Hemorrhage
Want to know why cocaine is used in the operating room? What toxin has been used in bombs, impregnated into clothing and sprayed on salad bars? What rat poison is treated with vitamins?
This is the Pick Your Poison podcast. I’m your host Dr. JP and I’m here to share my passion for poisons in this interactive show. Will our patient survive this podcast? It’s up to you and the choices you make. Want to know why cocaine is used in the operating room? What toxin has been used in bombs, impregnated into clothing and sprayed on salad bars? What rat poison is treated with vitamins?
Today's episode starts in the emergency department with your resident presenting the case of a 22-year-old man with epistaxis i.e. a nosebleed. His nose has been oozing for several hours, the bleeding just won’t stop. She examined him without finding an area amenable to cauterization, its oozing from both nostrils. She told him to hold pressure, then tried oxymetolazone, brand name Afrin in the US, a nasal spray causing vasoconstriction. Neither worked. She wants to try tranexaminic acid, a blood clotting medicine. She also wants to send labs, including coagulation markers.
You agree with the TXA, but the lab work seems unnecessary in this otherwise healthy patient without any past medical history who isn't taking any medicines.
Question number one. Other measures that might help include:
A. Cocaine
B. Turmeric
C. Hot packs
Answer: A. Cocaine is great for nosebleeds. Turmeric has anticoagulant properties, meaning it theoretically could increase bleeding. Hot packs cause vasodilation also potentially increasing bleeding. Conversely, Ice packs aren’t proven, but may help.
It’s less and less common these days, but liquid cocaine, is used by head and neck surgeons during surgery because it’s such a good vasoconstrictor and a topical anesthetic. I’ve used it myself a few times, on their advice, for refractory epistaxis. You soak a cotton pledget in the liquid, typically 4% solution, and put it inside the nose. I’ve also taken care of post-op patients with symptoms of cocaine toxicity like racing heart rate and high blood pressure, after it was used during surgery.
Wait a minute did I hear you say? Doesn’t cocaine cause nose bleeding? Yes. Also true, the difference is chronic use. Chronic vasoconstriction leads to loss of the blood supply in the nose, resulting in dryness and ultimately tissue deterioration particularly in the septum, leading to septal perforations and nosebleeds.
Epistaxis is an extremely common complaints in the ED. Question # 2. Nosebleeds are commonly caused by?
A. nose picking.
B. high blood pressure.
C. Dry Air
If you answered this one, you got it right. The answer: is A, B, and C. Most cases are low acuity. Very rarely, it’s possible for epistaxis to be life-threatening. We divide the blood vessels in the nose into two sections, anterior and posterior. The vast majority are anterior bleeds. Posterior nosebleeds are a true emergency and patients can actually bleed to death. I've only seen really one serious posterior nosebleed in my entire career and I'm not exaggerating when I say the entire room, including the walls, were covered in blood.
The resident insists on sending labs. Why? This is clearly not a life-threatening case. She reviewed his chart, noting he was just in the ER two days ago for hematuria ie blood in the urine. Hmm, this case is getting a bit more interesting. The urinalysis showed blood, not infection, but he was treated with antibiotics as a precaution. He didn’t have abdominal pain suggesting kidney stone or other pathology.
The patient is still having blood in the urine, and it’s gotten worse, though it’s still painless hematuria. She’s convinced you about the labs and sends a blood count and coags, also known as PT/INR and pTT.
In the room, the patient is pinching his nose. Nevertheless, blood is oozing from both nostrils. His vital signs are as follows temperature 98.6 or 36.9 Celsius, heart rate 90 bpm. Blood pressure 120/80, respiratory rate 18 and oxygen saturation 100% on room air. He gives you the same history he told the resident, so you move to the exam. His affect seems withdrawn, meaning he's not showing a lot of emotion and isn't making good eye contact, but to be fair he's trying to talk to you while pinching his nose. Looking inside, you agree, there’s no focal bleeding, just general oozing.
His heart and lung exam are normal as is his abdominal exam. You do notice a lot of bruising on his skin. He shrugs, saying he’s not sure how he got them, maybe bumping into something.
This seemed like a simple case, but now we’ve discovered some red flags. He’s got three signs of bleeding, nose, urine and skin. None of these problems are particularly concerning on their own, but taken together, are concerning for a coagulopathy the medical term for blood clotting disorders. We need to determine what’s happening, we don’t want to send him home to return with something that is life-threatening like an intracranial hemorrhage or a GI bleed. You ask if he’s had nose bleeds, easy bruising or any other bleeding before. He says no.
Ok. What could this be? Of course, you know about hereditary diseases like hemophilia. Acquired problems include use of anticoagulant medicines, all of which cause bleeding. Warfarin, dabigatran and rivaroxaban for example. Multisystem organ failure, can lead to DIC, or disseminated intravascular clotting, for example with severe sepsis.
