Pulmonary Embolism (also known as pulmonary embolus) is most commonly a complication of venous thromboembolism (VTE) from another source – e.g. a clot in the legs or pelvis (a DVT) that becomes dislodged, flows via the bloodstream through the right side of the heart and gets lodged in the pulmonary circulation.

It is not always a clot that causes a pulmonary embolism. Fat, air, amniotic fluid can all also be causes. For fat and amniotic fluid, these will normally resolve themselves with supportive care. Air is often an iatrogenic cause (e.g. accidentally injected intravenously).

• <5% if no haemodynamic instability
• 30% if shock present
• 70% with cardiac arrest (in hospital)

Risk factors

For VTE pulmonary embolism:

Clinical features

Signs

• Pyrexia
• Cyanosis
• Tachypnoea – 90% of patients have RR >16
• Tachycardia – 45% of patients
• Hypotension – 25% of patients
• Raised JVP
• Pleural rub
• Pleural effusion
• Look for signs that could indicate a cause – e.g. DVT, recent surgery, air travel – only 33% of patients have clinical evidence of DVT
• Atrial fibrillation (rare)

Symptoms

• Pleuritic chest pain (pain worse on inspiration) – 75% of patients
• Breathlessness – 85% of patients
• Cough – 50% of patients
• Haemoptysis – as a result of pulmonary infarct – 30% of patients
• Dizziness / pre-syncope – 15% of patients
• Syncope (loss of consciousness/fainting) – 15% of patients
• Non-pleuritic chest pain – 15% of patients

Shortness of breath typically occurs within seconds to minutes of onset, and pain develops later.

Beware of patients with unexplained syncope. In one study, 25% of patients admitted to hospital with unexplained syncope had PE.

Diagnosis

Probably the most important question is should I investigate? 

Defining risk of the probability of PE is important. There are two tools to help with this:

PERC Score

PERC stands for Pulmonary Embolism Rule-out Criteria.The PERC score is useful to rule out PE in low risk patients. If the patient’s score = 0, then there is a <2% chance of PE, and in the absence of convincing clinical signs, you can usually safely exclude PE as a differential.

Each factor below gives a score of 1. All factors must be negative for a negative PERC score. Any positive factor results in the need for further work up (move onto the Well’s Score)

• Age >50
• HR >100
• SaO2 on room air <95%
• Unilateral leg swelling
• Haemoptysis
• Recent surgery or trauma
• Previous PE or DVT
• Exogenous Oestrogen – oral contraceptives, hormone resplacement or other oestrogen hormones

Well’s score for PE

This can stratify patients as low or high risk. In high risk patients, you should proceed straight to imaging. In low risk patient, you should consider a D-dimer test.

Interpretation of Well’s Score

Traditional interpretation

• Score >6.0 — High (probability 59%)
• Score 2.0 to 6.0 — Moderate (probability 29%)
• Score <2.0 — Low (probability 15%)

Alternative interpretation

• Score > 4 — PE likely. Consider diagnostic imaging.
• Score 4 or less — PE unlikely. Consider D-dimer to rule out PE.

D-Dimer

D-Dimer is a fibrin degradation product – and as such, levels are raised by the presence of a blood clot in the circulation. A D-Dimer blood test can be useful to rule out PE or DVT as a differential. A negative D-Dimer PLUS a low Well’s score means that PE or DVT is extremely unlikely. Conversely, many factors can cause a positive D-Dimer – so having a raised D-Dimer does not necessarily mean there is a clot.

• D-Dimer should only be used as a ‘rule-out’ test in low probably cases – based on the Well’s score
• A positive D-Dimer in a low probably case indicates the need for further investigation (e.g. CTPA or VTE)
• In high probably cases, you should skip the D-Dimer and go straight to imaging

In reality it can be a tricky test to use. Even just a recent common cold can result in a raised D-Dimer! Almost any factor that causes inflammation will also result in a raised D-Dimer. Do be selective when requesting a D-DImer for your patients. Even if your patient has a low risk Well’s score, doing a D-Dimer might not always be the best option – for example if they have recently had cellulitis or some other infection.

“Should I do a D-Dimer?” is often a difficult questions which should involve consultation with your senior clinicians. Common pitfalls include:

• Delaying of imaging in cases with a high probably – D-Dimer not necessary
• Clinical confusion in cases which could have been ruled out clinically (e.g. PERC rule), which subsequently report a positive D-Dimer (most likely caused by another factor unrealted to any potential VTE). In these cases patient’s often undergo unnecessary imaging to “exclude” a PE.

