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[Dr. Shapiro] This is Dr. Samantha Shapiro, executive editor of Harrison's Principles of Internal Medicine. Harrison's Podclass is brought to you by McGraw Hill's AccessMedicine, the online medical resource that delivers the latest trusted content from the best minds in medicine. And now, onto the episode.
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[Dr. Handy] Hi everyone, welcome back to Harrison's Podclass. We're your co-hosts. I'm Dr. Cathy Handy.
[Dr. Wiener] And I'm Dr. Charlie Wiener, and we're joining you from the Johns Hopkins School of Medicine.
[Dr. Handy] Welcome to episode 103, a 57-year-old with a swollen knee.
[Dr. Wiener] Okay, Cathy, so today we have a 57-year-old man who presents to your clinic with an acutely swollen and tender right knee. He's an avid pickleball player, and two days ago returned from a wellness clinic in Florida where for one week, he ate only fresh fruits, nuts, vegetables and eggs. Yesterday during a vigorous pickleball game, he fell during it, and he recalls banging his right knee. This morning he woke with the knee swollen, red, and tender. His past medical history is only notable for having had a mechanical mitral valve replacement due to rheumatic heart disease, and that was eight years ago. He takes 5 milligrams a day of warfarin, and his INR has been stable at 2.4 to 2.6 for the past three years.
[Dr. Handy] That's probably going to be an important point in this question.
[Dr. Wiener] Okay. Well, on the other hand, he's never had any bleeding problems on warfarin. As far as other symptoms go, he denies any recent fevers, chills, nausea, vomiting, or diarrhea, and other than a tense, swollen, red right knee, the remainder of his physical exam is normal. What are you thinking?
[Dr. Handy] Well, you've given me a bunch of interesting tidbits but in essence, we have a man that's chronically on warfarin with an acutely painful, swollen joint. The big categories on the differential diagnosis that I think of for monoarticular arthritis of a large joint, like this person has with his knee being swollen, include an infection, crystalline arthropathy, hemarthrosis, trauma or osteoarthritis can cause this, and then rheumatologic disease. Now, while there are causes of infectious monoarthritis, he has no symptoms that lead me to think that he's infected. And you also told me that he's on a blood thinner, so I'm leaning towards this being a traumatic hemarthrosis, especially given his history of a fall while playing pickleball.
[Dr. Wiener] Yeah, and I just want to highlight the fact that he also changed his diet dramatically recently during his wellness clinic. So let's review quickly warfarin. So warfarin interferes with the synthesis of vitamin K-dependent clotting proteins, which include prothrombin or factor two, and factors seven, nine, and ten. Remember, the synthesis of the vitamin K-dependent anticoagulant proteins, protein C and protein S, are also reduced by vitamin K antagonists. He's been on these for years though, and he tells us this has never happened before. Why now?
[Dr. Handy] And you sort of hinted at it already, because you mentioned food. So warfarin is metabolized mostly in the liver by CYP2C9. There are a few relatively common genetic polymorphisms in this enzyme that can influence warfarin metabolism, but in addition to the genetic polymorphisms, there are a number of drug supplements and food that can also influence the metabolism of warfarin, so clinicians and patients, of course, need to be aware of them, and you described a drastic change in his diet while on this retreat. So that's what I suspect is the reason why he's maybe having bleeding issues now, where he hadn't had any in the past. What's the question asking?
[Dr. Wiener] Okay, so the question asks, which of the following foods is most likely related to his acute presentation? And these are all foods that he ate during his wellness retreat. Option A. is chia seeds; option B. is eggs; option C. is kale; option D. is pomegranates; and option E. is turmeric.
[Dr. Handy] The answer is D. pomegranates. So pomegranates, grapefruit, cranberries, those can all inhibit CYP2C9, and therefore inhibit the metabolism of warfarin. So I would suspect that his INR is now above 3, and when he landed on his knee, he developed a traumatic hemarthrosis.
[Dr. Wiener] Well, once again, you're exactly right. So his clinicians ordered a stat INR, and it came back at 5, and his CBC showed that his hemoglobin was stable at 14. So let's talk a little bit about the bleeding complications with warfarin and how we treat them.
