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Clotting Factor Deficiencies

by Carlo Raj, MD

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    00:01 Here, we’ll take a look at bleeding disorders.

    00:02 This is an important section.

    00:05 A lot of details here, beautiful summary coming up, so that you can integrate many of the issues that you may have had prior.

    00:16 We’ll begin by looking at, well, let me set up this picture.

    00:21 Our focus is gonna be quite a bit on that picture.

    00:25 We’ll be focusing upon what you see here in red.

    00:30 You see the red circles in the picture? The red circles in the picture represent the diseases.

    00:37 What kind of diseases? We’ll take a look at the list overall.

    00:42 Bernard-Soulier, Glanzmann, hemophilia B, vitamin K deficiency.

    00:46 Those are patients that are walking through a door and are they in a state of hypercoagulation or are they bleeding? Okay, bleeding, right? Next, once we get through the diseases, then on the next section where you see the green circles there represent the medications that may once again induce bleeding.

    01:11 In other words, this will be a nice little list of blood thinners that by the time we’re done with each and every single one of these issues, either disease or medication, it’d be nice to review as to you will know how this fits in to well, the patient’s body.

    01:31 Let’s begin with number one.

    01:34 Now, what you’re seeing here in the picture, the circles themselves, the pink circles represent obviously, the most integral portion of this picture which is the platelet itself, right? That’d be the platelet itself.

    01:47 What you’re seeing on the far right.

    01:49 You see the green cells there and those are your endothelial cells.

    01:55 Now, what’s gonna happen is that the endothelial cells are going to then be ripped off.

    02:01 Ripped off of what? Well, it’d be ripped off the scaffolding.

    02:06 The scaffolding would be obviously the subendothelial collagen that you see all the way back in your foundation.

    02:14 So now, you wanna ask yourself if the endothelial cells are being damaged for whatever reason, hypertension, hyperhomocysteinoia or excuse me, hyperhomocysteinemia, smoking, what have you.

    02:28 Then what should happen is that the platelets should hardly come in and then, you should then start filling in that pothole or in other words, forming a thrombus.

    02:37 But Dr. Raj, I thought you said that were gonna cause bleeding.

    02:39 Yes, if the normal function was to fill up that pothole to form a thrombi, then the diseases would be ones in which the pothole cannot be filled resulting in bleeding.

    02:55 Do you understand the overall picture now? So the picture itself is a clotting picture but obviously, in pathology, we’ll be dealing with clotting disorders and depending as to which clotting factor, let it be a platelet factor or a coagulation factor is then going to result in a bleeding.

    03:16 Now, with that said, you’ll notice now that the endothelial cell is missing from one end to the other.

    03:24 The subendothelial collagen has not been exposed and you’ll notice, go down to number one in the red circle, and that then represents the Von Willebrand factor, the ligand which is being expressed by the subendothelial collagen, do you see that? Remind me again that Von Willebrand factor’s then supposed to bind to which receptor? Glycoprotein Ib.

    03:48 Now, you wanna think of a condition in which the Von Willebrand factor is not functioning properly.

    03:55 The most common subtype of what’s known as Von Willebrand disease.

    04:01 Now, let me ask you a very important question.

    04:04 In this picture and in this background, where if Von Willebrand factor wasn’t present in its normal concentration or percentage, and it wasn’t there to bind to glycoprotein Ib, what is the test that you’re going to choose to assess this situation only? Bleeding time, correct? At this point, there is no discussion whatsoever of bringing in our Factor VIII yet.

    04:36 Number one represents Von Willebrand disease in which Von Willebrand factor is in decreased percentage resulting in excessive bleeding in your patient.

    04:47 A young female for instance in which so far, we find an increase in bleeding time.

    04:53 In a little bit, I’ll remind you that Von Willebrand factor’s also required for stabilization of Factor VIII.

    05:00 And so, if Factor VIII isn’t functioning properly, you’re going to find an increase in PTT.

    05:06 From here, we’ll take a look at number two.

    05:09 Take a look at the circle number two.

