Anticoagulation PReP-TEAM ENG

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Anticoagulation

PReP-TEAMKnow Your Team - Know Your Treatment

Required prior knowledge

Can describe the role of your own profession in relation to pharmaceutical care.

Can describe when to use anticoagulants for which indications

Can describe the concept of pharmacodynamics and can recognize which principle protein targets medications interact with.

Can describe the concept of pharmacokinetics, including the terms absorption, distribution, metabolism, and excretion of medication.

Learning objectives anticoagulations

Have knowledge of other healthcare worker's tasks in anticoagulation therapy

Have knowledge of anticoagulation medication and their effect

Have knowledge of general coagulation process

+ INFO

Many things can go wrong in the medication process. This may lead to hospital admission or prolonged hospital stay. The HARM Study identified anticoagulant and antiplatelet drugs as major causes of medication-related hospital admissions. One of the reasons why medication-related mistakes are made is ineffective and innefficient communication between healthcare professionals. In order to promote good teamwork between healthcare professionals, you need good experiences in interprofessional collaboration and good insight into what your colleagues know and contribute to the medication processIn this e-learning you'll build common knowledge about anticoagulation so you can effectively communicate about the topic during the workgroup. You will learn about:
When you should use anticoagulants
How the anticoagulants work
Which things you have to look out for with anticoagulant therapy

Learning objectives e-learning

When you see the icon of your profession on a page, it contains additional information specific to your profession!

MEDICINE

NURSING

PHARMACY

Navigating the e-learning

The pages of this e-learning have a navigation system. Click on the house to return to the main starting page.Click on the three lines to go to the chapter index.

Navigating the e-learning

Key messages per profession

When do I use anticoagulants?

Anticoagulants and their mechanisms

Meet our patient

What is coagulation and how does it work?

Chapters

What is coagulation and how does it work?

When a vein is damaged, blood may leak into the tissue, causing a bruise. When the skin is broken, it causes you to openly bleed. An open cut leads to blood loss but also gives an opportunity to pathogens to enter our body. In order to prevent this from worsening, the vein has to be fixed as quickly as possible. This is done through blood clotting, also called coagulation. This process runs through several steps which involves a multitude of proteins.

What is coagulation?

Click on thebold words!

When a blood vessel is damaged, the first component of our blood that comes to the rescue are the (1) thrombocytes, also known as blood platelets. These platelets change shape when active to facilitate the formation of a "plug". This plug sits at the site of the wound to block off further blood loss. Also the muscles in vessel walls constrict to minimise blood loss. Blood platelets on themselves don't form the strongest barrier and need further adhesion to properly close off the damaged vessel. Therefore, (2) fibrinogen fibres start adhering to plug as well for a stronger barrier. Outside the blood vessel, on the surface of the wound, the fibrinogen proteins get exposed to (3) thrombin, which is not normally found within the blood vessel. This exposure turns them into sticky fibrin fibers, making even more blood platelets, (4) blood cells, and other blood components to stick. The clot is formed and develops into a (5) scab. Underneath, the skin and blood vessel start (6) healing again.

What is coagulation?

Pharmacy | Nursing | Medicine

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The coagulation cascade is a very complex process with many interdependent proteins as you can see in the figure. In the end, the goal of the coagulation cascade is the formation of a blood clot to prevent bleeding. Anticoagulants target some of these proteins which will lead to decreased production of cross-linked fibrin clots. You can see how these work in the following chapters of this e-learning.

The coagulation cascade

extrinsic = = INR

intrinsic = APTT

00:00

Click on thebold words!

How fast the coagulation cascade finishes is measured with the (1) prothrombin time (PT). A prolonged PT means either an issue in the extrinsic pathway or the intended effect of anticoagulation. However, not all laboratories measure the PT in the same way. That's why an (2) international WHO standard is used as a reference value. This is then used to calculate the (3) International Normalized Ratio (INR). This INR is the ratio between a "normalized" PT (e.g. 12 seconds) and patients' PT. A person with regular coagulation would have the standard INR=1. When you use vitamin K antagonists (VKAs), the target values for the INR would be 2.0-3.0, or 2.5-3.5 for patients with a mechanical heart valve. On the other hand, we have the (4) Activated Partial Thromboplastin Time (APTT). This measures the speed of the intrinsic coagulation cascade. Normally APTT is 20-30 seconds, but with anticoagulation therapy this increases to 50-80 seconds. Reference values may differ depending on the lab that measures the APTT.