[Dr. Handy] Well, at least half of the bleeding complications with warfarin occur when the INR exceeds the therapeutic range as in this case, so you mentioned that his INR level was high at 5. Bleeding complications can be mild such as epistaxis or hematuria, or they could even be more severe, such as a retroperitoneal bleed or gastrointestinal bleeding. Life-threatening intracranial bleeding can also occur. Now obviously, trauma like in this patient is also a big risk factor for bleeding.
[Dr. Wiener] So how do you treat it?
[Dr. Handy] The goal INR for most people is 2 to 3. In asymptomatic patients whose INR is between 3.5 and 10, warfarin should just be withheld until the INR returns to the therapeutic range. If the INR is over 10, oral vitamin K can be administered at a dose of 2.5 to 5 milligrams, although there's no evidence that doing so reduces the bleeding risk. Higher doses of oral vitamin K produce more rapid reversal of the INR, but they may render patients temporarily resistant to warfarin when the drug is restarted.
[Dr. Wiener] What about patients not like this one, but with more serious bleeding such as the ones you mentioned before with retroperitoneal or GI bleeding?
[Dr. Handy] Patients with serious bleeding will need more aggressive treatment, and these patients should be given IV vitamin K, 5 to 10 milligrams, or additional vitamin K may need to be given until the INR is in the normal range. And treatment with vitamin K should be supplemented with four-factor prothrombin complex concentrate, that contains all four vitamin K-dependent clotting proteins. And prothrombin complex concentrate normalizes the INR more rapidly than transfusion of fresh frozen plasma, so that's why that's the preferred agent.
[Dr. Wiener] What about patients that have significant bleeding while they have a therapeutic INR?
[Dr. Handy] Warfarin-treated patients who experience bleeding when the INR is in the therapeutic range require investigation into the cause of the bleeding, 'cause they may have an underlying lesion, especially in those with gastrointestinal or genitourinary bleeding.
[Dr. Wiener] So let's go back to our patient. What are you going to recommend for him?
[Dr. Handy] So he's hemodynamically stable and had a clear precipitating event. If we think clinically the bleeding has stopped, we can just hold his warfarin and keep him away from the pomegranates and probably the pickleball court, too. I'd discuss with my orthopedic colleagues whether he'd benefit from an arthrocentesis to relieve the discomfort and hasten the healing of the knee.
[Dr. Wiener] Yeah, that's probably even more important given that he has the mechanical valve and you don't want to overcorrect him, right?
[Dr. Handy] Correct.
[Dr. Wiener] Okay, let's finish by telling me, are there any other foods associated with medicine interactions that we should just highlight?
[Dr. Handy] Yeah, and just going through some of the answer choices that you mentioned before, so- And just to start out too, most patients receiving warfarin can likely take the occasional pomegranate or grapefruit or cranberry, especially when it's steady over time. Large amounts of chia seeds, kale, or turmeric may cause some GI discomfort. Kale does contain oxalate, which can be relevant to those with oxalate kidney stones, and kale and other leafy greens are high in vitamin K, but that usually causes a lower INR. Bottom line is that none of these in moderation are dangerous to the typical person.
[Dr. Wiener] Great, so the teaching point in today's case is that warfarin, which is metabolized by the CYP2C9 pathway, is sensitive to high doses of certain foods such as pomegranates, grapefruits, and patients really need to be educated about these things, and clinicians need to be aware because the INR could vacillate as a result of excessive ingestion of these foods.
[Dr. Handy] And if you want to read more about this, you can refer to the Harrison's chapter on antiplatelet, anticoagulant, and fibrinolytic drugs.
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[Dr. Shapiro] Thanks for listening to Harrison's Podclass. You can listen to this episode and more on AccessMedicine.com, which includes the complete Harrison's Principles of Internal Medicine text, Harrison's review questions, which complement and expand upon the questions in this episode, and much more. AccessMedicine.com may already be available to you via your academic institution. Check it out.
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