Clotting Factor Deficiencies

00:01 Here we’ll take a look at bleeding disorders. This is an important section.

00:04 A lot of details here, beautiful summary coming up so that you can integrate many of the issues that you may had have prior.

00:13 We begin by looking at well, let me set up this picture.

00:19 Our focus is gonna be quite a bit on that picture.

00:23 We’ll be focusing upon what you see here in red.

00:29 You see the red circles in the picture? The red circles in the picture represent the diseases. What kind of diseases? We’ll take a look at the list overall. Bernard-Soulier, Glanzmann, Hemophilia B, Vitamin K deficiency, those are patients that are walking through the 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 would 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 you will know how this fits into, well, the patient’s body.

01:30 Let’s begin with number 1.

01:33 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 would be the platelet itself.

01:47 What you’re seeing on the far right, you see the green cells there and those are your endothelial cells.

01:54 Now, what’s gonna happen is that the endothelial cells are going to then be ripped off. Ripped off of what? Well, it will be ripped off the scaffolding.

02:06 Scaffolding would be obviously the subentity like collagen that you see all the way back in your foundation.

02:12 So now you wanna ask yourself, if the endothelial cells are being damaged for whatever reason - - hypertension, hyperhomocysteinemia, smoking, what have you - then, what should happen is that the platelet should hardly come in and then you should then start filling in that pothole or in other words forming a thrombus but I bet you said they were gonna cause bleeding.

02:40 Yes, if the normal function was to fill up that pothole to form a thrombi then the diseases would be once in which the pothole cannot be filled resulting in bleeding.

02:56 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, yes, 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.

03:23 The subendothelial collagen has now been exposed and you’ll notice, go down to number 1, in the red circle, and that then represents the Von Willebrand factor, the ligand which is being expressed by the subendothelial collagen, you see that? Remind me again that Von Willebrand factor is then supposed to bind to which receptor? Glycoprotein 1b.

03:47 You wanna think of a condition in which the Von Willebrand factor is not functioning properly.

03:54 The most common subtype of what's known as the Von Willebrand Disease.

04:00 Now let me ask you a very important question.

04:03 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 1b, 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.

04:35 Number 1 represents Von Willebrand disease in which Von Willebrand factor is in decrease percentage resulting in excessive bleeding in your patient, a young female for instance in which therefore we find an increase in bleeding time.

04:53 From here, we’ll take a look at number 2. Take a look at the circle number 2.

04:58 Now this then represents deficiency, hereditary of glycoprotein 1b.

05:03 And here once again, we don’t have proper function of your platelet.

05:08 We're gonna find an increase in bleeding time, aren’t we? By this increase in bleeding time is it a step in adhesion or aggregation that we're having issues with? Adhesion -- glycoprotein 1b deficiency, Bernard-Soulier.

05:25 I want you identity red circle number 3.

05:30 This is now referring to glycoprotein 2b3a that normally should be binding creating a bridge or aggregating with another platelet with the help of fibrinogen.

05:42 If there's a hereditary deficiency of glycoprotein 2b3a, once again, you’re gonna find an increase in bleeding time or what step of platelet functioning has now been compromised? Aggregation -- welcome to Glanzmann’s thombasthenia.

05:59 Now at this point, I want you to sit back a little bit and think of what should happen next? Remember that fibrinogen should be cleaved by thrombin.

06:14 And now 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 4, you have a deficiency of factor IX.

06:35 If there's a deficiency of factor IX, a before b, then it’s hemophilia b. Identify red circle number 4.

06:46 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 the intrinsic pathway.

06:58 Next, if it’s the intrinsic pathway that you’re dealing with, what is the test that is going to properly and accurately assess the functioning of the intrinsic pathway? Good, that’s PTT. Therefore, hemophilia B, you'd only find an increase in PTT.

07:17 Now, we’re coming to vitamin K deficiency. Now vitamin K deficiency, identify number 5.

07:24 In vitamin K deficiency you should be thinking automatically your vitamin K dependent factors.

07:30 Now, vitamin K deficiency is different from warfarin for the following reason.

07:36 Warfarin is a clinical situation. Warfarin, therefore clinically as we have discussed over and over and over again, you're gonna follow clinically by using PT/INR.

07:48 However, if you have a patient who’s not consuming enough let’s think green, you think vitamin K -- I want you to think of just quickly kale, what color is kale? Green.

08:02 So you have a patient who may not be consuming enough greens may also be suffering from vitamin K deficiency or could be a child, right? So now, if the child or the patient is vitamin K deficient, then all of your vitamin K dependant factors are not being synthesized properly.

08:22 Different situation. Two is your thrombin, no proper amounts of that. VII part of extrinsic, IX part of intrinsic.

08:32 So in vitamin K deficiency, you will find an increase in PT and PTT. Is that clear? In vitamin K deficiency you will find an increase in PT and PTT.

08:45 Now I'm coming to liver disease.

08:48 In liver disease as you know, you’re gonna be producing every single coagulation factor except for factor VIII.

08:56 Factor VIII is going to be expressed by your endothelial cell. That takes care of liver disease.

09:02 This now takes care of the major pathologies in the picture in which in a patient with anyone of these is going to present how? Bleeding.

09:14 Let’s take a look at medications.

09:17 Now these are the medications, what would you call these medications that are going to promote clotting? No, 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. Take a look at number 1. NSAIDs means what to you? It means I’m gonna block reversibly a COX, cyclooxygenase.

09:38 And when you do so you don’t have thromboxane.

09:41 If you don’t have thromboxane then what cannot do with your platelet? You cannot effectively aggregate. That’s number 1.

09:50 Tell me about any drug in which you find the letters g-r-e-l - grel. Good! You should be thinking about inhibiting ADP through antagonism of what's known as your P2Y12 receptor.

10:05 If ADP is not properly expressed and platelet is not activated, you're not or the platelet is not going to express 2b3a.

10:15 Welcome to another issue, right, with your platelet on purpose, welcome to a blood thinner known as clopidogrel.

10:22 Abciximab, monoclone antibody we've talked about over and over again targeting 2b3a.

10:27 Heparin, identify number 4, please, in green.

10:32 That works through antithrombin III.

10:37 Remember, thrombin is going to cleave normally the fibrinogen so therefore if there's something that inhibits your thrombin such as antithrombin III via heparin very quickly, I'm going to have a blood thinner.

10:53 Warfarin, we've talked about number 5, referring to the fact that we have our vitamin K dependent factors that works through the gamma-carboxylation disruptor and we have epoxy reductase inhibitor.

11:07 Do not forget that warfarin through polymorphisms of something called vitamin K, VK, epoxy reductase is designated medicine as a letter O complex one-protein.

11:20 Polymorphisms in VKOC1 may then determine the activity level or effectiveness of warfarin. Do not forget that.

11:31 Remember, what if a patient is 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.

12:03 Now the problem is with dabigatran that you may have toxicity with bleeding.

12:08 The antidote or the name of the antidote is a monoclonal antibody called idarucizumab. Make sure you know that well.

12:16 May I ask you, what is the antidote for heparin? You should know that as being what? Protamine sulfate.

12:23 What is the therapy for warfarin toxicity? Fresh frozen plasma or prothrombin complex concentrates.

12:33 Next, I told you that any drug that you see with the letter x in it, you should be thinking, is this a drug that’s inhibiting directly factor X? This then brings us to apixaban, rivaroxaban, or a heparin derivative called fondaparinux, X-X-X 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 had the letters what in them? A-S-E. Tenecteplase, alteplase, streptokinase, and so forth.