Even though warfarin (Coumadin) has been the standard in anticoagulant (blood thinner) drugs for more than 50 years, it lacked perfection, making way for a new generation of blood thinners, including Xarelto (rivaroxaban). In clinical studies, Xarelto was shown to be more effective than warfarin in treating patients with atrial fibrillation (AF) who are at an increased risk for stroke. And while Xarelto had less cranial hemorrhage (bleeding in the brain) incidents than warfarin, it was shown to have a similar overall number of bleeding incidences when compared to the number of bleeding events in patients taking warfarin.
But despite this finding, and its lack of antidote (reversal agent) for serious bleeding, Xarelto rose to popularity, making up a significant portion of the billion-dollar anticoagulant drug industry in the United States. Even after an investigation into its clinical trial, known as the ROCKET-AF study, upon which its U.S. Food and Drug Administration (FDA) approval hinged, the drug continues to be prescribed by doctors to patients with AF and as a prophylaxis for deep vein thrombosis (DVT), which can lead to pulmonary embolism (PE), after total hip and knee replacement surgeries.
But as more and more evidence surfaces as to the risks afforded to patients taking Xarelto, including an increased risk of wound complications following surgical procedures, severe bleeding with no antidote to stop its serious consequences, as well as reports of platelet deficiencies, hepatitis and Stevens-Johnson syndrome (SJS) (a severe skin reaction), some heart doctors are becoming a bit more cautious with the blood thinner.
Director of anti-coagulation services at the Veterans Administration (VA) health care system in Loma Linda, California, Dr. Alan Jacobson, reported to Reuters, “The good news is you now have an alternative to warfarin… The bad news is you can kill a patient as easily with the new drug as you could with the old drug;” he explained, when it’s not handled properly.
"The good news is you now have an alternative to warfarin… The bad news is you can kill a patient as easily with the new drug as you could with the old drug."
- Dr. Alan Jacobson, Director of anti-coagulation services at the VA in Loma Linda, CA
Xarelto and Internal Bleeding
Janssen and parent company Johnson & Johnson market its anticoagulant drug Xarelto as a safe and more convenient choice in blood thinners compared to warfarin. But pre-market clinical studies and post-marketing reports have shown that taking Xarelto leaves many patients vulnerable to internal bleeding that can result in death for some users.
In a 2017 annual report issued by the Institute for Safe Medication Practices (ISMP), it was stated that oral anticoagulant drugs, including Xarelto (rivaroxaban), showed “unacceptably high risks,” according to two government data sources, the FAERS adverse events reports for 2016 and a new systematic study by the Centers for Disease Control and Prevention (CDC).
Did you know
Of the 22,000 reports of serious injuries resulting from anticoagulant drugs, Xarelto accounted for 15,043 cases alone.
According to an analysis of 2016 FDA adverse event data conducted by the ISMP, anticoagulant (blood thinner) drugs accounted for nearly 22,000 reports of serious injuries in the United States, led by Xarelto, which accounted for 15,043 cases alone. These numbers also included 3,018 reported deaths, with most injuries being the result of hemorrhages, making bleeding one of the most frequently reported serious adverse drug effects from medications such as Xarelto.
Gastrointestinal hemorrhages made up the largest number of cases, followed by cerebral hemorrhages. From early testing, hemorrhage has always been an apparent increased risk associated with lowering the risk of strokes from blood clots.
In late 2016, the CDC released a separate study that found that “anticoagulant drugs accounted for more emergency department visits for outpatient adverse effects than any other class of drugs in therapeutic use, including opioids (non-abuse visits), antibiotics and diabetes drugs.” Most of these adverse events were severe, with nearly 50 percent requiring a hospital stay. The ISMP estimated in its QuarterWatch report that just over 6 percent of patients using anticoagulants for one year will need to visit the emergency room, with about half of those patients requiring hospitalization.
Overall, the CDC found in its systematic study that the FDA’s FAERS voluntary reporting underestimates anticoagulant drug-related injuries. The CDC discovered that approximately 228,600 emergency department visits occur each year due to the use of blood thinner drugs, including Xarelto, which is 10 times more than the FAERS total number of voluntary reports.
