Oral anticoagulation e-book

Question 1

Pathophysiology of coagulation

Answer 1

Blood coagulation is a complex process fundamental to many haemostatic reactions. It undergoes a cascade pathway leading to haemostasis ultimately protecting from significant blood loss. This pathway functions to aid rapid healing and, furthermore, act to prevent spontaneous bleeding. Coagulation occurs through one of two pathways, either the intrinsic or extrinsic path, or both. Irrespective of the route by which coagulation incurs, both meet to form a common pathway leading to fibrin activation and the stabilisation of the platelet plug using a fibrin mesh. The intrinsic pathway is activated upon exposure of the endothelial collagen whilst the extrinsic pathway is activated due to external damage.
Pathology occurs in the coagulation process in the form of a thrombus (a clot). The formation of a thrombus depends on three factors: blood clotting components, abnormal blood flow and the blood vessel wall, and this is known as Virchow’s triad.
With regards to blood clotting, this happens when platelets become stuck together by fibrin and sometimes white and red blood can get caught in this clot. This clot can then remain wedged inside either an artery leading to problems such as a stroke or myocardial infarction,
or in a vein which can result in a pulmonary embolism or deep-vein thrombosis (DVT). A decrease in coagulation inhibitors such as antithrombin III, protein C and S and heparin cofactor can lead to hypercoagulation which can also lead to DVT

Question 2

Deep Vein Thrombosis

Answer 2

Deep vein thrombosis (DVT) is a thrombus that develops within a deep vein. It is a common post-operative complication and usually occurs in the large deep veins of the lower limbs. DVT. It has been reported that individuals with DVT can experience leg pain, swelling and in severe cases venous ulcers. An embolism is the most common cause of deaths relating to DVT

Question 3

DVT is typically referred to as

Answer 3

● Provoked DVT is associated with a transient risk factor such as significant immobility, surgery, trauma, and pregnancy or puerperium. The combined contraceptive pill and hormone replacement therapy are also considered to be provoking risk factors
● Unprovoked DVT occurs in the absence of a transient risk factor. The person may have no identifiable risk factor or a risk factor that is persistent and not easily correctable (such as active cancer or thrombophilia). Because these risk factors cannot be removed, the person is at an increased risk of recurrence

Question 4

Deep vein thrombosis (DVT) risk

factors

Answer 4

Deep vein thrombosis (DVT) is more likely to occur in people with continuing or intrinsic risk factors, such as:
● Previous venous thromboembolism.
● Cancer (known or undiagnosed).
● Age over 60 years.
● Being overweight or obese.
● Male sex.
● Heart failure.
● Severe infection.
● Acquired or familial thrombophilia.
● Chronic low-grade injury to the vascular wall (for example from vasculitis, hypoxia from venous stasis, or chemotherapy).
● Varicose veins.
● Smoking.

Question 5

Risk factors that temporarily raise the likelihood of DVT include

Answer 5

● Immobility (for example following a stroke, operation, plaster cast, hospitalization, or during long-distance travel).
● Significant trauma or direct trauma to a vein (for example intravenous catheter).
● Hormone treatment (for example oestrogen-containing contraception or hormone replacement therapy).
● Pregnancy and the postpartum period.
● Dehydration.

Question 6

Signs and symptoms

Answer 6

Suspect DVT in a person with typical signs and symptoms, and especially if the patient has high risk such previous venous thromboembolism and immobility. Signs and symptoms of DVT are:
● Pain and swelling in one or both legs.
● Tenderness, changes to skin colour and temperature.
● Vein distension.

Question 7

Diagnosis

Answer 7

For people with suspected DVT, two level DVT Wells scores assess the probability of DVT.
Based on the results of the two-level DVT Wells score; other tests are then carried out to confirm the possibility of DVT. A number of scoring systems have been created to help estimate the pre-test probability of DVT. One of which is the D-dimer assay which is highly sensitive but relatively low specificity (false positive results are common). During this test, D-dimer (a degradation product of fibrin which is generated by the fibrinolytic response to thrombus formation) is measured. Negative D-dimer assay determines that thrombosis is not occurring. A positive D-dimer results can indicate thrombosis, other possible causes of a raised D-dimer include liver disease, inflammation, malignancy, pregnancy, trauma and recent surgery. Whilst a negative D- dimer may be useful in excluding DVT, a positive
D-dimer is of no diagnostic value, and thus requires further testing.
DVT can also be diagnosed using real-time imaging such as duplex and colour-flow Doppler, and the computed tomographic pulmonary angiography (CTPA) can be used as a non-invasive test to diagnose pulmonary embolism