D-Dimer also rises with age. Some centres now report an age specific reference range for D-Dimer.

• Traditional reference range for D-Dimer – normal <0.50
• Example of age adjusted:
  • Age <50 – normal <0.50
  • Age >50 – normal range is <0.50 PLUS 0.1 for every decade of life over the age of 50, e.g.:
    • Age 60 – normal <0.60
    • Age 70 – normal <0.70

Other factors that caused an increased D-Dimer include liver disease, high rheumatoid factor, malignancy, trauma, pregnancy and recent surgery.

Investigations

CXR

Will often be normal. The main reason CXR is performed is to exclude other causes.

ECG

• S waves present in lead I
• Q waves present in lead III
• T wave inversion in lead III

VQ scan

• VQ scans should not be performed in patients with CXR abnormalities –  the abnormalities on the x-ray are likely to cause abnormalities on VQ, irrespective of the presence of PE. VQ is only suitable for patients who have been previously well, and not for those with chronic disease.

ABG

• O2 may often be low
• CO2 may often be normal or low

Troponin

Troponin is raised in 20-40% of patients with PE as a result of the extras stress and stretch placed on the right ventricle in PE patients (due to increased pulmonary arterial pressure).

Higher troponin has been associated with a worse prognosis.

Echocardiography

Is used to look for right ventricle strain and dilatation in patients with suspected massive PE. The degree of RV dysfunction can be used as a predictor of death. 

Treatment

PE with signs of right heart strain in the haemodynamically unstable patient (raised troponin, heart motion abnormalities on echo – often done at the bedside in ED) should be considered for thrombolysis – e.g. 50mg alteplase (be wary of a long list of contraindications!).

This type of PE is sometimes termed “massive PE”. This scenario is typically caused by a “saddle” PE – sitting at the major bifrucation of the pulmonary veins.

Typically this is a decision made by the treating consulting in hospital (usually ED physician) perhaps in conjunction with respiratory and or haematology specialists. These patient will also require ongoing anticoagulation as below.

The vast majority of patients do not require thrombolysis and do not have massive or saddle PE.

The other main treatment is anticoagulation. This can be done either with warfarin, or a NOAC – such as rivaroxaban. In most circumstances a NOAC is favorable as it does not required monitoring, and it does not require the use of a heparin at the start of the treatment period.

Example of warfarin treatment

• Anticoagulate with LMWH – e.g. dalteparin 200u/Kg/24hrs. The max dose is 18,000.
• At the same time start oral warfarin 10mg
• Stop the heparin when the INR is >2, and continue warfarin for a minimum of 3 months, aiming for an INR of 2-3.

In patients with recurrent thrombus despite anticoagulation a vena cava filter may be considered – but remember that implanting a filter without adequate anticoagulation will increase the risk of thrombus.

Continuation of anticoagulant therapy

This decision made be made in conjunction with a haematologist.

• At the very minimum – 6 weeks. Usually in cases of obvious ‘provoked’ PE (e.g. after surgery)
• Those with an identifiable and reversible risk factor – 3 months
• Those with idiopathic disease – 6 months
• Those with recurrent clots – often longer than 6 months – sometimes lifelong
• There is also evidence that low-intensity warfarin (INR 1.5-2.0) not only reduces the risk of thromboembolism, but also has a lower risk of bleeding.

• They will often travel to the brain, and cause a stroke.

Differentials

Like any chest pain presentation, differentiating PE can be difficult. Typically, larger PE’s (and sicker patients) are easier to differentiate. Using the Chest Pain Differentializer might be useful.

Differentials include:

• Acute Coronary Syndrome
• Pleuritic chest pain
  • Pneumonia (viral or bacterial)
• Pericarditis
• Musculoskeletal back pain
• Embolus of other cause (fat, amniotic fluid, air)
• Dissecting Aortic Aneurysm
• Anxiety
• Syncope of another cause
• Exacerbation of COPD

References

• Age Adjusted D-Dimer Testing
• Clinical presentation, evaluation, and diagnosis of the non-pregnant adult with suspected acute pulmonary embolism – UpToDate

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The post Pulmonary Embolism – PE appeared first on almostadoctor.

Coagulation is the process by which blood changes from a liquid into a blood clot, to cause the cessation of blood loss from a blood vessel.

The process involves the activation, adhesion and aggregation of platelets, and the deposition of fibrin.

