Drugs that make you bleed

Sometimes I find it hard to imagine how it can be that everybody in the world is different. Out of 7 billion people, there isn’t anyone who has the same fingerprint, which essentially blows my mind. Likewise, everybody has a different affinity to form clots in the body: for some, clots form easily… while others do not form clots well at all. This affinity is a kind of spectrum, where being on either extreme of the spectrum can be dangerous. Medication can be used to assist high risk individuals to reduce risk of haemorrhage or stroke. These medicines influence enzymes in the coagulation cascade, but in order to learn about how that works, it is important to have a firm grasp on how the cascade works.

For the next few paragraphs, I am going to go into some depth about the blood clotting pathway - known as the coagulation cascade - and try to explain how it works. If you want the short version, here it is: when a blood vessel is damaged, enzymes in the body produce fibrin which will ‘glue’ platelets together, forming a stable plug over the damaged area (see figure 1). If you want a longer version of how this works, read on:

Figure 1: Repairing a damaged blood vessel.

The Cascade (see figure 2):
There are 13 compounds involved known as clotting factors which are normally present in the body. The clotting factors are assigned to roman numerals (I to XIII), although there is nothing assigned to factor VI for some reason. These factors are mostly proenzymes, meaning that they are in their inactive form. When they are activated (denoted by an “a” next to their name i.e. factor VIIa), they will perform their task in the cascade. Specialized blood cells called “platelets” also play an important role. I will now try to provide a clearer picture of how this cascade works.

I enjoy beginning with the end in mind because it helps me understand why certain things are happening, so keep in mind that the end goal of the coagulation cascade is to produce fibrin. This fibrin will bind to platelets and other blood components, producing a stable blood clot and stopping blood loss. But how does this cascade start? Lets take a look:

Once a blood vessel is damaged, a few things happen at the wound site: tissue factor is released, tissue phospholipids are released, and collagen becomes exposed. The exposure of these molecules mark the start of the cascade, which is comprised of two different pathways: the extrinsic pathway and the intrinsic pathway. I will now talk about each pathway individually.

The released tissue factor will start the extrinsic pathway by forming a complex with blood coagulation factor VII. This complex, with the help of the tissue phospholipids, will activate factor X to factor Xa. Xa will complex with factor V and tissue phospholipids to form the prothrombin activator. Prothrombin activator will split prothrombin (blood clotting factor II) into pieces, one of those pieces being thrombin (factor IIa). Thrombin will then interact with fibrinogen (factor I) and cleave off two small pieces. The result is the active monomer form of fibrin (factor Ia) that will polymerize at the wound site in the form of fibrin threads with the help of factor XIII. These threads will adhere together, trapping platelets, blood cells, and plasma to form the blood clot. The clot will then adhere to the damaged opening of the vessel and stop bleeding.

Meanwhile, platelets in the bloodstream as well as Factor XII will bind to collagen and become active, initiating the intrinsic pathway. XIIa then activates XI, and XIa subsequently activates IX. IXa will act with factor VIII and platelet phospholipids in order to activate factor X. The rest of this pathway proceeds the same way as the extrinsic pathway, except that the phospholipids involved are from platelets, not the tissue. The following diagram gives a visual on how this process works.

Figure 2: The clotting cascade in all its glory.

Now, one might ask why two different pathways are needed to form a blood clot. Surely one would be enough? The extrinsic pathway is more of a “first responder” in this cascade. It can take as little as 15 seconds to form a clot via the extrinsic pathway, where it can take around 2 to 6 minutes for the intrinsic pathway alone to form a clot. Since the extrinsic pathway happens so quickly, it uses up the tissue factors and phospholipids from the damaged site quickly and then slows down due to lack of nearby resources. The intrinsic pathway is a more sustainable pathway that uses compounds from the platelets to drive the cascade, which are constantly flowing through the bloodstream. Having two pathways allow for a quick response while being able to keep driving the cascade if necessary.