Question 8

Pulmonary Embolism

Answer 8

A pulmonary embolism occurs when an emboli usually form a blood clot in the veins, which causes an obstruction in the pulmonary arterial system, forming an intra-pulmonary dead space. This then leads to a reduction in gas exchange of the affected lung tissue causing low oxygen concentration in the blood (hypoxaemia) and a decrease in cardiac output. The obstruction of the embolism also contributes to not only a high ventilation to perfusion ratio but also inflammation.This inflammation releases cytokines that leads to bronchoconstriction which reduces the amount of oxygen inhaled, explaining the origins of common PE
symptoms such as hyperventilation, tachypnoea and dyspnoea. Pleuritic chest pain is another common symptom that originates from the release of inflammatory mediators in the pleuretal pleura that trigger local pain receptors. Large or multiple emboli can result in shock, hypotension and sudden death. Previous history of a DVT can be a risk factor of a pulmonary embolism

Question 9

There are two subtypes of pulmonary embolisms

Answer 9

• Provoked pulmonary embolisms: these PEs are associated with a transient risk factor, such as pregnancy, significant immobility, surgery of trauma. Medications
  such as COCs and hormone replacement therapies can also be seen as risk factors.
  Once these risk factors are removed i.e. patient stops medication or has given birth, the risk of recurrence is reduced.
• Unprovoked pulmonary embolisms: These PEs occur in the absence of a transient risk factor. As these cannot be removed, the patient is at an increased risk of recurrence. The patient may have risk factors that are either difficult to identify or difficult to identify such as active cancer or latent diseases

Question 10

Risk factors of PE

Answer 10

● Though PE is preceded by DVT, they do not exhibit all the same risk factors. In fact, the risk factors for venous thromboembolism vary widely and the magnitude of each
are uncertain.
● Along with Virchow’s triad (venous stasis, injury to the vein wall and enhanced coagulability of the blood), those with malignant neoplasm are more likely to acquire DVT
● The risk of DVT also increases among patients with neurologic disease, paralyzed legs and had previously had a stroke. Whereas, the prevalence of PE increases
amongst individuals with paraplegia.
● The identification of risk factors helps to ascertain a clinical diagnosis of VTE whilst also guiding decisions about prophylactic measures and the potential need for repeat testing in borderline cases

Question 11

Sources of embolisms

Answer 11

● Pulmonary embolism occurs when a deep vein thrombosis breaks free, passes through the right side of the heart, and lodges in the pulmonary arteries.
● Only 15% of people with pulmonary embolism have signs of DVT although around 90% of pulmonary emboli come from the legs, with most involving the proximal (popliteal or more central) veins.
● Without anticoagulation, the risk of recurrent venous thromboembolism (DVT or pulmonary embolism) within 3 months of a pulmonary embolism is thought to be 50%

Question 12

Clinical presentation of PE

Answer 12

Suspect pulmonary embolism (PE) in a person with:
● Dyspnoea
● Tachypnoea
● Pleuritic chest pain
● Features of deep vein thrombosis
The clinical effects of an embolus depend upon the extent of pulmonary obstruction, the duration of obstruction as well as the pre-existing condition of the patient. With all of these factors varying so widely from patient to patient, PE can produce hugely different clinical pictures

Question 13

Parenteral anticoagulants to treat VTE

Answer 13

• Low molecular weight heparins (LMWH)- dalteparin, enoxaparin
• Fondaparinux sodium