Symptoms of Internal Bleeding
At its onset, internal bleeding, unless it’s a severe hemorrhage, may not cause any symptoms apparent to the patient taking Xarelto. However, dependent on where the bleed is located in the body, the patient will soon begin exhibiting signs and symptoms that will be their indication to seek immediate medical attention. Patients who are in poor health or over the age of 65 are more likely to suffer serious, potentially life-threatening bleeding complications.
Patients taking Xarelto should seek immediate emergency treatment if they are experiencing any of the following signs or symptoms of bleeding:
- Frequent nose bleeds
- Unusual bleeding in the gums
- Red, pink or brown urine
- Severe uncontrolled bleeding
- Headaches, weakness or dizziness
- Feeling lightheaded or fainting
- Low blood pressure or loss of consciousness
- Bright red or black stool that looks like tar
- Vaginal bleeding or menstrual bleeding that is heavier than normal
- Wounds with pain, swelling or new drainage at the site
- Coughing up blood or blood clots
- Blood in vomit or vomit that looks like “coffee grounds”
Internal Bleeding Treatment
According to the National Institutes of Health (NIH), when a person bleeds (whether internally or externally), the body’s natural response is to form a clot to stop the bleeding. However, when a patient is taking a blood thinner, such as Xarelto, a drug designed to prevent blood from clotting, it can become much more difficult for the body to respond in its normal way.
Severe bleeding that does not stop requires emergency treatment. A “lay person” is unable to stop internal bleeding. If a patient is exhibiting signs of shock (a potentially life-threatening condition in which delivery of oxygen to the organs is diminished and a patient’s blood pressure is abnormally low), the individual should be laid down with their legs elevated while awaiting emergency medical care.
While all blood thinners carry the risk of bleeding, Xarelto may be more dangerous than some because it currently does not have an antidote, or reversal agent, to stop the bleeding. Nor is there any specific treatment with proven efficacy for severe bleeding related to Xarelto or complications associated with its effects, according to an abstract published by NIH.
On the contrary, an older blood thinner, warfarin, may also cause bleeding; but emergency health care professionals can use a vitamin K antidote to stop the bleeding. Additionally, warfarin has a few other options available to treat urgent bleeds in patients.
Dialysis, or flushing certain wastes or toxins (or drugs) from a patient’s bloodstream, has also been shown to be ineffective in the treatment of bleeds associated with the use of Xarelto due to the medication’s high plasma protein binding. Therefore, treatment will likely aim only to handle and minimize any resulting complications from the bleeding, according to one pharmacological expert on the matter.
Xarelto and Wound Infections
In 2016, a 2015 study published by The Journal of Arthroplasty, found that the use of rivaroxaban (Xarelto) to prevent deep vein thrombosis (DVT) (a blood clot in a vein deep within the body) following total hip and knee replacement surgeries led to significantly higher incidences of deep surgical site infections (SSIs) in patients. The authors of the study noted that such infections within the patients’ joints are “disastrous complications,” and that the use of Xarelto is directly linked to an increased risk of these wound infections, as well as SSI drainage (leakage).
Another study published by the National Institutes of Health (NIH) in 2012, found that when Xarelto was administered to 559 British patients undergoing knee and hip replacement surgeries, the rate of wound complications rose significantly. The blood thinner drug was used in place of tinzaparin (another anticoagulant in the heparin group) for thrombophylaxis, or the prevention of thromboembolic disease, following lower limb arthroplasties (a surgical procedure to reconstruct or replace a nonfunctioning or diseased joint).
Signs and symptoms of a surgical wound infection that may require immediate medical attention include:
- Pus (can form an abscess) or drainage
- Bad smell coming from the wound
- Fever and/or chills
- Area hot to touch
- Redness and/or swelling
- Pain or area sore to touch
- Wound reopening
Researchers concluded that aside from the higher wound complication rate, longer-term studies needed to be conducted to assess any potential relationships between the wound complications and joint stiffness, latent infection (a condition in which there is a virus within the body but it lays dormant) and limb consequences of DVT.
