ACUTE INTERRUPTION OF ORAL ANTICOAGULANT THERAPY: A THROMBOTIC RISK?

It is still on discussion how oral anticoagulant therapy must be interrupted. A progressive diminution of drug intake have been proposed in order to avoid a MreboundM of vitamin K-dependent procoagulant factors. At the present, it is well known that coumarin drugs affect not only the biologic activity of factors II, VII, IX and X but also Protein C (PC), an inhibitor of coagulation kinetics, and their cofactor Protein S. With the aim to determine the recovery level of PC in relation with the others vitamin K-dependent factors, the effect of suppression of anticoagulant therapy in patients under chronic treatment with acenocoumarin was studied.Quick time, functional factors II, VII, X (one stage methods), functional PC (Francis method) and immunological Factor II and Protein C (Laurell) were determined before and 36 hours after suspension of acenocoumarin administration.Results showed that: 1) Recovery levels of functional Protein C (increased from 28.55% ±2.57 to 72.64% ±5.9) were significantly higer than functional Factor II (22.09% ±2.34 to 30.73% ±8.64), Factor VII (22.55% ±2.01 to 40.73% ±4.85) and Factor X (23.27% ±2.66 to 39.18% ±3.19). Statistical analysis (Newmann-Keuls test) showed at least a p<0.01 between PC increase and factors II, VII or X increment.2) No significant differences were seen between immunological levels of Factor II before and after suspension of acenocoumarin.3) Levels of immunological PC in patients under anticoagulant therapy were higer than functional PC. After acenocoumarin suppression, not correlation was seen between immunological and functional Protein C recovery.It is concluded that acute suppression of acenocoumarin does not induce a thrombotic tendency because the recuperation of functional Protein C is more important than factors II, VII and X recovery.

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Oral anticoagulation reduces activated protein C less than protein C and other vitamin K–dependent clotting factors

Blood ◽

10.1182/blood-2002-01-0329 ◽

2002 ◽

Vol 100 (12) ◽

pp. 4232-4233 ◽

Cited By ~ 6

Author(s):

Marleen J. A. Simmelink ◽

Philip G. de Groot ◽

Ronald H. W. M. Derksen ◽

José A. Fernández ◽

John H. Griffin

Keyword(s):

Anticoagulant Therapy ◽

Vitamin K ◽

Oral Anticoagulant ◽

Protein C ◽

Anticoagulant Activity ◽

Oral Anticoagulant Therapy ◽

Activated Protein C ◽

Clotting Factor ◽

Factor X ◽

Clotting Factors

Oral anticoagulant therapy, which is used for prophylaxis and management of thrombotic disorders, causes similar reductions in plasma levels of vitamin K–dependent procoagulant and anticoagulant clotting factor zymogens. When we measured levels of circulating activated protein C, a physiologically important anticoagulant and anti-inflammatory agent, in patients on oral anticoagulant therapy, the results unexpectedly showed that such therapy decreases levels of activated protein C substantially less than levels of protein C, prothrombin, and factor X, especially at lower levels of prothrombin and factor X. Thus, we suggest that oral anticoagulant therapy results in a relatively increased expression of the protein C pathway compared with procoagulant pathways not only because there is less prothrombin to inhibit activated protein C anticoagulant activity, but also because there is a disproportionately higher level of circulating activated protein C.

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Inhibition of Activated Protein C Anticoagulant Activity by Prothrombin

Blood ◽

10.1182/blood.v94.11.3839 ◽

1999 ◽

Vol 94 (11) ◽

pp. 3839-3846 ◽

Cited By ~ 50

Author(s):

Mikhail D. Smirnov ◽

Omid Safa ◽

Naomi L. Esmon ◽

Charles T. Esmon

Keyword(s):

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Protein C ◽

Anticoagulant Activity ◽

Oral Anticoagulant Therapy ◽

Membrane Surface ◽

Activated Protein C ◽

Significant Risk ◽

Thrombotic Risk ◽

Factor Va

Abstract In this study, we test the hypothesis that prothrombin levels may modulate activated protein C (APC) anticoagulant activity. Prothrombin in purified systems or plasma dramatically inhibited the ability of APC to inactivate factor Va and to anticoagulate plasma. This was not due solely to competition for binding to the membrane surface, as prothrombin also inhibited factor Va inactivation by APC in the absence of a membrane surface. Compared with normal factor Va, inactivation of factor Va Leiden by APC was much less sensitive to prothrombin inhibition. This may account for the observation that the Leiden mutation has less of an effect on plasma-based clotting assays than would be predicted from the purified system. Reduction of protein C levels to 20% of normal constitutes a significant risk of thrombosis, yet these levels are observed in neonates and patients on oral anticoagulant therapy. In both situations, the correspondingly low prothrombin levels would result in an increased effectiveness of the remaining functional APC of ≈5-fold. Thus, while the protein C activation system is impaired by the reduction in protein C levels, the APC that is formed is a more effective anticoagulant, allowing protein C levels to be reduced without significant thrombotic risk. In situations where prothrombin is high and protein C levels are low, as in early stages of oral anticoagulant therapy, the reduction in protein C would result only in impaired function of the anticoagulant system, possibly explaining the tendency for warfarin-induced skin necrosis.