Measuring coagulation

Sex category (Female)

Age 65-74 years

Vascular disease

Stroke

Diabetes

Age > 75 years

Hypertension

Congestive heart failure

1 pt

2 pt

1 pt

2 pt

1 pt

Sc

S2

A2

Sometimes a complication only requires anticoagulation when you've properly balanced out the risks of (excessive) coagulation and (excessive) bleeding. This can be assessed with the CHADS-VASc score, which scores the risk of a stroke based on certain riskfactors. Try to recall for yourself which riskfactors contribute to an increased risk of stroke. Click on the Letters for the answers.

What is the CHADS-VASc score?

02 when do i use anticoagulants?

ANSWER

Prevention of thrombo-embolism with atrial fibrillation or mechanical heart valve

Treatment of VTE's

Prevention of venous thrombo-embolism (VTE)

Indications for anticoagulation

As you have seen, coagulation is a complex and intricate process. So when complications in this process occur (primarily in excess), we wish to decrease the rate of coagulation as this can lead to unwanted clotting.

Complications in Coagulation

For which general indications are anticoagulants used? Click the button below for feedback.

Prevention of VTE complications after hip or knee replacement surgery

Patients with a mechanical heart valve

Prevention of thrombo-embolism with atrial fibrillation

Short notice surgical procedures

High risk (life-threatening) lung embolism

Bridging of oral anticoagulation

There are some exceptions to the indications. Some examples are given here. Click the box if you think the anticoagulant applies to the indication. When finished, click here to see the answer.

When to use anticoagulants

03 Meet ourpatient

Mr. Whitaker is 76 years old and suffers from atrial fibrillation (AF). He takes apixaban twice daily for his AF. Mr Whitaker will have to be admitted to the hospital for an elective knee surgery in two weeks, which means some of his medication has to be paused. This causes a lot of confusion for him. "Why do I need to stop certain medication and continue with others? I have been taking my medication very consistenly and staying active so my heart stays good too! I hope they won't change too much..."Sometimes he doesn't want to take his medications. He says that he has been getting more bruises after he was diagnosed with atrial fibrillation.

Mr. Whitaker

Meet Our Patient

Acenocoumarol is a VKA and prevents blood clotting due to AF

Enalapril is an ACE-inhibitor and is used to treat hypertension/heart failure

Diltiazem is a calcium antagonist and "adjusts" the heart rate in AF

Apixaban is a DOAC and prevents blood clotting due to AF

Paracetamol is a painkiller and is not used directly to treat AF

Omeprazole is a PPI and is used to treat excessive acid in the stomach

Povidone eye drops are used to treat Mr. Whitaker's dry eyes

Amitriptyline is a tricyclic antidepressant and is not used to treat AF

Lorazepam is a benzodiazpine and is used for sleep complications

Candesartan is an ARB and is used to treat hypertension/heart failure

Metoprolol is a bèta-blocker and "adjusts" the heart rate in AF

Enalapril is an ACE-inhibitor and is used to treat hypertension/heart failure

Correct! Acenocoumarol is a VKA and prevents blood clotting due to AF

Correct! Diltiazem is a calcium antagonist and "adjusts" the heart rate in AF

Correct! Apixaban is a DOAC and prevents blood clotting due to AF

Paracetamol is a painkiller and is not used directly to treat AF

Omeprazole is a PPI and is used to treat excessive acid in the stomach

Povidone eye drops are used to treat Mr. Whitaker's dry eyes

Amitriptyline is a tricyclic antidepressant and is not used to treat AF

Lorazepam is a benzodiazpine and is used for sleep complications

Candesartan is an ARB and is used to treat hypertension/heart failure

Correct! Metoprolol is a bèta-blocker and "adjusts" the heart rate in AF

Apixaban is used for Mr. Whitaker's AF. Which other medication could be indicated for AF as well? Click on the medications in the medication history below you think are indicated for AF.Click here to see the answers.

Current medication:
Metoprolol
Candesartan
Lorazepam
Amitriptyline
Apixaban
Povidone eye drops
Omeprazole
Paracetamol
Medication from history:
Diltiazem
Acenocoumarol
Enalapril

Mr. Whitaker's medication history

anticoagulants and their mechanisms

+ INFO

Low Molecular Weight Heparins

In short, these are the different anticoagulants that are used to treat excessive clotting.To jump to one anticoagulant-group, click

The Different Anticoagulants

Heparin

Direct Oral Anticoagulants

Vitamin K Antagonists

Click on thebold words!

