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Anticoagulant Drugs – Thrombosis and Anti-Thrombotic Therapy

by Paul Moss, PhD
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    00:00 perhaps MRI scan is also needed.

    00:03 There are many drugs which have been developed for use as anticoagulants to prevent venous thrombosis. Here are some of them. Heparin, warfarin, oral anticoagulants and anti-platelet agents and we will talk about each of these in more detail. They also want to mention physical methods to prevent from those. These are widely used and highly effective.

    00:33 One is the use of support stockings for the legs and many patients who admitted to hospital who have these applied. Some people use them when they go on aeroplanes for long plane journeys.

    00:44 And at the bottom something more invasive but also effective sometimes if patients needed inferior vena cava filter, they have clogs in the legs and these clogs are traveling up with veins threatening the lungs, you can put a filter in the inferior vena cava to block their movement. It can be quite effective. Heparin is very widely used in modern medicine.

    01:17 It is a mucopolysaccharide, but it cannot be orally ingested and, therefore, has to be injected either intravenously or subcutaneously and its activity is to increase antithrombin activity. Antithrombin is not only active against thrombinocell, but a range of coagulation factors as an important anticoagulant. There are two major forms of heparin. The most common form these days is called low molecular weight heparin. You can see the molecular weight that it is 2000-10,000k and is widely used as prophylaxis to prevent or indeed its treatment for thrombosis. Often given as a subcutaneous injection once a day without monitoring of the blood test. Many many patients who get admitted to hospital for whatever reason are now given low molecular weight heparin injections to prevent the development of thrombosis.

    02:24 The older original form of heparin is the standard unfractionated heparin. This is given as an infusion or as regular injections. We used to use this and still do in some situations to increase the APTT that is the clotting time that we use to access this as a fact and one of the beauties of this heparin is you can slow and stop and reduce it and titrate it to the need of the patient. That can be very useful perhaps the patient is going for an operation in a few hours. Warfarin is being used widely in medicine over the past few decades. It is a tablet, which acts as an antagonist vitamin K and you will see on the top left, several coagulation factors II, VII, IX and X and dependent on vitamin K for their activation. Just take a time to look at that diagram on the right and you will see on the top left in pale colour that these coagulation factors are initially inactive after they are being synthesized by the liver and they need to undergo something called Gamma-glutamyl carboxylation. Oxygen has to come in and this carboxylation event takes place. Then they are activated and combined calcium and take part in the coagulation cascade and you will see the vitamin K is very important in this process of carboxylation. But it needs to be reduced again to be activated for reuse and warfarin actually inhibits vitamin K epoxide reductase. So vitamin K leads to a decrease in the top right the activated factors of II, VII, IX and X. Warfarin tends to be given for several months after patients have had an episode of thrombosis probably easier to take a tablet every day when to have injections of heparin, for instance, but also patients who had heart valves particularly the older heart valves, which were mechanical. They need warfarin for life and warfarin was a key factor leading to the success of cardiac operations. It is also used very often in patients who have an irregular heartbeat, atrial fibrillation because that can predispose people to thrombosis. The problem with warfarin is that you need to constantly check how much you are giving by titrating it against the blood test, but blood test is the prothrombin time also known as the INR, the International Normal Ratio. So initially when you start one warfarin, you might test this every few days, but hopefully when a patient is stable, you can test it every few weeks. Here we have a range of clinical indications on the left and on the right, the target INR that you might aim for with these conditions.

    05:47 So you can see a deep vein thrombosis perhaps in the legs you might want to go for an international normal ratio of 2.5. That means the prothrombin time is 2.5 times higher than the control within the laboratory and you can see by working down those indications, the source of areas where warfarin can be useful in clinical practice. However, what is quite interesting of the current time is that we are now getting a range of new tablets, which can act as oral anticoagulants and these may well replace warfarin and heparin in certain situations.

    06:33 These have a direct action on components of the haemostasis system and we will see in a minute one of the advantages is they do not need monitoring in many situations.