It can be divided into:

• Primary haemostasis – the formation of a platelet plug
• Secondary haemostasis – the activation of the clotting cascade which results in despoliation of fibrin to strengthen the platelet plug

Haemostasis

Haemostasis – is the technical name for the cessation of bleeding, and has 3 separate stages:

• The vascular phase
• The platelet phase
• The coagulation phase

In reality, these are not distinctly separate, and all occur simultaneously as a result of multiple cascades.

The vascular phase

Damage to the blood vessel wall will cause contraction in that particular area of the blood vessel. This vasoconstriction can last from 30 minutes to a few hours and can completely occlude the vessel. It occurs as a result of damage to the endothelial cells. This damage causes them to release various factors, including:

• ADP
• Tissue Factor – aka factor III – required for the activation of thrombin from prothrombin
• Prostacyclin – kind of a feedback mechanism; thisprotein actually causes vasodilation and prevents formation of the platelet plug
• Endothelins – these are the primary hormones involved in the vascular phase. They stimulate smooth muscle contraction and stimulate cell division of endothelial cells, smooth muscle cells and fibroblasts, thus aiding repair of the damaged site.

Endothelial cells also become ‘sticky’ and will express surface proteins that allow them to ‘stick’ to other endothelial cells, in an attempt to close of the damaged area.

The platelet phase

If the damage to a blood vessel is small enough, it can be ‘plugged’ by a platelet plug.
Platelets – aka thrombocytes:

• Contain actin and myosin, and as a result are actually able to contract
• They also contain another contractile protein known as thrmobosthenin
• Have no nucleus, and are thus not able to reproduce
• Have a large ER and golgi apparatus for storage of calcium ions
• Have plenty of mitochondria for formation of ATP
• Produce plenty of prostaglandins and fibrin-stabilising factor
• Produce platelet derived growth factor (PDGF) – which helps vascular repair
• Produce thromboxane A2 – which is a prominent vasoconstrictor
• They are actually cell fragments rather than actual cells – as during their development, their precursors break down to form them
• Have a special glycoprotein membrane that prevents adhesion to normal epithelium, but that promotes adhesion to damaged epithelium. they are particularly adherent to collagen – which will only be present when deep areas of the cell wall are exposed
• About 1/3 of platelets are stored in the spleen and other vascular organs at any one time – waiting to be mobilised
• Low platelet count – thrombocytopaenia – this is a process either of high platelet destruction, or low platelet production.
•  High platelet count – thrombocytosis – this is usually a result of increased platelet formation, most commonly seen in response to infection, inflammation, and cases of cancer.

Platelet formation is controlled by TPO (thrombopoietin – this is basically the platelet version of EPO!). TPO is produced mainly by the liver – thus in diseases of the liver, problems with clotting (mainly seen as manifestations of bruising) are commonly seen.
The platelet phase begins as soon as platelets begin to attach themselves to damaged areas of endothelium – normally collagen. This process begins within 15 seconds of injury.
The attachment of platelets to exposed surfaces is called platelet adhesion. As more and more platelets arrive, we get platelet aggregation, and finally, once a certain mass of platelets is reached, we have platelet plug formation.
This is a totally normally process, and will occur thousands of times a day. People with problems with platelet formation may get thousands of tiny haemorrhages, and problems bruising easily.

When a platelet becomes attached to a damaged endothelial surface, it will actually changes it own size and shape:

• It will swell, and become large and irregular
• The contractile proteins contract causing the release of granules…
• ADP, thromboxane and Ca2+ ions are all released – these can act on nearby platelets, and attract them to the site, causing them to adhere to the platelets already present. This creates a positive feedback loop, causing aggregation of more and more platelets.

There are two types of granule released by platelets:

• α – these contain growth factors, like fibrinogen and PDGF – a disease caused by a lack of α granules is called grey platelet syndrome. This is a rare genetic disorder (autosomal dominant) that causes. It will just basically cause reduced clotting.
• Dense – these contain non-protein things, like thromboxane, serotonin, adrenaline, histamine, calcium, ATP and ADP

Negative feedback of the plug formation is controlled by prostacyclin released by the endothelium. This reduces platelet aggregation. White cells in the area also release proteins that prevent the clot getting out of control. Plasma enzymes will also break down ATP that is found circulating near the plug, and thus reduce the amount of energy available to the platelets.
Fibrin – is the activated form of fibrinogen – which is produced by the liver, and also by platelets. It is activated in the clotting process, and forms lots of fibrin threads – which help to stabilise a platelet plug, as well as isolating it from the normal circulation, thus acting as a further feedback mechanism.  Fibrin is possibly the single most important protein involved in clotting!

