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Word97 - Study No

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    Study No. 1

    Monitoring of Anticoagulation Treatment with Warfarin

     1Prof. MUDr. J. Martínková, CSc 2 MUDr. P. Dulíček, PhD2Prof. MUDr. L. Chrobák, CSc

    1. Department of Pharmacology, Charles University of Prague, Faculty of Medicine, 50001 Hradec Králové, Šimkova 870, Czech Republic

    Tel: 420 49 5816 233; Fax: 420 49 5513 022; e-mail: martinkova@lfhk.cuni.cz

2. Department of Hematology, University Hospital, Hradec Králové

    Hradec Králové, Czech Republic

    Tel: 420 49 5832686, fax: 420 49 5832011

Case information:

    A 28-year-old married Caucasian woman.

    Family history: Parents are alive and healthy.

    Personal history: She had a deep venous thrombosis in her left leg 2 years ago, otherwise she has been healthy, no surgery in personal history.

    This young woman was admitted to the Department of Internal Medicine for a painful swelling of the right lower extremity, which had been present for 3 days. These symptoms arose after a long bike trip. During the last two days she also had two episodes of dyspnea twice a day. As mentioned above, she had suffered from deep venous thrombosis in the left leg complicated by pulmonary embolism 2 years ago. After this thrombotic event she discontinued taking oral contraceptive pills and anticoagulation treatment with warfarin (4-hydroxycoumarin) 5 mg daily was started. She decided to withdraw warfarin 6 days ago. INR at the time of admission to the hospital was 1.4. The medical report from the previous event was not available, because she was treated at a local district hospital. Physical examination: Normosthenic habitus, body weight 60 kg, blood pressure 120/80, heart rate 80/min, no signs of dyspnea. Physical finding was normal except for swelling of the right extremity - below the knee with a positive plantar and Homan's signs.

Laboratory tests

    A. Sinus rhythm, heart rate 76/min.

    B. X - ray examination of the lungs and the heart did not reveal any abnormality. C. INR = 1.4.

    D. APTT : control plasma time = 32.1 s., patient plasma time 33.6 s.

    E. D- fibrinogen dimer = 1000 µg/ml.

    F. pH =7.4, pO = 9.6 kPa, pCO = 3.5 kPa. 22

    G. Venous ultrasound revealed deep venous thrombosis in the right extremity. H. Perfusion - lung scanning did not detect any diminished perfusion.

Question No. 1

    2 years ago, warfarin was administered to use for its effect on:

    A. Inhibition of platelet aggregation.

    B. Anticoagulation effect.

    C. Fibrinolytic effect.

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    Answer No.1

    A. False. Warfarin does not have an antiaggregation effect and moreover the inhibition of

    platelet aggregation is not indicated in the prophylaxis of venous thromboembolism. B. True.

    C. False. Warfarin does not induce fibrinolysis.

Question No.2

    What is the main mechanism of action of warfarin? Warfarin

    A. Potentiates antithrombin III activity

    B. Antagonises vitamin K in its role in activation F II, VII, IX and X. C. Inhibits factor Xa.

Answer No. 2:

    A. False. This mechanism belongs to unfractionated heparin.

    B. True. Warfarin prevents the synthesis in liver of the vitamin K-dependent coagulation

    factors - F II, VI, IX and X (inactive precursors). Active forms of these factors contain

    residues of carboxyglutamic acid. Activation is due to carboxylation of a glutamate

    residue in the peptide chain of the precursors. This process is accomplished by cycling of

    vitamin K between epoxide, quinone and hydroquinone forms. Warfarin with closely

    related chemical structure to vitamin K is able to inhibit vitamin K epoxide reductase. C. False. It is typical of LMWHs.

Question No. 3:

    Anticoagulation action of warfarin can be seen :

    A. Only in vivo.

    B. Only in vitro.

    C. In vivo and in vitro.

Answer No. 3:

    A.True. Warfarin acts in the liver.

    B. False.

    C. False.

Question No. 4

    By which route is warfarin administered?

    A. I.V.

    B. Orally.

    C. Subcutaneously.

Answer No. 4

    A. False.

    B. True.

    C. False.

Question No. 5

    The anticoagulation treatment with warfarin can be monitored by:

    A. Measurement of plasma level of this drug.

    B. Measurement of its anticoagulation effect - pharmacodynamic principle. C. Monitoring is not necessary and not possible.