    06:47 Look at the diagram on the left. We got the coagulation pathway from the tissue factor, VIIa complex, which is a grade initiator of collaboration through activation of X and the amplification through factor IX leading to activation of X and Xa and of course X is activated, you can activate thrombin and fibrin and you can see down this cascade where these drugs have been targeted. Many of them inactivate factor Xa. They inhibit Xa, rivaroxaban, apixaban, edoxaban whereas at the bottom the bigger trial is the IIa inhibitor, so acting at a slightly different point in the pathway. There are some of the advantages of these agents over warfarin include the general predictable in the dosage you can give to patients, blood tests that are need to be done for monitoring of the patient and there is a lower need to adjust the dose, fewer interactions with food and fewer interactions with other drugs.

    08:10 There is some concern that the reversibility of these drugs if a patient has an acute bleed.

    08:16 That can be difficult. Finally, I want to mention fibrinolysis. We cannot just talk about the creation of fibrin and the platelet clot without talking about how it is dissolved in the body, of course, has very sophisticated systems to dissolve established clots. This is called fibrinolysis. And you will see on the right how this is achieved. A protein called plasminogen needs to be activated. We need to generate plasmin.

    08:52 Plasmin can then break down fibrin and fibrinogen into those things called fibrin degradation products. How is plasminogen activated or by a range of molecules and you can see them at the top plasminogen activators the most important one is tissue plasminogen activator, which is released from vessels at the time of injury. There are also other factors there.

    09:22 Urokinase, which is isolated from urine and important one streptokinase, which is a bacterial product being widely used in medicine over the last few years. So these agents proved very effective in the cases of acute thrombosis. So she has acute myocardial infarction, heart attack or perhaps a very severe pulmonary embolus when the patient's life is at stake and so you can inject tissue plasminogen activator, streptokinase or urokinase and they can directly lead to the dissolution of a clot. Of course, there is a risk of bleeding associated with these agents but used appropriately the balance of risk is in favour of the administration.

    10:11 Finally, let us look at antiplatelet drugs because these are so widely used every day of the current time. Aspirin, this inhibits cyclo-oxygenase and that leads to a reduction in the production of thromboxin and if you take an aspirin that will inhibit your platelets for several days. It is an irreversible step. Clopidogrel is another widely used agent, which blocks the binding of ATP, which is a receptor. ATP is very important in platelet aggregation and release. Dipyridamole, which is a phosphodiesterase inhibitor and modulates the cyclic KMP level within the platelet Let us use our knowledge of thrombosis and antithrombotic therapy to overview haemostasis and see how these fit into the response to vessel damage. At the top, we will see damage to the vessel wall and the three major responses to this. Going downwards platelet addition, aggregation and release. On the left vessel constriction and to the right activation of the coagulation cascade and that leads as you see to the bottom to the stable haemostatic plug. We have seen in this lecture how patients who are deficient in protein C or protein S or who carry the factor 5 allele, factor 5 T are more prone to thrombosis because of their inability to inactivate activated coagulation factors. We have seen how Heparin and Warfarin are also important in inactivating coagulation factors and we see in the centre the important role of antiplatelet agents in reducing the risk of thrombosis. In summary, arterial and venous thrombosis are major clinical problems in current medicine. Inherited thrombophilia and a range of environmental conditions can increase the risk of thrombosis. Heparin, Warfarin and Aspirin are well established, they are used widely for the prophylaxis and treatment of thrombosis, but excitingly a range of new oral treatments is now available which may replace those agents in many situations.

    12:41 I hope you have enjoyed this lecture.


    About the Lecture

    The lecture Anticoagulant Drugs – Thrombosis and Anti-Thrombotic Therapy by Paul Moss, PhD is from the course Hematology: Advanced.


    Included Quiz Questions

    1. Low molecular weight heparin
    2. Warfarin
    3. Streptokinase
    4. Rivaroxaban
    5. Aspirin
    1. Factor V Leiden makes the protein easier to cleave by activated protein C.
    2. Up to 30% of patients with venous thrombosis have a genetic predisposition to thrombosis.
    3. Activated protein C inactivates the activated forms of factors V and VIII.
    4. Homozygotes for factor V Leiden have a 30-140 increased risk of thrombosis.
    5. Protein S is a co-factor for protein C.

    Author of lecture Anticoagulant Drugs – Thrombosis and Anti-Thrombotic Therapy

     Paul Moss, PhD

    Paul Moss, PhD


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