• Fibrinogen is soluble, but fibrin is insoluble, and thus once fibrin becomes activate it begins to ‘precipitate’ out of the plasma.
• Activated fibrin will basically entangle platelets, and passing red blood cells in a big nasty ball – a blood clot!

The coagulation phase

This begins about 30 seconds after the initial injury. It involves a complex sequence of events, that ultimately lead to the activation of fibrin from fibrinogen.

The Clotting Cascade

The intrinsic pathway

• Begins in the blood stream. It is basically activated when blood is exposed to collagen (or other damaged surfaces, but collagen is the main thing involved).
• Factor XII is activated to XIIa by exposed collagen
• XIIa, with the help of HMW kininogen,activates XI to XIa. This can proceed more quickly in the presence of prekallikrein.
• XIa combines with calcium, and activates IX to IXa
  • Simultanesouly, platelets will release PF3, and also simultaneously, VIII will be activated to VIIIa.
• IXa, (with the help of PF3) will join together with VIIIa and form factor X activating factor (‘tenase’)

The extrinsic pathway

• This VIIa-tissue factor complex is quickly inactivated by antithrombin III!

The Common Pathway

• X is activated, either by VIIa or tenase , to form Xa – aka prothrombinase
• Xa, with the help of calcium ions, and Va will turn prothrombin into thrombin!
  • Thrombin is factor IIa
  • Factor V is not activated until it has come into contact with thrombin itself. Thus V is not required for this step, but when present will increase the rate.
• Thrombin will then activate fibrinogen to fibrin. Fibrin strands will begin to join together, and with the help of XIIIa this will cause the cross-linking of fibrin strands.
  • XIII is also activated by thrombin. XIII is also known as fibrin stabilising factor.

• It can activate factor VII directly
• It activates factor V

Regulation of the pathways

Drugs that affect coagulation

Heparin

HL – approx 30 minutes – but this is unpredictable! It can increase to up to 2-3 hours with larger doses.
The majority of heparin is metabolised by endothelial cells – hence its unpredictability. The rest is mainly metabolised by the liver, and some is excreted by the kidney. The half-life gets longer the greater the amount of drug you use because once you get past the ‘saturation point’ the endothelial cells can no longer cope with the drug, and thus slower mechanisms, such as renal excretion are the primary method of metabolism, until the level of drug drops below the saturation point again.
It can be given either subcutaneously or intravenously:

• Subcutaneous – low doses are often given in this manner. Bio-availability is only about 30% when you give it by this route though, so it is not good for large doses or emergencies (i.e. PE). It also takes up to an hour before the action of the drug is seen.
• Intravenous – more rapid (immediate), and much greater bioavailability. Thus in the emergency situation, it is often given as an initial IV dose, followed by subcutaneous infusion.

LMWH

• These have approximately 2x the duration of action (HL), and are far more predictable than unfractioned heparin.
• They have a lower affinity for binding sites (particularly the binding sites on endothelial cells) than unfractioned heparin, hence the greater duration of action and greater predictability.
  • Note that this will also mean that more of the heparin is metabolised by the liver than when you give unfractioned heparin.
• They have a greater effect on factor Xa, than on IIa, which suggests that they produce an equal anti-coagulant effect to heparin, but that they have a reduced risk of causing bleeding – therefore good news all round!

• Haemorrhage! – the risk is greatest in the elderly, and may be exacerbated by alcohol intake. This is by far the most common side effect.
• Protamine sulphate – This will prevent the action of unfractioned heparin – so you can give it to reverse its effects. However, it DOES NOT work for LMWH’s.
• Osteoporosis – can occur if the drug is used for more than a few weeks. This does not occur with LMWH’s.
• Thrombocytopaenia – can occur after 7-10 days of therapy. It is a result of heparin induced antiplatelet antibodies.
• Hyperkalaemia – due to inhibition of aldosterone secretion
• Hypersensitivity

• Mast cells and basophils – basically the same cells, but mast cells are found in connective tissue, and basophils are found in the blood stream.

