by Pravin Shukle, MD

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    00:01 Let's move on to heparin. So heparin is a huge molecule, you can see the chemical structure here.

    00:07 Obviously you don't need to know the chemical structure, just know that unfractionated heparin can have a multiplicity of molecular weight. Some of the heparin molecules are 3000 Daltons in weight. Some of the molecular weight are 25000.

    00:22 We call that unfractionated heparin. It's old school. It is highly acidic so it's neutralized by a base, and that base can be protamine. So protamine zinc is commonly as an antidote to heparin. Now heparin binds to antithrombin III and it forms a complex. And that complex inactivates thrombin. And it also inhibits factor Xa and other factors that we won't get into right now. The important point is, is that unfractionated heparin has a multiplicity of molecular weights, and it's a large molecule. It's always given subcutaneously. We never ever want to give this drug intramuscularly.

    01:03 It may cause a moderate, transient thrombocytopenia. And the thing that we always bring up in exams is heparin induced thrombocytopenia and thrombosis. It's a potentially fatal complication. I've had a few patients actually with HITT, and they are not fun to manage. This is something that we often ask on exams, so when you have a patient, clinical scenario on an exam, where they are starting to have thrombocytopenia and thrombosis and purpura, and they are on heparin, you should think about HITT. Heparin, the unfractionated version may also be linked to osteoporosis when you use it chronically. So, we had problems with unfractionated heparin, so we came up with a new type of heparin called low molecular weight heparin. They don't bind to thrombin but they do still inactivate factor Xa.

    01:53 Therefore the APTT test is not a reliable test when we are using the low molecular weight heparins.

    02:00 So sometimes we will use factor Xa levels to determine whether or not the low molecular weight heparins are working or not. But the real world issue is, is that because they are so predictable we rarely use blood test to confirm activity. They are usually given once a day or twice a day as a subcutaneous injection.

    02:20 The most commonly used are enoxaparin, dalteparin and tinzaparin. There are others that are on the market but these are the ones that you are going to see on your exam. Just remember the suffix, and you should be able to identify the low molecular weight heparin. The next interesting drug in the anticoagulation world, with respect to heparin is fondaparinux. Now if you like, take a look at this huge heparin molecule, you can see something that I've circled in green for you, and that five sided pentamer, is the active portion of heparin. And what some companies have done is they have actually isolated that pentamer. That is probably the most active portion of heparin and it activates antithrombin III. In fact it is so powerful that it actually increases the anticoagulation effects of antithrombin III by almost a thousand times. It does not inhibit thrombin and it's used daily subcutaneously.

    03:17 Look at this cute little guy, this is the medical leech. The medical leech, it's first name is Hirudo, and so not suprisingly we developed a drug that came from the toxin of the leech called hirudin.

    03:31 This particular direct thrombin inhibitor binds to thrombin itself and all of the thrombin substrates.

    03:38 And when it binds to the thrombin in the serum, it will cause less clotting. But what's unusual about this drug, and it's unlike heparin and the other drugs, is that it also binds to thrombin within the clot itself.

    03:52 Remember that heparin was this huge molecule. This is a small molecule that can get into clots.

    03:57 So one of the things that we like to use this drug for are for people who have had bad reactions to heparin, like HITT, we use this instead.

    04:07 We can use the APTT to monitor the effects of hirudin. There is bivalirudin, there is a bunch of other drugs that are used in this drug class. There is a short acting version of this drug that's used in the cath lab, and that particular agent binds to the thrombin only. We have a new drug class called the direct antithrombin inhibitors.

    04:31 These drugs are generally called NOACs because they stand for novel anticoagulant drugs. But because they have been on the market now for 5 or 6 years, we've kind of discarded the word NOAC. Pradaxa or dabigatran is used as a twice daily drug.

    04:46 You can see that it's much smaller than the heparin molecule. It's approved for stroke prevention in atrial fibrillation.

    04:53 It's also used for DVT prophylaxis in post-op hip and knee surgery. The antidote has just come out in March of 2016, called Praxbind. It is a monoclonal antibody. It was approved for use in March of 2016. It may or may not be on your exams.

    05:14 I can't actually tell you that now because the exams for 2016 have already been prepared and so this drug may have come out slightly after the exams have been made.

    05:24 Let's go to the old stand by warfarin. Warfarin is the most commonly used drug in the entire lecture class.

    05:32 There are several derivatives that are used in Latin America and in the European Union, but in general warfarin is the most commonly used globally. It is a small molecule, it's lipophilic, it does interfere with vitamin K dependant factors.

