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Oral anticoagulation

Oral anticoagulation

Oral anticoagulation

§   950,000 patients on Warfarin in the UK

§   Vitamin K dependant factors

§   Factor VII – half life of 4-6 hours

§   Factor IX – half life of 24 hours

§   Factor X – half life of 48 hours

§   Factor II – half life of 60 hours, therefore warfarin and heparin have to overlap for approx 4-5 days when starting treatment



§        Works by blocking the ability of vitamin K to carboxylate the factors, ie. stops glu to gla, thus leaving them in inactive form (unable to bind calcium).



§        Venous thromboembolism

§        LMWH may be advantageous in VTE complicating cancer

§        Target INR of 2.5

§        Recurrent VTE INR 2.5 v 1.5 v Placebo – recurrence rate 2.5% v 7.5% v 20%

§        INR 2.5 - lower recurrence rate and no increase in bleeding

§        Target INR of 1.75 in patients with a very high bleeding risk

§        If temporary risk factor

§        At least 6 weeks for calf vein thrombosis

§        At lest 3 months after proximal DVT

§        Idiopathic or permenant risk factors

§        6 months anticoagulation

§        Risk of recurrence

§        Elevated D-dimer 1 month after treatment may predict recurrence

§        Male gender

§        Unprovoked

§        Most likely to occur within the first 2 years (10%) after stopping treatment


§        Heritable thrombophilia

§        Recurrence rates whilst on anticoagulation with INR of 2.5 are similar to those without heritable thrombophilia


§        APLS

§        Target INR of 2.5 is recommended for venous thrombosis

§        Arterial thrombosis, insufficient evidence, but a target of 3.5 is often used


§        IVDU

§        treatment with LMWH is a safe alternative


§        Cardioversion

§        INR of 2.5 for 3 weeks before and 4 weeks after cardioversion

§        To minimise cancellations, a target of 3 can be used to prior to the procedure


§        Heart valve prosthesis

§        For patients in whom valve type and location are known

§        Bileaflet – aortic                                                        2.5

§        Tilting disk – aortic                                                        3.0

§        Bileaflet – mitral                                                        3.0

§        Tilting disk – mitral                                                        3.0

§        Caged ball/ caged disk – aortic or mitral                            3.5

§        Not known

§        INR of 3.0 for aortic

§        INR of 3.5 for mitral


§        Peripheral arterial thrombosis and grafts

§        First line is antiplatelets

§        If long term AC given to patients at high risk of femoral graft failure – INR of 2.5


§        Coronary artery thrombosis

§        Meta analysis found that aspirin and warfarin reduced incidence of MI and stroke, but was associated with higher bleeding risk

§        Included several studies performed before widespread coronary stenting

§        Target INR of 2.5 is recommended


§        PNH

§        10 year risk of thrombosis in those with large clones (PNH granulocytes >50%) = 44%  v. 5.8% in those with smaller clones

§        Long-term AC with target INR of 2.5 is recommended for patients with large clones and plts >100

§        Can also be considered for others if additional thrombotic risk factors


§        Cancer

§        LMWH superior to warfarin

§        CLOT study


§        Anticoagulation in the preoperative period

§        Unless very high risk of thromboembolism, AC should be temporarily discontinued

§        Does not need to be stopped for dental extraction if INR <3


§        Reversal for bleeding

§        IV Vit K 5-10mg (works quicker than oral)

§        Factor concentrate rather than FFP



§        Risk is variable according to the study

§        2.4 – 8% per patient year

§        Risk factors

§        Intensity of anticoagulation

§        Co-morbidity

§        Other medications

§        Quality of management

§        Age

§   Risk doubles for each point increase in the INR above 3



§   Rapid fall in Factor VII (short half-life), but also protein C (Vit K dependant with short half life also)

§   This may result in a hypercoagulable state rather than hypocaogulable and explains why some patients with protein C deficiency get skin necrosis when starting therapy



§   Corrects the PT ratio for differences in the sensitivity of thromboplastin reagents

§   Allows for comparison of results between labs

§   Patients PT/ Mean normal PT x International sensitivity index (ISI)

§        ISI is specific to each thromboplastin reagent



§   Polymorphisms in either CYP2C9 or Vitamin K epoxide reductase (VKORC1) affect warfarin sensitivity

§        Warfarin clearance is by hepatic metabolism largely mediated by CYP2C9 (part of the cytochrome P450 system)

§        Most important polymorphisms are CYP2C9*2 and *3 which result in a 30 and 80% reduction in enzymatic activity respectively, resulting in increased anticoagulant effect.

§        VKORC1 is the enzyme inhibited by warfarin

§        Polymorphisms result in either low or high level haplotypes; high level haplotypes require higher doses.

§        Factor IX propeptide  mutations

§        Highly sensitive to warfarin; APTT >> PT

§        Can treat with warfarin, but monitor FIX (10-15%)



§   Controversial, but could consider long term secondary prophylaxis with a reduced INR after an initial period  of normal anticoagulation – may be appropriate for those in whom frequent INR monitoring is difficult.

§   New drugs – direct Xa and thrombin inhibitors which don’t require monitoring


Oral anticoagulation and patient self-testing

§   Near patient testing

§   Patient self management


1.      Consider only in patients on long-term warfarin

§        Exceptional circumstances can be considered for patients  with short term indications

§        2-3 months before a patient becomes fully accustomed

2.      Contraindications

§        Previous non-compliance

3.      Previous stability of INR is not a prerequisite

§        unstable patients may benefit from autonomy and increased frequency of testing

4.      Target INR must be documented

5.      Must retain contact with a named clinican

6.      GP and clinician initiating warfarin must be informed

7.      Informed consent

§        Includes agreement to attend clinic regularly and record results accurately

8.      Training

§        Ideally national training programme as in Germany where 400,000 patients self dose

§        competence to perform an INR must be assessed

§        competence to interpret an INR must be assessed

§        based on an individual algorithm

9.      European-marked devices that have undergone evaluation by an expert independent body eg. MHRA

10.  Internal quality control

§        Electronic QC should be used every time monitor is used

§        IQC material should be used when new batch of test strips

§        IQC material should be used if unexpected result

§        IQC should be tested every 3 months

11.  External quality assessment

§        Formal EQA program eg. NEQAS

§        Assessed in a centre that is formally EQA accredited

§        Venous sample at same time as POC sample – every 6 months

12.  Abnormally high values

§        Repeat test if result between 4-8. The repeat analysis should be within 0.5

§        INR >8, venous sample is required