Warfarin

• VII – has a half life of 6 hours
• IX – has a half life of 24 hours
• X – has a half life of 40 hours
• II – has a half life of 60 hours

• Absorbed rapidly and completely from the gut
• Binds well to albumin
• Peak time of action is about 48 hours after administration, but peak concentration in the blood is about an hour after administration
• The effect on prothrombin time is initially seen after 12-16 hours, and lasts approximately 4-5 days.
• Half life is very variable, but is on average about 40 hours
• It crosses the placenta, and is teratogenic – thus it should not be given in pregnancy at all! In the early stages it can causes defects, and in the later stages it can cause haemorrhages in the foetus itself – usually intracranial haemorrhage.
• It is metabolised by the cytochrome P450 system – thus it interacts with many drugs – making administration and monitoring of dosage more difficult.
• Warfarin is monitored by using the prothrombin time (PT), which is expressed as the INR. The dose of warfarin is adjusted to give an INR of 2-4

• Haemorrhage – this is especially common to the bowel and brain. This can be counteracted by the administration of vitamin K, or giving fresh plasma containing clotting factors.
• Teratogenicity (causes birth defects)
• Necrosis of soft tissues – this occurs mainly to tissues in the buttock and breast and is a result of thrombosis in venules. It generally occurs shortly after administration, and is a result of inhibition of synthesis of protein C – which is another effect of warfarin, and which happens more quickly than the inhibition of activation of vit K. thus for a short time after the initial administration, patients are in a hypercoagulant state. This is rare, but serious.
• To combat this issue, treatment is usually started with heparin, before treatment with warfarin begins.

• Liver disease – this reduces the number of clotting factors produced (2,7,9,10 are affected)
• High metabolis rate; e.g. thyrotoxicosis and fever – as these increase the rate at which clotting factors are degraded

• Agents that inhibit hepatic metabolism – such as many antifungals, and other specific drugs, including cimetidine, ciprofloxacin, chloramphenicol, co-trimoxazole, imipramine, metronidazole and amiodarone.
• Drugs that inhibit platelet function – Aspirin, and other NSAIDs – as these inhibit platelet thromboxane synthesis. Also some antibiotics, including moxalactam and carbenicillin
• Drugs that displace warfarin from its binding site on albumin – e.g. NSAIDs and chloral hydrate – as this will increase the concentration of warfarin in plasma
• Drugs that inhibits synthesis of vitamin K – such as the cephalosporins

• Pregnancy
• Hypothyroidism – where there is reduced metabolis rate, and thus reduced breakdown of coagulation factors

• Vitamin K – it is found in some vitamin preparations and some form of parenteral feeding
• Drugs that induce hepatic cytochrome P450 enzymes – this increases the degredation of warfarin. Examples include rifampicin, carbamazepine, barbiturates and griseofulvin

• Named after the Wisconsin Alumni Research Foundation – after cows feed was changed in the USA, to contain sweet clover, and loads of cows died from haemorrhagic stroke.

• Method – similar to the PT – a sample is taken, then mixed with some proteins, and the time measured until a clot forms. The clot takes longer to form than in PT, because the fluid that the blood is mixed with to stimulate clot formation has no tissue factor (III) and thus the extrinsic pathway is not activated. The word ‘partial’ is used to indicate the lack of tissue factor.
• The value obtained is normally between 25 and 39 seconds. A prolonged APPT can be caused by:
  • Use of heparin
  • Haemophilia – coagulation factor deficiency

Signs of clotting deficiency

• Easy bruising
• Nosebleeds
• Menorrhagia
• Prolonged bleeding

• The main mechanism involved is the release of tissue plasminogen activator (tPA) by damaged endothelial cells.
• Another activator; urokinase is produced and released by the kidneys as a means of prevent small clots getting lodged in the kidney tissue.
• Kallikrien and neutrophil elastase are further fibrinogenic factors.
• These circulating activators will then convert plasminogen to plasmin, which then breaks down fibrin. This actively breaks down the clot – as oppose to anticoagulants, which just reduce the chance of further clot forming.
• Fibrin fragments are broken down into D-Dimers.
• tPA can itself be inhibited plasminogen aactivator inhibitor  (PAI), and plasmin is inactivated by α2 antiplasmin.
• A lipoprotein, called lipoprotein a also inhibits tPA, and high levels of lipoprotein a are associated with an increased risk of MI

• After streptococcal infection, or after the previous use of streptokinase, its efficacy cn be seriously reduced to the presence of antibodies in the circulation. These can persist for several years.
• Streptokinase has quite a long half-life, similar to that of tenectplase (but longer than that of alteplase and reteplase).
• It is usually administered as a 1hr infusion for treatment of coronary artery occlusion, although longer regimens may be used when treating PE or other arterial blockages.

