Effect of warfarin on plasma concentrations of vitamin K dependent coagulation factors in patients with stable control and monitored compliance

Abstract

Summary There is a discrepancy in the results of reported studies of levels of vitamin K dependent coagulation factors in patients on warfarin therapy. This may have arisen partly because of the problem of assuring compliance with therapy in outpatients. The plasma concentrations of the vitamin K dependent clotting factors II, VII, IX and X were studied in 23 outpatients whose adherence to prescribed warfarin therapy was determined using a pharmacological indicator of complicance. In these patients, who were shown to have consistently good compliance and stable anticoagulant control over a period of 3–6 months, the activities in plasma of the four coagulation factors were not equally suppressed. Factor IX levels were significantly greater than those of factor VII (P<0.0001) which in turn were significantly greater than the levels of factor II (P<0.0001) or factor X (P<0.0001). There was no significant difference between the levels of factors II and X which were depressed to a similar extent. The proportion of variability of the International Normalized Ratio (INR) explained by linear regression was 51–77% and a model was derived to predict the INR from the mean of the levels of the four clotting factors. The concentrations of the coagulation factors II, VII, IX and X are likely to be highly dependent on the degree of compliance with warfarin therapy which should be taken into account when investigating the behaviour of these factors.

Short‐term warfarin reversal for elective surgery – using low‐dose intravenous vitamin K: safe, reliable and convenient*

“…At baseline, FII and FX showed the greatest reduction as a consequence of warfarin therapy, with median levels of 0·27 iu/ml (range 0·21–0·51) and 0·13 iu/ml (range 0·05–0·40), respectively. FIX, as previously described, had higher levels when compared with the other factors (Kumar et al , 1990; Watson et al , 2001).…”

“…A concern is that an early INR response equally reflects replenishment of FVII activity, while FII and FX remain decreased, rendering patients still at a high‐risk of bleeding despite normalization of the INR. This study corroborated that stable warfarin therapy confers the greatest reduction in FII and FX activity, but more importantly, within 12–24 h of vitK IV administration, there was restoration of all vitK‐Factors (>0·30–0·40 iu/ml) (Kumar et al , 1990; Raj et al , 1999; Watson et al , 2001). Only four patients in our study fulfilled major bleeding criteria, all of whom achieved an INR ≤ 1·4 and vitK‐Factors > 0·30 iu/ml.…”

Phospholipid composition controls thromboplastin sensitivity to individual clotting factors

“…Coumarins depress the plasma levels of FVII, FX, and prothrombin to differing degrees, ranging from about 10–40% of normal in therapeutically anticoagulated patients [12,13,25–29]. To better compare thromboplastin properties using clotting factor deficiencies spanning the therapeutic range, we replotted PT ratio data from Fig.…”

“…Isolated factor depletions described in this study would not occur in patients on oral anticoagulant therapy, but this approach has allowed us to determine the relative sensitivities of thromboplastins to deficiencies in the three clotting factors suppressed by oral anticoagulation. Even in stably anticoagulated patients, the plasma levels of FVII, FX, and prothrombin may be depressed to different degrees [25–28]. Some studies have attempted to correlate the plasma activities of single coagulation factors with INR values from individual patients, variously concluding that INR correlates best with deficiency in FVII [12,25], a combination of FVII and prothrombin deficiency [29], or native prothrombin [35].…”

An Individualized Blood Coagulation Model to Predict INR Therapeutic Range During Warfarin Treatment

“…The action of flow and platelets is introduced in [4], [5], [8], [17], [25], [30], [31]- [33]. The second type is pharmacokinetics-pharmacodynamics (PK-PD) models developed to describe the response to anticoagulant drugs [11], [27], [21]. These models can suggest a practical solution to medical questions such as predicting the appropriate dose for individual patients, but they do not take into account the complexity of physiological processes.…”