A publication by the American Academy of Orthopaedic Surgeons (AAOS) stated that the switch from tinzaparin to rivaroxaban was made only after Xarelto was approved for “chemical thrombophylaxis” in the European Union. Though, the authors noted that “this recommendation was based solely on four sponsored studies.”
The AAOS also pointed out that the National Institute of Health and Clinical Excellence (NICE) had placed more focus on major bleeding events as the primary safety outcome, and less attention was paid to wound complications, “such as prolonged bleeding and/or oozing, and infection.”
Furthermore, in a 2008 edition of the New England Journal of Medicine (NEJM), a New York-based law firm, Weitz & Luxenberg (W&L) stated that an orthopedic surgeon, who was also a member of a steering committee for one of the rivaroxaban trials, wrote that “he would not recommend Xarelto for his patients,” explaining that “the risk of harm from Xarelto could significantly outweigh the risk of a pulmonary embolism.”
Wound Infection Symptoms
Wound complications in patients following total hip and knee replacements include:
- Abnormal drainage
- Abnormal/unusual oozing
- Hematoma (blood pooling)
- Poor range of motion
- Unrelenting pain
According to the National Institutes of Health (NIH), surgery that involves a cut (or incision) in the skin can lead to a wound infection, typically showing up within the first 30 days following the surgery. Surgical wounds can become infected for a number of reasons, including germs already present on the skin that spread to the surgical wound, germs that are inside the body or from the organ on which surgery was performed, germs that are in the air, infected hands of the health care provider and infected surgical instruments.
Patients are more at risk for a surgical wound infection if they have certain health conditions, such as poorly controlled diabetes, problems with their immune system, or are overweight or obese; if they are a smoker, if they have a surgery that lasts more than two hours, or if they take certain medications, such as corticosteroids (prednisone) or, as indicated by several studies, Xarelto.
Wound infections can be superficial (meaning only the skin area is affected), deep (meaning the infection goes deeper than the skin into the muscle and tissue) or organ/space infections (meaning the infections is deep involving the organ or space/joint where the surgery was performed.
Wound Infection Treatment
Most surgical site infections (SSIs), or wound infections, can be treated with antibiotics. The antibiotic prescribed to the patient will depend on the type of bacteria causing the infection. The wound may be tested to determine the best course of treatment. The length of time a patient needs to take the antibiotics can vary, but will typically be for at least one week. Antibiotics may initially be administered by IV and later switched to pill form.
Sometimes, patients with an SSI may require an additional surgical procedure to treat the wound infection. New York-based law firm, Weitz & Luxenberg (W&L), who has represented patients injured by Xarelto, reported that a 2011 study published in the Journal of Bone & Joint Surgery, found that 31 out of 1,000 observed patients required reoperation following an initial total hip and knee replacement surgery; and of those 31 patients, 22 were prescribed the anticoagulant drug.
Xarelto and Thrombocytopenia (Platelet Deficiency)
The FDA receives post-marketing reports for adverse reactions, or side effects, that are identified post-drug-approval. Several reports, voluntarily submitted by Xarelto users, indicated the occurrence of thrombocytopenia as a result of taking the blood thinner drug. Thrombocytopenia is a condition in which a person’s blood has an abnormally low amount of platelets, which are a part of the blood that help it to clot. This disorder can also sometimes be associated with abnormal bleeding.
Platelets are made in the bone marrow along with other kinds of blood cells. From there, they travel through the blood vessels sticking together (or clotting) to stop any bleeding that may occur if a blood vessel is damaged. Another name for a platelet is a thrombocyte, similar to how a clot is called a thrombus.
When an adult’s platelet count is “healthy,” their number of platelets can range from 150,000 to 450,000 platelets per microliter of blood. If a person’s platelet count falls below the lowest end of normal at 150,000, then the person is said to have thrombocytopenia. The risk for serious bleeding can occur when the count becomes very low, typically less than 10,000 to 20,000 platelets per microliter of blood. Mild bleeding can occur when an individual’s platelet count falls below 50,000 platelets per microliter.