Alteplase and associated compounds are metabolised by the liver.

• Altepplase is given as a long infusion of 3-24hr due to its short duration of action patients will also be given 48hrs of heparin to prevent re-occulsion, again, a result of the short half-life of the compound.
• Reteplase is given as two bolus injections, and tenectplase as a single bolus. Although there is little evidence to support it; heparin is also given with these compounds (although a guess it would be given anyway in situations involving clot! Just not necessarily for reasons related to the –plases.

• The bleeding can be stopped by antifibrinolytic drugs, or y giving fresh plasma (which is full of nice clotting factors).

• Internal bleeding
• Haemorrhagic cerebrovascular disease
• Pregnancy
• Uncontrolled hypertension
• Recent trauma – including vigorous CPR

• It can be given orally, or IV
• It is used to treat conditions where there is serious risk of haemorrhage; commonly including dental extraction, prostatectomy and menorrhagia, as well as for life-threateneing bleeding following thrombolytic drug administration.

• Inhibition of plasmin and therefore fibrinolysis
• Inhibition of platelet activation
• Anti-inflammatory effects
• Inhibiton of kallikrien – therefore inhibition of the clotting cascade and thus aprotonin also has anti-coagulant as well as antifibrinolytic effects.

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Anticoagulation (“blood-thinning”) is a therapeutic mechanism used to reduce the risk of blood clots, or to treat already established blood clots for various indications, including; venous thromboembolism (for prevent and for treatment), atrial fibrillation, after heart valve replacement, and after acute myocardial infarction.

The drugs used for anticoagulation typically target different aspects of the clotting cascade, to alter the process by which clots form. Clots are in a constant state of flux – of being broken down, and new clot forming. By slowing down the rate of new clot formation, but leaving the rate of clot break-down unaltered, anticoagulation can prevent the formation of clots, and speed-up the break-down of larger clots. Anticoagulants do not actively cause breakdown of clots – this can be achieved by another class of drugs through a process called thrombolysis. 

• Thrombolsys is typically reserved for life-sthreating situations – such as a large pulmonary embolism causing harm-dynamic instability, or large ischaemic stroke or myocardial infarction. Thrombolysis carries significant risks of bleeding (which can be fatal). The use of thrombolysis in MI and stroke is in decline, as intervention procedures such as PCI in MI and “clot retrieval” ins stroke have become more widely available.

There are typically three types of medication used for anticoagulation:

• Heparin – of which there are severeal types with different uses – e.g. unfractionated heparin, clexane
• NOACs – novel oral anticoagulants
  • The nomenclature for this can be confusing!
  • Newer guidelines no say that NOAC stands for non-vitamin K oral anticoagulant
  • Some people now refer to them as DOACs – direct oral anticoagulants
• Warfarin

NOACs are largely superseding the use of warfarin for many indications, as they are much more convenient for patients. However, they are not easily reversible in case of massive bleed. Heparins have a narrower range of indications, but are still used in many specific situations.

NOACs

Examples: Apixaban, dabigatran, rivaroxaban

There are two basic mechanisms for NOACS:

• Dabigatran is a thrombin inhibitor (NB Dabiga-T-ran inhibits T-rhombin)
• Apixaban and rivaroxaban are factor Xa inhibitors (Api-Xa-ban, rivaro-Xa-ban)

Indications

• Treatment of newly diagnosed DVT or PE
  • Unlike with warfarin, covering with heparin for first few days is not required
• Atrial fibrillation where CHA₂DS₂-VASc score suggests the need for anticoagulation
• Prevention of VTE after surgery

Particularly for treatment of VTE and AF NOACs have mostly superseded the use of warfarin due to ease of use for the patient.

Monitoring

• Unlike warfarin, there is no defined way of monitoring the effects of NOACs

Contraindications

• Valvular heart disease or mechanical heart valve
• Renal failure (CrCl <30)
• Liver failure
• Active bleeding or history of bleeding disorder
• Pregnancy or breast feeding

Reversal

• Reversal is not straight-forward – unlike for warfarin
• A reversal agent exists for dabigatran – Idracizumab – but its efficacy is not well established
• No reversal agents exists for rivaroxaban or apixaban. Academic studies have shown that prothrombin complex (prothrombinex) can normalise prothrombin time, but it is not routine clinical practice to use it
• Dialysis may help to remove active drug from the blood and normalise clotting
• Guidelines for management of bleeding in patients taking NOACs suggest:
  • Withhold further doses
  • Send coagulation profile
  • If ingested in last two hours – use activated charcoal – especially in cases of overdose
  • Discuss with haematologist on call