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Plasma levels of protein C and vitamin K-dependent coagulation factors in patients on long-term oral anticoagulant therapy.

The Tohoku Journal of Experimental Medicine ◽

10.1620/tjem.149.351 ◽

1986 ◽

Vol 149 (4) ◽

pp. 351-357 ◽

Cited By ~ 8

Author(s):

HOYU TAKAHASHI ◽

MASAHARU HANANO ◽

SENJI HAYASHI ◽

YUTAKA ARAI ◽

NORIKO YOSHINO ◽

...

Keyword(s):

Anticoagulant Therapy ◽

Vitamin K ◽

Plasma Levels ◽

Oral Anticoagulant ◽

Protein C ◽

Oral Anticoagulant Therapy ◽

Coagulation Factors

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Inhibition of Activated Protein C Anticoagulant Activity by Prothrombin

Blood ◽

10.1182/blood.v94.11.3839.423k07_3839_3846 ◽

1999 ◽

Vol 94 (11) ◽

pp. 3839-3846 ◽

Cited By ~ 1

Author(s):

Mikhail D. Smirnov ◽

Omid Safa ◽

Naomi L. Esmon ◽

Charles T. Esmon

Keyword(s):

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Protein C ◽

Anticoagulant Activity ◽

Oral Anticoagulant Therapy ◽

Membrane Surface ◽

Activated Protein C ◽

Significant Risk ◽

Thrombotic Risk ◽

Factor Va

In this study, we test the hypothesis that prothrombin levels may modulate activated protein C (APC) anticoagulant activity. Prothrombin in purified systems or plasma dramatically inhibited the ability of APC to inactivate factor Va and to anticoagulate plasma. This was not due solely to competition for binding to the membrane surface, as prothrombin also inhibited factor Va inactivation by APC in the absence of a membrane surface. Compared with normal factor Va, inactivation of factor Va Leiden by APC was much less sensitive to prothrombin inhibition. This may account for the observation that the Leiden mutation has less of an effect on plasma-based clotting assays than would be predicted from the purified system. Reduction of protein C levels to 20% of normal constitutes a significant risk of thrombosis, yet these levels are observed in neonates and patients on oral anticoagulant therapy. In both situations, the correspondingly low prothrombin levels would result in an increased effectiveness of the remaining functional APC of ≈5-fold. Thus, while the protein C activation system is impaired by the reduction in protein C levels, the APC that is formed is a more effective anticoagulant, allowing protein C levels to be reduced without significant thrombotic risk. In situations where prothrombin is high and protein C levels are low, as in early stages of oral anticoagulant therapy, the reduction in protein C would result only in impaired function of the anticoagulant system, possibly explaining the tendency for warfarin-induced skin necrosis.

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A Comparison Between Thrombotest And Factor-X Amidolytic Activity In Stable And Non-Stable Anticoagulated Patients

10.1055/s-0038-1653088 ◽

1981 ◽

Author(s):

E M van Wijk ◽

L H Kahlé ◽

A Jeletich ◽

J W ten Cate

Keyword(s):

Anticoagulant Therapy ◽

Vitamin K ◽

Oral Anticoagulant Therapy ◽

Factor Vii ◽

Factor X ◽

Amidolytic Activity ◽

High Turnover ◽

Long Term Treatment ◽

Anticoagulated Patients

We tested a mechanized amidolytic factor-X assay in 2222 patients on long term anticoagulant therapy. A good correlation was found between this assay and the routinely performed Thrombotest (r= 0.78). With a therapeutic range between 150 and 300 units/L of factor-X amidolytic activity we obtained the same information about the state of anticoagulation in 81 % of these 2222 patients. Factor-X activity was assayed in 32 stable anticoagulated patients together with Thrombotest on at least three subsequent occasions in each patient. A fairly constant Thrombotest-factor X ratio was observed.(mean 0.38±0.06) Changes in Thrombotest and factor-X amidolytic activity ran consistently parallel in a group of 20 unstable anticoagulated patients.(mean ratio 0.45±0.08) Changes in Thrombotest were occasionally more pronounced than changes in factor-X activity in some patients, which could be due to the high turnover of factor VII. Relative very high or low factor-VII levels as compared to the other vitamin-K dependent factors disturbed the balance between Thrombotest and factor X. The therapeutic consequence in these unbalanced states is, that the prescribed dosage scheme of the anti-vitamin K drug could depend on the very moment of blood sampling. As a result of the high turnover of factor VII, bloodsampling one day earlier or later would then result in another dosage scheme of the drug. Therefore it might be concluded that oral anticoagulant therapy, guided by a factor-X assay could result in more stable long term treatment. Large prospective comparative trials are required to support this hypothesis.