If this were hereditary, he’d most likely have had prior episodes of bleeding and he’s obviously not in multisystem organ failure while sitting comfortably on the stretcher. He says he’s not taking any medicine.
An hour later, the resident tells you the tranexamic acid worked, the nosebleed stopped. His labs are back, his hemoglobin i.e. his blood count is normal, so are his platelets, important for blood clotting as I’m sure you know. Surprisingly, his PT/INR and his PTT are elevated or prolonged as we say. These tests reflect the function of different parts of the coagulation cascade. And not mildly abnormal, but extremely elevated, so high the lab doesn’t report an actual number but says the INR is > 10 and the PTT > 140 seconds. In fact, we’re lucky he’s only having bruising, a nosebleed and some bloody urine. He’s at serious risk for having an intracranial hemorrhage or other emergency with these numbers. You and the resident try to figure out what this means. The nurse interrupts to tell you the patient is vomiting up blood.
Neither of you is alarmed, patients with nose bleeds also swallow blood. And blood is very caustic to the stomach, causing a lot of nausea and vomiting. This happens alot. The resident checks on him, saying the blood is red, rather than darker like old blood, but his vital signs are fine. She sits back down to discuss what these coags indicate.
Before you get anywhere, the nurse insists you come to the room. He’s vomiting up a copious amount of red blood, making it difficult to believe this is just a residual effect from the now resolved nosebleed. His heart rate starts to go up, suggesting a potentially significant amount of bleeding.
You tell the nurse to start a second IV, start IV fluids, add on liver function tests and repeat the hemoglobin in 4 hours to see if there’s any change. You tell the resident to call GI and hematology. You ask more questions, he denies alcohol and certainly doesn’t have any stigmata of cirrhosis or liver disease. His LFTs come back normal.
The patient’s mother is now at the bedside. She says he’s been depressed and she worried he “took something.” She doesn’t know what. The patient continues to deny everything, but you did notice his flat affect on exam, ie his lack of reaction, which is a sign of depression. You ask her what medicines are in the house. She says her metoprolol, warfarin, aspirin and acetaminophen or Tylenol. This isn’t a metoprolol overdose, that’s a blood pressure medicine causing slow heart rate and low blood pressure. This isn’t Tylenol, it generally doesn’t cause bleeding and his liver function tests are normal. Could it be aspirin or warfarin overdose? You ask her how much warfarin was at home in the bottle. She doesn’t know and doesn’t know when it was prescribed, so it could be any amount.
You go to tell the resident, who in the meantime has spoken to hematology. They said coagulopathy with elevated PT and INR but normal platelets, could be caused Vitamin K deficiency, clotting factor deficiencies, like factor 5 or factor 10. They recommend more tests, including levels of some clotting factors which the resident orders. Hematology recommends a medicine to help stop the bleeding. That's question number 3. What is it?
A. vitamin A.
B. vitamin B 12.
C. Vitamin C.
D. Vitamin K.
The answer is D. Vitamin K. Let's talk briefly about how your blood clots, then come back to why vitamin K helps.
Blood clots form via multitude of steps. First, the platelets form an unstable plug. Our patient isn’t having a problem here, but with the second part, the clotting cascade.
This is an amazing, but complicated, sequence of events activated by bleeding. Clotting factors catalyze a sequence of reactions to form a stable plug, ie blood clot. We could spend an entire episode discussing it, though I’d probably die of boredom, so let me sum it up as succinctly as possible. Clotting factors are named with Roman numerals from 2-12. Hemophilia is factor VIII (8) deficiency. The basic test we use to evaluate this process are the coags I mentioned earlier, the PT/INR and PTT.
Medicines can disrupt this process. Aspirin is an anti-platelet agent, causing platelet dysfunction. This isn’t an aspirin overdose, in acute overdoses it causes acidosis, rapid breathing and an altered mental status. Bleeding occurs with chronic exposure, and even if it happens it doesn’t affect the PT/PTT, because it doesn’t work on the clotting factors.
True anticoagulants work on the clotting cascade. Warfarin, brand name coumadin, thins the blood by inhibiting vitamin K. How? Factors II, VII, IX and X require Vitamin K for activation. Without Vitamin K clotting factors can’t work, leading to it’s blood thinning effect. Warfarin requires frequent Pt/INR checks to ensure the blood is thin enough to prevent blood clots, but not so much so the bleeding risk outweighs the anticoagulation benefit. Newer anticoagulants, called DOACs work on other parts of the clotting pathway. Could the patient have taken his mother’s warfarin? Yes. I’d be very suspicious that was the case, but other bleeding disorders still need to be investigated by the inpatient team.