VKAs inhibit the enzyme (1) vitamine K-epoxide-reductase. This breaks down the vitamin K production cycle. (2) Procoagulation factors IX, X, XII and II are vitamin K dependent for their production. You can remember this with the mnemonic 1972. Inhibiting these will prevent formation of (3) fibrin clots. Anti-coagulant factors (4) APC and protein S are vit. K dependent as well and react faster to a decreased vit. K than the other factors. That's why the first few days, there is more net bleeding than net anticoagulation.Important to note is that ALREADY PRODUCED procoagulation factors are NOT impacted, only the production of NEW factors.

Vitamin K antagonists (VKAs)

Vitamin K is a natural antagonist of a VKA. Try to keep food intake with high vitamin K content (like green leafy vegatables) to a minimum. Substances that can increase bleeding, like alcohol, nicotine NSAIDs and corticosteroids, can lead to more substantial bleeding in combination with a VKA. Other interactions to look out for are CYP-interactions.

VKAs can't be used in all cases. Contra-indications are: pregnancy, use close to surgery of the eye or central nervous system, bleeding tumors, sepsis or increased fibrinolytic activity. An increased risk of bleeding with these indications is of higher concern. VKAs cross the placental barrier, which can lead to deformities in the unborn child, which makes the use in pregnancy dangerous.

VKAs inhibit coagulation, so the risk of bleeding is increased. Important signs of bleeding to look out for is (excessive) bruising and blood in the stool of patients. These are cases of internal bleeding.

Click on the boxes to see the answer

Things to look out for with VKA use

What adverse effects can occur?How do you observe and treat them?

Which complications or patient characteristics are not suitable for VKA use?

What comedications or substances should not be taken concomitantly with VKAs?

In case of a patient bleed, we measure the INR and stop lower the dose or stop the VKA. In case of a heavier bleeding, an antidote might be necessary. Which antidote may be appropriate in this case?

2.5-3.5

2-3 days

Cofact

3.0-4.0

1.5-2.5

Idarucizumab

Andexanat ɑ

1 week

1 day

It takes some time before a VKA has reached full effect, because they only inhibit production of NEW factors . That's why we start with a loading dose. How long does this loading phase take normally?

5-6 days

Fytomenadion

2.0-3.0

(Maintanance) dosage of VKAs depends on the indication and the INR. This is adjusted routinely. What is the INR reference range?

Dosing of VKAs

Click on thebold words!

DOACs have a similar effectiveness as the VKAs, but directly inhibit the coagulation factors. These are the (1) factor Xa for apiXaban, rivaroXaban and edoXaban and (2) thrombin for dabigatran.DOACs have a shorter halftime than VKA's: 2 vs. 5 days. This makes DOACs safer to use around high-risk operations. There's also no need for routine screening.

Direct Oral AntiCoagulants (DOACs)

Important interactions to look out for are with CYP3A4 or Pgp-inducers & inhibitors. Examples of inducers are rifampicin or carbamapazin. These lower the DOAC concentration (decreased anticoagulant effect). Examples or inhibitors are antifungal medication (-azoles) and HIV protease inhibitors, like ritonavir. These increase DOAC levels (increased bleeding risk).

There are several DOAC specific antidotes: Idaracuzimab for dabigatran and Andexanet alfa for apixaban and rivaroxaban. Edoxaban does not have a registered specific antidote yet. In case these antidotes aren't available, prothrombin complex (Cofact) can be used.

Click on the boxes to see the answer

Things to look out for with DOAC use

Age, bodyweight, and kidney function are the main patient characteristics to take into account. In case a patient is older, has a lower weight or decreased kidney function the dosage is lowered.

What comedications or substances should not be taken concomitantly with DOACs?

What patient characteristics decidethe dosage of DOACs?

How do you treat bleedings caused by DOACs?Which antidotes are available?

(1) It is possible to directly switch from a VKA to a DOAC without overlap. (2) It is possible to directly switch from a DOAC to a VKA without overlap.

70 years

1: False | 2: True

1: False | 2: False

1: True | 2: False

80 years

65 years

From what age should you consider halving the dosage of apixaban as a risk factor?

75 years

1: True | 2: True

Below which kidney function (in creatinine clearance ml/min) is dabigatran contra-indicated for adult patients?

Dosing of DOACs

Click on thebold words!

Unfractionated heparin (UFH) directly inhibits activated coagulation factors, (1) thrombin and (2) factor Xa. In low doses, heparin mainly targets Xa, in high doses heparin also thrombin. It works quickly, after intravenous administration within 20-60 minutes. Its effect is sustained over 12-24 hours. Heparin also (3) activates anti-thrombin (III) to a lesser extent.LMWHs contain heparin fragments with a lower molecular weight. The smaller fragments stick less to the arterial walls or proteins, which makes their effect a lot more predictable. LMWHs are 2-3 times more active against factor Xa than thrombin compared to UFH.

