As discussed in the article “The Clotting Cascade Made Easy”, a blood clot is formed when activated platelets are trapped in stabilised cross linked fibrin. The process of fibrin formation is controlled by procoagulation factors (factors that promote blood clotting) and anticoagulation factors (factors that inhibit blood clotting). If the ability of the body to maintain this equilibrium is disrupted, we could either bleed to death or become one big blood clot!
If a person has a higher risk of clot formation, there are various drugs available that work on different areas of the clotting cascade to disrupt the clotting process. There are three main types of drugs used in the management of blood clots.
Anticoagulant drugs: for people with a tendency to form clots in the slow-flowing blood in the venous system. They have the ability to stabilise an existing clot so that it does not break away and become a circulation stopping embolism, but they cannot actively break down the clot. The main drugs we will explore in this article include:
- Unfractionated Heparin
- Low Molecular Weight Heparin (LMWH)
Antiplatelet drugs: for people with a tendency to form clots in the fast-flowing blood in the arterial system. They reduce the ability of platelets to stick together when the blood flow is disrupted, thereby reducing the risk of clot formation. This group includes drugs such as Aspirin, Clopidogrel, Abciximab, Tirofiban and Dipyridamole; which will not be covered within the scope of this article.
Thrombolytic/fibrinolytic drugs: for people requiring emergent breakdown of a clot that has already formed. These drugs are administered intravenously only in hospital following an acute blockage of a blood vessel within the heart, lung or brain. This group includes drugs such as Alteplase, Reteplase, Tenecteplase and Streptokinase; which will not be covered within the scope of this article.
In order to discuss how anticoagulants work, we need to revisit the clotting cascade (hopefully this flowchart is now a lot easier to understand after reading the article mentioned above):
Antithrombin III is one of the opposing anticoagulation factors naturally occuring within the body. It’s function is to prevent the activation of thrombin, factor 10 and factor 9. Unfractionated Heparin, generally referred to as Heparin, binds to antithrombin III within the blood. This causes a conformational change to antithrombin that accelerates the inactivation process of thrombin and factor 10 by 2000 – 4000 fold. This significantly slows down the conversion of prothrombin to thrombin, thereby resulting in a decreased ability for the blood to clot.
If we start to look further into the clotting cascade, we find that thromboplastin is a plasma protein that catalyses the conversion of prothrombin to thrombin. The period of time taken for this conversion to occur through the intrinsic and common clotting pathways is measured by an Activated Partial Thromboplastin Time (aPTT). This time is normally between 30 – 40 seconds. If this time is prolonged, the clotting cascade is slowed down thereby reducing the ability of the body to clot. It is for this reason that a high aPTT is associated with an increased risk of bleeding. As Heparin directly influences the conversion of prothrombin to thrombin, the anticoagulant effect of Heparin is monitored via the aPTT of the patient.
Low Molecular Weight Heparin (LMWH)
The most common LMWHs currently utilised are Enoxaparin (Clexane) and Dalteparin (Fragmin). As with unfractionated Heparin, LMWHs also bind to antithrombin III within the blood. Once again, this causes a conformational change to antithrombin III. However, this change predominantly accelerates the inactivation process of factor 10 with little effect on thrombin. As LMWHs do not directly impact the conversion of prothrombin to thrombin, the measurement of an aPTT is not required. Due to a more predictable pharmacokinetic profile, decreased monitoring requirements and ease of use; LMWHs are becoming more popular than unfractionated Heparin when choosing an anticoagulant therapy for a patient.
Warfarin inhibits the synthesis of vitamin K dependent coagulation factors which are our Australian TV channels: factors 2 (prothrombin), 7, 9 and 10. The greater the dose of Warfarin administered, the greater the degree of inhibition. By looking as the clotting cascade above, it is clear to see that this inhibition will have the most potent effect on the ability for the body to clot.
To optimize the therapeutic effect of Warfarin without risking dangerous side effects such as bleeding, close monitoring of the degree of anticoagulation is required. The period of time taken for blood to clot through the extrinsic and common clotting pathways is measured by a Prothrombin Time (PT). This time is normally between 11 – 13 seconds. The International Normalised Ratio (INR) is calculated by the PT of the patient divided by the expected PT in healthy subjects in the following manner:
INR = (prothrombintest / prothrombincontrol)ISI
Therefore, a normal INR should be between 0.8 – 1.2 as follows:
- 11 seconds / 13 seconds = 0.8
- 13 seconds / 11 seconds = 1.2
The international sensitivity index (ISI) further takes into account the variability of results obtained utilising different commercial systems around the world, allowing the INR to be compared readily on an international level.
If Warfarin lengthens the PT of a patient to 26 seconds or 52, they would have an INR of approximately 2 or 4 respectively if normal PT is said to be 13 seconds:
- 26 seconds / 13 seconds = INR 2
- 52 seconds / 13 seconds = INR 4
What the INR is effectively telling us is how many more times the PT of the patient is when compared to a normal PT. The target INR level varies from case to case depending on the reason the patient is on Warfarin therapy, but tends to be 2 – 3 in most conditions. These conditions include stabilising pre-existing clots or to prevent the formation of clots in people who have atrial fibrillation and/or valvular heart disease. A higher INR of 2.5 – 3.5 tends to be required in patients with mechanical valves. In order to closely monitor INR within the target range, patients on Warfarin are required to have regular blood tests.
It is important to note that there are two brands of Warfarin currently available in Australia, Coumadin and Marevan. The interchangeable use or switching of these two brands have traditionally been avoided as differences in the excipients between the different brands may theoretically affect bioavailability. However, systematic review comparing six international Warfarin brands found that switching brands was relatively safe. Regardless, another important deterrent for switching brands is the potential for confusion in patients due to different strengths and colours of the medications, potentially resulting in incorrect dosage. The manufacturer has been approached to phase out one brand, with a recommendation that Coumadin be primarily used.
For the longest time, Warfarin was the only oral anticoagulant available on the market and was the mainstay for long term anticoagulation. This has changed in recent times with the introduction of the New Oral AntiCoagulants (NOACs) such as Apixaban (Eliquis), Rivaroxaban (Xarelto) and Dabigatran (Pradaxa). These NOACs boast a reduced requirement for blood tests due to the mode of effect, which is an entire article on it’s own and therefore will be discussed in a separate upcoming article.
- Chen, F., Wang, I., Graudins, L., & Hopper, I. (2015). Warfarin brands. Australian Prescriber, 38(5), 150 – 151. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4657302/pdf/austprescr-38-150b.pdf
- Merli, G. J. & Groce, J. B. (2010). Pharmacological and clinical differences between low-molecular-weight heparins: Implications for prescribing practice and therapeutic interchange. Pharmacy and Therapeutics, 35(2), 95 – 105. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827912/pdf/ptj35_2095.pdf
- Therapeutic Goods Administration. (2017). Product information: Clexane and clexane forte. Retrieved from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06891-3
- Therapeutic Goods Administration. (2017). Product information: Coumadin. Retrieved from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-02588-3
- Therapeutic Goods Administration. (2017). Product information: Heparin injection. Retrieved from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-06999-3
- Therapeutic Goods Administration. (2017). Product information: Marevan tablets. Retrieved from: https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2009-PI-00943-3
- Zehnder, J. L. (2017). Clinical use of coagulation tests. Retrieved from: https://www.uptodate.com/contents/clinical-use-of-coagulation-tests
If you liked this post, why not subscribe to Blogging for your Noggin? Be one of the first to know when new content becomes available! I promise there will be no annoying spam!