Question 14

Adverse effects - Parenteral anticoagulants to treat VTE

Answer 14

haemorrhage, thrombocytopenia

Question 15

Parenteral anticoagulants to treat VTE - monitoring

Answer 15

During treatment of DVT and PE:
● Blood is taken for testing anti-Factor Xa 3-4 hours after a administering a dose of dalteparin
● The recommended plasma concentration of anti-factor Xa 0.5-1 Unit/ml
● Monitoring is not required for once-daily treatment and neither necessary for a twice daily dose.
Monitoring is necessary for patients with increased risk of bleeding (e.g in renal impairment [CrCl<30ml/min], underweight, overweight,patients with unexpected bleeding whilst on therapy).
● All patients should be monitored for platelet count in the first week of treatment or day one of repeat treatment to exclude thrombocytopenia(deficiency of platelets in the blood).
● Monitoring is not required in pregnancy

Question 16

Low molecular weight heparins (LMWH)- dalteparin, enoxaparin

Answer 16

LMWHs have lower binding affinity for circulating and cellular proteins than heparin, and have a reduced ability to inactivate thrombin. The action of LMWHs occurs principally by inactivating FXa. LMWHs have a better bioavailability at lower doses, a prolonged biological
half-life and a more predictable dose response than unfractionated heparin. As a consequence, they have become the treatment of choice for most patients with VTE, providing a simplified treatment option that may be administered to outpatients since coagulation monitoring is not required.

Question 17

Fondaparinux sodium

Answer 17

Fondaparinux is a direct FXa inhibitor licensed for the prevention of VTE in patients undergoing surgery and the treatment of superficial vein thrombosis. Fondaparinux binds to AT with a higher affinity than heparins, causing a conformational change in AT and increasing the ability of AT to inactivate FXa. It does not bind to thrombin or plasma proteins and cellular elements and has a lower affinity for PF4. Therefore, it is not likely to cause heparin-induced thrombocytopenia. Fondaparinux has good subcutaneous bioavailability and a predictable dose response when administered daily and routine coagulation monitoring is not required. Extended anticoagulant treatment is necessary to prevent recurrent VTE and oral vitamin K antagonists are the treatment of choice.

Question 18

Key counselling points for patients before being initiated on warfarin

Answer 18

● The patient will need to have their blood tested regularly
● Take the dose of warfarin at the same time each day
● They should not miss doses, or take additional doses, without advice from a healthcare professional. If they have missed a dose or taken too much, they should
let a doctor know.
● If any medication is started, stopped or the dose is changed, they should let the centre where they get their INR checked out.
● they should contact the centre where they have their INR measured if any medicine is started, stopped or the dose of regular medication is changed
● Their anticoagulant alert card should be carried at all times and their anticoagulant treatment booklet should be taken with them when they get their INR checked
● if they miss a dose accidentally, continue with the regimen as prescribed but never take a double dose unless specifically advised
● they should take their anticoagulant “yellow” treatment book with them when they attend the warfarin clinic to get their INR checked
● If they require surgery they may have to stop warfarin treatment temporarily. Most people do not have to stop warfarin if they are having dental treatment
● Warfarin has a number of adverse effects, the most common of which is bleeding;
they should seek immediate medical advice if:
o Spontaneous bleeding occurs whilst on warfarin, and the bleeding does not stop or recurs
o They get sudden back pain
o They experience chest pain, difficulty breathing or increased breathing rate – which are symptoms of a pulmonary embolism
● The patient should not become pregnant whilst on warfarin, as it is a known teratogen

Question 19

General Lifestyle advice:

Answer 19

• seek medical advice before undertaking any major changes in diet especially if their diet contains a lot of vitamin K rich foods (e.g. broccoli, kale or spinach)
• limit alcohol consumption to a maximum of 1-2 drinks a day and never binge drink
• expect to bruise more easily
• take extra care when brushing teeth due to increased risk of bleeding and consider using a soft toothbrush to reduce to risk
• take extra care when shaving due to potential cuts and consider using an electric razor to minimise risk
• inform a healthcare professional (including anticoagulant clinic staff, GP, pharmacist or nursing staff) of changes to their lifestyle like stopping, starting or changing doses of any medicines they take – including prescribed medicines, over the counter medicines e.g. aspirin, vitamins, food supplements, herbal remedies or homeopathic remedies

Question 20

For women of childbearing age:

Answer 20

• Advise the patient that she must not become pregnant while taking warfarin as it is a known teratogen
• If she becomes pregnant or is planning a pregnancy, she will need to stop warfarin and begin using low molecular weight heparin and should speak to a doctor as soon as possible about the desire to become pregnant or any suspected pregnancy

