Monitoring "mini-intensity" anticoagulation with warfarin: comparison of the prothrombin time using a sensitive thromboplastin with prothrombin fragment F1+2 levels

Abstract

Treatment with warfarin using a target International Normalized Ratio (INR) range of 1.7 to 2.5 is efficacious for many clinical indications, but the minimal intensity of anticoagulation required for antithrombotic protection has yet to be determined. To evaluate whether patients could be reliably monitored with a less intense regimen, we anticoagulated patients with warfarin for several months using a target INR range of 1.3 to 1.6 as determined by prothrombin time (PT) using a sensitive thromboplastin (Dade IS, International Sensitivity Index [ISI] = 1.3). Plasma measurements of F1+2, a marker of factor Xa action on prothrombin in vivo, were also obtained to determine the suppressive effect of warfarin on hemostatic system activity. Overall, 20 of 21 patients with a history of cerebrovascular events (mean age, 61 years) could be reliably regulated with warfarin in the target INR range. F1+2 levels were significantly suppressed from baseline in all patients, with a mean reduction of 49% (range, 28% to 78%). We found a significant relationship between the extent of suppression of prothrombin activation levels and the baseline measurements. A mean reduction of 65% was observed for those patients with baseline F1+2 greater than or equal to 1.5 nmol/L, but only 38% for baseline F1+2 less than or equal to 0.5 nmol/L. Overall, 68% of plasma samples obtained during stable anticoagulation were within the target INR range. PTs were also determined on all plasma samples with two thromboplastins of lower sensitivity (C+, ISI = 2.09; and automated simplastin, ISI = 2.10). Only 47% and 35% of PT determinations, respectively, were within the target range with these reagents. We conclude that prothrombin activation can be significantly suppressed in vivo with use of warfarin in an INR range of 1.3 to 1.6. This level of anticoagulation can be reliably achieved by monitoring PTs with a thromboplastin of high sensitivity.

Rebound after cessation of oral anticoagulant therapy: the biochemical evidence

“…The determination of TAT and FPA enables a direct estimate of the actual thrombin and fibrin generation in vivo. The general relevance is supported by their continuous increase with age and progressive atherosclerosis Hursting et al, 1993), their higher levels in the so-called prethrombotic states Bauer & Rosenberg, 1989;Bremme et al, 1992;Mannucci et al, 1992) and their suppression by anticoagulation therapy (Conway et al, 1987;Millenson et al, 1992). It may be interesting to assess the relevance of the data by comparing the relative increases in our patients with the ones found in prethrombotic states and overt thrombosis.…”

“…3-1 . 6 (Millenson et al, 1992) in the steady state and a gradual withdrawal over 3 weeks may approach this situation. These data collectively suggest that tapering the anticoagulant dose may efficiently suppress the biochemical rebound.…”

Low‐intensity warfarin reduces thrombin generation and fibrin turnover, but not low‐grade inflammation, in men at risk of myocardial infarction

“…It has previously been reported that warfarin, adjusted to an INR of 1AE6-2AE2 in 43 patients with atrial fibrillation, lowered median d-dimer levels by 50%, whereas neither aspirin nor a fixed dose of warfarin of 1 mg/d (which has minimal effect on INR) had any effect (Lip et al, 1996). In another study of 21 patients with a history of stroke, low-intensity warfarin, target INR 1AE3-1AE6, lowered F1AE2 levels by 50% (Millenson et al, 1992). The current findings for both d-dimer and F1AE2 confirm and extend these earlier observations in a larger study of men at risk of coronary events.…”

Effects of anticoagulation on markers of activation of clotting following major orthopedic surgery

“…Only a few reports include repetitive assays of markers conducted over several time points [2][3][4]. Perhaps only the changes from baseline should be reported, as in Millenson et al [5] and Koefoed et al [6], very few studies ask how clearly separated are the results from either untreated controls or from baseline. To be useful, there should be clear biologically meaningful differences in the results when reporting upon these markers.…”