Coagulation is a very helpful thing, although it can be very dangerous. Thrombin can have a direct influence on prothrombin, cleaving it into more thrombin and causing a potentially infinite feedback loop, but this is usually prevented by the removal of thrombin and other clotting factors from the clot site via the flow of blood. Since humans all have a varying affinity to form blood clots, some can have a higher chance of forming unnecessary blood clots in their bodies. Because the flow of blood is so important to the cessation of clot formation, people with conditions such as atrial fibrillation (irregularly irregular rhythm in the left atrium, causing blood flow to slow) can have a high risk of undesirable clot formation in their bodies. These clots can get stuck in places like the capillaries of the lung or in the brain and block the flow of blood, causing serious conditions like a pulmonary embolism or ischemic stroke. Let’s start looking at some drugs that influence this pathway in order to prevent these undesirable conditions.

Warfarin:
When we talk about influencing the coagulation cascade with medications, it is often useful to consider what the two pathways have in common. Somebody who is prone to clotting will see more of an effect on their coagulation if a drug that slows down both pathways is used.

Let’s start by talking about one of the oldest and most prescribed oral anticoagulants, Warfarin. An interesting fact about warfarin is that it was first used as a rat poison in the 1940s, and still is today to an extent. It works by inhibiting the rats’ ability to form blood clots, causing them to bleed to death. I first thought that the cause of blood loss would be from the rats rubbing against something and getting a scratch, but it is primarily caused by gastrointestinal bleeding. This makes sense, considering the harsh conditions inside the stomach and bowel. Warfarin works by inhibiting the vitamin K dependent synthesis of clotting factors. When warfarin is present, it binds to the protein vitamin K epoxide reductase (VKOR), preventing it from recycling vitamin K. Vitamin K is essential for the synthesis of the clotting factors (II, VII, IX, and X; see figure 2). When vitamin K is not present (which is essentially the case when it cannot be recycled), the clotting factors are synthesized in a biologically inactive form, rendering them unable to contribute to the clotting cascade. Warfarin is a very effective drug, however its use does have drawbacks.

When somebody is taking warfarin, they must monitor their vitamin K intake. If too much vitamin K is consumed, the effects of warfarin are diminished and the risk of clot formation increases. The consumption of vitamin K rich foods (leafy greens) has to remain consistent in order for warfarin to work properly.

Since warfarin works by causing the synthesis of biologically inactive clotting factors, the anticoagulant effects of warfarin are only noticeable once the biologically active clotting factors are degraded by the body, which takes up to 5 days. Frequent blood testing is required to ensure that the body is forming clots at an appropriate rate, indicating correct dosage of warfarin. If the blood test indicates that clots are forming too easily or too slowly, the dosage must be adjusted. The results of the adjusted dosage can only be observed another 2 to 5 days later, making it often difficult to maintain appropriate levels of drug in the body.

The shortcomings of the old “blood thinners” is what has driven the discovery of newer drugs. Let’s take a look a more recently discovered drug.

Dabigatran:
In recent years, more novel anticoagulants have been discovered with their own sets of advantages and disadvantages. Let’s take a look at Dabigatran (sold as Pradaxa), an alternative to warfarin that was brought into the market in 2010.

Pradaxa is a direct thrombin inhibitor (clotting factor IIa; see figure 2). It works by binding to the active site of thrombin, preventing it from cleaving fibrinogen. This step is shared by both clotting pathways, so inhibition will prevent clot formation. The advantage of dabigatran is that it will have its full effect on the body in as little as two hours. It has a half life of around 12 hours, which is much easier to work with when compared to warfarin’s half life that is multiple days long. The FDA studied Pradaxa versus warfarin and in 2014 concluded that Pradaxa had a lower mortality rate, as well as lower risks of cerebral bleeding and ischemic stroke. One of the main reasons people like taking dabigatran is that regular blood testing is not required.

Although dabigatran is in many cases preferable to warfarin, it still has its drawbacks. The instances of gastrointestinal bleeding are higher when taking dabigatran. While warfarin treatment costs a few cents a day, treatment with dabigatran is about 100 times more expensive, costing multiple dollars a day.

While the short half life is a good feature to have in dabigatran, 12 hours could still be too long for somebody to wait if they need to have emergency surgery. Research is being conducted on potential antidotes for dabigatran which I am excited to share with you in my next major post. For now, be sure to hold on to your life juice.

-Jeff

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