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RESPONSE OF PROTEIN C AND PROTEIN S INHIBITORS IN LONG-TERM ORAL ANTICOAGULANT THERAPY

10.1055/s-0038-1643877 ◽

1987 ◽

Author(s):

M Mukhlova Montiel ◽

H Bussey

Keyword(s):

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Protein C ◽

Oral Anticoagulant Therapy ◽

Anticoagulation Therapy ◽

Protein S ◽

Factor Vii ◽

Control Group ◽

Statistical Regression

Protein C (PC) and its coenzyme Protein S (PS) are physiologic inhibitors of activated factors Va and Villa. Deficiency of either one of these inhibitors has been associated with venous thrombosis. Their activity is dependent on vitamin K for hepatic gamma carboxylation and it is depressed during oral anticoagulant therapy. Because rebound thrombosis complicates cessation of anticoagulant therapy, we investigated the response of PC and PS during long term oral anti coagulation. The study encompassed 30 patients ranging between 26 and 76 years of age, who have received therapeutic doses of coumadin from 15 days to more than 8 years. The conditions for which treatment was initiated were deep vein thrombosis, cerebral vascular accidents and cardiac valve replacements.Factor VII and X activity was assayed by one step routine clotting assays. PC antigen (ag), total PSag and free PSag were assayed by Laurel 1 Rocket electroimmunodiffusion method. The measurement of the free PS was carried out after precipitation of C4b-binding protein with polyethylene glycol. PC activity was measured by clotting assay using PC deficient plasma to which was added patient plasma as a source of PC. Control group of 30 individuals in similar age group were assayed parallel with the patient samples. Compared with the control group the coumadin-treated patients showed substantial decrease of all factors studied. Statistical regression analysis of the coumadin group showed a significant increase in PS free (p = 0.014)during long term anti coagulation, while all of the other variables did not change significantly.PCag and total PSag were decreased and their activities, as expected, were more severely affected. The ratio of PC activity to PCag averages 0.39 (normal >0.80) and free PS represented only 27% of the total PSag (normal about 40%). The inhibitors' persistent activity parallels that of the depression of Factors VII and X and there appears to be a balanced coagulation-inhibi-tion system. If PC and PS play a role in rebound thrombosis after a prolonged anticoagulation therapy, the changes may occur after discontinuation of medication.

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The Relative Importance of the Factors II, VII, IX and X for the Prothrombinase Activity in Plasma of Orally Anticoagulated Patients

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646904 ◽

1989 ◽

Vol 62 (02) ◽

pp. 788-791 ◽

Cited By ~ 74

Author(s):

Ma Xi ◽

S Béguin ◽

H C Hemker

Keyword(s):

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Thrombin Generation ◽

Oral Anticoagulant Therapy ◽

Factor Ix ◽

Factor Vii ◽

Clotting Factors ◽

Factor Ii ◽

Anticoagulated Patients ◽

Prothrombinase Activity

AbstractThe individual importance of each of the four vitamin Independent clotting factors on the generation of prothrombinase activity in the plasma of orally anticoagulated patients has been investigated.Addition of purified factors VII, IX or X to plasma from deeply anticoagulated patients (International Normalized Ratio 2.8-4.8) did not influence the amount of prothrombinase activity or the amount of thrombin formed. Only the prothrombin level in the plasma determines the course of thrombin generation. Addition of increasing amounts of purified factor II, VII, IX or X to plasmas deficient in respectively factor II, VII, IX or X showed that the prothrombinase activity increases linearily with the concentration of factor II added and that the concentration below which the factors VII, IX and X start to have a measurable effect on prothrombinase activity are 5%, 20% and 30%, respectively. Half maximal prothrombinase activity was found at about 1% factor VII, 5% factor IX and 8% factor X respectively.From these observations we conclude that primarily the variation in factor II level determines thrombin generation and hence presumably the antithrombotic effect of oral anticoagulant therapy. It therefore seems likely that, for the control of oral anticoagulant therapy, tests that reflect factor II activity would be suitable.

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