Drugs for Thromboembolic Disorders

Another post on clotting! This post covers drugs that we can use to treat clotting. I've already touched on some of these drugs before, but this post has a lot more details.

Agents that deplete functional clotting factors

Warfarin

Warfarin, as mentioned here, inhibits the synthesis of prothrombin. But how does it do that? you may ask. The answer lies in the effects of warfarin on vitamin K.

Vitamin K actually exists in a reduced (active) and oxidised (inactive) form. When it is active, it is used as a cofactor in the carboxylation of decarboxyprothrombin, a prothrombin precursor made in the liver. (Yup, precursors of precursors.) This process oxidises vitamin K, thus inactivating it. Vitamin K is then made active again by an enzyme called VKORC1 (Vitamin K Epoxide Reductase Complex 1). Warfarin inhibits this enzyme, thereby preventing the recycling of vitamin K and the formation of prothrombin.

Aside from prothrombin, warfarin also inhibits the production of Factors VII, IX and X by a similar mechanism. All of these factors require around 24 hours to actually be depleted, so while warfarin works long-term, it's not that great if you want an immediate effect. Warfarin is also teratogenic, so it can't be used in pregnancy. Yet another issue with warfarin is that you might go too far in the other direction and cause excess bleeding (though this is a potential issue for most if not all anti-clotting drugs). One good thing about warfarin, however, is that it can be easily reversed in an emergency: you can either give the patient fresh donor plasma with the clotting factors that they need, or you can just give them a shitload of vitamin K.

Heparin

As mentioned here, heparin can block prothrombin from becoming thrombin. It does this by inactivating Factor Xa, which catalyses the formation of thrombin. It can also inactivate thrombin.

Heparin is a glycosaminoglycan (see here if you've forgotten what they are). Like other glycosaminoglycans, it is negatively charged. This allows it to bind to antithrombin III, which is positively-charged due to its high proportion of basic amino acid residues (such as lysine and arginine). When heparin binds to AT III, it actually increases its effectiveness by increasing its affinity for Factor Xa and thrombin. This, in turn, increases the rate of anti-coagulation.

Heparin has a couple of advantages over warfarin in that it can act rapidly and is not teratogenic. Like warfarin and other anticoagulants, it does have a risk of bleeding. One of the disadvantages of heparin is that it cannot be administered orally, otherwise our GI tract would just break it down before it could do its job.

Direct inhibitors of clotting factor enzymatic activity

Dabigatrin

Dabigatrin is a direct inhibitor of thrombin (a.k.a. Factor IIa).

Rivaroxaban

Rivaroxaban is a direct inhibitor of Factor Xa.

Antiplatelet drugs

Aspirin

See here for an explanation on aspirin's anti-thromboxane (and thus anti-platelet) activity.

Clopidogrel

Clopidogrel, once broken down to its active metabolite, can irreversibly block platelet ADP receptors. (As I mentioned in my last post, these are needed to help platelets aggregate and adhere during the clotting process.) A newer drug, called prasugrel, does the same thing, but it doesn't need to be broken down to an active metabolite.

Agents that accelerate clot lysis

As mentioned here, plasmin, produced from plasminogen with the help of tPA (tissue plasminogen activator), can break down a clot. tPA can also be produced as a recombinant protein and administered via IV in order to treat a clot rapidly.