As I said, our patient’s coags are extremely high, to the point where his blood might not clot at all. If we give him vitamin K, the inactivated clotting factors will start working.
We can administer it orally or intravenously. Oral vitamin K is very safe, but takes a while to work, 12-24 hours. IV Vitamin K is much faster with effects as early as 2-4 hours, but it’s riskier. IV Vitamin K causes severe anaphylactoid reactions, probably due the diluent it’s dissolved in. Remember anaphylactoid reactions are drug-induced histamine release, causing a reaction like anaphylaxis. It’s an uncommon, but serious side effect. A small number of patients have died from IV vitamin K.
You have to weigh the risks and benefits of oral vs. IV. In this case, the risk/benefit analysis favors IV, since he’s at risk for life-threatening bleeding. Your resident gives a dose in the ED, and admits him to the inpatient team who will monitor his coags and titrate the dose accordingly.
Five days later, your resident follows up on the case and tells you the patient’s INR is still abnormal, despite massive doses of Vitamin K. Every time the team tries to lower the dose, his INR goes right back up. All of his clotting factor levels are normal as is the workup for other rare diseases per the hematology evaluation.
Hmmmm. Now we have a case of an otherwise healthy man with a prolonged clotting problem in whom work up is negative. This raises the distinct possibility, in fact, distinct likelihood, this is due to a toxin. Just as you arrive at this conclusion, your phone rings. Heme wants a tox consult.
You re-interview the patient without learning any new information. Something is missing from the story. One of the difficult parts of medicine is determining when to believe the patient and went to suspect they're lying.
It’s on us to figure this out. So, toxins causing bleeding. Anticoagulants are at the top of the list. Particularly warfarin because it causes this pattern on the coags. Maybe he took a family member’s medicine. Certainly possible.
Question # 4. What plant is warfarin derived from?
A. St. John's wort
B. Clover
C. Foxglove
D. Mandrake
The answer is B Clover. In the 1920s in Wisconsin, it was noted that cows were dying of a hemorrhagic disease after eating spoiled sweet clover. Coumarin, a fairly benign compound in clover is converted by Penicillium mold into dicoumarol, which is deadly in large amounts. Warfarin, named after Wisconsin alumni research foundation, was marketed as both a rat poison, and a medicine.
Warfarin is both an extremely useful and an extremely dangerous drug. It’s been called one of the most dangerous. It was responsible for 33,000 hospitalizations in 2007-2009 per a New England Journal article. Its potency is affected by diet like eating food high in vitamin K, and a lot of drug interactions some as benign as antibiotic use. If frequent lab testing isn’t done for dose adjustment, patients can easily develop clots or bleeding.
So this looks like warfarin toxicity, but warfarin really shouldn’t last this long, his INR should at least be improving. What could cause this? Question # 5. It's time to pick your poison.
E. Scorpion envenomation
F. Pesticides
G. Rat poison
H. Methamphetamine
The answer is C. rat poison. On the podcast we’ve discussed tons of toxins used as rodenticide including arsenic, strychnine and carbamates, like aldicarb. (Check out episodes Murder and medicine, three little steps and the culinary catastrophe for more).
Our patient is poisoned by a superwarfarin, found in modern rat poison preparations. Shortly after the invention of warfarin, rats developed resistance, leading to further research and the development of superwarfarins. There are a bunch of different ones, but names include bromadiolone and brodifacoum. What's the difference between warfarin and superwarfarins? Only the duration of effect. Both work exactly the same, inhibiting vitamin K.. Warfarin lasts for days, effects of superwarfarins last for weeks or even months.
Back to our patient, I’d be very, very suspicious this is a superwarfarin exposure. How? Probably ingestion. These types of exposures are more common than you might think. Kids eat the pellets or bite the blocks fairly frequently. There’s good data showing they will be fine, the vast majority don’t even develop minor bleeding. This is because a bite or a pellet is a low dose. A small child, 20 lbs or 10 kg, would have to eat 8 pellets to get sick. This isn’t likely in an exploratory ingestion. If this happens, the poison center typically recommends a PT/INR in 48 hours, because both warfarin and superwarfarins take at least 2 days, possibly 3 to work, and strict precautions to avoid head injury, tho as I said, typically nothing happens, not even a bump in the INR.
On the other hand, intentional exposures, like with a suicidal person who eats rat poison, is much more serious. Suicidal patients will often eat boxes of rat poison.
Which reminds me of a case and the precautions you have to take. In the US, most suicidal patients have to wear a gown or paper scrubs ensuring nothing is concealed on their person. We even empty out the hospital rooms to prevent injury, including monitors as patients have tried to strangle themselves with the wires. That said I once consulted on a patient with a super warfarin rodenticide ingestion. Asking for specifics about the type and amount, they gestured to a bag, sitting in the room, which had another 10 boxes of rat poison in it. Fortunately, I got the bag out, before it was too late.
