risk in warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels

Abstract

warfarinized patients with a therapeutic international normalized ratio: the effect of low factor IX levels. J Thromb Haemost 2013; 11:1043-52.Summary. Objective: Bleeding is the main complication of warfarin therapy, even patients with an international normalized ratio (INR) in the target range can suffer bleeding, suggesting that INR does not perfectly reflect the therapeutic effect of warfarin. We hypothesized the INR might underestimate the level of anticoagulation in a subject with a lower factor (F) IX level than average. Methods and results: We modeled warfarin anticoagulation in our in vitro thrombin generation (TG) model by adjusting the levels of vitamin K-dependent factors to those of patients with an INR of 2-3. Variation in FIX had a marked effect on TG but had no effect on the prothrombin time (PT)-INR. A prospective observational, crosssectional clinical study including 341 consecutive patients admitted to the emergency department with an INR between 2 and 3, showed a statistically lower FIX activity in bleeders (P = 0.004) compared with others. No correlation was found between TG capacity and PT-INR results (P = 0.36). However, in patients, presenting with a warfarin-related hemorrhage, TG was significantly lower (P < 0.001) than others. A correlation on the boundary of significance was observed between TG capacity and FIX levels (P = 0.09). Conclusion: These data demonstrates that patients who bleed when their PT-INR is in the target range 2-3 might have defective TG related to a lower level of FIX than expected.

Prediction of bleeding risk in patients taking vitamin K antagonists using thrombin generation testing

“…In contrast, the plasma-based CAT did not discriminate between bleeding and non-bleeding patients. Other studies showed that plasma CAT was indicative of bleeding in different patient populations [19, 23, 24]. However, this finding could not be repeated in our study.…”

Factor IX from prothrombin complex concentrate augments low dose tissue factor-triggered thrombin generation in vitro

“…FIX activity is unappreciated by PT/INR, but it has been shown that low FIX activity may be a clinically pertinent modifier of haemostasis in warfarinised patients. 13 Although there was no direct correlation between INR (range, 2e3) and FIX activity, the relative risk of clinical bleeding was 2.89-fold (confidence interval, 1.35e6.20) higher with FIX below 50% compared with FIX above 50% (P¼0.009) while on warfarin with therapeutic INRs. 13 These clinical data corroborate our results in which 40% recovery (0.4 IU ml À1 ) of PCC in FIXdeficient plasma incompletely restored peak thrombin generation to the normal concentration.…”

Effect of five therapeutic strategies on the coagulation defect induced by the thrombomodulin c.1611C>A mutation

“…Despite normal levels of all coagulation factors, TG triggered with 1 pM TF was severely impaired in the patient's plasma. The ETP was 179 nmol/l/min compared to the normal values previously established in our laboratory in 100 healthy controls (ETP 1444 ± 278 nmol/l/min) (Dargaud et al , ).…”