Normal Hemostasis Pharmacologic Anticoagulants

by Carlo Raj, MD

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    00:03 Let’s take a look at some pharmacologic anticoagulants for us.

    00:06 First, we'll take a look at heparin.

    00:08 Remember, heparin will never be given for you, clinically.

    00:12 Will never been given outside of the hospital.

    00:14 Heparin will only be given parentally, not orally.

    00:18 Heparin can be given either in the form of IV, or can be given in the form of subcutaneous.

    00:25 Heparin, can it be given during pregnancy? Yes it can.

    00:30 It is not teratogenic.

    00:32 Warfarin, however, cannot be given during pregnancy.

    00:34 It must be removed.

    00:35 Warfarin will wage war upon the child, the fetus.

    00:39 You can’t do that.

    00:40 Heparin can be given if need be.

    00:43 How quickly does heparin work? Like that.

    00:47 Like that, because heparin works upon antithrombin three.

    00:54 What factor is thrombin? T as in thrombin, T as in two.

    01:00 So heparin like this, activates antithrombin three, in which it knocks out your thrombin.

    01:08 So if you don’t have the thrombin, guess what you cannot do.

    01:11 You can’t formally form a plug.

    01:13 It works within seconds, heparin does.

    01:16 And there's a small population, in which, look for this at the site of injection of your heparin.

    01:24 The patient may then form a clot.

    01:28 Excuse me, yes.

    01:30 There is a subset of population, who will develop autoantibodies that will activate platelet Factor IV on your platelet and instead of inhibiting platelet activation, it actually activates your platelet forming a thrombi at the site of injection.

    01:50 Now, here’s a scenario that you’ll be given.

    01:53 If this condition, we call heparin induced thrombocytopenia, HIT.

    02:01 Heparin induced.

    02:02 What did it do? In that subset of population, it formed a thrombi.

    02:06 Where? At the site of injection, number one and number two, it activate a platelet so much, and you form so many thrombi that the platelet count will decrease.

    02:16 Heparin induced thrombocytopenia.

    02:19 If that's the case, I want you to give me a drug or classification of drugs, that will be an alternate for giving heparin.

    02:29 It’s called dabigatran or maybe argatroban.

    02:34 Dabigatran is the only oral, direct acting thrombin inhibitor called dabigatran.

    02:41 We'll talk a little bit more as we proceed.

    02:44 What about warfarin? Warfarin completely different, Warfarin can be given orally.

    02:50 Another name for warfarin is coumadin.

    02:52 Now, warfarin could be given out.

    02:54 When would you even think about giving these drugs by the way? Will the thrombi be located more so on the arterial side or would it be located more in the venous side? That’s an interesting topic, isn’t it? Who was the patient that I gave you earlier.

    03:08 Who said, "Doc, I have pain." "Where?" "In my calf region, lower legs, especially when I dorsiflex." I gave you a female, and I told you maybe she was obese, or maybe she was pregnant, and maybe she was on a long plane trip.

    03:23 I gave you all of those risk factors because she's developing what kind of thrombi, please? A venous thrombi.

    03:28 What is it in that female that is prothrombotic, that hormone? Estrogen.

    03:34 Now wait, step back for a second.

    03:36 Estrogen is quite interesting, as you should know that estrogen on the arterial side, for thrombi formation, protects the lady, right? That's why a lady who develops coronary arterial disease, will be much later than it would be for male in which we don't have estrogen.

    03:56 But that protects you on the arterial side.

    03:58 Fascinating.

    03:59 And it’s mostly because on the arterial side the thrombi that you’re forming, You've called — you've heard of atheromatous and such, of course.

    04:05 We've had that discussion.

    04:07 Whereas in the venous side, it’s going to be purely a coagulation issue So therefore, heparin, thrombin, and warfarin works via warfarin works through vitamin K-dependent factors.

    04:21 There we go.

    04:21 What are they? II, VII, IX, X.

    04:24 Clotting or non-clotting? Clotting factors, prothrombotic.

    04:28 Now what are the other two? Protein C and protein S.

    04:31 Those are anticoagulants, naturally acting.

    04:35 Next, remind me about the short half life.

    04:37 Which one has the short half life? Protein C and S.

    04:41 Remind me, this vitamin K-dependent factors what’s the name about carboxylation.

    04:46 Gamma carboxylation.

    04:47 What’s the name of that enzyme, please? Epoxide reductase So what warfarin does is inhibit epoxide reductase.

    04:55 Therefore, you don’t activate or you don't synthesize new II, VII, IX and X from the liver, correct? What may then disappear in your patient? Protein C and S.

    05:06 Why? Because it’s half-life is so incredibly short.

    05:10 In such patients, what might still be circulating? II, VII, IX and X.

    05:14 Forming what maybe? Microthrombi up and down the body resulting in wide spread skin necrosis.

    05:24 You don’t get that point, make sure you repeat that 'cause it’s key that you understand the difference between the necrosis that'll take place with HIT with heparin, the site of injection.

    05:35 What versus the skin necrosis that may take place with warfarin.

    05:39 So therefore, it’s extremely important remember, heparin.

    05:42 What clinical test are you gonna use to measure the activity of heparin? Clinically, it's PTT.

    05:50 Warfarin, if you want, the mnemonic is cute.

    05:54 I'm not a huge in mnemonic man but at times, I think their fun.