Anyway, back to our patient. After a discussion with hematology, everyone is convinced this must be a superwarfarin. Heme recommends sending brodifacoum and bromadiolone blood levels which will take a week or so to come back.
Eventually, after several days, with the help of psychiatry, the patient finally reports ingestion of rodenticide due to suicidal thoughts. He ingested 10 boxes of rat poison he found in the back of his dad’s garage.
Quick aside, in the US, the EPA increased regulation of superwarfarins to protect wildlife, so many rat poison manufactures changed the ingredients to other types of poison. Does this mean our patient didn’t take a superwarfarin? No, for a bunch of reasons. First, people keep these things in their garages for years. See cases of people poisoned with coyote poison like compound 1080 long after it was banned. Second, you can get most things on the internet if you try hard enough. Third, commercial use of superwarfarins by pest control is till allowed in the US. A call to his father confirms it’s brodifacoum, a long acting superwarfarin.
Brodifacoum is 100x more potent than warfarin. It has a long half-life in humans with estimates ranging from 16 to 36 days. Hematology recommends ongoing, massive doses of oral vitamin K with INR checks every few days. Typical doses of Vitamin K are 5 to 10 mgs. For superwarfarin ingestions, doses as high as 400 mg per day have been reported.
Fortunately, the patient never develops life-threatening bleeding. If he did, we have another treatment option, a fresh frozen plasma transfusion or something called PCC or prothrombin complex concentrate. Both contain clotting factors.
What’s actually most difficult about cases like this is not the treatment, but figuring out the best disposition. Disposition means whether the patient stays in the hospital, goes home or somewhere else like a psychiatric facility. Why? Because the patient might be anticoagulated for weeks or even months. Staying in the hospital for that long, not only costs a fortune, but is associated with risks including infectious disease like Covid, antibiotic resistant infections, and medication safety errors.
If this was a patient who was, for some reason, accidentally exposed to a super warfarin, you could titrate the dose of vitamin K to a stable INR, then discharge for serial lab tests to taper it down. However, assuming a patient with suicidal ideation will take an antidote, much less follow up for blood tests is obviously not safe. In one case of superwarfarin ingestion, the INR was abnormal for 7.5 months! Each of these cases, in my experience raises specific issues and are managed on a case-to-case basis with input from hematology, toxicology and psychiatry.
Most cases of exposure to superwarfarins are due to ingestion. However, inhalation exposure is possible. There was an outbreak of bleeding after smoking K2, synthetic cannabis derivates across the US due to contamination with superwarfarins. Several patients died from intracranial hemorrhage. It was never discovered if the contamination was intentional or unintentional.
This outbreak raised another issue, the cost of Vitamin K in the US. Those exposed were regular, non-suicidal patients, so they were titrated to a vitamin K doss then discharged to follow up as an outpatient. Many of the patients returned to the hospital with bleeding. Why? Vitamin K cost as much as $65,000 per month. I was shocked to read this. For a vitamin?
After hearing all this, you probably won’t be surprised to hear superwarfarins have been used in murder and terrorism. A 70-year-old man was poisoned by his wife, upset he had a baby with a girlfriend. He required vitamin K for five months. A mentally ill person in Michigan sprayed a whole Foods grocery store food bar with brodifacoum, believing people were poisoning him. Meatloaf inside Rikers Island jail in NYC tested positive for brodifacoum was it a contaminate or revenge of the prison guards after the attempted sexual assault of a female guard, or something else altogether? No one knows.
A pipe-bomb in Washing state in 2011, fortunately unexploded, contained brodifacoum and it’s reportedly been used by Palestinian suicide bombers. This doesn’t make tons of sense from a toxicology standpoint, because the bleeding risk wouldn’t start until a few days after the injury at which point the victims would either be dead or alive, and as I mentioned earlier, small exposures are very low risk. There are allegations that the Rhodesian military poisoned insurgents in the 1970s with clothes impregnated with warfarins.
Back to our patient, attempts to find a psychiatric facility willing to accept a stable patient requiring ongoing medical management fail. He stays in the hospital for five weeks until his INR normalizes. This is a fictional case, as are all our cases, to protect the innocent. However, it is based on real poisonings.
The last question in today's podcast. Blood thinning drugs have been derived from all of the following, except?
A sweet clover.
B. Leaches
C pigs
D. Mussels
Follow the Twitter and Instagram feeds both @pickpoison1 for the answer. Remember, never try anything on this podcast at home or anywhere else.
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While I’m a real doctor this podcast is fictional, meant for entertainment and educational purposes, not medical advice. If you have a medical problem, please see your primary care practitioner. Thank you. Until next time, take care and stay safe.