There are three major causes of low platelet levels in the blood, including the bone marrow not making enough platelets, an increased breakdown of platelets in the bloodstream and an increased breakdown of platelets in the spleen or liver. Several conditions can affect the bone marrow’s ability to produce enough platelets, including cancer in the bone marrow, such as leukemia, a certain type of anemia (called aplastic anemia), liver scarring, folate deficiencies, infections in the bone marrow, a vitamin B12 deficiency and myelodysplastic syndrome, where the bone marrow doesn’t make enough cells or makes defective cells.
The use of certain drugs can also cause a lower than normal production of platelets in the bone marrow. While chemotherapy treatment is the most common medication associated with this condition, another drug known as heparin, used to prevent blood clots, has also been attributed to the development of thrombocytopenia, due to an immune reaction. This specific drug response is referred to as heparin-induced thrombocytopenia, or HIT. It results in an attack of a protein on the surface of the platelets that activate the platelets to initiate the formation of blood clots.
On the ClinicalTrials.gov website, a clinical trial recorded in May 2012 and started in January 2013 with 22 enrolled participants, was designed to study rivaroxaban (Xarelto) as a treatment for patients with suspected or confirmed HIT. The government site pointed out that a successful trial would result in a two-fold benefit, in that for patients with HIT, they would have “a safe and easy-to-use drug to protect them from developing further life or limb-threatening blood clots,” and, for the Canadian health care system, “the benefit [would be] having a drug that is much less expensive than the drugs currently used to treat HIT.”
However, the trial was terminated in July 2015, and no study results had been posted as of the website’s last verification and update in March 2016.
Symptoms of Platelet Deficiency
Patients who have thrombocytopenia may not have any symptoms, especially if their condition is mild. If patients have a health condition that is causing the increased breakdown of platelets in their blood, spleen or liver, they may experience symptoms of those conditions as well.
If symptoms do occur in an individual with drug-induced low platelet count, they may include:
- Bleeding in the mouth and gums
- Rash (pinpoint red spots called petechia)
In serious cases, where a patient’s platelet count drops dangerously low, the patient is at a greater risk for abnormal, sometimes severe or life-threatening, bleeding. In rare instances, the condition may also affect a patient’s spleen, which can become swollen, necessitating a surgery for its removal.
Platelet Deficiency Treatment
The length of time that the condition persists and its severity depends on the underlying cause of thrombocytopenia. It can last anywhere from days to years. Therefore, treatment of thrombocytopenia is also largely dependent on the cause and severity of the disorder, with more mild cases generally not requiring any significant interventions.
Certain tests may be performed by a patient’s health care provider prior to the onset of treatment, including a complete blood count (CBC), blood clotting tests (PTT and PT), bone marrow aspiration and/or a biopsy.
Severe bleeding, or hemorrhage, is the main complication associated with the disorder. The bleeding can occur in the brain or most commonly in the gastrointestinal tract. If the condition causes bleeding or puts the patient at an increased risk for bleeding, certain medications or even a transfusion of platelets may be needed to stop or prevent the bleeding.
The outcome is largely dependent on the underlying cause of the condition and the treatment received. While the condition can be fatal if not found and treated, the overall outlook for patients affected by thrombocytopenia is good, according to the National Institutes of Health (NIH).
Xarelto and Hepatitis
In May 2017, approximately 83 post-marketing reports voluntarily submitted by Xarelto users indicated hepatitis (including hepatocellular injury) as an adverse reaction sometimes experienced by patients taking the anticoagulant drug.
Groups of individuals taking Xarelto shown to be most affected by the acquisition of hepatitis included patients who were:
- Age 60 or older
- Had been taking the drug for less than one month
- Also taking the medication Cordarone (used to treat serious heart arrhythmias)
- Taking Xarelto to treat atrial fibrillation (AF)
Hepatitis is an inflammation of the liver. The liver is the largest organ inside the body, and it assists in the digestion of food, storing energy, and the removal of toxins and/or wastes. Most cases of hepatitis are caused by viruses. These types of hepatitis are named according to the virus that caused it, including hepatitis A, hepatitis B and hepatitis C. The use of certain drugs, including prescription drugs, and/or alcohol can also cause hepatitis, where the body “mistakenly attacks health cells in the liver,” as described by the National Institutes of Health (NIH).
