Anticoagulants: Direct factor inhibitors

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Introduction0:00–0:36

Anticoagulant medications help to prevent thrombi, or blood clots from forming. These medications work by interfering with the normal function of proteins called clotting factors in a chemical process called the coagulation cascade, or secondary hemostasis where hemo refers to blood, and stasis means to halt or stop.
While the most common anticoagulants like warfarin and heparin act on multiple coagulation factors, in this video we’re gonna focus on anticoagulants that work on a single coagulation factor; either thrombin or activated factor X.

Physiology0:36–3:34

Now, before we discuss heparin in detail we need to talk about the coagulation cascade which is where heparin exerts its effect.
The coagulation cascade starts via two pathways --the extrinsic and intrinsic pathways. The intrinsic pathway starts when circulating factor XII comes into contact with the surface of activated platelets or collagen.
Activated factor XII, then activates factor XI, which activates factor IX which activates factor X. Factor X starts the common pathway where it activates factor II, or thrombin, which activates factor I that builds the fibrin mesh.
When factor II gets activated it also activates 4 other factors: V, VIII, IX, and XIII. Factor V gets activated and acts as a cofactor for X, factor VIII acts as a cofactor for factor IX, and factor XIII helps factor I, or fibrin, form crosslinks.
In the extrinsic pathway, exposed tissue factor activates factor VII, which activates factor X and starts the common pathway.
Now, the most common point of clot regulation is when a coagulation factor called thrombin is produced. Thrombin, or activated factor II, is a very important clotting factor, because it has multiple pro-coagulative functions.
Think of thrombin as the accelerator on a car--the pedal that takes secondary hemostasis from 20 miles per hour to 100 miles per hour!
First, thrombin binds to receptors on platelets causing them to get activated. Activated platelets change their shape to form tentacle-like arms that allow them to stick to other platelets.
Second, thrombin activates two cofactors; factor V used in the common pathway, and factor VIII used in the intrinsic pathway.
Third, thrombin proteolytically cleaves fibrinogen or factor I, into fibrin or factor Ia which binds with other fibrin proteins to form a fibrin mesh.
And finally, thrombin proteolytically cleaves stabilizing factor or factor XIII into factor XIIIa. Factor XIIIa combines with a calcium ion cofactor to form cross links between the fibrin chains, further reinforcing the fibrin mesh.
The direct thrombin inhibitors and the direct factor Xa inhibitors inhibit the coagulation cascade by binding to their corresponding coagulation factors after they’ve been activated.
The direct thrombin inhibitors can bind to thrombin that’s in the circulation and those already attached to a forming clot.
Factor Xa inhibitors have the same function on Xa, however, it has an overall greater effect on anticoagulation since it’s higher up in the coagulation cascade, so each molecule of the medication can prevent multiple thrombins from being activated by a factor Xa.

Laboratory Parameters3:34–4:09

Now, in terms of laboratory parameters, direct thrombin inhibitors prolong thrombin time, and have less effect on prothrombin time, or PT, which assesses the extrinsic and common coagulation pathways, and partial thromboplastin time, or aPTT, that assesses the intrinsic and common coagulation pathways.
Direct factor Xa inhibitors prolong both PT and aPTT, but have no effect on thrombin time. However, both classes of direct factor inhibitors do not require routine monitoring.
Now, let's discuss each class of medications in more detail starting with the direct thrombin inhibitors like bivalirudin, lepirudin, and argatroban, which are given intravenously, desirudin, which is given subcutaneously, and dabigatran, which is given peroral.