    05:11 Now, this then represents a deficiency, hereditary of glycoprotein Ib.

    05:17 And here once again, we don’t have proper functioning of the platelet.

    05:21 We’re gonna find an increase in bleeding time, aren’t we? But this increase in bleeding time, is it a step in adhesion or aggregation that we’re having issues with? Adhesion, glycoprotein Ib deficiency, Bernard-Soulier.

    05:39 I want you to identify red circle number three.

    05:44 This is now referring to glycoprotein IIb/IIIa.

    05:48 That normally should be binding, creating a bridge, or aggregating with another platelet wiith the help of fibrinogen.

    05:56 If there’s hereditary deficiency of glycoprotein IIb/IIIa, once again, you’re gonna find an increase in bleeding time.

    06:03 Of what step of platelet functioning has now been compromised? Aggregation.

    06:10 Welcome to Glanzmann thrombasthenia.

    06:14 Now, at this point, I want you to sit back a little bit and think of what should happen next.

    06:22 Remember, that fibrinogen should be cleaved by thrombin.

    06:28 And that thrombin was collectively activated by the intrinsic and extrinsic branches of the coagulation pathway, all converging upon Factor X, and that Xa will then activate your thrombin, correct? Well, let’s say that number four, you have a deficiency of Factor IX.

    06:49 If there’s a deficiency of Factor IX, a before b, then it’s hemophilia B, identify red circle number four.

    07:00 So now, if there’s a deficiency of Factor IX, do you remember what branch of the coagulation cascade Factor IX belongs to? I’m hoping you remember it, the intrinsic pathway.

    07:12 Next, if it’s the intrinsic pathway that you’re dealing with, what does it test that is going to properly and accurately assess the functioning of the intrinsic pathway? Good.

    07:23 That’s PTT, and therefore, Hemophilia B, You’d only find an increase in PTT.

    07:32 Now, we’re coming to vitamin K deficiency.

    07:35 Now, vitamin K deficiency, identify number five.

    07:39 In vitamin K deficiency, you should be thinking automatically your vitamin K dependent factors.

    07:43 Now, vitamin K deficiency is different from warfarin for the following reason.

    07:49 Warfarin is a clinical situation.

    07:52 Warfarin therefore clinically as we’ve discussed over, and over, and over again.

    07:56 You’re gonna follow clinically by using PT/INR.

    08:02 However, if you have a patient who’s not consuming enough, let’s think green.

    08:08 You think vitamin K, I want you to think of just quickly kale.

    08:13 What color is kale? Green.

    08:15 So if you have a patient who may not be consuming enough greens, they may also be suffering from vitamin K deficiency or it could be a child, right? So now, if the child or the patient is vitamin K deficient, then all of your vitamin K dependent factors are not being synthesized properly.

    08:35 Different situation, two as your thrombin, no proper amounts of that.

    08:42 Seven part of extrinsic, nine part of intrinsic.

    08:46 So in vitamin K deficiency, you will find an increase in PT and PTT.

    08:51 Is that clear? In vitamin K deficiency, you will find an increase in PT and PTT.

    08:59 Now, we come into liver disease and liver disease as you know, you’re gonna be producing every single coagulation factor, except for Factor VIII.

    09:09 Factor VIII is going to be expressed by your endothelial cell.

    09:14 So as you can imagine here with liver disease, if you were to choose between PT, PTT, which one of those tests is considered to be a liver function test? Obviously, the PT.

    09:25 That takes care of liver disease.

    09:28 This now takes care of the major pathologies in the picture in which in a patient with any one of these is going to present.

    09:36 How? Bleeding.

    09:40 Let’s take a look at medications.

    09:42 Now, these are the medications, would you call these medications that are going to promote clotting? No.

    09:48 These are the medications that are going to promote bleeding, so these are blood thinners, aren’t they? So now, you’re gonna identify the green circles.

    09:55 Take a look at number one.

    09:57 NSAIDs means what to you? It means, I’m gonna block reversibly a COX, cyclooxygenase, and when you do so, you don’t have thromboxane.