Question 21

Vitamin K Antagonists - Warfarin, Acenocoumarol, Phenindione

Answer 21

Antagonise the effects of vitamin K with the full anticoagulant effect occurring within 48-72 hours with warfarin the drug of choice. For immediate effect, low molecular weight or unfractionated heparin can be given concomitantly, however patients receiving prophylaxis
treatment for atrial fibrillation and rheumatic heart disease do not require rapid anticoagulation. Warfarin can be continued in specific patients who have been taking the medication long-term and their risk of thromboembolism is high.
The baseline prothrombin time should be measured but there shouldn’t be a delay in the initial dose while waiting for this result.
Warfarin, acenocoumarol and phenindione exert their anticoagulant effect by interfering with the synthesis of vitamin K dependent clotting factors and by inhibiting the enzyme vitamin K epoxide reductase. They however have a slow onset of action, unpredictable and variable dose response, narrow therapeutic window and propensity for many drug and food interactions necessitate regular coagulation monitoring.

Question 22

Indications of vitamin K antagonists include:

Answer 22

● Prophylaxis of embolisation in rheumatic heart disease and atrial fibrillation,
● Prophylaxis after insertion of prosthetic heart valve,
● Prophylaxis and treatment of venous thrombosis and pulmonary embolism,
● Transient ischaemic attacks

Question 23

vitamin K antagonists dose

Answer 23

Adult Dose (By mouth):
● Initially 5–10 mg, to be taken on day 1; subsequent doses dependent on the prothrombin time, reported as INR (international normalised ratio), a lower induction dose can be given over 3–4 weeks in patients who do not require rapid anticoagulation, elderly patients to be given a lower induction dose; maintenance 3–9 mg daily, to be taken at the same time each day

Question 24

vitamin K antagonists- monitoring

Answer 24

● The international normalised ratio (INR) should be monitored. INR is a measure of the anticoagulant effect of warfarin.
● When a patient is first started on warfarin, the INR should be measured daily or once every 2 days until it is within therapeutic range. This value is normally between
2.0-3.0 on two consecutive measurements.
● After the INR is in range, it should be measured twice a week for 1-2 weeks until at least 2 measurements are in therapeutic range.
● If the INR is stable after this, it can be measured up to every 12 weeks.
Treatment duration for warfarin varies but the risk of recurrence of the thromboembolism should be considered as well as anticoagulant-related bleeding. According to the British Society of Haematology it is:
● 6 weeks for isolated calf-vein deep-vein thrombosis
● 3 months for venous thromboembolism provoked by surgery or other transient risk factor (e.g. combined oral contraceptive use, pregnancy, plaster cast)
● at least 3 months for unprovoked proximal deep-vein thrombosis or pulmonary embolism; long-term anticoagulation may be required
The main adverse side effect of anticoagulant treatment is haemorrhage, so the INR should be checked, doses omitted as appropriate and if stopped, INR should be measured a 2-3 days later to ensure it is falling.
Monitoring should be carried out more frequently in the following groups of patients:
● Severe renal impairment
● Changes in condition for patients with liver disease
● Patients starting new medication or presenting with new illness

Question 25

vitamin K antagonists- interactions

Answer 25

The effects of coumarins can be reduced or abolished by vitamin K, including that found in health foods, food supplements, enteral feeds, or large amounts of some green vegetables or green tea. Major changes in diet (especially involving salads and vegetables) and in
alcohol consumption can affect anticoagulant control. Pomegranate increases the INR in response to warfarin.
Should be avoided in severe hepatic impairment, especially if prothrombin time is prolonged, used with caution in mild-moderate renal impairment and INR should be monitored more frequently in severe renal impairment, while avoiding use in 1st trimester of pregnancy.
● Common interactions-
○ Antibiotics e.g. amoxicillin, clarithromycin, flucloxacillin alter anticoagulant effect
○ Aspirin and clopidogrel- increased risk of bleeding
○ SSRIs e.g. citalopram and sertraline- increased risk of bleeding
○ Ibuprofen- increased risk of bleeding
○ Corticosteroids- increase anticoagulant effect
○ Cranberry Juice- increased anticoagulant effect

Question 26

vitamin K antagonists- ADR

Answer 26

● Haemorrhage
● alopecia (loss of hair)

Prevention of haemorrhage and major bleeding
Vitamin K substitutes such as phytomenadione given as slow intravenous injection combined with dried prothrombin complex or fresh frozen plasma can be administered for patients with major bleeding or in minor bleeding accompanied with a INR >5. Note patients with no bleeding but an INR >8, phytomenadione should still be given.