    05:48 It inhibits specifically the vitamin K epoxide reductase or VKOR. So VKOR, or vitamin K epoxide reductase may be a term that you see in your exam, and in your exam prep, remember that warfarin inhibits that. Warfarin therefore inhibits factors II, VII, XI and X. You need to know those factors. These are factors that we like to ask questions on.

    06:15 What's interesting about warfarin and what's fun about warfarin is that it actually inhibits factors C and S as well.

    06:21 So although it inhibits procoagulant factors, it also inhibits inhibitory factors too. Why is that important? Well I'll show you.

    06:31 Take a look at this graph. You can see in blue that factor C is one of the first factors that's inhibited by warfarin.

    06:42 So, inhibition starts with the inhibitory factors, protein C and S. This actually gives a procoagulant effect.

    06:51 So that means that after day 1, the other factors are affected but overall you have initial period of hypercoagulability followed by hypocoagulability. This makes for a real headache in the real world. So sometimes we have patients, when we put them on warfarin actually form clots more, when we start them on the drug. That's why in high risk patients we bridge them. So we may bridge patients who are high risk with heparin for a couple of days, when we first start warfarin.

    07:22 And then once they get past that procoagulant activity, and these other factors start to come into play, that's when we can drop the heparin and just use warfarin on it's own. And then we monitor INR.

    07:35 Now there is going to be a number of interactions with warfarin. There is non-pharmacological interactions and there is pharmacological interactions. Let's talk first about non-pharmacological interactions. Normally, vitamin K is produced in part by gut flora or normal bacteria in the gut. If we give a patient antibiotics we may kill off some of these bacteria and therefore you have lower levels of vitamin K. When you have lower levels of vitamin K you don't produce clotting factors as quickly. So often, 3 to 7 days after you start a broad spectrum antibiotic, the INR's start to climb.

    08:14 So it's very important if you have patients on warfarin, you monitor the INR's about once a month if they are stable but as soon as they're started on an antibiotic, you have to monitor them once a week. I have 1200 patients on warfarin, it's a real headache. It's one of the reasons why most doctors don't like to use warfarin, because it's so much work.

    08:34 The inhibitors of warfarin which are listed here, reduce the clearance of warfarin and therefore the INR will climb.

    08:40 So it's really important knowing that there are a lot of drugs that are going to interact with warfarin, as well as the antibiotics through a non-pharmacological pathway. The new class of drugs that are factor Xa specific, directly bind to factor Xa. They are known as rivaroxaban and apixaban. There are few more coming out in 2017 that you will also need to know. They all end in -xaban. So that's how you can remember them. They are approved for use in stroke prevention in non-valvular atrial fibrillation. Now there are studies going on right now to figure out if we can use it in people with artificial heart valves and significant valvular disease as well, and we will just have to wait and see if those indications come through as well. They are also used extensively in post-op hip and knee patients to prevent deep veneous thrombosis. And they may soon be used in aspirin replacement therapy. So there is a study going on right now called the COMPASS study, looking at one of these drugs in replacement of aspirin at low doses. At this point in time we have no specific antidote to these drugs.

    09:50 We use drugs like Octiplex and other platelet rich plasma transfusions to try and mitigate the effect of them.

    About the Lecture

    The lecture Anticoagulants by Pravin Shukle, MD is from the course Pharmacology of Blood Coagulation. It contains the following chapters:

    • Anticoagulants: Heparins and Fondaparinux
    • Anticoagulants: Direct Thrombin Inhibitors
    • Anticoagulants: Warfarin
    • Anticoagulants: NOAC's – Factor Xa Inhibitors

    Included Quiz Questions

    1. Osteoporosis
    2. Thrombocytosis
    3. Thrombosis
    4. Vitamin K deficiency
    5. Injection site reaction
    1. Dabigatran
    2. Dalteparin
    3. Fondaparinux
    4. Enoxaparin
    5. Unfractionated heparin
    1. Factor Xa
    2. aPTT
    3. Adenosine
    4. Fibrinogen
    5. INR
    1. Direct thrombin inhibitors
    2. Warfarin
    3. PDE inhibitors
    4. COX inhibitors
    5. Unfractionated heparin
    1. Factor C & S
    2. Factor II
    3. Factor X
    4. Factor IX
    5. Factor VII

    Author of lecture Anticoagulants

     Pravin Shukle, MD

    Pravin Shukle, MD

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