Rivaroxaban and Factor Xa
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A 65 year old female presented to Aurora Grafton ICU with a proximal femoral fracture as a result of a car accident. The accident occurred because the patient experienced a seizure while driving home from the airport from a trip to Maryland. Injuries were extensive, including a hip fracture with a break in the upper quarter of her femur, resulting in a possible hip replacement. Looking over the patient's medication history, it was discovered that she was on aspirin 81mg by mouth daily, furosemide 40mg by mouth twice daily, atorvastatin 20mg by mouth nightly. Past medical history and procedures stated that the patient had a knee replacement three years ago. With this new injury, the patient will need hip replacement surgery. At Grafton, the patient was given enoxaparin 40mg subcutaneous daily for anticoagulation therapy until surgery. There was further discussion on whether to start the patient on rivaroxaban (Xarelto) pre/post-surgical procedure. The pharmacist noted that this patient is at higher risk of bleeding when administering rivaroxaban with aspirin. The staff was to monitor for signs and symptoms of bleeding such as excessive bruising. After further discussion, this patient was started on rivaroxaban 10mg by mouth daily for 35 days after a total hip replacement.
Deep vein thrombosis (DVT), prevalent in 40-60% of hip fractures and replacement surgeries, are a major cause of death in surgical patients1. This is due to the body's natural healing response of activating the clotting cascade. To treat a DVT, specific areas of the clotting cascade must be impacted, inhibiting the continued activation process. Rivaroxaban (Xarelto) is a fairly new oral anticoagulant medication used to reduce the risk of blood clots by binding to Factor Xa (FXa)2. Studies have shown rivaroxaban to be statistically significant in efficacy for DVT prophylaxis post-orthopedic surgery. The Venous Thromboembolism practice guidelines state that rivaroxaban should be started 6 hours after surgery for prophylaxis in total hip replacement procedures1. Rivaroxaban is initiated in patients undergoing surgery to prevent DVT.
Venous thromboembolism (VTE) is a frequent, potentially fatal complication in patients undergoing major hip or knee surgery. Without prophylaxis, patients have a 40 to 60% risk of DVT and 1 to 30% risk of pulmonary embolism (0.1 to 7.5% fatal), depending on expositional and dispositional risks3. The factors that play a role in thrombus production are specifically being targeted to better control overall action. In 2011, the FDA approved rivaroxaban for prophylaxis of deep vein thrombosis (DVT) in adults undergoing hip and knee replacement surgery1. Rivaroxaban, a direct thrombin inhibitor, blocks FXa in the thrombin pathway in order to decrease the possibility of clot formation leading to a venous thromboembolism. The chemical structure and properties of this medication are what make it very effective for prophylaxis of VTE.
Rivaroxaban, or 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, has many important characteristics that make it beneficial for prophylaxis4. High oral bioavailability ranging from 66-100% (dose dependent), a half-life in healthy patients of 5 to 9 hours with a maximum therapeutic effect achieved 2-4 hours after administration plays a major role in how the drug is delivered. It is hepatically metabolized by CYP3A4 and transported by P-glycoproteins therefore patients are advised to avoid medications that inhibit these enzymes and transport proteins when starting rivaroxaban. This is because inhibiting these enzymes would increase the half-life and serum concentration of rivaroxaban further disabling the coagulation pathway and increasing risks for unintended perfuse bleeding. More specifically, rivaroxaban is an oxazolidinone derivative directly inhibiting FXa. It is highly selective at blocking the prothrombinase complex or active site of FXa at the central point in the coagulation cascade4. Through this, rivaroxaban blocks both free and complexed FXa, inhibiting the intrinsic and extrinsic pathways where FXa plays an important role.
Factor Xa, also known as prothrombinase, is an enzyme involved in the main coagulation cascade after endothelial injury. This enzyme is deemed a serine endopeptidase (protease group S1) and is synthesized in the liver when vitamin K is present. Factor X is then activated into FXa, which is the first component of the final common pathway, also known as the thrombin pathway. In the thrombin pathway, FXa converts prothrombin to thrombin by cleaving specific peptide bonds, arginine-threonine and arginine-isoleucine, yielding activated thrombin. Protein Z-dependent protease inhibitor (ZPI), which is a serine protease inhibitor (serpin), inactivates FXa after a clot plug has been formed. In the presence of protein ZPI, the affinity for FXa is increased 1000-fold. All of this occurs due to the crystal structure of FXa and the multiple areas in which molecules can bind5.
The crystal structure of the active site of FXa is divided into four sub pockets: S1, S2, S3, and S4. The most important sub pocket that deals with affinity is S1. The rim of the S1 sub pocket contains S3 when it is exposed to solvent. The sub pocket S1 is the major determinant of selectivity and binding to the protein, while sub pocket S2 is small, shallow, and not well defined. Three ligand binding domains make up the S4 sub pocket, the hydrophilic box, cationic hole, and water site. Inhibitors of FXa such as rivaroxaban by and large bind in an L-shaped conformation which is formed when one ligand binds the anionic S1 pocket lined by amino acids (tyrosine228, asparagnine189, serine195) and another ligand takes place in the aromatic S4 pocket also lined by amino acids (tyrosine99, phenylalanine174, tryptophan215). The two interaction sites are linked in a rigid fashion. FXa plays a vital role in the coagulation cascade with its intricate mechanism of activation and crystal structure.