Question 27

Thrombin Inhibitors - Dabigatran, Bivalirudin

Answer 27

Dabigatran etexilate is an orally active thrombin inhibitor, a prodrug that is rapidly absorbed and converted to dabigatran by hydrolysis. It is renally excreted and not associated with cytochrome p450 metabolism. There is no requirement for coagulation monitoring, although
coagulation monitoring parameters such as INR are affected by the drug in a dose-independent manner. Dabigatran etexilate is licensed for the prevention of VTE in patients undergoing elective surgery for total hip or knee replacement.

Question 28

Thrombin Inhibitors - Dabigatran, Bivalirudin - ADR

Answer 28

Hepatic abnormality, anaemia and haemorrhage (less common than other oral anticoagulants)

Question 29

Thrombin Inhibitors - Dabigatran, Bivalirudin - monitoring

Answer 29

● Monitor renal function at least annually - Cockcroft and Gault to be used to calculate renal function in all patients before initiating treatment.
● Monitor for signs of bleeding or anaemia - if this becomes severe then treatment should be stopped
● No routine anticoagulant monitoring required (INR tests are unreliable)

Question 30

Thrombin Inhibitors - Dabigatran, Bivalirudin - dose

Answer 30

When used for prophylaxis of VTE following knee or hip replacement surgery, reduce initial dose to 75 mg and subsequent doses to 150 mg once daily if creatinine clearance 30–50mL/minute; reduce dose to 75 mg once daily if creatinine clearance 30–50 mL/minute and patient receiving concomitant treatment with verapamil.
Treatment duration should be consider bleeding risk vs benefit of treatment, while shorter treatment duration (at least 3 months) should be based on transient risk factors i.e recent surgery, trauma, immobilisation, and longer treatment duration should be based on permanent risk factors, or idiopathic DVT or PE.

Question 31

Class factor Xa Inhibitors- Apixaban

Answer 31

Apixaban is a direct factor Xa inhibitor that is greatly used in VTE prophylaxis undergoing knee or hip replacement surgery.
Used in VTE prophylaxis for cerebral ischaemia and systemic embolism in patients with non-valvular atrial fibrillation, that present with one or more risk factors including previous stroke or transient ischaemic attack; 75 years or older; diabetes mellitus; hypertension or
symptomatic heart failure.
Apixaban may pose the lowest risk of bleeding in patients with atrial fibrillation.

Question 32

Class factor Xa Inhibitors- Apixaban - ADR

Answer 32

Anaemia, haemorrhage, nausea

Question 33

Class factor Xa Inhibitors- Rivaroxaban

Answer 33

Rivaroxaban is an orally active inhibitor of both free and clot-bound factor Xa, which inhibits the conversion of prothrombin to thrombin but does not act on AT with a rapid onset of action. It is metabolised by cytochrome p450. Therefore, there are issues with interactions, while one-third of the drug is eliminated unchanged in the urine.
Rivaroxaban is indicated for VTE prophylaxis in knee/hip replacement surgery and treatment of deep vein thrombosis and pulmonary embolism.

Question 34

Class factor Xa Inhibitors- Rivaroxaban ADR

Answer 34

Anaemia, diarrhoea, constipation, haemorrhage, hypotension

Question 35

Class factor Xa Inhibitors- Rivaroxaban - monitoring

Answer 35

● Blood tests to check liver and renal function. These need to be done once a year, but more often if the person has kidney problems or becomes unwell.
● Patients should be monitored for signs of bruising or bleeding and anaemia.
Treatment should cease if there is severe bleeding.
● INR tests are unreliable for this class of drugs, therefore regular monitoring on INR is unnecessary.
● With Edoxaban, additional monitoring of renal and hepatic function is required. Renal and hepatic function should be tested before initiating treatment, with repeat renal testing whenever indicated and repeat hepatic function after one year if long-term treatment.

