AssessmentsAnticoagulants: Direct factor inhibitors
Anticoagulants: Direct factor inhibitors
Contributors:Tanner Marshall, MS, Sam Gillespie, BSc, Samantha McBundy, MFA, CMI, Robyn Hughes, MScBMC, Ursula Florjanczyk, MScBMC, Sean Watts, MD
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.
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. 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. 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.
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