Low Molecular Weight Heparins (LMWH) & Heparins

Click here to see how HIT develops

Things to look out for with heparin/LMWH use

Bleeding is a major concern with heparin and LMWHs, but heparin induced thrombocytopenia (HIT) can occur in rare cases. This is a life threatening syndrome, which develops within 5-15 days after exposure to heparin or LMWHs. The chances of developing HIT are lower with LMWH use than unfractionated heparin. HIT is diagnosed based on clinical symptoms such as fever, hypertension, tachycardia, shortness of breath and thrombotic events. In lab testing, you observe decreased platelet count. The heparin should be stopped and the patient should never receive UFH or LMWHs again, as a "cross-reaction" may occur. It is important to register this as a contra-indication. As an alternative, danaparoid of fondaparinux may be used as substitute fast-acting anticoagulants without eliciting HIT.

The Tmax of heparins is roughly 4 hours. That's the best time to measure the aPTT.

10hr.

9hr.

8hr.

7hr.

6hr.

5hr.

4hr.

3hr.

2hr.

1hr.

The activity of UFH is measured with an aPTT screening (do you remember what this value is with heparin use?). It is important to time this measurement well to get a good indication of the effect. When should the aPTT be measured with heparin use? Click on timeline below.apTT should be measured [...] after UFH initation

ObesityDecreased kidney function (< 30 ml/min)Liver diseasePregnancyHypertensionNeonates/children

Measuring effectiveness

Because an LMWH mostly targets factor Xa, the effectiveness in therapeutic use is measured through anti-Xa activity screening. This is not always relevant to measure, only for certain patients. Which of the following factors does NOT require anti-Xa screening?

Protamine can be used as an antidote for UFH but is less effective against LMWHs (25-50% effective)

LMWHs are dosed per weight-range. For nadroparin for example: 5700 IE for 60–69 kg, 4750 IE for 50-59 kg. In patients with obesity, it's not clear yet what the optimal dosing is; whether it should be capped or still dosed based on bodyweight. Anti-Xa screenings are also not accurate. So in obese patients, dosing LMWHs can be quite difficult.

Heparin is dosed based on kg AND the aPTT, where adjustment of dosage may be necessary. That's why administrating heparin via pump is more convenient, as you can adjust the administration rate quickly.

Both are used either intravenously or subcutaneously.

+ INFO

UFH and LMWH are dosed based on weight and indication. For LMWH, kidney function is important as well, as it is excreted via the kidneys.

Dosing UFH & LMWH

DOACs generally don't require monitoring, whereas VKAs require regular monitoring of the INR to adjust dosage. LMWHs and heparin do not require routine monitoring for prophylactic doses, but may require monitoring at therapeutic doses. This is only the case with certain characteristics; in children, and patients with decreased kidney function, high BMI, or pregnancy.

DOACs have a similar (and possibly even lower) risk of bleeding compared to VKAs. With VKAs, however, these risks are easier to monitor when the INR gets too high. Both have their specific antidotes, where fytomenadion is cheaper than idarucizumab or andexanet alfa.LMWHs and heparins have a higher bleeding risk, especially in higher doses. That's why for therapeutic use with high doses, an intramural setting with controlled patient monitoring is more appropriate.

For patients with an inconsistent lifestyle, DOACs are preferable. When it comes to polypharmacy, both VKAs and DOACs have many drug-interactions. That's why it's important to stay vigilant of a patient's medication list. For patients in unstable conditions or declining health, keeping an eye on their kidney function can be crucial, as DOAC dosage may have to be adjusted. DOACs may also not be used in patients with a mechanical heart valve.

Because DOACs have a set dose, it's more patient friendly. The frequent dose monitoring and dose adjustments of the VKA's make it less patient friendly.Because LMWHs/heparins are taken intravenously or subcutaneously, it's less patient friendly. That's why their use is limited to bridging in an outpatient setting.

DOACs and VKAs are first choice to prevent and treat thrombo-embolic events. Nowadays, patients are almost always started on DOACs unless there's a contra-indication. Patients who use VKAs and react well to them are mostly kept on VKAs and are not necessarily switched to DOACs.LMWHs and heparin are used as prophylaxis of thrombo-embolic events, especially in cases where oral anticoagulants are not appropriate, for example right after surgeries, when anticoagulation is urgent, or in pregnancy.