Advantages of NOACs vs Warfarin

• Do not require monitoring
• Standardised dosing
• Onset of action within 3 hours – and so concurrent use of heparin as is indicated with warfarin for the first few days – is not required
• Less likely to interact with other drugs and pre-existing conditions than warfarin
• (Unproven) – possibly lower incidence of life-threatening bleeding events

Disadvantages of NOACs vs Warfarin

• Reversal is not possible with some agents, and difficult with others
• Narrower range of indications (not suitable in case of heart valves, or valvular heart disease)
• (Unproven) – possibly higher risk of GI bleeding

Warfarin

Introduction

Warfarin is a vitamin K antagonist. It is very useful, because unlike heparins, it can be taken orally.

• Remember that the extrinsic pathway produces a bit of fibrin quickly whilst the intrinsic pathway produces large amounts but takes a while to get going. Thus the PT, which is a measurement of how quickly a small clot forms, relies on the extrinsic pathway.
• INR – the internal normalised ratio. This is basically a comparison of the patients clotting ability compared to the ‘average’ of the population. It is a ratio of the patient’s PT (prothrombin time)to that of the average PT – and as a result, this test only looks at the extrinsic clotting pathway. You can use it to look at liver function, warfarin dose and vitamin K status.

 

The ISI is a different value for different drugs, but is normally between 1.0 and 2.0.
The normal INR value is between 0.9 and 1.3. When someone is on warfarin therapy, the target is usually between 2-4 but may vary for individuals. i.e. this basically means the target when on warfarin therapy is to have a prothrombin time 2-4x greater than that of the ‘average’ person
Patients on warfarin (and other vit K antagonists) need to have individualised doses, and this means the treatment in both inconvenient and has a low margin of safety. 

Mechanism

By preventing the activation of vitamin K, warfarin reduces the production of factors II, VII, IX and X.

Pharmacokinetics

• Absorbed rapidly and completely from the gut
• Binds well to albumin
• Peak time of action is about 48 hours after administration, but peak concentration in the blood is about an hour after administration
  • For immediate effect anti-coagulation, you have to give HEPARIN for the first few days of warfarin therapy
• The effect on prothrombin time is initially seen after 12-16 hours, and lasts approximately 4-5 days.
• Half life is very variable, but is on average about 40 hours
• It crosses the placenta, and is teratogenic – thus it should not be given in pregnancy at all! In the early stages it can causes defects, and in the later stages it can cause haemorrhages in the foetus itself – usually intracranial haemorrhage.
• It is metabolised by the cytochrome P450 system – thus it interacts with many drugs – making administration and monitoring of dosage more difficult.
  • Warfarin is monitored by using the prothrombin time (PT), which is expressed as the INR. The dose of warfarin is adjusted to give an INR of 2-4

Unwanted effects

• Haemorrhage – this is especially common to the bowel and brain. This can be counteracted by the administration of vitamin K, or giving fresh plasma containing clotting factors.
• Teratogenicity (meaning it causes birth defects)
• Necrosis of soft tissues – this occurs mainly to tissues in the buttock and breast and is a result of thrombosis in venules. It generally occurs shortly after administration, and is a result of inhibition of synthesis of protein C – which is another effect of warfarin, and which happens more quickly than the inhibition of activation of vit K. thus for a short time after the initial administration, patients are in a hypercoagulant state. This is rare, but serious. To combat this issue, treatment is usually started with heparin, before treatment with warfarin begins.

Interactions with warfarin

Things that potentiate the effects of warfarin

• Liver disease – this reduces the number of clotting factors produced (2,7,9,10 are affected)
• High metabolic rate; e.g. thyrotoxicosis and fever – as these increase the rate at which clotting factors are degraded

• Agents that inhibit hepatic metabolism – such as many antifungals, and other specific drugs, including cimetidine, ciprofloxacin, chloramphenicol, co-trimoxazole, imipramine, metronidazole and amiodarone.
• Drugs that inhibit platelet function – Aspirin and other NSAIDs – as these inhibit platelet thromboxane synthesis. Also some antibiotics, including moxalactam and carbenicillin
• Drugs that displace warfarin from its binding site on albumin – e.g. NSAIDs and chloral hydrate – as this will increase the concentration of warfarin in plasma
• Drugs that inhibits synthesis of vitamin K – such as the cephalosporins