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    Answer No. 5

    A. False. The measurements of plasma levels are not routinely used for monitoring of

    warfarin therapy. It is only valuable in the investigation of patients with unusual resistance

    to warfarin, it helps to distinguish poor compliance, abnormal pharmacokinetics or

    dynamics.

    B. True.

    C. False.

Question No. 6

    Treatment with warfarin is monitored by:

    A. Bleeding time.

    B. APTT.

    C. INR.

    D. Thrombin time.

Answer No. 6

    A. False. Bleeding time is prolonged in the following cases: thrombocytopenia,

    thrombocytopathy, von Willebrand disease and vasculopathy.

    B. False. APTT serves for monitoring of treatment with unfractionated heparin (UFH). APTT

    is also prolonged in deficiency of coagulation factors of the intrinsic pathway and in the

    presence of a circulating antibody, e.g. lupus anticoagulant.

    C. True.

    D. False.

Question No. 7

    Was the INR of 1.4 at the time of admission to hospital high enough for prophylaxis of venous thrombosis?

    A. Yes, because the INR was not within the normal range (1.0 - 1.2).

    B. No, because higher value is necessary for this purpose.

Answer No. 7

    A. False. INR 1.4 is not sufficient for prophylaxis of venous thromboembolism. B. True. For this purpose the INR has to be maintained in the therapeutic range (2.0 3.0).

Question No. 8

    How often should the INR be monitored?

    A. It depents on patient's decision (personal feeling).

    B. Every week.

    C. Once a month.

Answer No. 8

    A. False. However the patient should consult the physician on his own initiative if he

    suspects development of recurrent thrombosis or in case of manifestation of bleeding. In

    such a case the patient's INR will be measured and therapy adjusted. B. False. Once the maintenance dose is know and the patient stable, the INR is checked

    weekly for the first six weeks and than monthly.

    C. True. More frequent monitoring is inevitable in case of change of the dietary habits or

    administration of a new drug, which can interfere with the efficacy of warfarin.

Question No. 9

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    Warfarin has been taken since the last thrombotic event because:

    A. She is a young woman and the incidence of venous thromboembolism is low in this age

    category.

    B. Of risk of spontaneous onset of thrombosis.

    C. An inherited thrombophilia was diagnosed 2 years ago.

    D. Duration of anticoagulation therapy was not established.

    E. Duration was established, but she decided herself to withdraw this therapy.

Answer No. 9

    A. False. The incidence of venous thromboembolism is approximately 1/10 000 in patients <

    45 years of age, but the age itself is not factor, which influences duration of the

    anticoagulation treatment.

    B. False. Previous thrombotic event was not spontaneous. It was associated with use of

    hormonal contraceptive pills.

    C. False. The medical report was not available and therefore we do not know if

    thrombophilia workup was done or not. Diagnosis of inherited thrombophilia can

    influence strategy of anticoagulation treatment.

    D. False.

    E. True. Duration of anticoagulation therapy was established for 3 years but she decided to

    interrup this treatment. She was feeling well and she considered two years of therapy as

    sufficient.

Question No. 10

    The patient stopped taking warfarin 6 days ago. Her INR 1.4 at the time of admission to hospital signals that the INR:

    A. Was not already high enough at the time of withdrawal.

    B. Could have been high enough at the time of the beginning of symptoms but not at the time

    of admission to hospital.

    C. Was likely to be within the therapeutic range at the time of withdrawal, but not at the time

    of the beginning of symptoms.

Answer No. 10

    A. False. The INR reached 1.4 six days after withdrawal of warfarin and therefore we can

    assume a therapeutic range of the INR at the time of interruption of therapy. Moreover,

    the INR was 2.3 on the last visit a month ago.

    B. False. Taking into consideration the last INR 2.3 we can expect the INR below the

    therapeutic range at the beginning of symptoms development.

    C. True. INR was probably below the therapeutic range at the time of her bike trip and this

    fact in association with strenuous physical activity could cause the onset of recurrent

    thrombosis.

Question No. 11

    What do you consider to be important for predicting the duration of effect of warfarin? A. Its pharmacological properties.