    05:58 WEPT, WEPT.

    05:59 W-E-P-T.

    06:02 W - Warfarin, E - Extrinsic system, Primarily.

    06:07 Granted.

    06:08 Every single resident and student asks me this question.

    06:12 "Doctor Raj, Factor II, it’s thrombin.

    06:15 That's part of both with intrinsic and extrinsic.

    06:18 I get it.

    06:19 Factor VII, okay, I get it it’s part of extrinsic.

    06:23 But then IX and X, X is part of both and IX is part of intrinsic.

    06:29 What am I trying to get at?" Interesting enough, II, VII and IX and X, they're components of both intrinsic and extrinsic, aren’t they? But clinically, what test are you gonna measure only? PT, INR.

    06:43 W-E-P-T If it’s not warfarin, it’s heparin.

    06:47 If it’s not extrinsic, it’s intrinsic.

    06:49 If it’s not PT, then it’s PTT.

    06:51 It’s just the opposite.

    06:52 There you have it.

    06:52 Two of the major drugs.

    06:54 Now, warfarin is teratogenic.

    06:55 You can’t use it.

    06:57 Not in pregnancy.

    06:59 Now, warfarin, we'll talk about this in a bit.

    07:01 I have to give you new drugs.

    07:03 Warfarin has been proven over and over for about 50 years now to be extremely effective in preventing prophylactically a emboli from the left side of the heart let's say, secondary to Afib going up in the carotid resulting in a cerebrovascular accident, AKA stroke effectively.

    07:26 However, there are new drugs that you must know that could be a substitute for warfarin for such embolization from the left atrium.

    07:36 These drugs include direct acting thrombin inhibitors.

    07:39 I mentioned this a few times.

    07:41 Dabigatran, the oral agent or maybe a Factor X inhibiter called apixaban or rivaroxaban.

    07:49 It has a letter X in there.

    07:51 Interesting.

    07:55 Let’s talk about that PT.

    07:57 I gave you the pneumonic WEPT.

    07:59 W, warfarin.

    08:01 E, extrinsic O, PT.

    08:02 We can go through this quickly now.

    08:04 PT, the time is 11 to 15 seconds.

    08:08 Take a look at the picture here over to the far right.

    08:10 The extrinsic system begins with which coagulation factor? Factor VII, there you go.

    08:16 And there's PT.

    08:17 a drug here primarily would be your warfarin.

    08:20 Take a look at this.

    08:22 Step back for a second and take a look at the picture.

    08:24 You formed an X.

    08:26 It's both the extrinsic and intrinsic will converge upon factor X.

    08:32 PT.

    08:34 Your gamma carboxylate and vitamin K dependent factors from the liver.

    08:39 So if a patient has liver disease, whatever type of hepatitis? NASH, Auto immune, alcoholic, viral, whatever it may be, you would expect there to be an elevated PT.

    08:52 Warfarin obviously, an increase in PT.

    08:57 Then over to your left, there’s an intrinsic.

    09:00 How do I know? The intrinsic, you have memorized at this point, begins with which factor? Factor XII.

    09:06 It will be measured by PTT.

    09:10 What's the time here for PPT? Twenty five to forty seconds.

    09:15 Please remind me what the drug here, that primarily works or you will be measuring PTT? If it's not warfarin, then it will be heparin.

    09:24 A couple of other things here, exclusively.

    09:26 See where it says hemophilia? Remind me, A before E, so therefore, VIII before IX.

    09:34 In other words, if the patient is Factor VIII deficient, then you’ll find an elevated PTT only, and that patient has hemophilia A.

    09:43 How do you know? Might be a child and such, and might have severe gingival bleeding.

    09:48 Might have bleeding into the joints called hemarthrosis versus the Won Willebrand disease patient I've talked about over and over again.

    09:57 In Von Willebrand disease, what are the two tests to be elevated? Bleeding time and PTT.

    10:03 In hemophilia, it’s only PTT.

    10:06 Is that understood? Whereas if the patient’s deficient of Factor IX, then there will be hemophilia B.

    10:14 We’re all doctors here, so we don’t get 12 days of Christmas, we’re gonna get 9 days of Christmas.

    10:20 What am I getting at? Another name for Factor IX deficiency is Christmas disease hemophilias.

    About the Lecture

    The lecture Normal Hemostasis Pharmacologic Anticoagulants by Carlo Raj, MD is from the course Hemodynamics.

    Included Quiz Questions

    1. Anti thrombin 3
    2. Plasminogen
    3. VWF
    4. Vitamin K
    5. Protein C
    1. Auto antibodies
    2. Infection
    3. Air embolism
    4. Trauma
    5. Leukaemia
    1. INR
    2. Bleeding time
    3. APTT
    4. Clotting time
    1. Teratogenicity
    2. Excessive bleeding
    3. Vasovagal syncope
    4. Autoimmunity
    5. Vascular damage to placenta
    1. Lady with History of cerebral vascular incident
    2. Lady in her 1ˢᵗ trimester of pregnancy
    3. Lady with Acute pulmonary embolism
    4. Lady in 2ⁿᵈ trimester of pregnancy
    5. Lady in 3ʳᵈ trimester of pregnancy

    Author of lecture Normal Hemostasis Pharmacologic Anticoagulants

     Carlo Raj, MD

    Carlo Raj, MD

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