While some forms of hepatitis are mild, others can be quite serious, with some even leading to scarring of the liver, called cirrhosis, or liver cancer. Hepatocellular injuries are diseases of the liver that can either be an infection or cancer. This can also occur from the use of medications or toxic chemicals.
The liver helps the body break down certain medicines. These can include over-the-counter (OTC) drugs as well as prescription drugs. When the breakdown process is slower in some individuals, this can result in an increased likelihood of resulting liver damage. This can even occur with drugs taken in small doses, and even when the liver breakdown process is normal.
Hepatocellular injury accompanied by jaundice is called hyperbilirubinemia. This condition is associated with death rates as high as 50 percent, with the chance of a patient’s recovery being low without a liver transplant. This type of injury is most often linked to a patient’s use of drugs, such as acetaminophen and, as indicated in post-marketing reports, Xarelto.
Symptoms of Hepatitis
Some patients with hepatitis have no symptoms of the disease. Other symptoms experienced by individuals affected by the potentially serious health condition can vary based on the cause and severity of the hepatocellular injury, and the length of time affected by the disorder.
The most common symptoms of hepatitis, including drug-induced hepatocellular injury, include:
- Abdominal pain and/or distension or swelling of the abdomen
- Severe itching of the skin
- Dark (or tea-colored) urine
- Jaundice – yellowing of the skin and eyes
- Intermittent blood in the stool
- Fatigue, often extreme
- Loss of appetite
- Nausea and vomiting
- White, pale or clay-colored stools
Blood tests will be performed by a patient’s health care provider to check liver function. Liver enzymes will be higher than normal if an individual is diagnosed with hepatitis. A doctor can also check a patient by physical exam for an enlarged liver and abdominal tenderness in the right upper part of the belly where the liver is located.
Sometimes hepatitis can go away on its own, and sometimes it requires treatment. The liver is very resilient so it is often capable at healing itself, making the majority of liver problems acute in nature, meaning they last for only a short time. If treatment is needed, it will involve rest and avoiding substances that may cause added harm to the liver, such as heavy exercise, alcohol and acetaminophen. If nausea and vomiting is severe, IV fluids may be necessary to prevent dehydration.
In chronic instances, where the disease persists, or in severe cases, especially when hepatocellular jaundice and impaired liver function is apparent, liver transplantation may be required.
When hepatitis or hepatocellular injury is caused by exposure to a medication, early drug withdrawal will provide the best patient outcome. When caught early on, a full recovery is typically expected. Drug-induced liver injury usually resolves within days or weeks after the patient stops taking the drug. However, in rare instances, it can lead to liver failure.
Antidotes are also available for certain medications resulting in this adverse reaction, but Xarelto is not yet one of them with an antidote.
Xarelto and Stevens-Johnson Syndrome (SJS) (Severe Skin Reaction)
According to information compiled by the FDA, at least 15 individuals taking Xarelto voluntarily reported having Stevens-Johnson syndrome (SJS) as an adverse reaction as a result of taking the drug; and since these reports are voluntary and often only include the most severe cases, these numbers may be underrepresented as to the actual number of patients affected.
SJS, also called erythema multiforme major, is a severe skin reaction often triggered by certain medications, but it can also be caused by certain infections and whole body (systemic) illnesses, such as Chron’s disease or systemic lupus. This serious and potentially deadly condition typically affects adults between the ages of 20 to 40 years old, with twice as many men than women acquiring the disorder. Patients who have SJS often have had a family member affected by the severe skin condition as well.
Because the skin normally acts as our protective barrier from outside elements and substances, severe skin damage and damage to mucous membranes associated with SJS make the condition a life-threatening disorder. Extensive damage to the skin can also result in a dangerous loss of fluids and allow for infections to develop and invade the body. About 10 percent of individuals who acquire SJS will die from the disease.