    10:06 If you don’t have thromboxane then what can you not do with your platelet? You cannot effectively aggregate.

    10:13 That’s number one.

    10:15 Tell me about any drug in which you find the letters G-R-E-L, GREL Good.

    10:22 You should be thinking about inhibiting ADP through antagonism of what's known as your P2Y12 receptor.

    10:30 If ADP is not properly expressed and platelet is not activated, the platelet is not going to express IIb-IIIa.

    10:40 Welcome to another issue, right? With your platelet on purpose, welcome to a blood thinner known as clopidogrel.

    10:46 Abciximab, monoclonal antibody we’ve talked about over and over again targeting IIb-IIIa.

    10:52 Heparin, identify number four, please in green.

    10:57 That works through antithrombin III.

    11:02 Remember, thrombin is going to cleave normally the fibrinogen, so therefore if there is something that inhibits your thrombin such as antithrombin III via heparin very quickly, I’m going to have a blood thinner.

    11:18 Warfarin we’ve talked about, number five.

    11:21 Referring to the fact that we have our vitamin K dependent factors that works through the gamma-carboxylation disruptor and we have epoxide reductase inhibitor.

    11:31 Do not forget that warfarin through polymorphisms of something called vitamin K, VK, epoxide reductase is a designated medicine as a letter O complex one protein.

    11:45 Polymorphisms in VKORC1, may then determine the activity level or effectiveness of warfarin.

    11:54 Do not forget that.

    11:56 Remember, what if a patient was suffering from HIT, heparin-induced thrombocytopenia, and the patient now, instead of bleeding resulting in hypercoagulability, necrosis at the site of injection, and I told you as an alternative, you may then be using or you may choose as an alternative a direct acting thrombin inhibitor which is the only direct acting thrombin inhibitor that is or can be taken orally, dabigatran.

    12:28 Now the problem is with dabigatran that you may have toxicity with bleeding.

    12:33 The antidote or the name of the antidote is a monoclonal antibody called idarucizumab.

    12:38 Make sure you know that well.

    12:41 May I ask you? What is the antidote for heparin? You should know that as being what? Protamine sulfate.

    12:48 What is the therapy for warfarin toxicity? Fresh, frozen plasma or prothrombin complex concentrates.

    12:59 Next, I told you that any drug that you see with the letter X in it, you should be thinking, huh, is this a drug that’s inhibiting directly Factor X.

    13:10 This then brings us to apixaban, rivaroxaban or a heparin derivative called fondaparinux, XXX.

    13:20 Then we have a fibrinolytic that we talked about earlier in which you may directly or indirectly be able to convert plasminogen into plasmin, and these then have the letters what in them? A-S-E.

    13:34 Tenecteplase, alteplase, streptokinase, and so forth.


    About the Lecture

    The lecture Clotting Factor Deficiencies by Carlo Raj, MD is from the course Hemodynamics.


    Included Quiz Questions

    1. Vitamin k
    2. NSAIDs
    3. Warfarin
    4. Heparin
    5. Clopidogrel
    1. Glycoprotein 1b
    2. Glycoprotein 1a
    3. Glycoprotein 1c
    4. Glycoprotein 2b
    5. Glycoprotein 3a
    1. Bleeding time
    2. Clotting time
    3. Thromboplastin time
    4. Prothrombin time
    5. International normalisation ratio
    1. Platelet adhesion
    2. Platelet deficiency
    3. Thrombocytopenia
    4. Platelet aggregation
    5. Platelet dissociation
    1. Glanzmann thrombasthenia
    2. Bernard soulier
    3. Thrombocytopenia
    4. Von Willi brand factor disease
    5. Haemophilia
    1. Partial thromboplastin time
    2. Prothrombin time
    3. International normalisation ratio
    4. Activated partial thromboplastin time
    5. Clotting time

    Author of lecture Clotting Factor Deficiencies

     Carlo Raj, MD

    Carlo Raj, MD


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