Things that decrease the effects of warfarin

• Pregnancy
• Hypothyroidism – where there is reduced metabolic rate, and thus reduced breakdown of coagulation factors

• Vitamin K – it is found in some vitamin preparations and some form of parenteral feeding
• Drugs that induce hepatic cytochrome P450 enzymes – this increases the degredation of warfarin. Examples include rifampicin, carbamazepine, barbiturates and griseofulvin

Therapy regimens

• The initial PT will be measured and an individual dose will be calculated. In an emergency situation, this step may be skipped.
• Patients will usually take an initial dose of 5-10mg. Then they will have subsequent doses of 5mg. Often at day * in the INR is measured, but it is unlikely the dose will be altered at this stage as the INR is likely to be too low.
• in patients requiring rapid anticoagulation, you can give 10mg/day for 2 days
• The maintenance dose is usually between 3-9mg. This needs to be taken at the same time every day.
• Monitoring – the INR has to be monitored regularly:
• Until the target INR is reached, it needs to be monitored EVERY DAY.
• The target INR is reached when you have consistent INR values on 2 consecutive days
• Then you monitor 1-2 per week, until the week INR is stable.
• Now you can monitor every 6-12 weeks
• A change in the patient’s status, e.g. diagnosis of a new condition, requires more frequent monitoring.
• Monitoring is usually carried out at Anti-coagulant clinics. These may be available in primary or secondary centres
• Some patients may be able to self-monitor – this involves some training, but is accurate, and more convenient for patients. This basically involves an electronic portable coagulation monitoring device e.g. coagucheckS®. This looks a little bit like a glucose monitoring kit. Patients using such devices will still need regular checks at hospital to check they are using the device correctly, and managing their INR

General advice

• Take the prescribed dose at the same time every day
• Report and bruising or bleeding immediately
• Avoid pregnancy
• Avoid aspirin and other NSAID’s– use alternative painkillers / drugs. Paracetomol also interferes with the metabolism of warfarin, and vice/versa.
• Advise patients they can take up to 6 paracetomol/day when on warfarin – if they need further pain relief – seek medical advice.
• Avoid contact sports and other activities with a high risk of (head) injury
• Alcohol – can interfere with warfarin therapy, but general social/light drinking is ok. Patient’s should avoid bingeing. As long as they drink roughly the same amount from week to week, the impact on warfarin will be minimised
• Cranberry juicecan alter the metabolism of warfarin
• Drug interactions – warfarin interacts with lots of drugs. Check with a pharmacist (or BNF) before prescribing to check conflicts with patients current medications. Tell the patient to speak to their doctor or pharmacist before taking any (including herbal) medications. Also ask the patient to inform every medical practicioner that they come into contact with that they are on warfarin.
• Macrolide antibiotics – e.g. clarithromycin, erythromycin are a particularly common group of drugs that should be avoided whilst on warfarin.

Complications

• Severe haemorrhage – e.g. GI bleed – stop therapy immediately and admit to hospital
• Mild bleeding – e.g. haematuria, epistaxis (nose bleed) – stop warfarin and give IV vit K 5-10mg.

• If there are additional RF’s for bleeding, then you can give 5mg vit K IV. If the INR is still high after 24 hours, you can give another 5mg.
• If the INR is 6-8, then stop warfarin, and restart when it is in the therapeutic range
• A high INR is often due to a drug interaction. Check. Interaction include:
  • Alcohol
  • Paracetomol
  • SSRI’s
  • Lipid regulating drugs
  • Cranberry juice
  • Flu vaccine
  • St. John’s Wort
  • Allopurinol (treatment for gout)
  • Advise patients to check with pharmacists / alternative therapists when they start any new medications for interactions with warfarin
  • Changes in diet can also affect therapy – particularly big changes involving salads and vegetables.

Stopping therapy

Special instances

• Surgery – anticoagulants should be stopped before surgery. In those at particularly high risk, Heparin can be used short term. For dental surgery, as long as the INR is in the therapeutic range, then no special measures need to be taken
• Cancer patients – LWMH is better at reducing risk of embolism in these patients
• IV drug user – LMWH is preferred due to difficulties in monitoring INR due to the lifestyle of these patients.

• Warfarin is named after the Wisconsin Alumni Research Foundation – who discovered the drug after cows feed was changed in the USA, to contain sweet clover, and loads of cows died from haemorrhagic stroke.

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