    B. Its formulation (pharmaceutical availability).

Answer No. 11

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    A. True. First, the duration of anticoagulant effect of warfarin depends on t (half-life). 0,5

    Warfarin is a racemic mixture of S and D stereoisomers. The active component is only S enantiomer having a tof 18-35 hours. It means that after one tplasma concentrationof 0,5 0,5 .

    warfarin drops to 1/2, after two tplasma concentration drops to 1/4 and so on. The result is 0,5

    that plasma concentration of warfarin declines slowly. Second, the anticoagulation effect of warfarin is determined by the time needed for the vitamin-K-dependent coagulation factors (II, VII, IX and X) to reach again their effective value (let us remember that t of the factors 0,5

    involved are: II, 60 hours; VII, 6 hours; IX, 20 hours and X, 40 hours). B.False.

Question No. 12

    Venous ultrasound revealed deep venous thrombosis in her right extremity. She should be treated with:

    A. Fibrinolytic therapy.

    B. Anticoagulation therapy with unfractionated heparin.

    C. Anticoagulation therapy with low molecular weight heparin.

    D. Warfarin.

Answer No. 12

    A. False. This therapy is indicated only in patients with phlegmasia alba dolens or venous

    gangrene.

    B. False. Although this is a possible therapy, it is no longer the treatment of choice today. C. True. Low molecular weight heparin (LMWH) is the "treatment of choice" for deep

    venous thrombosis. LMWH has a longer biological half - life, better bioavailability and

    easily predictable therapeutic response. Moreover this therapy does not need to be

    monitored.

    D. False. Therapy with warfarin should follow LMWH because of its delayed onset of action.

Question No. 13

    Why warfarin cannot be recommended as the first drug? Because the onset of its action appears:

    A. Extremely fast and causes toxic effects.

    B. Slowly.

Answer No. 13

    A. False.

    B. True. there is a delay between administration and effect of warfarin. Since warfarin acts

    by inhibiting synthesis of active vitamin-dependent clotting factors anticoagulation

    following dosing awaits the catabolism (consumption) of preformed factors. This

    catabolism depends on t of clotting factors (see also Answer No 8). 0,5

Commentary and Summary

    The patient was treated with LMWH - Fraxiparin 0,6 ml s.c. bid for 7 days and warfarin was administered after that. Warfarinization was undertaken rapidly: during last three days LMWH was given together with initial dose of warfarin (10 mg a day).Then administration of LMWH was discontinued and the dose of warfarin was decreased (5 mg a day). When the INR was within the therapeutic range (2-3) for 2 consecutive days the patient was discharged from hospital.

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    Thrombophilia workup was done and 2 inherited thrombophilic markers were found. Resistance to activated protein C (APC - R) with a heterozygous form of F V Leiden and a mutation in the prothrombin gene - F II 20210 A. This congenital predisposing factors to thrombosis contributed to the onset of thrombosis in risk situations (use of an oral contraceptive and a bike trip) in this patient.

    We recommended she takes prophylactic measures in all risk situations associated with venous thrombosis (immobilization, surgery, pregnancy etc.) and all her first degree - family members were evaluated for the above mentioned genetic mutations as well.

References:

    1. Hirsh J, Dalen JE, Deykin D et al.: Oral anticoagulant. Mechanism of action, clinical

    effectiveness and optimal therapeutic range. Chest, suppl. 102: 312, 1992. 2. Hirsh J.: Mechanism of action and monitoring of anticoagulants. Semin Thromb Hemost 1:

    1, 1986.

    3. Duncan A.: Warfarin. A case report. Applied Therapeutic Drug Monitoring Vol. II.

    Review and Case Studies. Ed. T. P. Moyer, R. L. Boeck, Washington 1994. 4. Martínková J, Chrobák L.: Antikoagulační terapie. Modelová studie, Remedia 2, 119-120,

    1992.

    5. Anticoagulant and Antiplatelet Drugs. In: Textbook of Clinical Pharmacology, Third ed.

    Edited by J.M.Ritter, L.D.Lewis, and T. G. K. Mant , Edward Arnold, 1995, pp 322-335. 6. Lin R, Zhuo-Wei Hu: Hematological disorders. In: Melmon and Morrelli ?s Clinical Pharmacology. Fourth ed. Editors: SG Carruthers, BB Hoffman, KL Melmon, DW Nierenberg. McGRAW-HILL, 2000, pp.737-795

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