The protein which rivaroxaban binds is FXa. The FXa protein has two major binding pockets in which rivaroxaban associates, the S1 pocket and the S4 pocket. There are a variety of interactions within each of these pockets between FXa and rivaroxaban. Not found in either of the two major binding pockets, S1 or S4, a glycine (Gly219) of the backbone forms two hydrogen bonds between the drugs oxazolidinone core. These hydrogen bonds give rivaroxaban its bent, L type shape. This L shape is what makes it possible for the oxazolidinone core structure to direct the morpholinone residue into the S4 pocket and the chlorthiophene moiety into the S1 pocket4.
The S4 pocket is narrow and hydrophobic. It is primarily formed by the aromatic rings of several aliphatic amino acids of the FXa (Tyr99, Phe174, and Trp215). The aryl ring of rivaroxaban extends across the indole ring of Trp 215, and the morpholinone moiety is located between Try 99 and Phe 174. The carbonyl group that is located on the morpholinone does not interact with FXa directly. Instead, the carbonyl is responsible for the planarization of the morpholinone ring and orients it perpendicular to the aryl ring. This carbonyl group results in a 60 fold increase of potency compared to other compounds which use a morpholine, which does not have the carbonyl group. This important interaction for increasing potency is key for drug function but the most important interaction takes place in the S1 pocket4.
Within the S1 pocket the chlorine atom of Rivaroxaban interacts with the aromatic ring of Tyr228. This is a key interaction that leads to not needing a basic or positively charged group for high FXa affinity. With this high affinity in a nonbasic compound, good oral bioavailability and high potency was achieved with rivaroxaban4.
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Rivaroxaban plays a major role in the prevention of VTE occurrences. It has been proven in multiple studies to be superior to other standard anticoagulants when used for venous thrombosis prophylaxis post hip/knee surgery7. Rivaroxaban has high affinity for the receptor due to the key interaction of the chlorine in the S1 binding pocket. This allows rivaroxaban to inhibit both free and complexed FXa, resulting in decreased conversion of prothrombin to thrombin. Thrombin is key in stabilizing fibrin clots by converting the platelets cross-linker, fibrinogen, to a stronger fibrin, strengthening the thrombus formation. Fibrinogen forms bridges between platelets, by binding to their GpIIb/IIIa surface membrane proteins. Without thrombin, successful stabile fibrin thrombus formation is hindered, reducing the risk of having a thromboembolic event after total joint replacements. Factor X/Xa plays a major role in the coagulation cascade, specifically the thrombin pathway. The normal process for factor X is to be synthesized in the liver and inactivated by protein Z-dependent protease inhibitors and serine protease inhibitors. It is involved in many different steps of the process, but a crucial area is converting prothrombin to thrombin. By inhibiting FXa, prothrombin stays inactive, preventing a clot from forming. For our 65-year- old female patient undergoing hip surgery, rivaroxaban is a very good option for prophylaxis treatment for VTE. This is supported by many studies, including one that compared enoxaparin to rivaroxaban. In this particular study, more than 50% of the subjects were females in their 60s. In this trial, rivaroxaban proved to be superior to enoxaparin for post-surgery venous thrombosis prophylaxis2. In addition to being a good choice for VTE prophylaxis, the burden of rivaroxaban is less than other options. This drug shows ease of use for patients in that it is readily bioavailable when taken orally. It is more convenient in that patients do not need to poke themselves with needles multiple times a day. The oral bioavailability is made possible by the same chlorine binding in the S1 pocket that is also responsible for higher binding affinity. This is presumed to be because the chlorinated thiophene metabolite of rivaroxaban is more effective are reaching the site of action.
With this knowledge, the healthcare team decided to go forward with starting the patient on rivaroxaban. When prescribed this medication, the patient was to be educated on adverse side effects, such as bleeding, and drug-drug interactions. From the patient's medication history, there were no known drug-drug interactions with the current medications. However, there was concern for a possible increase in bleeding risk due to the concurrent use of aspirin. The physicians were not concerned with this and kept the patient on both medications for the time being. A major adverse effect with rivaroxaban is the risk for bleeding, illustrated by a 5.8% risk of bleeding in hip or knee replacement patients. If a bleeding event were to occur, there is no current accepted method of reversal for this medicationl3. A study has shown that Prothrombin Complex Concentrate (PCC) was effective in immediate and complete reversal of rivaroxaban. This outcome was found in only one study conducted with healthy patients8. Therefore, the results may be inconclusive and lack enough evidence to warrant its use. Medications that are strong CYP3A4 and P-glycoprotein inhibitors should be avoided when using rivaroxaban due to increased plasma concentrations, increasing the risk of severe bleeding. At this time, no daily or routine monitoring is necessary for this anticoagulant, but studies are still underway.
We would like to thank the following preceptors for participating in discussions about this project and contributing to the development of our knowledge of pharmacy practice: Mike Gillard, RPh, Wheaton Franciscan, Franklin, Wisconsin; Dr. Eleanor Shterenfeld, PharmD, Aurora, Grafton, Wisconsin. We would also like to thank Dr. Sem for assisting us with this project.
Thank you to Aaron and Ki for producing the Jmol images and for writing the medicinal chemistry section; to Ariel and Michelle for writing the case synopsis; to Cecilee and Tamika for writing about the background and mechanism of action of rivaroxaban; to Cassie, Melinda, and Ariel for showing how the mechanism of action relates to the case. Finally, thanks to Ariel, Cassie, Cecilee and Melinda for editing the paper.
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