David Foster Wallace wrote novels that were dense and impenetrable, but his essays were breezy, and they sparkled with wit and wisdom. One of my favorites was called “Consider the Lobster,” commissioned by Gourmet Traveler, about the Maine Lobster Festival. (August 2004; http://bit.ly/2BYyoo1.) He wrote so well, so beautifully, that you could see the sunshine dancing on the yachty harbor, you could just about taste the melted butter from the freshly cooked lobster, smell the spritz of the lemon.
But then, fairly quickly, the essay turned, morphing into something darker, and we were shown Disneyland-grade queues of sweating, overweight people who were watching live lobsters being plunged into a boiling pot in front of them. The essay turned out to be about rather different things: Is it right and moral to boil sentient creatures alive for our own gluttonous pleasure? Do these simple animals feel pain? But as interesting as these neurobiological arguments are, really what I want is for you to hold two things in your head. One is that sometimes the main learning points of an essay or talk are hidden off in the shadows, in the periphery, and two, the image of a lobster.
But let's get clinical. I am the consultant on duty, and it's close to midnight. I get a phone call from a hospital about 60 km away. They've got a 72-year-old farmer who has had a big anterior infarct. Quite rightly, because of the time and the distance, they have thrombolized him. His chest pain is settling, his ST segments are coming down, and they want to send him to us. I say, we'd love to have him. Several minutes later, I get another phone call, quite panicked, and the unwelcome has happened: massive hematemesis.
Say what you like about us emergency physicians, but when things become unexpected and messy, that is our bread and butter. I say, I know how to reverse this. Not much works, but what you should do is throw the kitchen sink at him. Unfortunately, they only have the tepid water of the kitchen sink (FFP), but I say just get him on his way, and we'll be ready. Don't you worry; it will all be good.
Hold the Sink
While I'm waiting for this patient, I look at his name, and I realize he is a very dear old friend of mine. I don't know about you, but when you know someone, you start to second-guess yourself. Throwing the kitchen sink at him now sounds terrible. Do I really know what the best treatment is? Am I going to make him reclot again if I start pouring stuff in? I don't know the answers as well as I thought I did. So I'm madly googling, looking for guidelines, and I come up with...nothing.
So I ring the hematologist on call for his advice, and he says, ring the emergency physician, and I say, that's me. The patient is suddenly on our doorstop, doing a bit poorly, but luckily, he does fine.
Afterwards, I thought this is not good. This is a big knowledge hole; reversing the effects of thrombolysis. So I did a very scientific study—all the researchers would be proud of me—I asked a hematologist, a neurologist, a respiratory physician, a cardiologist, an intensivist, and an emergency physician, “How do you reverse thrombolysis?” They all came up with the same thing: Throw the kitchen sink at them. Throw all the products at them, and good luck to you. Not much works.
I'm not happy here. All I'm left with is a big fat pile of questions. So I read and read, and I performed a literature review, some of which I'll present here. The thing is, the more I read, the more I realized that not only do we not know how to reverse the effects of thrombolysis, we hardly even know how tPA works. And not only that, we hardly even understand the coagulation-fibrinolysis system.
About this time I go to the museum under the pretense of taking my 12-year-old son, but it's really because I love dinosaurs. There, next to the T-Rex bones, is a plaque that says, “On this bone is evidence of clot.” I thought, whoa! Two hundred million years ago, we were clotting. I had never considered how old this whole clotting system is. How far back am I going to have to go to really understand coagulation so I can return and understand what we do to it now? As Carl Sagan said, “If you wish to bake an apple pie from scratch, you must first invent the universe.”
Understanding Clotting and tPA
I had to learn about how clotting evolved. What I discovered, what's fascinating about the evolution of clotting, is that it is held up, along with the human eye, by creationists as an example that evolution cannot possibly exist because it is an example of something called irreducible complexity, meaning a biological system so complex that if you take away one part, the whole system can't work. It couldn't just evolve, piecemeal, over time.
This, of course, is completely bollocks, and lots of wonderful bits of evidence show us how clotting and fibrinolysis evolved. One of the great pieces of evidence comes back to our old mate, the lobster, who is a very, very distant archeological relative of ours. He has managed to evolve his very own fibrinogen, which works exactly the same but has come from a very different protein called vitellogenin, a yolk protein, which is very cool.
This is how we teach the clotting-fibrinolysis connection; this is how we all learn it in med school. (See diagram.)
Now, this is ridiculously, preposterously oversimplified. Really it is much more of a swirling concatenation of these elements, and so much more. It is so complex; it is not just those proteases that we all learned about, those nice cascades, it is cellular, it is endothelial, there are amplifications, dampenings, there are positive feedback loops, negative feedback loops. The clotting cascade has effects on almost countless other cascades in the body. It is so utterly complex.
Into it we bring this: recombinant tPA, very similar to our endogenous tPA. You all remember how tPA works. It activates plasminogen to form plasmin, and plasmin dissolves the ropey fibrin around the clot, usually in about three to six days, and the clot goes away. But if you actually asked tPA, it would be highly insulted that it was given this name because tPA is what is known as a highly pleiotropic molecule, meaning it has many, many, many functions, including stimulating these matrix metalloproteinases, which cause breakdown of the blood-brain barrier, and extracellular proteolysis. It causes vasoconstriction. It has many effects on exocytotoxic transmission, and it has an extensive role in neuronal remodeling in embryos and in later life. And we have no idea what role all of these things play in us because we are only finding them out in animal models.