Direct Thrombin Inhibitors4:09–6:38

This class of medications was initially isolated from the saliva of leeches due to its anticoagulant effect. Although they are not as frequently used as heparin, they can be a 2nd line medication in people with a history of deep vein thrombosis to prevent pulmonary embolism, or atrial fibrillation to prevent strokes.
Direct thrombin inhibitors are especially useful when heparin causes an adverse reaction called HIT, or heparin induced thrombocytopenia.
HIT occurs when some people produce antibodies, which bind to heparin bound to a protein on the surface of platelets called platelet factor 4.
The complex antibody-heparin-platelet factor 4 leads to platelet activation and aggregation, hence thrombosis. There is also destruction of platelets by cells of the spleen called macrophages, resulting in a low platelet count.
These medications are also used in combination with antiplatelet agents like aspirin and clopidogrel to prevent clot formation in patients undergoing coronary artery surgery.In terms of toxicity, direct thrombin inhibitors are associated with GI symptoms like dyspepsia and gastritis.
However, the most dangerous thing is the risk of increased bleeding when taken in excess. This could lead to uncontrollable internal bleeding from simple falls or trauma.
Thankfully a reversal agent called idarucizumab, an antibody, which binds to and inactivates dabigatran can be administered to people who experience uncontrolled bleeding from this medication.
For the other direct thrombin inhibitors, there is no reversal agent available. Prothrombin complex concentrate, also known as PCC, which contains the coagulation factors II, VII, IX and X along with proteins C and S, or antifibrinolytic agents, like as tranexamic acid, can be used.
Other common toxicities with these medications include hypersensitivity reactions, especially with lepirudin and bivalirudin.
Direct thrombin inhibitors should not be discontinued suddenly as it leads to increased thrombosis and risk of strokes. Now, the direct factor Xa inhibitors like apixaban, edoxaban and rivaroxaban are all peroral medications.

Direct Factor Xa Inhibitors6:38–7:50

They have "xa" in their name which should help you remember they act on factor Xa. Factor Xa inhibitors are becoming more commonly used for the treatment and prevention of deep vein thrombosis, pulmonary embolism, and stroke prevention in patients with atrial fibrillation.
They are becoming a useful alternative to the anticoagulant medication warfarin, because they dont require laboratory monitoring, have fewer drug interactions, and have a rapid onset of action.
The main toxicity of these medications is also uncontrollable bleeding; the FDA just approved andexanet alfa as a reversal agent for Factor Xa inhibitors.
Andexanet alfa binds to factor Xa inhibitors, inhibiting them from binding to factor Xa. Furthermore, they are metabolized by an enzyme called cytochrome P450, so any medications that inhibit this enzyme like cimetidine, metronidazole, trimethoprim/sulfamethoxazole, and amiodarone, can cause the accumulation of these medications in the body, leading to bleeding.All right, so now let’s make a simple and fun mnemonic that’ll help you efficiently memorize these pharmacology facts!

Memory Palace7:50–9:27

Let’s have a hitchhiker sticking out a hand with a huge thumb for the direct thrombin inhibitors, and further away, there’s a tent for factor Xa inhibitor.
The hitchhiker’s pet reindeer, Rudolph, represents the 3 drugs that end in “rudin” like bivalirudin, lepirudin, and desirudin.
On its back, it's carrying the hitchhiker's two gatling guns. Argatroban is the single barreled variant and dabigatran is the double barreled variant, where the barrels are big lips to help you remember this is the only peroral medication in this class.
The hitchhiker was practicing his shooting earlier, and there’s a target nearby with bullet holes in it to help you remember these medications are used by people with heparin induced thrombocytopenia, or HIT.
Finally, let’s put 2 darts in the barrels of the dabigatran gun to represent idarucizumab, which can inhibit the medication if it causes uncontrolled bleeding.
For the direct factor Xa inhibitors, let’s go back to the tent which belongs to the members of a rock band, or ROX BAND, which represents the medications with “xaban” in their name, like rivaroxaban and apixaban.
The lead singer has a huge lip to help you remember these medications are peroral. A giant chrome colored cell is sneaking up to engulf the band, which represents the cytochrome p450 that metabolizes these medications.
Finally, let’s put a banner above them that says “make music not war,” since they can be used as an alternative to warfarin.
All right, as a quick recap… Direct coagulation factor inhibitors are anticoagulants used for the prevention of serious conditions like strokes and pulmonary embolism.

Review9:27–10:08

Direct thrombin inhibitors like bivalirudin, lepirudin, desirudin, argatroban, and dabigatran can be a useful replacement for heparin in people with a history of HIT.
Direct factor Xa inhibitors like rivaroxaban and apixaban are becoming more commonly used as an alternative to warfarin.
Both classes of medications have uncontrolled bleeding as their main toxicity, but the effects of dabigatran and factor Xa inhibitors can be reversed by idarucizumab and andexanet alfa, respectively.
But wait, there's more: Here's a mind map with all of the mnemonics from the video. Go ahead and pause the video so you can test yourself to see what you remember.

Mind Map10:08–10:20

Stay tuned for the answers at the end. Go ahead and pause a video so you can test yourself to see what you remember.
Stay tuned for the answers after the credits.