Moreover, selective restoration of prothrombin sensitized warfarin-treated rabbits to coagulation more severe than observed in nontreated control rabbits. One may extrapolate from these data that depression of both factor X and prothrombin are required for warfarin's clinical antithrombotic efficacy and that depression of plasma prothrombin is particularly important.
Abstract We have evaluated the contribution of depression of individual procoagulant vitamin K-dependent clotting factors to the ability of warfarin to protect rabbits against tissue factor-induced coagulation.
Publication types Research Support, U. Gov't, P. All blood samples that had a measurable heparin level lower limit of detection, 0. In a secondary analysis, the effect of warfarin on the APTT was assessed in blood samples from the same patients that had either no heparin present heparin recently discontinued or heparin levels below the lower limit of detection.
Prothrombin times were determined with a commercial human placental thromboplastin Thromborel S, international sensitivity index, 1. The therapeutic range for heparin with this APTT assay is 60 to 85 seconds in our laboratory. With this technique, the coefficient associated with each variable ie, INR or heparin level reflects its additional explanatory effect independent of the other variables in the regression model.
The further addition of a product variable ie, INR times heparin level allows one to investigate whether the 2 variables have a multiplicative interactive effect on the outcome of interest ie, APTT. The proportions of the variances of the APTT that were accounted for by different factors singly or in combination are reported as r 2 value.
All P values are 2 tailed. Unless otherwise stated, only these samples were included in the analyses. However, after controlling for differences in INR, a relationship between APTT and heparin levels was evident Figure 3 ; for each increase in the heparin level of 1. Analyses were performed to explore the mechanism of the increase in the APTT caused by warfarin.
Blood samples were categorized as supratherapeutic, therapeutic, or subtherapeutic according to APTT therapeutic range, seconds and heparin levels therapeutic range, 0. There was agreement between APTT and heparin levels in only 36 of the 77 samples.
Of the 41 samples with discordant results, the intensity of heparin therapy was higher according to APTT results in 36 and higher according to heparin levels in 5.
Only 6 of the 29 samples that had supratherapeutic APTT results also had high heparin levels. This study shows that, in patients who are being treated with concomitant heparin and warfarin, APTT reflects the effects of both drugs. Consequently, in patients treated with oral anticoagulation, decreasing heparin dose in response to high APTT often results in subtherapeutic heparin levels.
However, when APTT was low, heparin levels were usually low also; therefore, increasing heparin dose in response to low APTT increases the chance of achieving a therapeutic heparin level. Our finding that oral anticoagulation has a marked effect on the APTT is consistent with earlier reports. However, as the international sensitivity index of the thromboplastin that was used to measure the prothrombin ratio was not reported, these data are difficult to interpret.
Our study quantifies the effects of warfarin and heparin on APTT results and supports the concept that these effects are additive. It is important to emphasize that this study was performed with the use of a single thromboplastin and a single APTT reagent. The relationship of APTT to heparin levels varies with different reagents and other technical factors, 6 , 8 and consequently, quantitative interactions are expected to differ among laboratories.
However, major differences are unlikely, and the interactions we have described should be generalizable to clinical practice. Our finding that, independent of heparin levels, factor X levels were most closely related to APTT suggests that a decrease in the level of this factor is an important mediator of warfarin-induced prolongation of the APTT. However, because there were strong interrelationships between the levels of the vitamin K—dependent coagulation factors, and because factor IX activity was not assessed in this study, this finding is inconclusive.
There was evidence that heparin had a minor effect on INR analyses not shown , suggesting that the relationship between APTT and INR is partly accounted for by the confounding effect of heparin levels on both assays. Indirectly, our findings question the role of laboratory monitoring of heparin therapy. Laboratory monitoring of heparin therapy by means of the APTT was introduced at a time when it was usual to postpone starting warfarin therapy for at least 5 days, and when there was limited understanding of optimal heparin dosing.
Consistent with these observations, a recent meta-analysis failed to find an association between subtherapeutic APTT during the first 48 hours of therapy and subsequent recurrent venous thromboembolism in patients with acute venous thromboembolism who were treated with an average dose of at least U of continuous intravenous heparin per day.
Five days of heparin therapy is effective treatment for patients with acute venous thrombosis despite the possibility that heparin levels may be subtherapeutic for much of this time because of the concomitant effect of warfarin on the APTT. Indeed, the value of any form of laboratory monitoring is uncertain if patients are being treated with appropriate doses of heparin. In summary, this study identifies that warfarin has a major effect on APTT and questions the appropriateness of reducing heparin dose in response to high APTT in patients who are receiving oral anticoagulants.
Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy Continue. Figure 1. View Large Download. Relationship of activated partial thromboplastin time APTT to heparin levels.
Heparin for 5 days as compared with 10 days in the initial treatment of proximal venous thrombosis. N Engl J Med. Hirsh J Heparin. Ann Intern Med. Refn IVestergaard L The titration of heparin with protamine. Scand J Clin Invest. Kitchen SPreston FE The therapeutic range for heparin therapy: relationship between six activated partial thromboplastin time reagents and two heparin assays. Thromb Haemost.
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