Question 36

Key Management Information

Answer 36

Starting warfarin therapy:
Usually initiated in secondary care (hospital and community care) or within a dedicated clinic
When rapid anticoagulation is required:
- 5-10mg OD for 2 days should be given and INR measured on day 3 then subsequent doses decided dependent on the INR.
- A lower initiation/loading dose of less than 5mg may be better suited, and is usually given for certain groups of patients e.g. elderly, low body weight, hepatic impaired, in
cardiac failure and those already at high risk of bleeding.
- In cases like DVT or pulmonary embolism, heparin or low molecular weight heparin is given alongside and is done is secondary care. This is due to warfarin taking longer to take effect
- It takes 48-72 hours or the anticoagulant effect of warfarin to fully develop.
- There is no evidence that a 10mg loading dose is better than a 5mg loading dose in people with acute thrombosis, but the target INR is achieved more rapidly with a 10mg warfarin dose on day 1.
For patients with atrial fibrillation:
- No need to achieve anticoagulation rapidly and a slow loading regimen is safer and achieves therapeutic anticoagulation in the majority of people within 3-4 weeks.
- The slow loading regimen is often 1-2mg of warfarin daily to start
- A low starting dose is more suitable for certain patient groups e.g. frail, elderly or at high risk of bleeding
- The average maintenance dose is usually around 5mg daily, but there are wide variations with daily doses being between 1 and 15mg for some
- Warfarin should be taken at the same time each day

Question 37

Duration of warfarin therapy

Answer 37

For people with DVT or Pulmonary Embolism:
- Duration with vary for each individual but it should be at least:
- 6 weeks for people with distal DVT (calf vein thrombosis)
- Three months for people with proximal DVT or PE where there are known temporary risk factors AND the patient is considered low risk for recurrence
- Six months for people with proximal DVT due to an unknown cause
- Long term if there have been recurrent DVTs or PE
Warfarin can be stopped abruptly, with no need for a ‘weaning off’ period when treatment is complete.
For people with atrial fibrillation:
Warfarin treatment is usually long term
If the person is going to have cardioversion (medical procedure where the arrhythmia is converted to a normal rhythm) – the target INR should be maintained for at least 3 weeks prior and for 4 weeks after.
People who have undergone cardioversion and have a high risk of atrial fibrillation recurring will require ongoing long-term warfarin therapy. People at high risk of atrial fibrillation recurring include:
- People with a history of failed attempts of cardioversion
- Structural heart disease (e.g. left ventricular dysfunction or an enlarged left atrium)
- Prolonged history of atrial fibrillation (longer than 12 months)
- Previous recurrences of atrial fibrillation: For people with mechanical prosthetic heart valves warfarin in usually a long-term treatment

Question 38

Monitoring warfarin

Answer 38

Anticoagulant effect is measured as the INR. Generally, INR should be measured:
- Daily or on alternate days when initiated until it is within the therapeutic range on 2 consecutive occasions
- Twice weekly for 1-2 weeks followed by weekly measurements until at least 2 INR measurements are within therapeutic range
After this, INR doesn’t need to be measured as regularly and the frequency of checks depends on the stability of the INR and longer intervals (up to 12 weeks) can be agreed.
More frequent routine monitoring 1-2 weekly is recommended if the person has increased risk of overcoagulation, is at risk of bleeding or if the patient may find adherence difficult.
Self-testing, where a patient tests their own INR and contacts a healthcare professional for dose adjustments, is possible but the availability of training and support for this varies across the UK and the suitability for this has strict guidance

Question 39

Contraindications and cautions for warfarin therapy

Answer 39

Contraindications include:

• Haemorrhagic stroke
• Clinically significant bleeding
• Within 72 hours of major surgery with risk of severe bleeding
• Within 48 hours post-partum
• Pregnancy (due to teratogenicity)
• Bleeding disorders (e.g. thrombocytopenia, haemophilia, hepatic failure, renal failure)
• Potential bleeding lesions (e.g. active peptic ulcer, oesophageal varices, aneurysm, proliferative retinopathy, recent organ biopsy or trauma/surgery to the head/spine)

Cautions include:

1. people at increased risk of haemorrhage – risk factors include:
   - age 65 years or older
   - previous bleeding episode, history of GI haemorrhage and anaemia
   - recent ischaemic stroke, hypertension, heart disease, renal disease, liver disease, active peptic ulcer, cerebrovascular disease
   - recent or imminent surgery or trauma
   - Excessive alcohol intake or frequent or significant falls
   - regular use of NSAIDs or use of other medications or natural remedies that can have an anticoagulant effect
   - Treatment factors that increase risk of bleeding such as: duration of treatment, intensity of treatment and concomitant use of other drugs that increase risk of bleeding
   - Uncooperative or unreliable patients – due to poor compliance and issues with follow ups and INR testing
   - Prone to repeated falls or those who are unstable in movement – due to increased chance of injury including head trauma
   - Patients with protein C deficiency (SPC)

Question 40

Adverse effects warfarin

Answer 40

Most common:
Bleeding – people who take warfarin have a 2-4% risk per year of having a bleeding episode that requires a transfusion and a 0.2% risk per year of having a fatal bleed

Common:
Nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia,
purpura and rash

Rare:
Skin necrosis – a rare but serious adverse effect of warfarin. Treatment with warfarin should be stopped if warfarin related skin necrosis is suspected.
- Skin necrosis is more likely in people with acute heparin induced thrombocytopenia or in people with pre-existing congenital protein C or protein S deficiency
- It presents as painful, localised skin lesions within the subcutaneous fat. The lesions can occur in areas of fatty tissue (e.g. breasts or abdomen) or in the extremities
Calciphylaxis – a rare but very serious condition that causes vascular calcification and cutaneous necrosis. This condition has a high mortality rate. People taking warfarin should be advised to seek urgent medical advice if they develop a painful skin rash

Question 41

Drug Interactions - warfarin

Answer 41

When a patient starts a drug that may interact with their warfarin therapy, their INR should be checked 3-5 days after initiation. Drugs and food products that can enhance the effect of warfarin:
Alcohol, amiodarone, antibiotics, antidepressants, aspirin, azoles (like fluconazole, miconazole etc), cranberry juice or cranberry containing products, clopidogrel, dipyridamole, corticosteroids, direct acting antivirals for treating chronic hepatitis C, fibrates, glucosamine,
NSAIDs, tamoxifen, thyroxine.
Drugs and OTC items that can reduce the effect of warfarin:
Tricyclic antidepressants, St John’s wort, griseofulvin, rifampicin, carbamazepine, phenobarbital, primidone, phenytoin, vitamin k containing vitamin complexes
Monitor INR when warfarin is used alongside these drugs/situations, especially in the elderly due to reported interactions:

Allopurinol, azathioprine, grapefruit juice, influenza vaccine, methylphenidate, orlistat, zafirlukast, paracetamol in prolongs regular use, propafenone, proton pump inhibitors, statins (particularly Fluvastatin and rosuvastatin), and when quitting smoking.

Question 42

Advice for healthcare professionals

Answer 42

At the start of treatment ensure:
● The patient is given an anticoagulant “yellow” treatment booklet. This includes advice for people taking anticoagulants and a section for recording INR results.
● The patient receives counselling including how to take warfarin, what dose they should take, when their next appointment to have their INR checked is, what adverse
effects to expect, what to do if they experience a bleed and what factors (e.g. medicines, food, alcohol etc) can put their INR out of range

Question 43

Warfarin In surgery or dental treatment

Answer 43

If a patient needs surgery or another invasive treatment, they may need to temporarily stop their warfarin therapy.
In general, for surgery, warfarin is stopped 5 days before planned surgery and once the patient’s INR is less than 1.5 surgery can go ahead. Ideally, this should be checked the day before surgery to allow administration of phytomenadione if the INR is 1.5 or above. Warfarin
is usually resumed at the normal dose on the evening of surgery or the next day If homeostasis is required.
Outpatient general procedures (including extractions) can usually be done without temporarily stopping or reducing the dose of warfarin but it is recommended that the INR is
checked 72 hours before dental surgery. The risk of significant bleeds in patients with a stable INR between 2 and 4 is very small but the risk of thrombosis is higher if warfarin therapy is stopped or reduced for the treatment