According to the National Institutes of Health (NIH), those who survive SJS often experiencing many long-term effects, including:
- Changes in skin coloring
- Dryness of the skin and mucous membranes
- Excessive sweating
- Difficulty urinating
- Genital abnormalities
- Vision impairment (rare)
- Hair loss
- Abnormal growth or loss of the fingernails and toenails
- Impaired taste
- Chronic dryness or inflammation of the eyes (rare)
- Increased sensitivity to light (rare)
Symptoms of SJS
Stevens-Johnson syndrome (SJS) often begins with flu-like symptoms, which is then followed by a painful red or purplish-colored rash that spreads and blisters. This eventually results in the top layer of the skin blistering, dying and then shedding (or peeling), forming raw, painful areas called erosions. These erosions typically begin on the face and chest, and in most individuals, it also damages the mucous membranes, including the lining of the mouth and the airways, which can cause difficulty with breathing and swallowing.
The blistering can also affect the urinary tract, genitals and various parts of the eyes, sometimes resulting in vision loss. Serious complications of SJS include pneumonia, bacterial infections (sepsis), shock, multiple organ failure, and even death.
Signs and symptoms of SJS can include:
- General ill feeling (malaise)
- Nausea and vomiting
- Weight loss
- Eye pain
- Mouth sores
- Itchy skin
- Joint aches
- Many skin lesions (sores or other abnormal areas on the skin)
- Bloodshot eyes
- Dry eyes
- Eye burning, itching or discharge
- Vision problems
Patients who have Stevens-Johnson syndrome (SJS) require hospitalization, as it is an emergency medical condition. Treatment of the condition can be difficult and may necessitate admission to an intensive care or burn unit as soon as a diagnose of SJS is suspected. Severe symptoms may require antibiotics to control skin infections, corticosteroids (such as prednisone) to control inflammation, intravenous immunoglobulins to stop the progression of the disease, and treatment for the eyes, including artificial tears, antibiotics and corticosteroids.
Other treatments may include stopping any medications that are believed to have caused SJS, taking an antihistamine to control itching, moist compresses applied to the skin, pain medications to reduce fever and discomfort, and mouthwashes to treat mouth sores, especially those that interfere with eating and drinking.
Skin regrowth following treatment of SJS generally occurs rapidly within two to three weeks, but overall recovery can take anywhere from weeks to months. For some patients, the condition may result in chronic complications that can develop within weeks to months of an SJS diagnosis. In some instances, about 3 to 7 percent of cases involving adults, according to the National Institutes of Health (NIH), recurrence has been known to happen, and it is often associated with SJS caused by medications, such as Xarelto.
Kristin Compton is a medical writer with a background in legal studies. She has experience working in law firms as a paralegal and legal writer. She also has worked in journalism and marketing. She’s published numerous articles in a northwest Florida-based newspaper and lifestyle/entertainment magazine, as well as worked as a ghost writer on blog posts published online by a Central Florida law firm in the health law niche. As a patient herself, and an advocate, Kristin is passionate about “being a voice” for others.