Certain things are important to consider when working with anticoagulants for Mr. Whitaker. Click on the (+) for more information about these different considerations for each anticoagulant group. Click on the (+) again to hide the Tooltip. After this, we wrap up the e-learning with 6 follow-up questions with Mr. Whitaker.

Considerations for anticoagulants

True

False

7 days

5 days

3 days

72 hours

1 day

48 hours

24 hours

Anti-Xa

INR

aPTT

1 hour

(1 of 2)

Patients receiving an elective knee surgery on apixaban should always be bridged with an LMWH.

Which laboratory test is most appropriate for assessing bleeding risk pre-surgery (considering apixaban)?

How many hours post surgery should he resume his apixaban to balance risk of thrombosis and bleeding?

How many days before the scheduled knee replacement surgery should Mr. Whitaker discontinue his apixaban?

Follow-up with our patient

Mr. Whitaker's surgery

In a few days, our patient's surgery is planned. The orthopedic surgeon advises to discontinue his apixaban a few days before the procedure to minimize bleeding risks during surgery.

Mr. Whitaker's surgery

In a few days, our patient's surgery is planned. The orthopedic surgeon advises to discontinue his apixaban a few days before the procedure to minimize bleeding risks during surgery.

(2 of 2)

Follow-up with our patient

The patient suffers from AF or a CHA2DS2VASc > 5

The patient has a decreased kidney function

The patient has a mechanical heart valve

"Wait until the surgical wound is completely healed before restarting apixaban."

The patient had a stroke, episode of systemic emboli or VTA in the last 3 months

"Contact your healthcare provider if you experience unusual bleeding/bruising after restarting apixaban."

"Resume apixaban immediately after surgery to prevent blood clots."

What key information should Mr. Whitaker receive regarding the resumption of apixaban after surgery?

"Take a higher dose of apixaban for the first week after surgery."

In which of these scenario's would bridging therapy NOT be advisable for a patient with VKA use?

Pharmacy | Nursing | Medicine

Proceed for

05 key messages per profession

Finish the e-learning

Regular monitoring and assessment of coagulation parameters is necessary for effective and safe treatment.
Individual variations in patient characteristics (especially metabolism) may influence the response to anticoagulants. Personalised care is important
Identify and avoid drug interactions and contraindications of anticoagulants, especially in patients with complex drug regimens.
Collaboration with physicians and nurses, in managing anticoagulation is important in reducing risks to patients.

Anticoagulation | Pharmacy

Finish the e-learning

Regular monitoring and assessment of coagulation parameters is necessary for effective and safe treatment.
Be wary of bleeding in patients, mainly in the form of bruising. Try to keep these bleeding risks to a minimum.
The use of VKAs can be complicated for patients due to adjustments in doses. Therefore, monitor adherence carefully.
Subcutaneous administration of LMWHs can also be a problem. In this, good guidance is crucial.Collaboration with doctors and nurses, in managing anticoagulation is important in reducing risks for patients.

Anticoagulation | Pharmacy

Finish the e-learning

DOACs are now first choice for oral anticoagulation, but there are still exceptions. Prefer to keep patients who respond well to VKAs on VKAs.
The coagulation cascade offers great insight into when and why anticoagulants work. Knowing and understanding this helps with pharmaceutical decision making.
HITs are rare but life-threatening. Stay vigilant for symptoms that arise after a few days that may indicate this.
Collaboration with pharmacists and nurses, in managing anticoagulation is important in reducing risks to patients.

Anticoagulation | MEDICINE

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We've gone through several aspects of anti-coagulation for the different professions. We will discuss your perceptions of roles and responsibilities in pharmacotherapy and work on a case-simulation in interprofessional groups. For this, do the following:1) Reflect on these statements and bring you answers to the workgroup.
How do you represent your health care profession in anticoagulation therapy?What are your responsibilities?
How do you think other health care professions are involved in this process?
What skills/competencies do you need to possess to participate in collaborative practice?
2) Download the app Team Up! Find Team Up! in the Google Play Store/App store or scan the QR codes below.

Other risk factors are a body weight < 60 kg and a serum creatinin > 133 µmol/L. When a patient has 2 of the 3 mentioned risk factors, the apixaban dosage should be halved.

This is the right answer

Click on (X) to try again.

This is the wrong answer

Restarting apixaban 48 hours after surgery increases the risk of thrombosis as he won't be treated for his atrial afibrillation in time.

This is the wrong answer

This is the right answer

Cofact, also known as prothrombin complex, is a mix of different coagulation factors which have been inhibited by anticoagulants. The excessive depletion by VKA will be counteracted by supplying more factors. Cofact is a good option in case fytomenadion was not effective enough.

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