Let's try to understand that whole clotting-fibrinolysis web a little bit better by thinking about it as a regency dance. In a normal situation, it is a very cultured and genteel situation, and things happen at the right time. We clot, and in three to six days, tPA comes in, bows, does its bit, and leaves. That's how it should work. But when we give tPA, basically we pour this souped-up, narcissistic-brute-on steroids, this recombinant tPA, and things go to hell in a handbasket. Everything happens at once. I was taught that tPA was fibrin-specific, but that is mildly rubbish too. It is fibrin-selective but not -specific, so you get this interesting thing called early fibrinogen degradation coagulopathy, fairly newly coined and fascinating. The whole clotting system, that massive Van Gogh swirl of things has to try to catch up once you've done this.
But I've been skirting around the elephant in the room, which is, using tPA in stroke. If it weren't for the cerebral hemorrhages we cause by giving thrombolysis, we wouldn't care that tPA doesn't do much for strokes. We are causing this horrendous complication, however. Six to eight percent get cerebral hemorrhages, and there is no coming back from it. It is terrible. That may not sound like a lot, but if it's something you've done, an iatrogenic injury, then those numbers are much more important.
To argue with myself for a moment, we don't actually know it's the tPA that's causing these patients to have the intracranial hemorrhages. We know when we reperfuse anoxic brain, it's highly at risk for bleeding anyway, and we know that mechanical thrombectomies cause almost as many intracranial hemorrhages without the tPA. We don't know how much tPA badness is going on. But we sure know we need to attempt to reverse the effects of thrombolysis if there is a bleed.
Let me briefly summarize the evidence we do have about reversing the effects of thrombolysis. One, we don't really know the extent of what tPA is doing. Two, it seems the patients who have the greatest drop in their fibrinogen level after tPA are the ones who bleed, and this is the only solid piece of evidence we've got. We don't know if it's causal or correlative, but that's what we've got. It's not the nadir of the fibrinogen level; it's the biggest drop. Three, when we look at all the retrospective and observational studies to see who does what to try to reverse the effects of thrombolysis in intracranial hemorrhage, it's a dog's breakfast. Everyone is doing something different, and there is no consensus at all. And, four, there is no single agent that seems to make a difference.
What is in our guidelines? The best chance we have, based on simple biologic plausibility, is cryoprecipitate. We in the colonies don't get the lovely fibrinogen concentrate, so we get this martini of fibrinogen, fibronectin, factor XIII, factor VIII, von Willebrand factor, and a few other secret ingredients. (Update: We do now. Will it make any difference? Who knows?) They both have fibrinogen, however, and the consensus is that if your fibrinogen is low with a bleed, give the stuff.
Tranexamic acid, you all remember, is a lysine analogue and stops fibrinogen from being activated. Brilliant drug in certain circumstances. But, in post-thrombolysis hemorrhage, fibrinogen has already been activated—the drug has been and gone—if we're trying to reverse thrombolysis, it probably doesn't have much role at all except that it sounds like a good idea. We often revert back to that academically cachectic argument: Well, it doesn't cost very much, it doesn't do much harm, let's just give it anyway.
Using platelets, surprisingly, has a reasonable biologic rationale. There is a complex way that platelets become activated and grow dysfunctional after tPA because of all the downstream effects. Having said that, of course, the PATCH trial found that antiplatelet agents don't make a difference in intracranial hemorrhage anyway. (Lancet 2016;387:2605.)
FFP? This is weak tea. There are just not enough factors in there to make a difference at all.
What about prothrombinex? We have three-factor prothrombinex; a lot of places have four factors. We've got II, IX, and X. But, when you think about it, the factors are blameless in post-thrombolysis bleeding. They have done nothing. They are not depleted at all. We have given tPA at the other end of the clotting dance, and that is where the mischief is occurring, at the fibrinolysis end. You can also soup up the protease cascade with factors, give so many inappropriate numbers of prothrombins, that you can make patients clot in all of the unhappy places that people don't want to clot.
We have to ask the singular question in biology. Do I know an incredible amount or do I know absolutely nothing? I'm not sure here.
The future in thrombolysis in strokes is that we won't be looking for agents that reverse thrombolysis better. We'll be looking for agents that are actually able to remove the clot from the stroked out area without causing bleeding and having the problems with reperfusion.
Why did I tell you about evolution? I figure medicine isn't much without a whole lot of wonder, and it's all about the future. To quote another David to finish, “David Bowie: Tomorrow belongs to those who hear it coming.”
This article was gleaned from a lecture Dr. Johnston gave at DAS SMACC. Watch a video of it and view the accompanying slides at http://bit.ly/2H09QAP.
Dr. Johnston is a board-certified emergency physician, thus the same as you but with a weird accent. She works in a trauma center situated down the unfashionable end of Perth, Western Australia. She is exceptionally skilled in the avoidance of meetings, as well as being very keen on teaching and getting her hands (very) dirty with clinical care. Any time left over is spent writing odd fiction. This leaves no time for domestic duties, at which she is an abject failure. She is the author of the novel Dustfall, available on her website, http://michellejohnston.com.au/. She also contributes regularly to the blog, Life in the Fast Lane, https://lifeinthefastlane.com. Follow her on Twitter @Eleytherius.
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