- Brimmo, O. et al. (2015). Rivaroxaban Use for Thrombosis Prophylaxis Is Associated With Early Periprosthetic Joint Infection. Retrieved from: http://www.arthroplastyjournal.org/article/S0883-54031501108-0/fulltext
- Brophy Marcus, M. (2016). Questions raised about clinical trial of popular heart drug. Retrieved from: http://www.cbsnews.com/news/xarelto-warfarin-clinical-trial-bmj-report-raises-questions/
- CDC. (N.D.). FAQs: about “Surgical Site Infections.” Retrieved from: https://www.cdc.gov/HAI/pdfs/ssi/SSI_tagged.pdf
- ClinicalTrials.gov. (2017). Rivaroxaban for Treatment of Patients With Suspected or Confirmed Heparin-Induced Thrombocytopenia. Retrieved from: https://clinicaltrials.gov/ct2/show/study/NCT01598168
- eHealthMe. (N.D.). Xarelto and Hepatitis – from FDA reports. Retrieved from: http://www.ehealthme.com/ds/xarelto/hepatitis/
- Genetic and Rare Diseases Information Center, National Institutes of Health. (N.D.). Stevens-Johnson syndrome. Retrieved from: https://rarediseases.info.nih.gov/diseases/7700/stevens-johnson-syndrome
- Hepatocellular.org. (N.D.). Hepatocellular Diseases of the Liver. Retrieved from: http://www.hepatocellular.org/hepatocellular-diseases-of-the-liver.html
- Herrine, MD, S. K. (N.D.). Liver Injury Caused by Drugs. Retrieved from: https://www.merckmanuals.com/professional/hepatic-and-biliary-disorders/drugs-and-the-liver/liver-injury-caused-by-drugs
- Jameson, SS. et al. (2012). Wound complications following rivaroxaban administration: a multicenter comparison with low-molecular-weight heparins for thromboprophylaxis in lower limb arthroplasty. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/22832942
- Johns Hopkins Medicine. (N.D.). Surgical Site Infections. Retrieved from: http://www.hopkinsmedicine.org/healthlibrary/conditions/surgical_care/surgical_site_infections_134,144/
- Kaji, MD, PhD, A. H. (N.D.). Internal Bleeding. Retrieved from: http://www.merckmanuals.com/home/injuries-and-poisoning/first-aid/internal-bleeding
- MedFacts.com. (N.D.). Study of possible correlation between Stevens-Johnson Syndrome and Xarelto. Retrieved from: http://factmed.com/study-XARELTO-causing-STEVENS-JOHNSON%20SYNDROME.php
- MedlinePlus, NIH. (2016). Drug-induced liver injury. Retrieved from: https://medlineplus.gov/ency/article/000226.htm
- MedlinePlus, NIH. (2016). Erythema multiforme. Retrieved from: https://medlineplus.gov/ency/article/000851.htm
- MedlinePlus, NIH. (2016). Hepatitis. Retrieved from: https://medlineplus.gov/hepatitis.html
- MedlinePlus, NIH. (2016). Thrombocytopenia. Retrieved from: https://medlineplus.gov/ency/article/000586.htm
- MedlinePlus, NIH. (2016). Rivaroxaban. Retrieved from: https://medlineplus.gov/druginfo/meds/a611049.html
- MedlinePlus, NIH. (2016). Surgical wound infection – treatment. Retrieved from: https://medlineplus.gov/ency/article/007645.htm
- MedlinePlus, NIH. (2017). Bleeding. Retrieved from: https://medlineplus.gov/bleeding.html
- Monson, PharmD, K. (2017). Xarelto Overdose. Retrieved from: http://arthritis.emedtv.com/xarelto/xarelto-overdose.html
- NIH. (2012). What Is Thrombocytopenia? Retrieved from: https://www.nhlbi.nih.gov/health/health-topics/topics/thcp
- NIH. (2017). Stevens-Johnson syndrome/toxic epidermal necrolysis. Retrieved from: https://ghr.nlm.nih.gov/condition/stevens-johnson-syndrome-toxic-epidermal-necrolysis
- Pierson, R. (2012). Pradaxa and Xarelto: Top Heart Doctors Concerned Over New Blood Thinners. Retrieved from: http://www.huffingtonpost.com/2012/06/14/pradaxa-xarelto-blood-thinner-doctors-heart_n_1595971.html
- PubMed.gov, NIH. (2013). Bleeding with dabigatran, rivaroxaban, apixaban. No antidote, and little clinical experience. Retrieved from: https://www.ncbi.nlm.nih.gov/pubmed/23866358/
- QuarterWatch, ISMP. (2017). Annual Report Issue. Retrieved from: http://www.ismp.org/quarterwatch/pdfs/2016Q4.pdf
- Stanton, T. (2012). Switch to Rivaroxaban Led to Higher Complication Rate. Retrieved from: https://www.aaos.org/News/The_Daily_Edition_of_AAOS_Now/2012/Wednesday,_February_8/AAOS17_2_8/?ssopc=1
- Weitz & Luxenberg. (2015). Xarelto May Cause Wound Complications After Surgery. Retrieved from: https://www.weitzlux.com/firm-news/xarelto-may-cause-wound-complications-after-surgery/